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[00:00:00.160 --> 00:00:01.920] Welcome to the Found My Fitness Podcast.
[00:00:01.920 --> 00:00:03.760] I'm your host, Rhonda Patrick.
[00:00:03.760 --> 00:00:05.280] Today's episode features Dr.
[00:00:05.280 --> 00:00:06.640] Peter Attia.
[00:00:06.640 --> 00:00:06.960] Dr.
[00:00:06.960 --> 00:00:13.520] Peter Attia is a highly respected expert in preventative medicine with a special focus on applied science of longevity.
[00:00:13.520 --> 00:00:21.360] His deep engagement with the topic of longevity is the cornerstone of his New York Times best-selling book, Outlive: The Science and Art of Longevity.
[00:00:21.360 --> 00:00:21.680] Dr.
[00:00:21.680 --> 00:00:31.120] Atia also extends his expertise into his clinical practice, Early Medical, and shares his knowledge through his popular podcast, many of you are already aware of, The Drive.
[00:00:31.120 --> 00:00:42.640] In this episode, you will learn why APOB is a superior predictor of cardiovascular disease over LDL particle number and managing the four main factors that elevate APOB.
[00:00:42.640 --> 00:00:46.800] Why APOB exists in humans when it doesn't in most species?
[00:00:46.800 --> 00:00:56.880] Whether or not low LDL is a risk factor for cancer, and a variety of other surprising facts about LDL biology you really can't find anywhere else.
[00:00:56.880 --> 00:01:00.240] Peter's opinion on APOB reference ranges.
[00:01:00.240 --> 00:01:18.880] Whether there is an APOB level low enough that it is impossible to die from atherosclerosis, which dietary factors increase APOB, how statins and other lipid-lowering pharmacotherapies work, including their side effects and costs, and what the alternatives are.
[00:01:18.880 --> 00:01:22.160] The pros and cons of different statin alternatives.
[00:01:22.480 --> 00:01:36.800] How increased muscle mass helps achieve lower blood sugar levels, which may play a pivotal role in reducing overall mortality, and the potential for glycemic control to be suboptimal well before doctors identify it.
[00:01:36.800 --> 00:01:42.080] Peter's 80% zone 2, 20% BO2 max training protocol.
[00:01:42.080 --> 00:01:46.400] The dangers of visceral fat and why it correlates with increased cancer risk.
[00:01:46.400 --> 00:01:53.360] Peter outlines the benefits and risks of aggressive cancer screening and offers insights on optimal screening timing.
[00:01:53.360 --> 00:01:58.480] He also clears up misconceptions about the radiation used in mammograms.
[00:01:58.480 --> 00:02:10.840] The hormonal changes of menopause and their significant impact on women's health, along with how hormone replacement therapy influences the risk of dementia, cancer, and heart disease in women.
[00:02:10.840 --> 00:02:15.000] Vitamin D, sunlight versus supplementing in optimal levels.
[00:02:15.000 --> 00:02:24.840] Why symptoms of low testosterone are often more important than actual levels when deciding whether or not to go on testosterone replacement therapy.
[00:02:24.840 --> 00:02:31.000] Why Peter's recommended testosterone replacement therapy dosing schedule differs from the standard.
[00:02:31.000 --> 00:02:37.880] Peter's protocol for treating low testosterone and why testosterone replacement therapy isn't always the right answer.
[00:02:37.880 --> 00:02:43.480] Methods for lowering blood pressure, exercise, nitrates, hot tub, and cocoflavanols.
[00:02:43.480 --> 00:02:50.600] Peter's exercise, sleep, nutrition, and alcohol routines for optimizing longevity, and so much more.
[00:02:50.600 --> 00:02:52.360] Before we dive into our discussion with Dr.
[00:02:52.360 --> 00:02:57.000] Peter Artea, I'd like to highlight a valuable resource available for you.
[00:02:57.000 --> 00:03:05.560] It's a comprehensive report I've compiled focusing on evidence-based strategies to optimize cognition and slow down brain aging.
[00:03:05.560 --> 00:03:19.560] This report delves deep into the best exercise practices for boosting brain-derived neurotrophic factor, a key neurotrophic factor integral to learning, memory, mood regulation, and combating brain aging.
[00:03:19.560 --> 00:03:38.120] Additionally, it encompasses a range of lifestyle approaches, including specific protocols for heat exposure through sauna or hot baths, along with detailed guidance on omega-3 and polyphenol intake, all targeted at elevating brain-derived neurotrophic factor levels.
[00:03:38.120 --> 00:03:45.280] You can find that detailed protocols report at bdnfprotocols.com.
[00:03:41.480 --> 00:03:46.320] Once again, that's bdnfprotocols.com.
[00:03:50.640 --> 00:03:52.800] And now on to the podcast with Dr.
[00:03:52.800 --> 00:03:54.560] Peter Atia.
[00:03:54.880 --> 00:03:55.600] Hi, everyone.
[00:03:55.600 --> 00:03:58.080] I'm sitting here with the amazing Dr.
[00:03:58.080 --> 00:03:59.680] Peter Atia.
[00:03:59.680 --> 00:04:02.640] Many of you don't need an intro to him.
[00:04:02.640 --> 00:04:14.640] He has changed our understanding of the scientific literature, preventative medicine with respect to longevity, improving health span.
[00:04:14.640 --> 00:04:21.200] He's a number one New York Times best-selling author of the book Outlive, amazing book.
[00:04:21.200 --> 00:04:29.840] Also, he has a very popular podcast on health and medicine, one of the few podcasts that I listen to called The Drive.
[00:04:29.840 --> 00:04:34.880] And he's also a renowned speaker, so public speaking, he does a lot of that as well.
[00:04:34.880 --> 00:04:38.320] And you can find a lot of lectures he's given on YouTube.
[00:04:38.320 --> 00:04:43.360] So I'm very excited to be sitting here with you today, Peter, and having this conversation.
[00:04:43.360 --> 00:04:46.560] You were on the podcast many years ago, about eight years ago.
[00:04:46.560 --> 00:04:49.040] Yeah, I was going to say, like probably 2016, right?
[00:04:49.040 --> 00:04:50.160] I think it was earlier.
[00:04:50.240 --> 00:04:50.640] You might have been.
[00:04:51.600 --> 00:04:56.800] You might have been one of the first, I don't know, six or seven guests.
[00:04:56.800 --> 00:04:59.760] I mean, you were like one of the first guests that I had on the podcast.
[00:04:59.760 --> 00:05:00.640] So it was a long time ago.
[00:05:00.640 --> 00:05:02.000] You were still at New C.
[00:05:02.080 --> 00:05:02.240] Yep.
[00:05:03.040 --> 00:05:04.240] So it was a while ago.
[00:05:04.240 --> 00:05:05.840] Well, thank you for having me back.
[00:05:06.400 --> 00:05:18.800] So let's dive into maybe a general question that I kind of have for you, which is what ignited your interest in the field of longevity?
[00:05:19.120 --> 00:05:25.840] I mean, I think it's a it was kind of an intersection of two things, but I think the critical spark was the birth of my daughter.
[00:05:26.400 --> 00:05:48.520] And I write about this a little bit in the book, but you know I think you know I'm in my mid-30s she's born and all of a sudden that became a manner in which I contemplated my own mortality and it's not like I hadn't been aware or had been blind to my family history, but I have a very bad family history for cardiovascular disease.
[00:05:48.520 --> 00:06:00.040] And so now the idea that I had this daughter and boy, she was like, I mean, I just adored her more than I could have imagined during my wife's pregnancy.
[00:06:00.040 --> 00:06:01.400] It was so real.
[00:06:01.400 --> 00:06:16.120] And I also kind of realized, like, you know, if I don't figure out what's going on here, I'm going to potentially leave this planet sooner than I would like and therefore leave her and potentially other kids to come along.
[00:06:16.120 --> 00:06:26.040] So it was really those two things that really catapulted me into, at the time, just trying to understand everything I could with respect to cardiovascular disease.
[00:06:26.040 --> 00:06:27.960] That became my initial obsession.
[00:06:27.960 --> 00:06:30.760] So it was really less about longevity and more about that.
[00:06:30.760 --> 00:06:39.880] But of course, once you dive into that, you realize, well, you know, what does it benefit you if you figure out how to not die of heart disease, but you die of some other thing?
[00:06:40.040 --> 00:06:46.520] Or what does it, you know, eventually, what does it benefit you to delay your death, but have a lousy quality of life?
[00:06:46.520 --> 00:06:49.720] So then, you know, all of these things just came as an evolution out of that.
[00:06:49.720 --> 00:06:55.000] It's funny because I actually have a very similar story about the birth of my son.
[00:06:55.000 --> 00:07:12.280] And my, I mean, I remember times like, you know, within the first couple of years of my son being born, going for my long runs and stopping in the middle of my run and literally bawling my eyes out because I knew there was a time that I was going to be gone and he was going to be without me.
[00:07:12.280 --> 00:07:15.000] And it was so hard to think about that.
[00:07:16.560 --> 00:07:27.760] And so, you know, like everything that you just said completely resonates with me, where it's like, I want to be around when my grandkids are, you know, getting older.
[00:07:27.760 --> 00:07:30.400] I want to be not only around, but I want to be jumping rope with them.
[00:07:30.400 --> 00:07:32.320] I want to teach them to jump rope.
[00:07:32.320 --> 00:07:36.320] And so, like, all of those things have sort of crossed my mind at the same time.
[00:07:37.200 --> 00:07:58.640] With respect to the cardiovascular disease that you mentioned, and you talk about this in the book as well, there's a statistic that I've read from the National Health Statistics website, which is that every 33 seconds, someone dies from cardiovascular disease in the United States.
[00:07:58.960 --> 00:08:05.760] So, when people hear the word cardiovascular disease, I mean, at least even me, when I, cardiovascular disease, what is that?
[00:08:05.760 --> 00:08:06.560] What does it mean?
[00:08:06.560 --> 00:08:08.320] Where is atherosclerosis coming to play?
[00:08:08.320 --> 00:08:10.160] Where does coronary heart disease?
[00:08:10.160 --> 00:08:12.160] What is cardiovascular disease?
[00:08:12.480 --> 00:08:19.040] I mean, you could define it very broadly and include valvular disease and cardiomyopathies and all of those things.
[00:08:19.040 --> 00:08:35.920] But when we talk about ASCBD, atherosclerotic cardiovascular disease, which is the leading cause of death in the United States and globally, it's leading cause of death for men and women, what we're referring to is the disease of coronary arteries that leads to ischemia.
[00:08:35.920 --> 00:08:52.640] And, you know, just to take a step back for a moment, when you think about all of these chronic diseases, which I'm sure we'll get into today, cancer, neurodegenerative diseases, et cetera, things that you and I have spoken about a lot, including when you were on my podcast, it's important to understand that this is the disease for which we have the clearest understanding.
[00:08:52.640 --> 00:09:01.880] So, you know, our understanding of what initiates and propagates cancer is very small compared to our understanding on the cardiovascular front.
[00:09:02.120 --> 00:09:05.080] Our understanding of this on the neurodegenerative side is also quite small.
[00:08:59.840 --> 00:09:07.080] There are still many things we don't understand.
[00:09:07.400 --> 00:09:19.000] So, you know, everything we're about to talk about on the cardiovascular side should be at least thought of in the context of how wonderful is it that we understand these things because we have the most tools for prevention here.
[00:09:19.000 --> 00:09:26.920] So, with that said, what we're really talking about that does the lion's share of killing, and again, I'll bracket for a moment that there are other things.
[00:09:26.920 --> 00:09:33.880] There are people that are dying from, you know, cardiomyopathies, there are people that are dying from valvular cardiovascular disease and things of that nature.
[00:09:34.200 --> 00:09:41.720] But the majority of what's happening is a disease that leads to plaque formation inside of coronary arteries.
[00:09:41.720 --> 00:09:50.680] And we can go as deep or as shallow as you want into that and why that happens and how that's a function of endothelial injury, lipoprotein burden, and inflammation.
[00:09:50.680 --> 00:09:58.440] But this leads to a reduction in blood flow to key parts of the heart, muscle.
[00:09:58.440 --> 00:10:01.480] And when that happens, the heart undergoes an ischemic event.
[00:10:01.480 --> 00:10:04.760] Now, sometimes that can be chronic, and sometimes that can be acute.
[00:10:04.760 --> 00:10:11.880] And if an acute event occurs in a region where enough muscle of the heart is compromised, that's going to result in sudden death.
[00:10:11.880 --> 00:10:13.080] That's a heart attack.
[00:10:13.080 --> 00:10:20.520] And it's important to understand that a little, when I was in medical school, it was more than 50%.
[00:10:20.520 --> 00:10:24.120] It's now a little less than 50%, but it's still a very high number.
[00:10:24.120 --> 00:10:30.760] A little less than 50% of people's first brush with a symptom of coronary artery disease is sudden death.
[00:10:31.000 --> 00:10:35.240] That's worth repeating because we couldn't, I remember, I still remember being asked this question in medical school.
[00:10:35.240 --> 00:10:46.480] You know, you're sitting there as a first-year medical student in cardiovascular pathology class, and the pathologist said, what's the single most common presenting feature for someone having cardiovascular disease the first time?
[00:10:46.480 --> 00:10:50.160] And everyone was like, chest pain, shortness of breath, you know, rattling off all the usual stuff.
[00:10:50.160 --> 00:10:51.760] He goes, no, sudden death.
[00:10:53.040 --> 00:10:59.040] Again, today it's not quite 50%, but that's a very sobering statistic.
[00:10:59.360 --> 00:11:00.400] Absolutely.
[00:11:00.800 --> 00:11:10.080] I do want to dive into some of the major causes of the atherosclerosis and the atheroscleric cardiovascular disease that you're talking about.
[00:11:10.080 --> 00:11:19.760] So, lipoproteins, you mentioned, and most people know, they hear about lipoproteins, they hear about LDL or HDL.
[00:11:20.320 --> 00:11:25.440] But APOB, why should people know about ApoB?
[00:11:26.080 --> 00:11:32.000] Well, again, I think it's worth maybe just getting everybody on the same page with cholesterol.
[00:11:32.000 --> 00:11:32.800] Let's start with that, right?
[00:11:32.800 --> 00:11:39.200] So, everybody's heard of cholesterol, and I think most people would probably even have kind of a negative valence when they think about it.
[00:11:39.200 --> 00:11:41.280] It's like cholesterol is a bad thing.
[00:11:41.280 --> 00:11:43.920] So, it's worth explaining that that's not really true, right?
[00:11:43.920 --> 00:11:47.040] Cholesterol is an essential thing, right?
[00:11:47.040 --> 00:11:49.360] So, without cholesterol, we wouldn't be alive.
[00:11:49.360 --> 00:11:58.400] And, you know, there are really rare, fortunately, genetic conditions in which cholesterol synthesis is compromised, and those tend to be fatal in utero.
[00:11:58.400 --> 00:12:08.080] So, if an organism can't make enough cholesterol, it ceases to exist because cholesterol is the thing that gives every cell fluidity, the membrane of every cell fluidity.
[00:12:08.080 --> 00:12:11.040] And it's the precursor to some of the most important hormones we make.
[00:12:11.040 --> 00:12:19.520] So, in the case of us as humans, right, testosterone, estrogen, progesterone, cortisol, these essential hormones are all made from cholesterol.
[00:12:19.520 --> 00:12:24.640] So, every cell in the body, with the exception of red blood cells, makes plenty of cholesterol.
[00:12:24.640 --> 00:12:28.840] The lion's share of it is probably done by the liver and the steroidal tissues.
[00:12:29.160 --> 00:12:33.000] And we have to figure out a way to move this stuff around the body.
[00:12:28.800 --> 00:12:35.320] And the highway system of the body is the blood.
[00:12:35.480 --> 00:12:37.720] And the blood, of course, is water.
[00:12:37.720 --> 00:12:46.680] So if we want to move things that are water-soluble throughout the body, like proteins and ions, it's easy because they dissolve freely in water and they move around.
[00:12:46.680 --> 00:12:57.160] But when you want to move something around water that is not water-soluble, such as cholesterol as a lipid, you have to wrap it in something that is water-soluble.
[00:12:57.160 --> 00:12:59.960] And that something is the lipoprotein.
[00:13:00.280 --> 00:13:07.000] And the big protein on the surface of that sphere is called an apolipoprotein.
[00:13:07.000 --> 00:13:11.400] And there are, broadly speaking, two classes of apolipoproteins.
[00:13:11.400 --> 00:13:14.120] There are the A class and the B class.
[00:13:14.760 --> 00:13:20.920] So some of the lipoproteins are wrapped in an apolipoprotein called ApoB100.
[00:13:20.920 --> 00:13:23.320] And we just abbreviate that to ApoB.
[00:13:23.320 --> 00:13:26.120] But I'll just say it this one time and we'll never talk about it again.
[00:13:26.120 --> 00:13:31.640] There's also an ApoB48 that wraps another type of lipoprotein called a chylomicron.
[00:13:31.640 --> 00:13:35.480] We won't talk about that again because it doesn't really factor into cardiovascular disease.
[00:13:35.480 --> 00:13:56.440] So ApoB is short for apolipoprotein B100, which is the structural apoprotein that sits on low-density lipoproteins, abbreviated LDLs, intermediate density lipoproteins, abbreviated IDLs, very low density lipoproteins, abbreviated VLDLs.
[00:13:56.440 --> 00:14:07.320] The APO A's, and this is big A, never to be confused with apo-little A, which we may talk about, those wrap the family of high-density lipoproteins.
[00:14:07.320 --> 00:14:11.880] They're much more complicated than Apo-Bs, believe it or not, and there are many of them.
[00:14:12.200 --> 00:14:14.920] But nevertheless, broadly speaking, that's what's going on.
[00:14:15.840 --> 00:14:18.720] So, why do we care about all this stuff?
[00:14:18.720 --> 00:14:37.040] Well, in the 1950s, when it became clear that cholesterol was playing a role in cardiovascular disease, The first observation was people with very, very, very high total cholesterol, because at the time that was all that could be measured, was total cholesterol.
[00:14:37.040 --> 00:14:46.160] By the way, what that meant was the total amount of cholesterol in all of your lipoproteins, in your HDLs, in your LDLs, and in your VLDLs.
[00:14:46.160 --> 00:14:52.480] Those three lipoproteins constitute the amount of total cholesterol you have in the lipoproteins.
[00:14:52.480 --> 00:14:54.480] We can come back to this idea because it's important.
[00:14:54.480 --> 00:14:58.160] That represents about 10% of the total cholesterol in your body.
[00:14:58.800 --> 00:15:06.320] The total cholesterol concentration was loosely correlated with cardiovascular outcomes, but only at extremes.
[00:15:06.320 --> 00:15:16.880] Meaning, if you took people whose total cholesterol was in the top 5% and compared them to people whose total cholesterol was in the bottom 5%, there was a clear association with cardiovascular disease.
[00:15:16.880 --> 00:15:30.000] March forward many, many decades, we came to realize that actually this low-density lipoprotein, which is a subset of your total cholesterol, but it's the cholesterol contained within the low-density lipoproteins, that's much more strongly associated.
[00:15:30.320 --> 00:15:39.280] And what we now know is the case is there's an even better way to predict risk than just saying how much cholesterol is contained within the low-density lipoproteins.
[00:15:39.280 --> 00:15:46.000] A better way to predict risk is to add up the concentration of all the APOB particles.
[00:15:46.000 --> 00:16:00.000] So that number, APOB, measured in milligrams per deciliter, is the concentration of the entire burden of particles that are capable of undergoing something that I'm sure we'll talk about, which is the initiation and progression of atherosclerosis.
[00:16:00.440 --> 00:16:09.560] So how, how, the APOB number, can you talk about how that, so you mentioned LDL, total, total LDL cholesterol?
[00:16:09.880 --> 00:16:13.720] That number is like some is like determined by some equation, right?
[00:16:14.120 --> 00:16:16.360] Well, it can be, but it can also be measured directly.
[00:16:16.360 --> 00:16:17.000] Yeah, so there's.
[00:16:17.160 --> 00:16:18.440] Would that be particle number though?
[00:16:19.080 --> 00:16:19.240] No?
[00:16:19.960 --> 00:16:21.560] So there's two ways to go about doing this.
[00:16:21.560 --> 00:16:29.080] So in the olden days, and unfortunately many labs still do this, they rely on an equation called the Friederwald equation.
[00:16:29.080 --> 00:16:32.520] So total cholesterol is relatively easy to measure.
[00:16:33.400 --> 00:16:41.480] So you draw the plasma, you spin it down, and you basically lyse all of the lipoproteins, and you can measure total cholesterol.
[00:16:41.480 --> 00:16:50.840] So if you just basically apply something to lyse all of the proteins, you'll say, all of the lipoproteins, you'll say total cholesterol is 200 milligrams per deciliter.
[00:16:51.160 --> 00:16:54.040] Then they directly also measure two other things.
[00:16:54.040 --> 00:17:04.120] They can directly measure total triglyceride concentration, and using a separate assay, they can measure the total concentration of cholesterol within the HDL particles.
[00:17:04.440 --> 00:17:10.200] So now you've measured total cholesterol, HDL cholesterol, and triglyceride.
[00:17:10.200 --> 00:17:23.400] The Friederwald equation stems from an observation that kind of sort of on average sometimes, VLDL cholesterol is approximately one-fifth the triglyceride concentration.
[00:17:23.400 --> 00:17:27.960] So the Friederwald equation is quite literally used to estimate LDL as follows.
[00:17:27.960 --> 00:17:38.600] LDL cholesterol is estimated as total cholesterol, less HDL cholesterol, less triglyceride concentration divided by five, if you're doing everything in milligrams per deciliter.
[00:17:38.600 --> 00:17:41.720] And unfortunately, most labs still do that.
[00:17:41.720 --> 00:17:55.760] So when you look at your cholesterol report, it'll say LDLC, it'll give a number, and unless it says direct, you can assume they've done the Friederwald equation, which is, I've seen that wrong more often than I've seen it right.
[00:17:56.080 --> 00:17:58.320] A good lab will do a direct assay.
[00:17:58.320 --> 00:18:05.760] They will actually measure LDL concentration and they will give you in milligrams per deciliter the total concentration of LDL C.
[00:18:06.080 --> 00:18:10.960] That is still an inferior predictor of risk relative to APOB.
[00:18:10.960 --> 00:18:11.440] Yes, okay.
[00:18:11.440 --> 00:18:18.480] So let's, the reason I wanted to mention that LDLC is because, as you mentioned, many labs do measure it indirectly.
[00:18:18.480 --> 00:18:21.600] And there are many types of LDL, right?
[00:18:21.600 --> 00:18:23.920] So there are different densities and sizes.
[00:18:23.920 --> 00:18:34.080] So I'm curious about what your thoughts are on the different sizes of like more atherogenic sizes of LDL, such as the smaller dense particles.
[00:18:34.080 --> 00:18:43.280] And, you know, like how you view that, like the different particle sizes and the particle number, and then, of course, APOB.
[00:18:43.280 --> 00:18:44.160] So like the whole.
[00:18:44.800 --> 00:18:50.240] I mean, there's been a big evolution in the way we've practiced medicine in our practice with respect to this.
[00:18:50.240 --> 00:19:16.960] So 10 years ago, we were looking at LDL particle number, which both the MESA population, so the multi-ethnic study of atherosclerosis, and the Framingham offspring population have both demonstrated unequivocally that when you compared LDL particle number to LDL cholesterol, LDL particle number always predicted risk better than LDL cholesterol.
[00:19:16.960 --> 00:19:18.400] So, how would you do this?
[00:19:18.400 --> 00:19:27.360] You would follow people longitudinally for cardiovascular events, and you would do this in sort of a like a cumulative incidence graph.
[00:19:27.360 --> 00:19:42.440] So, on the x-axis, you have time, on the y-axis, you have incidence of cardiovascular disease, and you plot out everybody as a function of whether LDL-C was higher or lower as a percentile than LDLP.
[00:19:42.440 --> 00:19:49.080] So, LDLP stands for the number of particles, LDLC is the concentration of cholesterol.
[00:19:49.080 --> 00:19:50.840] And this was again unequivocally the case.
[00:19:50.840 --> 00:19:53.400] Particle number always predicted better.
[00:19:53.400 --> 00:19:55.320] So, how do you count the number of particles?
[00:19:55.320 --> 00:19:57.240] Well, it turns out there are different ways to do this.
[00:19:57.240 --> 00:19:59.240] You can do this using NMR.
[00:19:59.560 --> 00:20:02.920] So, nuclear magnetic resonance is like how an MRI works.
[00:20:02.920 --> 00:20:04.440] So, it's applying a magnetic field.
[00:20:04.440 --> 00:20:11.400] It's basically doing, I mean, this is being a little cheeky, but it's sort of like doing an MRI on the blood, and you can count the number of particles that way.
[00:20:11.400 --> 00:20:15.880] That's not actually the gold standard, but that's the way it's most commonly done in clinical practice.
[00:20:15.880 --> 00:20:17.960] It can also be done with ion motility.
[00:20:18.280 --> 00:20:23.880] We switched from NMR to ion motility for LDLP because it was more accurate.
[00:20:23.880 --> 00:20:30.200] But ultimately, and this is now about five years ago, we actually switched to APOB, which was superior on all fronts.
[00:20:30.200 --> 00:20:31.960] And here's the reason why.
[00:20:32.280 --> 00:20:35.160] First of all, there are different ways in labs to do this.
[00:20:35.160 --> 00:20:40.760] So, LabCorp, for example, and Boston Heart have different magnets and different algorithms for how they run their LDLP.
[00:20:40.760 --> 00:20:44.920] So, if you run an LDLP on each of those labs, you'll get a different number.
[00:20:44.920 --> 00:20:46.520] That's a bit disturbing to me.
[00:20:46.520 --> 00:20:53.960] I want to know that the APOB that I get at one lab is the same as the APOB I get at another lab, and it's standardized across all fronts.
[00:20:53.960 --> 00:21:02.200] But there's a more important reason why I favor APOB over LDLP, and that is it encompasses the total atherogenic burden.
[00:21:02.200 --> 00:21:14.120] And you can get burned and fooled by patients who have very high VLDL, meaning they have a high burden of very low density lipoproteins, even if their LDL burden is low.
[00:21:14.480 --> 00:21:26.000] So I won't go into it because it's so nerdy, it's not worth getting this deep in the weeds, but there are certain genetic conditions where people have completely normal LDL, but very elevated VLDL.
[00:21:26.000 --> 00:21:28.560] And they have a very high atherogenic risk.
[00:21:28.560 --> 00:21:32.240] And you will miss that if you're looking at LDLP or LDLC.
[00:21:32.240 --> 00:21:34.640] You will not miss that if you're looking at APOB.
[00:21:35.280 --> 00:21:48.560] What about the fact that if small dense LDL, which has been shown to be more athergenic, so APOB does become, so you mentioned the structural role of APOB in the lipoproteins, it's very important.
[00:21:48.560 --> 00:21:56.560] It also plays a role, as you mentioned, in allowing the lipids to be soluble in the plasma, right?
[00:21:57.520 --> 00:22:00.480] But it plays a role also in recycling.
[00:22:00.480 --> 00:22:04.960] So it gets, you know, it interacts with the LDL receptor and can be taken back up into the liver.
[00:22:05.200 --> 00:22:12.000] The small dense LDL particles, APOB is somewhat obscured as the LDL particle gets smaller in size and more dense.
[00:22:12.000 --> 00:22:12.960] Therefore, it's not taken.
[00:22:13.200 --> 00:22:13.760] Harder to clear.
[00:22:13.760 --> 00:22:15.200] Harder to clear, exactly.
[00:22:15.520 --> 00:22:23.120] So what about in the case, and the reason I'm asking is because, as you mentioned, ApoB is on VLDL, IDL, LDL, right?
[00:22:23.440 --> 00:22:34.160] But there's different sizes of these LDL, and the larger, more buoyant LDL is better than having a higher proportion of the smaller dense LDL.
[00:22:34.480 --> 00:22:37.680] Right, that's why ApoB, but ApoB captures that risk, right?
[00:22:37.680 --> 00:22:49.840] So in other words, this is another reason why I think that APOB is the great equalizer, because once you have the APOB concentration, you're accounting for the fact that clearance is going down.
[00:22:49.840 --> 00:22:59.360] I mean, the one way to think about this is anytime you see an elevated APOB, it always comes back to something on the clearance side is not working.
[00:22:59.400 --> 00:23:07.480] Now, there are really, broadly speaking, when I talk about this with patients, I go through the four sort of pillars of what elevates APOB.
[00:23:07.480 --> 00:23:15.000] So it can be driven by cholesterol synthesis, and we can talk about that because it's going to factor into dietary choices, for example.
[00:23:15.000 --> 00:23:19.080] So how certain dietary patterns will lead to higher LDL than others.
[00:23:19.080 --> 00:23:22.360] It's impacted by cholesterol reabsorption.
[00:23:22.360 --> 00:23:29.800] So we can talk about what the life cycle of cholesterol is, but again, it's, you know, we make it and we reabsorb it and it gets circulated.
[00:23:29.800 --> 00:23:32.120] It can have to do with triglyceride burden.
[00:23:32.120 --> 00:23:38.760] So this is where insulin resistance really factors into how APOB can go up.
[00:23:38.760 --> 00:23:41.000] And ultimately, it comes down to clearance.
[00:23:41.000 --> 00:23:50.760] And clearance has everything to do with the presentation of the LDL receptor on the liver, the confirmation of it, the number of them, and how long they survive on the liver.
[00:23:50.760 --> 00:23:56.520] And all of these things have an enormous effect, some of which we can manipulate with drugs.
[00:23:56.520 --> 00:24:05.000] So for example, all drugs that are used to treat LDL in some way or another, indirectly or directly, impact the LDL receptor.
[00:24:05.000 --> 00:24:12.360] Some do it really directly, like a PC-SK9 inhibitor directly does that by targeting a protein that breaks down LDL receptors.
[00:24:13.000 --> 00:24:24.840] So anyway, a long-winded way of saying, and this is another advantage of APOB, is it allows you to, in one measurement, capture all of that risk.
[00:24:24.840 --> 00:24:36.280] Because if you have small, if you have, you know, two individuals, like if you're just using LDLP as your risk, you might miss some of the elevated VLDLs.
[00:24:36.280 --> 00:24:40.040] If you're looking at LDLC, you'll clearly miss some of the size issues.
[00:24:40.360 --> 00:24:42.680] That should be captured in LDLP.
[00:24:43.320 --> 00:24:53.120] But again, I guess maybe what you're asking is, if you have a low APOB, but they're all small, is that worse than having a low APOB where they're all big?
[00:24:53.120 --> 00:24:59.200] And the answer is probably, but you'll also see that in...
[00:24:59.840 --> 00:25:04.480] Like there are other metrics that are kind of coming on board now, which are looking at LDL triglyceride levels.
[00:25:04.480 --> 00:25:08.320] So you can look at the degree to which the LDLs are cholesterol depleted.
[00:25:08.320 --> 00:25:10.080] And that can also give you a sense of risk.
[00:25:10.080 --> 00:25:12.320] The question is, is that a first or second order term?
[00:25:12.320 --> 00:25:15.200] And I think the first order term is still going to be the number of particles.
[00:25:15.200 --> 00:25:18.480] That's the biggest driver of risk.
[00:25:18.480 --> 00:25:19.840] And everything else factors into it.
[00:25:19.840 --> 00:25:26.000] In other words, that's not an independent risk because it's driven by the residence time of the LDL, which is driven by the clearance rate.
[00:25:26.320 --> 00:25:29.120] So let's talk about like the number.
[00:25:29.120 --> 00:25:37.920] So the LDL, sorry, the APOB number, because like if most people go to a standard lab and they measure their APOB, there's a reference range.
[00:25:37.920 --> 00:25:42.000] And it says, you know, okay, if you're less than 80 milligrams per deciliter.
[00:25:42.160 --> 00:25:42.960] You're excellent.
[00:25:42.960 --> 00:25:44.160] Then you're okay.
[00:25:45.440 --> 00:25:48.240] Where does that number come from?
[00:25:48.240 --> 00:25:55.680] And, you know, what, like, has anyone measured APOB levels across the lifespan?
[00:25:55.680 --> 00:26:01.280] Do we know, like, is there a correlation with APOB levels and the beginnings of atherosclerosis?
[00:26:01.280 --> 00:26:02.880] Has someone done those studies?
[00:26:02.880 --> 00:26:04.240] You know, that sort of thing.
[00:26:04.240 --> 00:26:11.360] Yeah, so the reference ranges are purely population-based distribution questions.
[00:26:11.360 --> 00:26:25.200] So every lab will have a different way of doing this, but a general, you know, sort of philosophy for labs is, you know, let, you know, so for the lab we use, and by the way, we completely ignore these reference ranges, but they're there.
[00:26:25.200 --> 00:26:25.920] We can't avoid them.
[00:26:25.920 --> 00:26:26.240] They're there.
[00:26:26.240 --> 00:26:29.720] And we explain to our patients that we're going to editorialize on top of them.
[00:26:29.720 --> 00:26:33.400] But, you know, the reference lab we use will say APOB below 80 is wonderful.
[00:26:29.360 --> 00:26:36.680] Well, 80 just happens to be the 20th percentile of the population.
[00:26:37.000 --> 00:26:44.200] It will say 80 to 100 is intermediate, or 80 to 120, it says is intermediate risk, and above 120 is very high risk.
[00:26:44.200 --> 00:26:53.800] So for the lab we use, we know that 80 is the 20th percentile, 120 is the 80th percentile or the 60th percentile, I can't remember.
[00:26:54.040 --> 00:26:59.080] So it's literally just putting you up against a population distribution, and that's it.
[00:26:59.080 --> 00:27:02.520] Now, our philosophy on APOB is completely different.
[00:27:02.520 --> 00:27:11.160] And as you may recall, I devote actually quite a bit of real estate to this in the book because I think it is such an important concept.
[00:27:11.160 --> 00:27:47.160] And it is, in my opinion, certainly top three failures of Medicine 2.0 is in failing to appreciate the point I'm about to make, which is that once you understand the causality of APOB, meaning once you understand that APOB is not just associated with cardiovascular disease, but it's causally linked to it, meaning it causes ASCVD, to get into this discussion about managing 10-year risk, thinking about being in this percent versus this percent makes no sense.
[00:27:47.160 --> 00:27:51.000] When you have causal things that cause disease, you eliminate them.
[00:27:51.000 --> 00:27:54.760] And the analogy I use is cigarettes with lung cancer.
[00:27:54.760 --> 00:28:00.760] So nobody disputes that cigarettes are causally linked to lung cancer.
[00:28:00.760 --> 00:28:01.240] They are.
[00:28:01.240 --> 00:28:04.840] It's as clear as, you know, Tuesday follows Monday.
[00:28:05.160 --> 00:28:13.800] But people forget that, you know, causality doesn't mean everybody who smokes will get lung cancer, and it doesn't mean that every person with lung cancer smoked.
[00:28:13.800 --> 00:28:20.240] So you don't need to be necessary and sufficient, necessary or sufficient to still be causal.
[00:28:20.560 --> 00:28:28.160] But our approach to patients who smoke is very clear, which is never smoke.
[00:28:28.160 --> 00:28:31.040] And if you do smoke, stop immediately.
[00:28:31.360 --> 00:28:39.920] Do we look at people who smoke and say, well, once your 10-year risk of lung cancer reaches this threshold, we're going to tell you to stop smoking.
[00:28:39.920 --> 00:28:48.320] Or once your PAC year smoking is above the 50th percentile or the 80th percentile, we're going to tell you to stop.
[00:28:48.320 --> 00:28:49.440] Absolutely not.
[00:28:49.440 --> 00:28:52.000] You immediately eliminate smoking.
[00:28:52.000 --> 00:29:06.640] And so similarly, it makes no sense that we would look at a causal driver of ASCBD in the case of APOB and kind of take an approach of, well, being at the 20th percentile or the 30th percentile, the 40th percentile is acceptable.
[00:29:06.640 --> 00:29:08.240] None of those things really make sense.
[00:29:08.240 --> 00:29:10.640] You have something that is causing the disease.
[00:29:10.640 --> 00:29:15.440] You should eliminate it as soon as possible because it is an area under the curve problem.
[00:29:15.440 --> 00:29:18.960] So atherosclerosis begins at birth.
[00:29:19.920 --> 00:29:31.120] When you do autopsies on people who are very young, in fact, I in the book include a photo of a guy who, you know, a man, I forget, I think maybe 26 years old who was a victim of a homicide or something.
[00:29:31.120 --> 00:29:33.920] So an completely unrelated death.
[00:29:34.480 --> 00:29:37.840] But you look at the autopsy sections of his coronary arteries.
[00:29:37.840 --> 00:29:40.560] I mean, he already had very advanced atherosclerosis.
[00:29:40.560 --> 00:29:42.640] Now, it wasn't clinically relevant.
[00:29:42.640 --> 00:29:45.520] It wasn't going to kill him anytime soon.
[00:29:45.520 --> 00:29:50.800] But the point is, this is a disease that takes decades to progress.
[00:29:51.120 --> 00:29:58.560] And one of the biggest drivers of it, in addition to things like high blood pressure and smoking and insulin resistance, is APOB.
[00:29:58.880 --> 00:30:13.080] So to be able to take that off the table sooner rather than later is going to certainly have the potential to take atherosclerosis off its pedestal at the top of the list of killing.
[00:30:13.400 --> 00:30:19.320] And so what do you, I mean, take, you obviously can't take it off the table completely, right?
[00:30:19.320 --> 00:30:20.760] We need ApoB.
[00:30:20.760 --> 00:30:23.320] But what can you do?
[00:30:23.320 --> 00:30:24.600] So let's think about it.
[00:30:24.600 --> 00:30:28.600] Yeah, so let's start with what we know.
[00:30:28.600 --> 00:30:31.000] Apo B rises with age.
[00:30:31.320 --> 00:30:31.960] Right.
[00:30:33.240 --> 00:30:35.240] We don't really know.
[00:30:35.240 --> 00:30:37.800] There are probably a lot of little reasons.
[00:30:38.360 --> 00:30:51.400] So there are, you know, endocrine changes, insulin resistance, senescence that, you know, might involve the decreased life of LDL receptors.
[00:30:51.400 --> 00:30:53.400] There's no clear reason, actually.
[00:30:53.400 --> 00:30:56.200] What about, so you were talking about clearance versus synthesis.
[00:30:56.200 --> 00:31:01.640] And I remember our mutual friend Ron Krause, like I've had, you know, many conversations with him.
[00:31:01.640 --> 00:31:03.800] I did my postdoc down the hall from his lab.
[00:31:03.800 --> 00:31:04.440] Right.
[00:31:05.240 --> 00:31:13.000] And I remember him telling me that, you know, ApoB, you're basically, your liver is constantly producing it.
[00:31:13.000 --> 00:31:16.200] You're making VLDL, just churning it out, right?
[00:31:16.200 --> 00:31:17.000] And it's just going, going.
[00:31:17.400 --> 00:31:19.800] And we also make LDL de novo, by the way.
[00:31:19.800 --> 00:31:20.200] Right.
[00:31:20.200 --> 00:31:23.240] Yeah, there's a de novo pathway plus the VLDL to LDL pathway.
[00:31:23.800 --> 00:31:38.360] But that, you know, the thing is, is that, you know, he was saying, well, from an evolutionary perspective, you're making this VLDL because, as you mentioned, you know, it's transporting things throughout the body to other organs, right?
[00:31:38.360 --> 00:31:41.400] Cholesterol, triglycerides, fatty acids.
[00:31:41.400 --> 00:31:45.520] It's also transporting, and this is where I was so intrigued, inflammatory proteins.
[00:31:44.920 --> 00:31:50.320] So, cytokines, Sirakoprotein also are being transported through VLDL.
[00:31:50.640 --> 00:32:00.560] Now, that was important pre-antibiotics, pre-everything that we do now to combat infectious disease and viruses and bacteria, parasites, whatever.
[00:32:01.120 --> 00:32:06.080] But before that time, that VLDL did serve that purpose too.
[00:32:06.080 --> 00:32:13.760] And that's why he thinks it's kind of a relic left over where the reason why we're constantly making is because it's a very large protein in size.
[00:32:13.760 --> 00:32:19.120] It's like tens of millions of the unit versus like 50,000 or something.
[00:32:19.120 --> 00:32:19.840] It's very big.
[00:32:19.840 --> 00:32:22.080] And so it takes time to make it.
[00:32:22.720 --> 00:32:30.320] And so I was thinking, well, like inflammation also does make it go up even further at the level of synthesis.
[00:32:30.320 --> 00:32:39.120] I don't know exactly the clearance, you know, how it's regulating clearance, but do you think the aging process is mostly affecting the clearance of it?
[00:32:39.120 --> 00:32:39.440] Or?
[00:32:40.240 --> 00:32:41.520] My intuition is yes.
[00:32:41.520 --> 00:32:50.320] My intuition is that it's primarily impacted on the clearance level, which is going to be, again, some facet of LDLR, LDLR meeting LDL receptor.
[00:32:50.320 --> 00:33:10.160] So is it we are making less of them, they are surviving less, the proteins that, you know, and that can basically done, there are many ways to regulate that process, but that's my intuition: it's less a conformational change in the LDLR and more a number of them and/or a reduced amount of time that they stay present.
[00:33:10.160 --> 00:33:25.840] One thing I'll add on the evolutionary front, you know, I had a guy named John Castellan on my podcast a few months ago, and he he proposed a really interesting idea, which completely makes sense evolutionarily, which you you could argue sort of like we don't really need APOB.
[00:33:25.840 --> 00:35:03.760] Like, this is the other thing: like, most species don't have apo b they don't require ldl but how i mean they have cholesterol but they don't they don't they don't require transporting all these you know you can do it with hdl you can transport everything with hdl yeah okay yeah they don't need the ldl i thought hdl was always going in reverse like it was bringing everything back to the no it's actually much more complicated i mean and in us ldl is doing the majority of what's called reverse cholesterol transport so rct which is kind of like the good movement of cholesterol you sort of think of the bad movement as taking cholesterol into the arteries the good movement is taking it back to the liver in us ldl is doing the majority of that so hdls are typically transferring their cholesterol to ldls and ldls are bringing them back to the liver um but john made an interesting point right which is that you know in in sort of following up on what you said the evolutionary cost of making cholesterol is enormous i mean it's a very labor intensive step right i can't remember the number of atps that are required to make a molecule of cholesterol but it's in the tens right like it could be 40 or something to that effect and so we evolved to have a system that prioritized having a lot of cholesterol being able to keep a lot of it around um because again this was an energy conserving system now this serves us no benefit today because today we can make plenty of it and we are we are in an energy abundant environment which we were not in you know hundreds of thousands of years ago.
[00:35:03.760 --> 00:35:15.600] And so this is a bit of an unfortunate vestige of our past it much in the way that a lot of the things that lead to insulin resistance are a vestige to things that were once very valuable.
[00:35:15.600 --> 00:35:25.840] I mean, the things that allowed us to leap up out of the swan with our swamp with big brains was primarily our capacity to store excess energy in a way that even primates can't.
[00:35:26.160 --> 00:35:29.520] Again, it served us really well until 150 years ago.
[00:35:29.520 --> 00:35:33.040] And I think the same is probably true of cholesterol and APOB.
[00:35:33.040 --> 00:35:36.400] So going back to your question, how much APOB is enough?
[00:35:36.400 --> 00:35:39.760] Well, it turns out you don't really need any of it to be perfectly fine.
[00:35:39.760 --> 00:35:48.240] So if you look at a child, they're born with an LDL cholesterol or APOB level, typically below 20 milligrams per deciliter.
[00:35:48.240 --> 00:35:54.480] So a kid, if you think about it, has the greatest need for growth, right?
[00:35:54.480 --> 00:36:08.720] Like, so you think about the cholesterol demand of myelinating the entire central nervous system, all of the enormous explosion of steroidal tissue, all of these things are done with lipoprotein levels that are incredibly low.
[00:36:08.720 --> 00:36:16.480] Again, what we call physiologic levels of LDL cholesterol and APOB are on the order of 10 to 30 milligrams per deciliter.
[00:36:16.480 --> 00:36:22.160] And yet there are no negative consequences to such low levels of that lipoprotein burden.
[00:36:22.160 --> 00:36:27.840] And it's only when we get, you know, when we become teenagers and in our 20s that we start to see those numbers go up.
[00:36:27.840 --> 00:36:34.400] And again, that's really just reflected by a reduction in clearance, then some need for additional LDL.
[00:36:34.400 --> 00:36:34.960] We don't have it.
[00:36:34.960 --> 00:36:39.120] The majority of what we need is actually, you know, before the age of 20.
[00:36:39.440 --> 00:36:52.560] Do you think, so like if you were to then estimate or speculate a level of APOB that you could say safely, well, I guess there's two things.
[00:36:52.560 --> 00:36:56.800] One, you're not going to die of atherosclerosis if you maintain a level below.
[00:36:57.040 --> 00:37:17.720] Yeah, so Peter Libby from the Brigham, who's one of the authorities on this topic, has argued, and I reference him in my book, that if you had an APO B level below about 30 milligrams per deciliter, 20 to 30 milligrams per deciliter, it wouldn't be possible to develop atherosclerosis.
[00:37:18.360 --> 00:37:20.840] What about not dying from atherosclerosis?
[00:37:20.920 --> 00:37:24.680] Like, what about if it's the major cause of death globally?
[00:37:24.680 --> 00:37:25.320] Yep.
[00:37:25.320 --> 00:37:31.160] And let's say like what it takes to get down to 30 probably is pretty aggressive.
[00:37:31.480 --> 00:37:36.680] Yeah, most people cannot get down to 30 without a pharmacologic intervention.
[00:37:36.680 --> 00:37:37.000] Yeah.
[00:37:37.480 --> 00:37:42.760] Do you think that you would die of atherosclerosis if you had, you know.
[00:37:42.760 --> 00:37:43.560] If you're at 60.
[00:37:43.560 --> 00:37:44.120] 60.
[00:37:44.440 --> 00:37:46.200] Well, it comes down to a couple of other things.
[00:37:46.200 --> 00:37:48.840] So the first thing is, how long are you at 60?
[00:37:48.840 --> 00:37:58.760] So if you say I've never exceeded 60, that's very different from saying, hey, I showed up and I was at 120 and you now lowered me to 60.
[00:37:58.760 --> 00:38:12.840] So again, I think of, you know, I imagine like everybody walks around and you've got a graph that on the x-axis is time and on the y-axis is APOB and you have a curve and you want to figure out what the area under that curve is.
[00:38:12.840 --> 00:38:15.400] And we want to minimize the area under that curve.
[00:38:15.400 --> 00:38:20.280] So if you took exactly so if you took, so again, very similar to smoking, right?
[00:38:20.440 --> 00:38:24.200] We talk about risk in pack years of smoking.
[00:38:24.200 --> 00:38:35.240] So if a person smokes a pack a day for 20 years or two packs a day for 10 years, you know, you have a way of kind of comparing apples to apples on those things.
[00:38:35.560 --> 00:38:42.760] So, to have a lifetime ceiling of 60 would also be a very, very low-risk individual.
[00:38:42.760 --> 00:38:48.640] 60 milligrams per deciliter is about the fifth percentile at the adult population level.
[00:38:48.960 --> 00:38:51.440] So, then that comes back to my question.
[00:38:51.840 --> 00:38:56.800] Sorry, one of the things I would add across the lifespan: when, like, when do you start measuring this?
[00:38:56.800 --> 00:39:01.520] Like, people aren't measuring their APOB in their teenage or 20.
[00:39:01.760 --> 00:39:09.360] Yeah, I mean, I would argue we should be, but I want to go back and say one other thing about your question, which I should have mentioned earlier, which is it also depends on other risk factors.
[00:39:09.360 --> 00:39:22.560] So, there are really four big things that are driving risk causally: APOB is one, insulin resistance is one, hypertension is one, and smoking is one.
[00:39:22.560 --> 00:39:24.720] Those are the big four.
[00:39:25.040 --> 00:39:33.920] So, you have to take everything we're saying on the APOB front and acknowledge that those other things are also causally linked to ASCBD.
[00:39:34.240 --> 00:39:39.600] So, again, it's a difficult situation to imagine, but it's certainly at least theoretically plausible.
[00:39:39.600 --> 00:39:46.720] You have somebody whose APOB is at 60, but they have uncontrolled hypertension, type 2 diabetes, and they smoke.
[00:39:47.040 --> 00:39:49.920] I mean, you could certainly arrive at that situation pharmacologically.
[00:39:49.920 --> 00:39:52.640] You're probably not going to arrive at that situation naturally.
[00:39:53.120 --> 00:39:55.360] Would I say that that person is free and clear?
[00:39:55.360 --> 00:39:56.640] No, I wouldn't.
[00:39:56.640 --> 00:40:04.480] So, we, you know, at the outset, I mentioned how the, you know, the downside of talking about ASCBD is it's the number one killer.
[00:40:04.480 --> 00:40:10.480] I mean, it's, you know, in fact, when you talk about it globally, the gap between ASCBD and cancer is even bigger.
[00:40:10.480 --> 00:40:14.320] It's like 19 million people annually to 12 or 13 million for cancer.
[00:40:14.320 --> 00:40:16.160] I mean, it's an enormous difference.
[00:40:16.800 --> 00:40:27.920] But the good news is, our understanding mechanistically of what drives this is so clear, and our tools for prevention are some of the best and most benign.
[00:40:28.240 --> 00:40:28.880] Okay.
[00:40:29.200 --> 00:40:38.040] So, let's say that a person is relatively healthy, you know, they're committed to exerciser, they're not insulin resistant.
[00:40:38.120 --> 00:40:44.280] I do want to talk about hypertension and insulin resistance, but okay, a healthy, generalized quote-unquote healthy person, right?
[00:40:45.000 --> 00:40:47.320] Wants to lower their APOB.
[00:40:47.640 --> 00:40:50.520] They want to try everything through diet, through lifestyle.
[00:40:50.520 --> 00:40:56.120] And you mentioned there are some major lifestyle dietary factors that can increase APOB.
[00:40:56.120 --> 00:40:57.240] So let's talk about those.
[00:40:57.240 --> 00:40:57.800] What are the major?
[00:40:58.120 --> 00:41:01.160] So the big two are anything that contributes to insulin resistance.
[00:41:01.160 --> 00:41:02.120] So we'll start with that.
[00:41:02.120 --> 00:41:07.560] And that does so mostly through the VLDL triglyceride pathway.
[00:41:07.560 --> 00:41:11.560] So we talked earlier about it, how there are really two ways we make LDL.
[00:41:11.560 --> 00:41:15.240] We make LDL directly, but most of the LDL is made through VLDL.
[00:41:15.240 --> 00:41:23.560] So if you're exporting a lot of VLDL, what you're doing is both making a lot of that lipoprotein, but you also have a lot of triglyceride in it.
[00:41:23.560 --> 00:41:28.760] Now, something I didn't mention a moment ago that's worth restating or stating in the first place.
[00:41:28.760 --> 00:41:35.000] The LDL is carrying around both cholesterol and triglyceride.
[00:41:35.320 --> 00:41:40.120] And the more cholesterol there is, all things equal, the more LDL you need.
[00:41:40.120 --> 00:41:42.600] But the same is true with triglyceride.
[00:41:42.920 --> 00:41:55.400] So the first mechanism in which we see a very clear relationship between diet and APOB is the higher the burden of triglycerides, the higher the burden of APOB.
[00:41:55.720 --> 00:42:25.600] To state this another way, if you take two people who have the exact same level of LDL cholesterol and the same total cholesterol, but one has very high triglycerides and one has very low triglycerides, the former is going to have a much higher APOB and therefore be at a much higher risk of atherosclerosis because they have more cargo and therefore require more ships in the analogy of cargo being cholesterol and triglycerides and the ships being the lipoproteins.
[00:42:25.600 --> 00:42:30.640] So step number one is lower the triglyceride as much as possible.
[00:42:30.640 --> 00:42:36.480] And the triglyceride being low is an enormous proxy for insulin sensitivity.
[00:42:36.480 --> 00:42:44.400] So this is one of the important ways in which managing insulin resistance is a key to keeping APOB in check.
[00:42:44.400 --> 00:42:46.240] And of course there are other issues as well.
[00:42:46.240 --> 00:42:56.320] So insulin and glucose by themselves, when elevated, also create problems at the endothelial level, which becomes another mechanism by which this is problematic.
[00:42:57.840 --> 00:43:06.960] It's pretty clearly observed from a dietary pattern perspective that carbohydrate restriction is the most effective tool at triglyceride reduction.
[00:43:07.280 --> 00:43:12.640] All carbohydrates, I mean like vegetables, fruits, yeah, refined and starchy carbohydrates.
[00:43:12.640 --> 00:43:13.520] Yeah.
[00:43:13.520 --> 00:43:25.200] So, but that actually feeds really nicely into the next observation, which is what's the next dietary pattern that impacts APOB, and that's saturated fat consumption.
[00:43:25.520 --> 00:43:28.560] And the reasons for that are twofold.
[00:43:28.560 --> 00:43:34.080] So the first is that saturated fat directly impacts cholesterol synthesis.
[00:43:34.080 --> 00:43:44.240] Now, this is not true equally of all saturated fats, but we don't really have great data on if certain saturated fats have a greater impact on cholesterol synthesis relative to others.
[00:43:44.240 --> 00:43:49.920] For example, a C16 might be potentially more so than a C18 or a C19.
[00:43:49.920 --> 00:43:52.160] But again, what foods would you find a C16 versus?
[00:43:52.240 --> 00:43:58.080] Oh, like a C16 would be more in, I believe, like a coconut oil or a palm oil or something like that.
[00:43:58.080 --> 00:43:58.800] Versus.
[00:43:58.960 --> 00:44:08.200] Also, by the way, you would also see that more a C16, like a palmitate, would be more of a synthesis, would be more of a saturated fat you see in response to insulin resistance.
[00:44:08.200 --> 00:44:11.960] So it would actually be a de novo saturated fat synthesis.
[00:44:11.960 --> 00:44:16.600] So perhaps, so I think that's a big part of it.
[00:44:16.600 --> 00:44:18.200] I think cholesterol synthesis is a big part of it.
[00:44:18.200 --> 00:44:33.640] I think a bigger part of it might be that excess saturated fat inhibits the sterile binding, the sterile regulatory binding protein in the liver that results in fewer LDL receptors being made.
[00:44:33.960 --> 00:44:40.280] So saturated fat therefore has two things that it's doing that are driving up APOB.
[00:44:40.280 --> 00:44:44.520] And the susceptibility of this varies from different individuals.
[00:44:44.520 --> 00:44:48.440] So I was on a ketogenic diet for three years.
[00:44:48.440 --> 00:44:50.920] I was not one of the people who seemed to suffer from this.
[00:44:50.920 --> 00:45:05.320] So even on a ketogenic diet where I was getting 80% of my calories from fat and probably half of that was saturated fat, I did not have any sort of obnoxious increase in my APOB or LDLC or any of these metrics.
[00:45:05.320 --> 00:45:10.120] Similarly, we have some patients who are on very low carb, very high fat diets.
[00:45:10.120 --> 00:45:16.040] Some of them have completely normal levels of lipids and some of them have lipids that go absolutely haywire.
[00:45:16.040 --> 00:45:26.760] So it's not entirely clear what the difference is, but clearly there are different genes that will allow certain people to metabolize that saturated fat safely while others do not.
[00:45:26.760 --> 00:45:39.000] So I'm not in the camp that believes that, and there is an entire camp of people who believe this, that if you're on a low-carb, high-fat diet, and your APOB and LDL-C go through the roof, it's not problematic.
[00:45:39.160 --> 00:45:40.280] I don't believe that at all.
[00:45:40.280 --> 00:45:43.720] I think that that's a very bold claim, and I would not be willing to play that game.
[00:45:43.720 --> 00:45:59.840] I think if your ApoB goes haywire, even if you're very insulin-sensitive, and even if you're in energy balance and all the other wonderful things that might come with your ketogenic diet, I think you have to pay very close attention to if your lipids get out of whack.
[00:45:59.840 --> 00:46:04.240] So, those are basically your big manipulations dietary-wise.
[00:46:04.240 --> 00:46:11.600] It's the composition of fat, the quantity and composition of fat, and the dietary choices that address insulin sensitivity.
[00:46:11.600 --> 00:46:23.760] So, in the people that, let's say, they're eating a higher saturated fat diet, if they swap that out with monounsaturated fat or even polyunsaturated fat, which some camps also like to demonize the kind of polyunsaturated fat.
[00:46:24.320 --> 00:46:28.000] But if you swap that out, their Apo B levels are not.
[00:46:28.720 --> 00:46:43.600] In our experience, about half of the people who have this hyper-response to saturated fat, if you iso-calorically shift them to high monounsaturated fat, you fix the problem.
[00:46:43.920 --> 00:46:44.960] Yeah, okay.
[00:46:44.960 --> 00:46:47.280] It starts to get into a little bit of an issue, right?
[00:46:47.280 --> 00:46:52.160] Which is, and this is where you have to remember what problem you're solving.
[00:46:52.160 --> 00:47:00.000] So, for some people, that's an easy switch, you know, because they were kind of, some people tend to go out of their way to try to eat as much saturated fat as possible.
[00:47:00.000 --> 00:47:00.640] I'm not sure why.
[00:47:00.640 --> 00:47:08.240] Like, they sort of, you know, they're like, okay, well, I'm doing this, you know, ketogenic diet, and I'm just going to basically eat coconut oil and palm oil.
[00:47:08.240 --> 00:47:09.200] Like, it's my job.
[00:47:09.200 --> 00:47:10.080] Yeah, yeah, yeah, yeah.
[00:47:10.400 --> 00:47:14.240] And so, for those people, you just got to say, dude, like, stop doing that.
[00:47:14.240 --> 00:47:17.680] Just like use olive oil on your salad and like, let's be reasonable.
[00:47:17.680 --> 00:47:18.960] And then it fixes everything.
[00:47:19.200 --> 00:47:22.640] But for other people, you know, it's it just can't be addressed.
[00:47:22.640 --> 00:47:26.080] And I've heard other people say, oh, you know, this is crazy.
[00:47:26.080 --> 00:47:31.800] Like, we know that, you know, excessive fat restriction in the diet will lower cholesterol.
[00:47:29.840 --> 00:47:32.280] And that's true.
[00:47:32.440 --> 00:47:40.600] I mean, if you go on a really draconian fat-lowering diet, you will lower your cholesterol.
[00:47:41.560 --> 00:47:49.960] My view clinically is that makes very little sense because that usually comes with a whole bunch of other issues.
[00:47:49.960 --> 00:48:02.360] So a lot of times when I see people on these excessively restrictive fat lowering diets, they actually become insulin resistant, a lot of them, because they're really over-consuming a lot of poor quality carbs.
[00:48:02.600 --> 00:48:06.680] And they're suffering other consequences of really low fat intake.
[00:48:06.680 --> 00:48:09.640] Now, again, this doesn't mean that a low-fat diet is necessarily problematic.
[00:48:09.640 --> 00:48:17.960] The devil's in the details here, just like the devil's in the details on what constitutes a reasonable versus an unreasonable low-carb diet.
[00:48:17.960 --> 00:48:26.920] But the point I try to make to people is I believe that using nutrition to solve the lipid problem is not a good solution.
[00:48:26.920 --> 00:48:30.280] I think use nutrition to solve the nutrition problem.
[00:48:30.280 --> 00:48:44.280] Use nutrition to address energy balance, protein needs, anabolic structure, energy, all of these other things, and let your lipids fall where they may, because this is one of the few areas in medicine where we have amazing pharmacologic tools.
[00:48:44.280 --> 00:48:47.640] Most of medicine doesn't really have great pharmacology if you stop to think about it.
[00:48:47.640 --> 00:48:56.200] Like we don't have great, there's nothing pharmacologically that's adding brilliance to our Alzheimer's prevention strategy or our cancer prevention strategy.
[00:48:56.200 --> 00:49:01.080] I mean, we have some stuff, but it's nothing compared to what we can do with blood pressure and lipid management.
[00:49:01.080 --> 00:49:14.960] So I always say it's hard enough to find the right diet that's going to work for you in terms of your ability to be compliant with it, your ability to be within energy balance, which is the single most important thing, your ability to be insulin sensitive, your ability to get adequate amounts of protein.
[00:49:14.440 --> 00:49:19.120] If you solve that with a low-fat diet that also happens to keep your lipids low, great.
[00:49:19.440 --> 00:49:28.320] But if you solve that with a higher fat diet that does everything perfect for you except your lipids go haywire, don't put your head in the sand and act like having lipids that have gone haywire is a good thing.
[00:49:28.320 --> 00:49:34.160] No, just acknowledge it's not a good thing, but we can fix it with, again, myriad tools that didn't exist 20 years ago.
[00:49:35.520 --> 00:49:41.280] Are there people that are genetically have genetically low APOB?
[00:49:41.600 --> 00:49:45.040] And if so, what's their cardiovascular mortality?
[00:49:45.040 --> 00:49:46.400] They're all-cause mortality.
[00:49:47.040 --> 00:49:48.640] Yeah, so there are people.
[00:49:48.800 --> 00:50:05.680] So it turns out APOB and LDLC are highly genetic, which is what has allowed us to do the Mendelian randomization studies that act as one of the, you know, there are basically three cornerstones of data that make it unambiguously clear of the relationship between LDL or APOB and ASCVD.
[00:50:05.680 --> 00:50:11.200] So you have all of the epidemiologic data, which again, epidemiology is rife with problems.
[00:50:11.200 --> 00:50:18.640] But, you know, when the data is pretty much all in the same direction and you have the dose effect and all these other things, it becomes quite helpful.
[00:50:18.640 --> 00:50:23.280] You have all the clinical trial data, which I would divide into primary and secondary prevention data.
[00:50:23.280 --> 00:50:46.080] And then you have the Mendelian randomization data, which again, for listeners, is basically anytime there is a biologic variable of interest that is under a high degree of genetic control and produces a high degree of variability in the population, you can look at how nature has basically randomized it across people and you can look at outcomes of interest.
[00:50:46.080 --> 00:51:03.640] So, in the case of LDLC, because we know it is highly genetic, right, this is clear in that, and I don't just mean in extreme cases, but just across a population, you can see that lower lifelong exposure to APOB or LDL produces lower ASCVD risk over a lifetime.
[00:51:03.960 --> 00:51:10.680] So, using this, we can say there are people at really low and high extremes.
[00:51:10.680 --> 00:51:25.880] So, at the high extreme, you have the people who have what's called familial hypercholesteria, which is a genetically heterogeneous disease, meaning there are literally thousands of mutations that result in a similar phenotype.
[00:51:25.880 --> 00:51:33.800] The phenotype is defined as having an LDL cholesterol off-medication of more than 190 milligrams per deciliter, and there's a couple of other criteria.
[00:51:33.800 --> 00:51:39.000] But just to give you a sense of how high the LDL needs to be to meet that criteria.
[00:51:39.640 --> 00:51:45.720] At the other end of the spectrum, we have these people with very, very low LDLC or APOB.
[00:51:45.720 --> 00:51:53.720] And the most interesting group of these are the people who are folks that have a hypo-functioning gene for PCSK9.
[00:51:53.720 --> 00:52:01.320] So, Helen Hobbes made this discovery in probably the early 2000s.
[00:52:01.560 --> 00:52:04.520] My vague recollection, I remember reading this paper when it came out.
[00:52:04.520 --> 00:52:06.200] It was a really mind-boggling paper.
[00:52:06.200 --> 00:52:17.080] Call it like somewhere in 2004, 2005, 2006, somewhere in that neighborhood, which is, hey, there are these people walking around with LDLC of like 10 to 20 milligrams per deciliter.
[00:52:17.800 --> 00:52:18.840] And these are adults, right?
[00:52:18.840 --> 00:52:21.240] So normally we just never see that in adults.
[00:52:21.240 --> 00:52:22.760] And they weren't doing anything different, right?
[00:52:22.760 --> 00:52:27.320] They just, like they weren't on some crazy diet or clearly weren't taking any medication.
[00:52:27.320 --> 00:52:35.160] And these people were found to have a mutation in their PCSK9 gene that rendered a hypofunctioning protein.
[00:52:35.160 --> 00:52:39.080] And PCSK9 is a protein that degrades LDL receptors.
[00:52:39.080 --> 00:52:51.440] Now, another subset of these people, their mirror opposites, were discovered several years earlier, which had a hyper-functioning PCSK9 gene, or a gene that produced a hyperfunctioning protein.
[00:52:51.440 --> 00:52:54.160] And these people had sky-high LDL cholesterol.
[00:52:54.160 --> 00:52:58.320] They were a subset of the familial hypercholesterolemia syndromes.
[00:52:58.320 --> 00:52:59.200] And these people weren't.
[00:52:59.200 --> 00:53:04.720] And what was interesting to note is that they just didn't develop cardiovascular disease.
[00:53:04.720 --> 00:53:12.960] So I can't tell you what their life expectancy is because I haven't looked at those data.
[00:53:12.960 --> 00:53:19.520] But what I did confirm is they have no increase in the incidence of any other disease.
[00:53:19.520 --> 00:53:26.400] So in other words, they're absent ASCVD, but they don't make up for it with more cancer or more neurodegenerative disease or more diabetes.
[00:53:27.360 --> 00:53:29.600] That's interesting for a couple of reasons.
[00:53:29.600 --> 00:53:43.440] One, you see on Twitter a lot, you know, the very, very, you know, just the hyper-focused, very low-carb community that's like, you know, they share studies about, oh, low cholesterol.
[00:53:43.440 --> 00:53:46.320] People with low cholesterol have a higher all-cause mortality.
[00:53:46.320 --> 00:53:49.920] They're more likely to die from, you know, all these different causes of death.
[00:53:50.320 --> 00:54:04.000] Yeah, the problem with those studies is, I mean, I'll only address this once because I've done so much addressing this that I realize you can only waste so much time preaching to an audience that actually has no interest in understanding the truth.
[00:54:04.320 --> 00:54:18.960] But just to give you an example of the type of biases that creep into those studies, when you look at people who have very low LDL cholesterol, you're sampling a subset of people who are at very high risk for a disease, typically two diseases, right?
[00:54:18.960 --> 00:54:26.800] When you have very high LDL, you are at risk of ASCVD, cerebrovascular disease, and Alzheimer's disease and all causes of dementia.
[00:54:26.800 --> 00:54:35.000] So, therefore, the people who are at high risk for those are typically the people at a population level who have the lowest level because they're being treated the most aggressively.
[00:54:29.680 --> 00:54:37.080] So, this is kind of the problem with that stuff.
[00:54:37.720 --> 00:54:39.160] I'll give you an example.
[00:54:39.160 --> 00:54:41.880] There's a clear association in the epidemiology.
[00:54:41.880 --> 00:54:48.440] It doesn't come up often, but it's come up from time to time that the lower the LDL cholesterol, the higher the risk of cancer.
[00:54:48.760 --> 00:54:58.200] This is a great example of when Mendelian randomization becomes very valuable because you can actually go back and look at the genes that are controlling LDL.
[00:54:58.200 --> 00:55:08.920] You can look at how those are spread out, and you can ask the question: once you just look at the random assignment of those genes that control LDL cholesterol, does that have any bearing on cancer outcome?
[00:55:08.920 --> 00:55:11.640] And the answer is unequivocally, no, it does not.
[00:55:11.640 --> 00:55:24.120] So, when you do the MR, you get the answer that the EPI is clearly confounding with something else, which is, in other words, low LDL at the population level is a proxy for other illness.
[00:55:24.120 --> 00:55:25.240] This is the issue here.
[00:55:25.240 --> 00:55:26.360] Yes, thank you.
[00:55:27.320 --> 00:55:32.920] The other interesting point was with the actual gene that you were mentioning, the PCS canine, right?
[00:55:32.920 --> 00:55:44.920] So, when you were talking about we have pharmacological interventions that do very nicely lower APOB, one of them is PCS canine inhibitors.
[00:55:44.920 --> 00:55:45.400] Exactly.
[00:55:45.480 --> 00:55:47.400] Came right out of Helen Hobbes' observation.
[00:55:47.720 --> 00:56:01.160] So, I want to, let's, you know, let's touch on the pharmacological treatments, but also the PCS canine inhibitors, they're not necessarily available to everyone at the start, right out the gate.
[00:56:01.160 --> 00:56:18.880] And then I want to get your thoughts on some of the base editing trials that have started looking at literally like you're doing a gene edit, you know, and you're changing, you know, a nucleotide to essentially make a PC or the people that you're talking about walking around, right?
[00:56:18.880 --> 00:56:20.640] With no ASCB.
[00:56:20.640 --> 00:56:21.280] Yeah.
[00:56:14.840 --> 00:56:22.240] So.
[00:56:23.120 --> 00:56:27.120] Okay, so let's maybe just talk broadly about what the different pharmacologic strategies are, right?
[00:56:27.120 --> 00:56:40.800] So the very first drug that was ever used to lower lipids was a drug called, oh God, I'm always blanked on the name of this, like triperanol.
[00:56:41.120 --> 00:56:43.440] So this was done in the 1950s.
[00:56:43.440 --> 00:56:44.880] Yeah, well, there's a reason you never heard of it, right?
[00:56:44.880 --> 00:56:46.640] So it turned out to be a really bad drug.
[00:56:46.640 --> 00:56:53.040] So there used to be a day when, again, in the 1950s and 1960s, we just didn't know what the hell was going on.
[00:56:53.040 --> 00:56:56.960] So the idea was if you came up with any drug that lowered cholesterol, it must be a good thing.
[00:56:56.960 --> 00:57:07.600] Well, it turned out this drug lowered cholesterol by inhibiting an enzyme that was the final enzyme in the step that we used to make cholesterol.
[00:57:07.600 --> 00:57:16.800] So we make cholesterol using two pathways, but one of the pathways results in a molecule called desmosterol, which gets converted into cholesterol.
[00:57:16.800 --> 00:57:21.440] So there's an enzyme that facilitates that, and this drug blocked that enzyme.
[00:57:21.440 --> 00:57:24.080] And as a result, cholesterol levels went down.
[00:57:24.080 --> 00:57:29.040] And although no one was really paying attention at the time, desmosterol levels went sky high.
[00:57:29.040 --> 00:57:31.280] And it lowered cholesterol.
[00:57:31.280 --> 00:57:33.600] So on the basis of that, this drug was approved.
[00:57:33.600 --> 00:57:37.280] And back at the time, that was the only thing you were monitoring, was total cholesterol.
[00:57:37.600 --> 00:57:42.960] But it was found that the patients on this drug, even though they had lower cholesterol, had a higher incidence of heart attacks.
[00:57:42.960 --> 00:57:45.520] So the drug was ultimately pulled in the 1960s.
[00:57:45.520 --> 00:57:54.560] We now know today that it was almost assuredly the case that the desmosterol was even more athergenic than the cholesterol, or at least as atherogenic.
[00:57:54.560 --> 00:58:01.960] So, fast forward to the 1980s, the next class of drugs is developed called bile acid sequesterants.
[00:57:59.680 --> 00:58:06.840] We didn't really get into the life cycle of cholesterol, so it might be worth doing that now because it'll make sense in the context of the drugs.
[00:58:07.000 --> 00:58:09.720] So, every cell in the body is making cholesterol.
[00:58:10.040 --> 00:58:13.080] So, just think path one: synthesis of cholesterol.
[00:58:13.080 --> 00:58:16.520] If you synthesize less cholesterol, that's one way to lower it.
[00:58:16.520 --> 00:58:20.200] As you noted, all that cholesterol is making its way back to the liver.
[00:58:20.200 --> 00:58:28.600] When the liver gets a hold of all that cholesterol, it's putting a lot of it into bile, and we're using bile acids to digest food.
[00:58:28.600 --> 00:58:34.440] So, as bile via the bile duct is entering the small intestine, it is full of cholesterol.
[00:58:34.760 --> 00:58:38.840] The body reabsorbs much of that cholesterol.
[00:58:38.840 --> 00:58:46.840] So, each of the enterocytes, which are the gut cells that line your intestine, they have a couple of transporters on them.
[00:58:46.840 --> 00:58:54.600] So, one of the transporters on them, it's called a Neiman-Pixie 1-like one transporter, it absorbs all of the sterols.
[00:58:54.600 --> 00:58:59.160] And this is, I use the word sterol very carefully to distinguish it here from just cholesterol.
[00:58:59.160 --> 00:59:04.680] This is zoosterol and plant sterol, which is, or an animal sterol, which is called cholesterol.
[00:59:04.680 --> 00:59:05.960] It absorbs that all.
[00:59:06.280 --> 00:59:13.640] There are basically regulatory steps inside the cell that determine how much of that should be kept and how much should be excreted.
[00:59:13.640 --> 00:59:17.560] And a fraction of that then gets excreted through an ATP binding cassette.
[00:59:17.560 --> 00:59:22.040] So, point being, that's a second point of regulation at the absorption site.
[00:59:22.040 --> 00:59:25.080] But again, this is not the cholesterol we eat.
[00:59:25.080 --> 00:59:28.840] This is un-esterified cholesterol that's easy to get in and out of the body.
[00:59:28.840 --> 00:59:31.480] Esterified cholesterol can't be absorbed.
[00:59:31.480 --> 00:59:33.720] And most of the cholesterol we eat is esterified.
[00:59:33.720 --> 00:59:35.880] That's why we just poop it out.
[00:59:37.240 --> 00:59:48.560] So, bile acid sequesterants, which were the first version of drugs, the second version, I guess, of drugs to lower cholesterol, which are not used today, blocked that process in a very crude mechanical way.
[00:59:48.800 --> 00:59:53.200] They sequestered the bile acids and dragged all the cholesterol out the GI tract.
[00:59:53.200 --> 00:59:59.840] They were not a very successful class of drugs, and not the least of which because the side effects were pretty bad.
[00:59:59.840 --> 01:00:10.320] So, it really wasn't until the mid to late 80s, probably I think 1987, if my memory serves me correctly, that the first statin came to be developed.
[01:00:10.320 --> 01:00:22.240] And that was the real turning point in basically the pharmacologic tool that became valuable against ASCBD.
[01:00:22.320 --> 01:00:31.520] Now, the first, second, and third generation statins of that era are no longer in use today because their side effect profile was very harsh relative to what we can do today.
[01:00:31.520 --> 01:00:38.240] So, there are currently seven statins in existence, and each of them offers some strengths and advantages over others.
[01:00:38.240 --> 01:00:40.000] And they're not a benign class of drugs.
[01:00:40.000 --> 01:00:42.560] So, to be clear, they're an effective class of drug.
[01:00:42.560 --> 01:00:45.680] They're very effective at lowering LDL cholesterol.
[01:00:45.680 --> 01:00:50.960] They work by inhibiting the first committed step of cholesterol synthesis.
[01:00:50.960 --> 01:00:54.240] They do that everywhere, but primarily in the liver.
[01:00:54.240 --> 01:01:01.680] And the response of the liver when cholesterol synthesis is being shut down, the liver says, I got to get more cholesterol in here.
[01:01:01.680 --> 01:01:02.480] And what does it do?
[01:01:02.480 --> 01:01:06.000] It puts a whole bunch more LDL receptors all over the liver.
[01:01:06.000 --> 01:01:11.440] And that's what's primarily driving down LDL in the presence of a statin.
[01:01:11.760 --> 01:01:13.360] But the side effects are what?
[01:01:13.360 --> 01:01:17.200] Well, about 7% of people develop muscle aches on statins.
[01:01:17.200 --> 01:01:22.240] So, that's a, if you think about how many people are on those drugs or how many people are prescribed those drugs, that's a huge number of people.
[01:01:22.240 --> 01:01:24.720] The good news is that's a completely reversible side effect.
[01:01:24.720 --> 01:01:31.080] So, you put a person on a statin, they experience muscle soreness, you take them off, it's gone within a week or two.
[01:01:32.200 --> 01:01:37.880] The other big side effect, the one that I probably think about the most, is insulin resistance.
[01:01:37.880 --> 01:01:46.200] So, a very small set of subset of people, about 0.4% of people put on a statin, might go on to develop type 2 diabetes as a result of it.
[01:01:46.200 --> 01:01:54.040] Now, I think any doctor who lets a patient get to the point where they get type 2 diabetes because of their statin hasn't been paying attention.
[01:01:54.040 --> 01:01:58.360] We want to know the minute you're becoming insulin-resistant in response to the statin.
[01:01:58.360 --> 01:01:59.720] And those data are less clear.
[01:01:59.720 --> 01:02:13.720] You don't know exactly how many people are getting insulin-resistant, but this is a reason to be paying attention to bigger markers and more important markers than just hemoglobin A1C trips over the threshold of 6.5%, you have type 2 diabetes.
[01:02:13.720 --> 01:02:16.760] Here, you want to be able to say: is the hemoglobin A1C moving?
[01:02:16.760 --> 01:02:19.400] What's happening to the fasting insulin and glucose and these other markers?
[01:02:19.400 --> 01:02:21.000] Does a patient wear a CGM?
[01:02:21.000 --> 01:02:28.280] One of the reasons we like CGMs on patients when we put them on statins is we have a historical level of what their glucose control looks like.
[01:02:28.280 --> 01:02:41.960] And if all of a sudden their baseline average glucose goes up by 10 m

Prompt 2: Key Takeaways

Now please extract the key takeaways from the transcript content I provided.

Extract the most important key takeaways from this part of the conversation. Use a single sentence statement (the key takeaway) rather than milquetoast descriptions like "the hosts discuss...". 

Limit the key takeaways to a maximum of 3. The key takeaways should be insightful and knowledge-additive. 

IMPORTANT: Return ONLY valid JSON, no explanations or markdown. Ensure:
- All strings are properly quoted and escaped
- No trailing commas
- All braces and brackets are balanced
Format: {"key_takeaways": ["takeaway 1", "takeaway 2"]}

Prompt 3: Segments

Now identify 2-4 distinct topical segments from this part of the conversation.

For each segment, identify:
- Descriptive title (3-6 words)  
- START timestamp when this topic begins (HH:MM:SS format)
- Double check that the timestamp is accurate - a timestamp will NEVER be greater than the total length of the audio
- Most important Key takeaway from that segment. Key takeaway must be specific and knowledge-additive.
- Brief summary of the discussion

IMPORTANT: The timestamp should mark when the topic/segment STARTS, not a range. Look for topic transitions and conversation shifts.

Return ONLY valid JSON. Ensure all strings are properly quoted, no trailing commas:
{
  "segments": [
    {
      "segment_title": "Topic Discussion", 
      "timestamp": "01:15:30",
      "key_takeaway": "main point from this segment",
      "segment_summary": "brief description of what was discussed"
    }
  ]
}

Timestamp format: HH:MM:SS (e.g., 00:05:30, 01:22:45) marking the START of each segment.

Prompt 4: Media Mentions

Now scan the transcript content I provided for ACTUAL mentions of specific media titles:

Find explicit mentions of:
- Books (with specific titles)
- Movies (with specific titles)  
- TV Shows (with specific titles)
- Music/Songs (with specific titles)

DO NOT include:
- Websites, URLs, or web services
- Other podcasts or podcast names

IMPORTANT: 
- Only include items explicitly mentioned by name. Do not invent titles.
- Valid categories are: "Book", "Movie", "TV Show", "Music"
- Include the exact phrase where each item was mentioned
- Find the nearest proximate timestamp where it appears in the conversation
- THE TIMESTAMP OF THE MEDIA MENTION IS IMPORTANT - DO NOT INVENT TIMESTAMPS AND DO NOT MISATTRIBUTE TIMESTAMPS
- Double check that the timestamp is accurate - a timestamp will NEVER be greater than the total length of the audio
- Timestamps are given as ranges, e.g. 01:13:42.520 --> 01:13:46.720. Use the EARLIER of the 2 timestamps in the range.

Return ONLY valid JSON. Ensure all strings are properly quoted and escaped, no trailing commas:
{
  "media_mentions": [
    {
      "title": "Exact Title as Mentioned",
      "category": "Book",
      "author_artist": "N/A",
      "context": "Brief context of why it was mentioned",
      "context_phrase": "The exact sentence or phrase where it was mentioned",
      "timestamp": "estimated time like 01:15:30"
    }
  ]
}

If no media is mentioned, return: {"media_mentions": []}

Prompt 5: Context Setup

You are an expert data extractor tasked with analyzing a podcast transcript. 
I will provide you with part 2 of 4 from a podcast transcript. 
I will then ask you to extract different types of information from this content in subsequent messages. Please confirm you have received and understood the transcript content.

Transcript section:
ts are what?
[01:01:13.360 --> 01:01:17.200] Well, about 7% of people develop muscle aches on statins.
[01:01:17.200 --> 01:01:22.240] So, that's a, if you think about how many people are on those drugs or how many people are prescribed those drugs, that's a huge number of people.
[01:01:22.240 --> 01:01:24.720] The good news is that's a completely reversible side effect.
[01:01:24.720 --> 01:01:31.080] So, you put a person on a statin, they experience muscle soreness, you take them off, it's gone within a week or two.
[01:01:32.200 --> 01:01:37.880] The other big side effect, the one that I probably think about the most, is insulin resistance.
[01:01:37.880 --> 01:01:46.200] So, a very small set of subset of people, about 0.4% of people put on a statin, might go on to develop type 2 diabetes as a result of it.
[01:01:46.200 --> 01:01:54.040] Now, I think any doctor who lets a patient get to the point where they get type 2 diabetes because of their statin hasn't been paying attention.
[01:01:54.040 --> 01:01:58.360] We want to know the minute you're becoming insulin-resistant in response to the statin.
[01:01:58.360 --> 01:01:59.720] And those data are less clear.
[01:01:59.720 --> 01:02:13.720] You don't know exactly how many people are getting insulin-resistant, but this is a reason to be paying attention to bigger markers and more important markers than just hemoglobin A1C trips over the threshold of 6.5%, you have type 2 diabetes.
[01:02:13.720 --> 01:02:16.760] Here, you want to be able to say: is the hemoglobin A1C moving?
[01:02:16.760 --> 01:02:19.400] What's happening to the fasting insulin and glucose and these other markers?
[01:02:19.400 --> 01:02:21.000] Does a patient wear a CGM?
[01:02:21.000 --> 01:02:28.280] One of the reasons we like CGMs on patients when we put them on statins is we have a historical level of what their glucose control looks like.
[01:02:28.280 --> 01:02:41.960] And if all of a sudden their baseline average glucose goes up by 10 milligrams per deciliter, which I've seen in patients on a statin, I know it's, you know, that's not just a quick dietary trigger, especially when you take them off the statin and it comes right back down to normal.
[01:02:41.960 --> 01:02:47.640] So, even though they haven't become, you know, they haven't gone to the level of being diabetic, they're clearly becoming insulin-resistant.
[01:02:47.640 --> 01:02:54.120] And the third thing we see with statins is change in or an increase in the transaminases or the liver function tests.
[01:02:54.200 --> 01:02:59.720] Liver function test is a bit of a misnomer because the transaminases really tell us more about inflammation than function.
[01:02:59.720 --> 01:03:11.400] So, all that said, statins are still kind of, you know, they're doing the lion's share of the work in this area, but by no means should we say that that's the only thing that we have at our disposal.
[01:03:11.400 --> 01:03:13.320] About 20 years ago, another drug called azetamine.
[01:03:13.480 --> 01:03:15.000] Can I interrupt for a second and ask you about statins?
[01:03:15.280 --> 01:03:15.680] Yeah, you can.
[01:03:15.680 --> 01:03:16.000] Of course.
[01:03:16.320 --> 01:03:18.400] Because I have some questions about them.
[01:03:18.400 --> 01:03:26.400] So I'll never forget this conversation that, again, I had with our mutual friend Ron Kraus because he worked down the hall.
[01:03:26.400 --> 01:03:27.520] I worked down the hall from him.
[01:03:27.520 --> 01:03:29.840] And I collaborated with some of his postdocs.
[01:03:29.840 --> 01:03:43.920] And, you know, they would come over and show me data and we would talk because I had a lot of experience in assaying mitochondrial function and mitochondrial biology during graduate school.
[01:03:43.920 --> 01:03:46.640] And I remember saying this to Ron.
[01:03:46.640 --> 01:03:58.800] I'm like, you know, so statins are affecting the HMG CoA pathway that you mentioned, the cholesterol synthesis, which also is important for the synthesis of ubiquinol, right?
[01:03:58.800 --> 01:04:02.480] This is an important, or CoQ10, as I should probably call it.
[01:04:02.640 --> 01:04:04.720] This is important for mitochondrial function.
[01:04:04.720 --> 01:04:15.520] I mean, it's necessary for mitochondrial function for transferring electrons across the electron transport chain, which is essentially coupling the oxygen we breathe with the food that we eat to make energy.
[01:04:15.520 --> 01:04:20.320] And I remember saying, oh, so statins have a side effect of targeting mitochondria.
[01:04:20.320 --> 01:04:24.160] And he said to me, no, it's a direct effect.
[01:04:24.160 --> 01:04:33.760] So what are your thoughts on how statins are affecting mitochondria and through this pathway?
[01:04:33.760 --> 01:04:40.320] And obviously, you might mention supplementation with a reduced form of ubiquinol, right?
[01:04:40.560 --> 01:04:45.360] Measuring mitochondrial function in terms of BO2 max, something.
[01:04:46.240 --> 01:04:49.920] So it's a great question, actually, and something I have thought a lot about.
[01:04:50.720 --> 01:04:54.800] So the literature has nothing to offer here, unfortunately.
[01:04:55.040 --> 01:05:00.200] So I wish I could say, you know, Rhonda, the answer is this, because here's what the literature says.
[01:05:00.200 --> 01:05:02.200] Here's what I can tell you.
[01:04:59.360 --> 01:05:04.440] And this is not going to be a satisfying answer.
[01:05:04.760 --> 01:05:12.280] If there is an impact on mitochondrial function with statin use, it's very small.
[01:05:12.280 --> 01:05:21.800] based on what I consider to be the single best measurement we have to measure mitochondrial function, which is zone 2 testing with lactate production.
[01:05:22.120 --> 01:05:30.840] So I know you know what this is because we talk about this stuff all day long, but just for folks listening, this requires a little bit of explanation, but it's very important.
[01:05:30.840 --> 01:05:33.080] And I think it's, I'm glad you brought this up.
[01:05:33.080 --> 01:05:35.800] So everybody understands what the mitochondria do.
[01:05:36.040 --> 01:05:40.360] If they're listeners of your podcast, we don't need to explain the mitochondria.
[01:05:40.360 --> 01:05:45.320] But it's important to understand that a functional test is a very important test in medicine.
[01:05:45.320 --> 01:05:47.480] We don't have many functional tests, right?
[01:05:47.480 --> 01:05:50.600] Most of the things we talk about are biomarkers.
[01:05:50.920 --> 01:05:54.600] And by themselves, they don't tell you a huge amount of information.
[01:05:54.600 --> 01:05:57.560] They tend to be quite static and not dynamic.
[01:05:57.880 --> 01:06:10.440] But we understand that the healthier an individual is, the more they can rely on their mitochondria for ATP generation under increasing demands of the cell.
[01:06:10.440 --> 01:06:13.480] This is one of the hallmarks of health.
[01:06:13.480 --> 01:06:20.360] And by extension, one of the hallmarks of aging and one of the hallmarks of disease is an inability to do that.
[01:06:20.360 --> 01:06:32.600] Meaning, as the ATP demand on a cell goes up, there is an earlier and earlier shift to glycolysis as opposed to oxidative phosphorylation.
[01:06:32.600 --> 01:06:35.560] So, how do we, how can we measure that clinically?
[01:06:35.560 --> 01:06:41.800] Well, we can put a person in, because we can't, you know, rather than test a cell, let's test the whole organism, right?
[01:06:41.800 --> 01:06:45.200] So, we put a person in sort of an ergometer, right?
[01:06:45.200 --> 01:06:58.480] So, on a treadmill or on a bike or under some sort of demand where we can control the work that they have to do, and we can drive up the amount of work they do while sampling lactate.
[01:06:58.480 --> 01:07:00.080] And why does that, what does that tell us?
[01:07:00.080 --> 01:07:07.360] Well, just to remind everybody, you know, glucose enters a cell and it basically has two fates, right?
[01:07:07.360 --> 01:07:10.960] So, glucose will be converted into pyruvate regardless.
[01:07:10.960 --> 01:07:19.360] It has the fate at which oxygen is plentiful and the body has the time to make a lot of ATP where it goes into the mitochondria.
[01:07:19.360 --> 01:07:27.520] And it has the less efficient but quicker way to get ATP, which is converting lactate, pardon me, pyruvate into lactate.
[01:07:27.520 --> 01:07:33.520] So, this is the glycolytic pathway versus the oxidative phosphorylitic pathway.
[01:07:34.800 --> 01:07:39.680] The longer a cell can stay in that mitochondrial space, the better it is.
[01:07:39.680 --> 01:07:46.320] It makes way more ATP and it accumulates less lactate and hydrogen ion.
[01:07:46.320 --> 01:07:56.080] And the more lactate and hydrogen ion you accumulate, eventually the cell becomes effectively poisoned by that hydrogen ion, and it becomes very difficult for a muscular cell to contract.
[01:07:56.080 --> 01:07:59.200] So, we use this test with patients.
[01:07:59.200 --> 01:08:01.840] This is one of the most important metrics we care about.
[01:08:01.840 --> 01:08:18.720] Literally, it would be in the top 10 things we care about for our patients, which is how many watts can you produce on a bike, or how many METs can you exercise at on a treadmill or whatever vehicle you're using while keeping lactate below about 2 millimole.
[01:08:18.720 --> 01:08:30.000] 2 millimole is about the threshold beyond which you are now shifting away from the maximum capacity of the mitochondria to undergo this process.
[01:08:31.080 --> 01:08:39.480] Okay, all of this is to say I have clearly seen the effect of a drug like metformin at impacting that.
[01:08:39.800 --> 01:08:43.000] Metformin, which is a mitochondrial toxin, right?
[01:08:43.000 --> 01:08:47.320] Metformin impairs complex one of the mitochondria.
[01:08:47.320 --> 01:08:54.120] We immediately see a change in the lactate performance curve of an individual on metformin.
[01:08:54.120 --> 01:08:57.560] We see a complete reduction in their zone 2 output.
[01:08:57.560 --> 01:09:00.600] They hit that lactate of 2 much sooner.
[01:09:00.600 --> 01:09:09.560] We also see an increase, not big, but significant, meaning clinically significant, in their fasting, resting, lactate level.
[01:09:09.560 --> 01:09:13.160] So all things equal, their lactate is just getting higher.
[01:09:13.480 --> 01:09:17.160] To me, by the way, I don't know if that's necessarily harmful.
[01:09:17.160 --> 01:09:22.120] I don't think it's a good idea, which is why I don't believe in metformin as a girro-protective agent.
[01:09:22.120 --> 01:09:28.360] I think metformin is a good drug for someone who's diabetic, if they can't exercise enough and they can't get into energy balance.
[01:09:28.920 --> 01:09:34.120] But I don't think metformin is a great drug for someone like you or someone like me.
[01:09:35.400 --> 01:09:38.040] We don't see this with statins.
[01:09:38.360 --> 01:09:41.880] So if it's happening, it's dose-dependent or not.
[01:09:42.200 --> 01:09:42.920] Just don't see it.
[01:09:42.920 --> 01:09:45.160] Yeah, just don't see it.
[01:09:45.160 --> 01:09:48.680] So it could be happening, but we don't have the resolution to measure it.
[01:09:48.920 --> 01:09:55.080] So that's why I'm saying, like, I think one always has to have the humility, which I hope I have, to say, look, I don't know.
[01:09:55.400 --> 01:10:00.520] But what I do know is if there's an effect there, it's really small.
[01:10:00.520 --> 01:10:08.520] Now, you mentioned ubiquinol or CoQ10, and there are two states of it, ubiquinol and ubiquinone, but ubiquinol would be the state we would want to consider here.
[01:10:08.520 --> 01:10:16.960] There have been a number of clinical trials looking at using or supplementing ubiquinol with patients taking statins.
[01:10:16.960 --> 01:10:22.400] They have mostly done this to assess the muscle soreness issue.
[01:10:22.400 --> 01:10:30.320] So they've mostly done this as a way to ask the question: can you reduce the insulin, the incidence rather, of muscle soreness with statins?
[01:10:30.320 --> 01:10:32.640] I haven't looked at those literature in a couple of years.
[01:10:32.640 --> 01:10:36.080] The last I looked at them, there was still no difference.
[01:10:37.040 --> 01:10:45.440] That said, we have patients that really feel strongly about taking ubiquinol when they're on a statin, and I don't have any issue with that.
[01:10:45.840 --> 01:10:47.600] I don't think there's any harm in taking it.
[01:10:47.600 --> 01:10:49.120] I really don't think there is.
[01:10:50.320 --> 01:10:53.440] And if there's a chance of benefit, then I would say let's take it.
[01:10:53.440 --> 01:11:01.840] But again, unless something has happened in the last couple of years that I'm unaware of, I don't think we have great data that ubiquinol offsets that.
[01:11:01.840 --> 01:11:10.560] And more importantly, to your point, it's not clear to me that that effect translates to a functional deficit in the mitochondria.
[01:11:10.880 --> 01:11:20.320] When you're measuring, so using the zone 2, you know, lactate threshold training to kind of measure mitochondrial function.
[01:11:21.920 --> 01:11:27.760] So buying the lactate meter, Nova Biomedical or something like that.
[01:11:28.240 --> 01:11:29.520] It's like a yellow-purple one.
[01:11:29.840 --> 01:11:35.440] I got it per year recommendation, but for people listening, if they want to get one.
[01:11:35.440 --> 01:11:45.040] But also knowing how, because there's, when you go to like any sort of, if you were to go talk to an exercise physiologist and you say lactate threshold, like they kind of know.
[01:11:45.360 --> 01:11:46.160] And they're going to push you up.
[01:11:46.200 --> 01:11:48.480] The lactate threshold is a different number.
[01:11:48.480 --> 01:11:48.640] Right.
[01:11:48.640 --> 01:11:50.480] So this is like lower level.
[01:11:51.040 --> 01:11:52.320] This is below your lactate threshold.
[01:11:52.560 --> 01:11:53.520] Yeah, this is lower.
[01:11:53.520 --> 01:11:56.320] So how do people know?
[01:11:56.320 --> 01:12:02.120] Let's like, let's say they have a Peloton at home, okay, and they get on their Peloton and they want to do a zone two test.
[01:12:02.120 --> 01:12:02.760] Okay.
[01:12:03.800 --> 01:12:15.080] Can you somehow use a percent max rate, heart rate, sorry, max heart rate proxy to kind of know like there are lots of different ways to estimate this.
[01:12:15.080 --> 01:12:23.160] And to be clear, like I'm one of the very few people that is checking his lactate every, you know, every day that he's on his bike, which is four days a week for me.
[01:12:23.160 --> 01:12:29.400] And by the way, I'm also doing it while using all the other metrics that I'll explain in a moment.
[01:12:29.400 --> 01:12:38.440] Mostly just in an ever, never-ending quest to just have as much data as possible to understand when is lactate the best predictor?
[01:12:38.440 --> 01:12:40.280] When was RPE the best predictor?
[01:12:40.280 --> 01:12:42.120] When was heart rate the best predictor?
[01:12:42.120 --> 01:12:44.120] When was absolute wattage the best predictor?
[01:12:44.120 --> 01:12:46.440] Like there's a lot of stuff going on here.
[01:12:46.440 --> 01:12:54.280] So first thing I always say to people, namely my patients, when they say, I don't want to get that lactate meter, I don't want to be poking myself in the finger.
[01:12:54.280 --> 01:12:55.640] I'm like, great, don't.
[01:12:55.640 --> 01:12:56.680] You don't have to.
[01:12:56.680 --> 01:13:01.880] There are like other ways that you can pretty much approximate your zone two output.
[01:13:01.880 --> 01:13:07.720] And the only reason I brought up the whole lactate testing is it is the gold standard and it is the most objective way to do this.
[01:13:07.720 --> 01:13:12.840] And therefore, if I'm trying to really understand the impact of say metformin or astatin, that's what I want to do.
[01:13:12.840 --> 01:13:19.080] But let's put that aside for a moment and answer the relevant question, which is, hey, how does someone exercise in this zone?
[01:13:19.400 --> 01:13:26.600] I think the most important tool for virtually anybody is rate of perceived exertion.
[01:13:26.600 --> 01:13:29.240] I think that will almost never let you down.
[01:13:29.880 --> 01:13:37.480] In fact, I would argue that for a really, really out-of-shape individual, rate of perceived exertion is even better than lactate.
[01:13:37.800 --> 01:13:44.640] And the reason for that is you take somebody who's got, for example, type 2 diabetes, their resting lactate may already be at 2.
[01:13:44.200 --> 01:13:47.680] So in those patients, we actually never use lactate.
[01:13:47.840 --> 01:13:54.320] Until you get somebody to a certain level of fitness, we only use rate of perceived exertion, and we will provide heart rate guidance.
[01:13:54.320 --> 01:13:56.560] So here's two ways to think about it.
[01:13:57.840 --> 01:14:02.960] RPE, rate of perceived exertion, we give people the test, which is the talk test.
[01:14:02.960 --> 01:14:13.280] So when you are in zone two, you should be able to speak to somebody, but it should be uncomfortable and not something you want to do.
[01:14:13.280 --> 01:14:16.800] If you can't speak, you're out of zone two.
[01:14:17.600 --> 01:14:20.080] If you can't speak in a full sentence, you're not in zone two anymore.
[01:14:20.560 --> 01:14:22.080] You're north of zone two.
[01:14:22.080 --> 01:14:25.840] If you can speak the way you and I are speaking now, you're not working hard enough.
[01:14:25.840 --> 01:14:27.760] You're too far below it.
[01:14:27.760 --> 01:14:40.080] So there is that sweet spot where if you're on that Peloton and the phone rings and you answer it, the person knows you're exercising and you're going to let them do most of the talking.
[01:14:40.080 --> 01:14:45.360] But if they ask you a question and you have to answer it, you'll answer it and you can speak in a full sentence, but you're not that comfortable.
[01:14:45.360 --> 01:14:48.480] That's the single most important thing people need to understand about it.
[01:14:48.480 --> 01:14:59.120] As far as what heart rate guidance comes with it, Philmafitone uses a test that I think is a pretty good starting place, which is 180 minus your age.
[01:14:59.440 --> 01:15:03.600] Now, the fitter you are, the less relevant that becomes.
[01:15:03.600 --> 01:15:09.840] So I'm 50, so that would put me at 130, but I can tell you my zone two is above 130.
[01:15:09.840 --> 01:15:14.320] So if you're fitter, you may add five to 10 to that.
[01:15:16.000 --> 01:15:26.320] I use another app that checks my HRV every single morning, and it predicts my zone two as a result of my HRV.
[01:15:26.320 --> 01:15:42.040] And so every day, what I'm doing is I'm looking at the heart rate predicted by the app, which can vary by as much as 10 beats per minute based on how much I slept, the quality of my sleep, how sore I am, a subjective measurement of how much I want to train that day, and my HRV.
[01:15:42.040 --> 01:15:44.760] So it's a Morpheus.
[01:15:44.760 --> 01:15:45.560] Morpheus.
[01:15:45.560 --> 01:15:45.960] Yeah.
[01:15:46.520 --> 01:15:49.080] So, and I have no affiliation with them or anything like that.
[01:15:49.080 --> 01:16:03.800] So, basically, so this morning I got up, my HRV was, I don't even remember, 78 milliseconds, slept seven hours, 15 minutes, good quality sleep, not sore, felt good.
[01:16:03.800 --> 01:16:06.040] So, I actually had a pretty high target today.
[01:16:06.040 --> 01:16:09.720] My target today was 141, the heart rate.
[01:16:09.720 --> 01:16:12.760] On a day, that's about as high as it will predict me to be.
[01:16:13.080 --> 01:16:17.240] On a day when everything sucks, it might tell me as low as 129.
[01:16:17.560 --> 01:16:21.640] Usually, it's about 136, 137, 138, is where it's predicting.
[01:16:21.640 --> 01:16:24.920] And that's generally aligning with where my lactate is.
[01:16:25.560 --> 01:16:28.520] That'll generally put me at a lactate of about 1.9.
[01:16:29.480 --> 01:16:32.680] And then, on top of that, I'm paying attention to the wattage, so I kind of know where to be.
[01:16:32.680 --> 01:16:36.440] But again, for somebody just starting out, RPE is all you need to know.
[01:16:36.440 --> 01:16:38.520] 180 minus your age is good.
[01:16:38.520 --> 01:16:49.000] And then, if a person is fit enough that they truly know their maximum heart rate, we tell them to start at somewhere between 75 and 80 percent of that number.
[01:16:49.320 --> 01:16:50.840] Great recommendations.
[01:16:51.000 --> 01:17:02.760] So, if a person is specifically trying to do this functional mitochondrial test, how long should they be in that zone two before they can measure their lactate?
[01:17:02.920 --> 01:17:06.360] We like to see people there for 30 to 45 minutes before we do it.
[01:17:06.360 --> 01:17:08.440] Yeah, so a true, true steady state.
[01:17:08.440 --> 01:17:09.320] Awesome.
[01:17:10.200 --> 01:17:18.960] So, I kind of want to, the other, going back, circling back to the statins, and here's my question to you.
[01:17:14.840 --> 01:17:19.200] Okay.
[01:17:20.320 --> 01:17:41.040] What questions do you think I should be asking and looking in the literature to convince myself that, let's say, a lipophilic statin that could, you know, cross the blood-brain barrier, get into the brain, inhibit, you know, HEM-CoA in the brain, particularly at higher doses.
[01:17:41.040 --> 01:17:54.000] But generally speaking, what question should I be asking myself to convince myself that it's not going to put me at a higher risk for both of the neurodegenerative disease that I'm terrified about?
[01:17:54.000 --> 01:17:55.360] One, Alzheimer's disease.
[01:17:55.360 --> 01:18:00.080] I have a genetic, it's family history, genetic risk factor, and Parkinson's disease, family history.
[01:18:00.560 --> 01:18:04.080] Both of those diseases have been associated with statin use.
[01:18:04.080 --> 01:18:10.800] They've also been, the literature, as you know, is, you know, you can find what you want, right?
[01:18:11.120 --> 01:18:13.680] So do you have any, you know, advice?
[01:18:13.920 --> 01:18:18.800] Yeah, I did a recent AMA on this, although it might not be out yet.
[01:18:18.800 --> 01:18:22.400] I lose track of when I record them and when they come out, so I apologize if it hasn't come out yet.
[01:18:23.600 --> 01:18:28.960] But I did an entire AMA on this topic because it is so important.
[01:18:28.960 --> 01:18:32.240] And I think it's, as you said, it's so confusing.
[01:18:32.880 --> 01:18:34.960] So I was actually surprised to learn this.
[01:18:35.520 --> 01:18:42.000] I was surprised to learn that there has never been, I shouldn't have been surprised, but regardless, here's what it is.
[01:18:42.000 --> 01:18:52.240] There has never been a study done that has looked at the use of statins and the incidence of Alzheimer's disease or dementia as a primary outcome.
[01:18:52.240 --> 01:18:53.600] Why is that important?
[01:18:53.600 --> 01:19:02.040] It's important because in clinical research, the primary outcome is the only thing you can really take to the bank because that's what the study is powered to detect.
[01:19:02.680 --> 01:19:24.200] There are more than a dozen, probably less than 25, so a big number of studies, call it 15, 16, that have used statins, have had a primary outcome of ASC V D, but a secondary outcome of dementia or Alzheimer's disease.
[01:19:24.200 --> 01:19:27.240] And I looked at every single one of those.
[01:19:27.880 --> 01:19:41.080] And I can tell you that every single one of those found neutral to benefit of statin use on the incidence of dementia and the incidence of Alzheimer's disease.
[01:19:41.080 --> 01:19:46.120] So that includes vascular dementia, I mean, that sort of makes more sense.
[01:19:46.360 --> 01:19:47.560] Parkinson's disease.
[01:19:47.560 --> 01:19:49.800] Have you seen, have you looked at the literature on that?
[01:19:50.120 --> 01:19:55.720] So Parkinson's is a little bit more confusing because the literature is way more sparse.
[01:19:56.360 --> 01:20:01.480] But I do want to go back and talk about Alzheimer's disease because I think there's an important caveat to everything I just said.
[01:20:01.480 --> 01:20:05.400] What I basically, oh, the other point I want to make, Rhonda, this actually surprised me.
[01:20:05.400 --> 01:20:16.600] There was no difference between hydrophobic and hydrophilic statins with respect to the difference whatsoever.
[01:20:16.600 --> 01:20:20.920] So counterintuitive, but no difference whatsoever.
[01:20:22.200 --> 01:20:29.000] So even though, again, you might think, well, gosh, you know, a statin that gets in the brain should have more of an impact, but it didn't.
[01:20:29.000 --> 01:20:29.800] It didn't seem to have.
[01:20:29.880 --> 01:20:35.960] Is there a difference in those two types of statins with respect to the diabetes, increased diabetes risk that you're talking about?
[01:20:36.600 --> 01:20:37.880] That's a really good question.
[01:20:38.680 --> 01:20:41.000] I didn't look at that in, and that wasn't looked at in this.
[01:20:41.480 --> 01:20:52.400] Yeah, here's what I can tell you: the highest incidence of diabetes is probably with atorvastatin, but that might also be because atorvastatin is the most widely used.
[01:20:52.400 --> 01:21:00.800] Like, I don't, we basically, first of all, there's only four statins that I think are even worth prescribing these days, maybe only three.
[01:21:00.800 --> 01:21:02.880] And I treat them all equally in terms of risk.
[01:21:02.880 --> 01:21:07.520] In other words, I would assume anytime you put somebody on a statin, you should be looking for any of the side effects.
[01:21:07.520 --> 01:21:13.840] And I don't particularly, because again, you might say at the population level, it's different, but at the individual level, who cares?
[01:21:14.320 --> 01:21:15.440] It's either one or zero.
[01:21:15.440 --> 01:21:16.560] You're going to get it or you're not.
[01:21:16.800 --> 01:21:17.520] What statins are those?
[01:21:18.080 --> 01:21:29.360] The ones that we would prescribe would be resuvastatin or atorvastatin or lipitor, patavastatin, livolo, and sometimes we use prevastatin or prevacol, but pretty rarely.
[01:21:30.080 --> 01:21:31.840] So usually those would be the big four.
[01:21:31.840 --> 01:21:41.520] Now, here's what I would say, and this is something that we spend an awful lot of time looking at in our practice.
[01:21:41.520 --> 01:21:50.880] And actually, just last week, Tom Dayspring gave us an internal presentation that was so incredible.
[01:21:51.360 --> 01:22:03.040] It was months in the making, looking at the relationship between statin use and desmosterol levels and dementia risk.
[01:22:03.040 --> 01:22:06.560] So you may recall a moment ago I mentioned desmosterol.
[01:22:06.560 --> 01:22:10.640] So desmosterol is, well, let's back up.
[01:22:10.640 --> 01:22:14.000] Remember how I said there were two cholesterol synthesis pathways?
[01:22:14.000 --> 01:22:22.240] Well, in the CNS, really only you have one pathway, and it's the pathway that goes through desmosterol to cholesterol.
[01:22:22.240 --> 01:22:30.000] So, desmosterol levels are actually a decent proxy for brain cholesterol synthesis.
[01:22:30.840 --> 01:22:40.200] Lithosterol, which is the penultimate molecule in the other pathway, is more of a proxy for peripheral cholesterol synthesis.
[01:22:40.520 --> 01:22:41.160] Are these measured?
[01:22:41.240 --> 01:22:42.440] You can measure these on a like.
[01:22:42.600 --> 01:22:44.760] They're very difficult to measure in most labs.
[01:22:44.760 --> 01:22:46.440] We use a lab that measures them.
[01:22:46.440 --> 01:22:53.240] So, we measure desmosterol and lithosterol in every patient with every blood draw.
[01:22:53.240 --> 01:22:55.240] Unfortunately, this is not standard of care.
[01:22:55.240 --> 01:22:56.920] Most labs can't measure this.
[01:22:56.920 --> 01:22:58.120] Boston Heart does this.
[01:22:58.120 --> 01:23:00.120] So, that's why we use Boston Heart.
[01:23:02.360 --> 01:23:15.960] There are enough data suggesting that if desmosterol levels are very low, the risk of AD does indeed go up, and the risk of dementia beyond AD goes up.
[01:23:16.600 --> 01:23:35.400] So, this is kind of what I would describe as personalized medicine/slash medicine 3.0 at its finest, which is you have to treat every patient individually, and we're doubly careful in patients with an APOE4 gene and/or a family history.
[01:23:35.400 --> 01:23:40.520] And in those patients, based on the literature, and I'd be happy to send you Tom's presentation.
[01:23:40.520 --> 01:23:43.320] He would not have a hard time with me sharing that, even though it was kind of an internal presentation.
[01:23:43.320 --> 01:23:49.720] In fact, I could share with you the recording Tom made because we recorded the internal meeting because it was so valuable.
[01:23:50.040 --> 01:23:52.760] But basically, the cutoff we use is 0.8.
[01:23:52.760 --> 01:24:04.520] So, if desmosterol falls below 0.8 milligrams per deciliter, we think the risk of dementia is sufficiently high enough that we would abort the use of the statin.
[01:24:04.840 --> 01:24:05.960] Very good information.
[01:24:05.960 --> 01:24:10.160] And you think there is a correlation with APOE status on that?
[01:24:10.640 --> 01:24:13.720] No one has done that study yet.
[01:24:14.120 --> 01:24:15.040] In your clinical practice.
[01:24:14.440 --> 01:24:18.240] But in our clinical practice, we just decided, like, why would we take the risk?
[01:24:18.720 --> 01:24:27.440] But yes, no one has done the study to show our desmosterol levels lower in ApoE4 individuals.
[01:24:27.440 --> 01:24:32.160] That's actually a very testable hypothesis, and it makes a lot of sense.
[01:24:32.160 --> 01:24:38.400] Because we know APOE is heavily involved in cholesterol activity in the brain.
[01:24:38.720 --> 01:24:50.160] And so it wouldn't be surprising to me if, you know, if you put people into three buckets, zero alleles, one allele, or two allele, E4 alleles, and then just looked at desmosterol levels.
[01:24:50.160 --> 01:24:53.760] Like that would be a very easy, mindless study to do.
[01:24:53.760 --> 01:24:57.920] Just a survey, like just a quick, is there a correlation, yes or no?
[01:24:58.960 --> 01:25:01.760] So that's one thing I'd love to know the answer to.
[01:25:02.240 --> 01:25:10.160] But even absent that knowledge, our view is there's simply no reason to take the risk.
[01:25:10.480 --> 01:25:20.560] You know, earlier I said it makes no sense to go on some crazy, obscure diet that has a whole bunch of unintensed consequences just to control your lipids.
[01:25:20.560 --> 01:25:22.880] Well, I would make the exact same statement here.
[01:25:22.880 --> 01:25:31.120] It makes no sense to get all, to take unnecessary risks with statins in a higher-risk individual when we have these other tools.
[01:25:31.120 --> 01:25:36.320] We have, as we talked about or we will talk about, azetamide, PCSK9 inhibitors, bempidoic acid.
[01:25:36.320 --> 01:25:41.360] These are unbelievable tools that have no bearing on brain cholesterol synthesis.
[01:25:41.360 --> 01:25:50.960] But Peter, aren't people that have an APOE4 allele more likely to be prescribed statins based on their LDL particle number by their physician?
[01:25:50.960 --> 01:25:53.760] Because the physician doesn't look at their none of this.
[01:25:53.760 --> 01:25:54.640] This isn't personalized.
[01:25:54.640 --> 01:25:55.920] It's not medicine 3.0, right?
[01:25:56.480 --> 01:25:56.880] Yep.
[01:25:56.880 --> 01:25:58.320] No, it's very frustrating.
[01:25:58.800 --> 01:26:05.720] And it's also frustrating that of those three drugs that are an alternative to statins, two of them are still very expensive.
[01:26:06.280 --> 01:26:09.400] Okay, so the three drugs, I know the PCSK9 inhibitor.
[01:26:09.400 --> 01:26:09.880] Yep.
[01:26:10.920 --> 01:26:18.920] Highly effective, insanely safe, zero side effects, cheaper than when they came out.
[01:26:18.920 --> 01:26:21.480] So they were approved in 2015.
[01:26:21.880 --> 01:26:25.640] And we have long-term data with the people walking around with a natural mutation, right?
[01:26:26.200 --> 01:26:27.000] Just amazing.
[01:26:27.000 --> 01:26:27.640] Yeah, exactly.
[01:26:27.640 --> 01:26:29.000] We have the natural experiment.
[01:26:29.000 --> 01:26:31.480] We have all of the data from these drugs.
[01:26:31.800 --> 01:26:39.160] And these drugs have been tested in really good trials, and they've gone head to head with every drug, and they always win, and there's no side effects.
[01:26:39.400 --> 01:26:40.440] But they're expensive, right?
[01:26:40.600 --> 01:26:43.960] It's a $500 a month drug in the United States.
[01:26:43.960 --> 01:26:46.680] It's cheaper outside of this country, so everything's better out of the U.S.
[01:26:46.680 --> 01:26:47.960] when it comes to drug pricing.
[01:26:47.960 --> 01:26:53.560] But in the U.S., you're talking about $500 a month for that drug if it's not covered by your insurance company.
[01:26:53.560 --> 01:26:54.200] Right.
[01:26:54.760 --> 01:26:58.120] And if you can get a doctor to say, I'm going to prescribe it to you.
[01:26:58.120 --> 01:26:58.520] I mean, like.
[01:26:58.920 --> 01:27:06.120] I mean, at this point, a doctor who's not willing to prescribe a PCSK9 inhibitor just is a fool.
[01:27:07.080 --> 01:27:23.240] So it's just a question of the cost, because unfortunately, most insurance companies will not cover it unless you meet certain criteria, such as having familial hypercholesteromia or having already had a cardiac event, like a heart attack, and not being able to tolerate a statin.
[01:27:23.240 --> 01:27:24.360] Or what about myopathy?
[01:27:24.360 --> 01:27:25.640] Like if you have muscle.
[01:27:25.800 --> 01:27:25.960] Yes.
[01:27:26.120 --> 01:27:32.600] Significant myopathy on multiple statins, but you'd also have to be at high enough risk to justify it.
[01:27:32.600 --> 01:27:35.400] So, insurance companies are going to go out of their way to not pay for this.
[01:27:36.200 --> 01:27:37.560] Then you have azetamib.
[01:27:37.640 --> 01:27:40.280] Now, azetamib is relatively inexpensive.
[01:27:40.280 --> 01:27:42.120] It's just not as potent.
[01:27:42.120 --> 01:27:50.000] So, azetamib also effectively serves to increase the LDL receptors on the liver, but it does so by impairing cholesterol reabsorption.
[01:27:50.080 --> 01:27:54.000] So, it blocks one of those two transporters I was talking about in the gut, the first one.
[01:27:54.000 --> 01:28:05.520] And by blocking that, the body is absorbing way less of its own cholesterol, and the liver senses that, and the liver says, Hey, I got to get more cholesterol, puts more LDL receptors on, pulls it out of circulation.
[01:28:06.800 --> 01:28:08.160] It's not as potent.
[01:28:08.160 --> 01:28:19.360] And as a monotherapy, the only times we see really head-over-heels responses are in patients who have defective ATP binding cassettes in their gut.
[01:28:19.360 --> 01:28:23.600] And we measure that by looking at phytosterol levels.
[01:28:23.600 --> 01:28:28.720] So, we measure two things: one is called cytosterol, one is called compesterol.
[01:28:28.720 --> 01:28:29.840] Those are phytosterols.
[01:28:29.840 --> 01:28:32.000] So, these are cholesterol we don't make.
[01:28:32.000 --> 01:28:33.520] It's zoosterol.
[01:28:33.680 --> 01:28:36.000] Pardon me, it's phytosterol, not zoosterol.
[01:28:36.000 --> 01:28:45.360] And so, when we measure those levels, we know that it speaks to how much plant sterol is being absorbed and not being excreted.
[01:28:45.360 --> 01:28:53.520] And so, when patients have really, really high levels of phytosterols, you know they have a defective ATP binding cassette.
[01:28:53.520 --> 01:28:57.120] And those patients respond really well to azetamib.
[01:28:57.520 --> 01:28:59.440] It's like a blockbuster in those people.
[01:28:59.440 --> 01:29:00.080] Wow.
[01:29:00.080 --> 01:29:04.320] Is that a common, you know, single nucleotide polymorphism?
[01:29:05.920 --> 01:29:08.800] You know, it depends how extreme it is.
[01:29:08.800 --> 01:29:24.960] So, it's not uncommon to see people who are above the 90th percentile, but I've only seen like probably three people that have a level that is so high you'd actually be concerned with it, just in and of itself.
[01:29:24.960 --> 01:29:29.400] Meaning, like the actual level, because phytosterols are actually more atherogenic than cholesterol.
[01:29:28.960 --> 01:29:33.560] And that's also like Boston Hart measured all these phytosterols.
[01:29:29.120 --> 01:29:34.120] Okay.
[01:29:35.000 --> 01:29:37.240] They're more atherogenic than cholesterol.
[01:29:37.240 --> 01:29:37.720] Yeah.
[01:29:38.040 --> 01:29:41.160] They're more prone to oxidation, more inflammatory.
[01:29:41.160 --> 01:29:43.800] Are they being carried in lipoproteins?
[01:29:43.800 --> 01:29:46.680] They're oxidized.
[01:29:46.680 --> 01:29:47.480] Are they oxidized?
[01:29:47.480 --> 01:29:48.440] They're more oxidized?
[01:29:48.440 --> 01:29:49.400] They're more oxidizable.
[01:29:49.400 --> 01:29:55.800] And this is, by the way, is a reason that we don't favor the practice of using phytosterols to lower cholesterol.
[01:29:55.800 --> 01:30:01.880] So there are a lot of sort of over-the-counter treatments where people use phytosterols to lower their cholesterol.
[01:30:01.880 --> 01:30:03.080] And it does.
[01:30:03.400 --> 01:30:17.160] So if you ingest a ton of phytosterols, you will out-compete cholesterol at that enterocyte, and your body will regulate, and you'll end up net reabsorbing less total cholesterol.
[01:30:18.280 --> 01:30:29.000] The problem with that is if you have a defective ATP binding cassette, which again, it's not that uncommon that you do, you will end up really absorbing a lot of those phytosterols.
[01:30:29.000 --> 01:30:40.840] And again, so this is sort of an example of that desmosterol point earlier where you can lower cholesterol, but if you're really raising desmosterol too much, it can be more atherogenic than cholesterol in the first place.
[01:30:40.840 --> 01:30:42.760] So desmosterol has shown up twice today.
[01:30:42.760 --> 01:30:45.320] It showed up in a good sense and in a bad sense.
[01:30:45.320 --> 01:30:54.120] So too much of it, if you're using a drug that blocks the enzyme that comes after it, that was the thing that was producing too much atherosclerosis in the 60s.
[01:30:54.120 --> 01:31:03.000] Too little of it could be a marker of too little cholesterol synthesis in the brain, and that can be a whole problem in and of itself.
[01:31:03.000 --> 01:31:12.040] The final drug, so we can just wrap this up because I'm sure the listeners are tired of hearing about this stuff, is a drug called bempidoic acid that is a pro-drug.
[01:31:12.040 --> 01:31:13.800] So, it's a very elegant drug.
[01:31:13.800 --> 01:31:23.920] It's taken as a pill, but it's ineffective until it's metabolized by the liver, and in the liver, it then inhibits cholesterol synthesis.
[01:31:23.920 --> 01:31:30.320] What makes this drug special is, unlike statins, this drug only works in the liver.
[01:31:30.320 --> 01:31:38.480] So, statins work throughout the body, they do most of their work in the liver, but technically every cell is impacted by a statin.
[01:31:38.480 --> 01:31:41.680] Only hepatocytes are impacted by bempidoic acid.
[01:31:41.680 --> 01:31:43.040] And it lowers APOB.
[01:31:43.360 --> 01:31:43.840] Same way.
[01:31:43.840 --> 01:31:45.200] Lowers cholesterol synthesis.
[01:31:45.280 --> 01:31:53.440] Liver says, I need more cholesterol, puts more LDL receptors up, pulls more LDL in, LDL and cholesterol go down, but no side effects.
[01:31:53.440 --> 01:31:54.560] No type 2 diabetes.
[01:31:54.720 --> 01:31:55.360] Nothing.
[01:31:55.520 --> 01:31:56.560] Nothing, nothing.
[01:31:56.560 --> 01:31:59.360] It's just, it's only acting in the liver.
[01:31:59.680 --> 01:32:03.280] Well, that sounds same problem as PCSK9 inhibitor.
[01:32:03.280 --> 01:32:05.440] It's a $500 a month drug.
[01:32:05.440 --> 01:32:06.000] Okay.
[01:32:06.000 --> 01:32:06.560] Yep.
[01:32:06.560 --> 01:32:08.880] So, again, we'd have every.
[01:32:09.200 --> 01:32:17.600] Look, honestly, at this point, like, if money were no issue, you'd probably just be on PCSK9 inhibitors, azetamib, and bempidoic acid.
[01:32:17.600 --> 01:32:19.040] I mean, eventually we'll get there, right?
[01:32:19.040 --> 01:32:20.800] Yeah, we just have to come down in price.
[01:32:21.120 --> 01:32:34.080] For people that want a more clear picture of the plaque accumulation in their arteries and their vascular system, the best way to do it, I think I've heard about CT angiogram.
[01:32:34.080 --> 01:32:34.480] Okay.
[01:32:34.480 --> 01:32:43.520] And is that something, you know, like you think people should start at a certain age, or certainly if they have measured their, you know, APOB?
[01:32:43.920 --> 01:32:46.800] Yeah, I mean, you know, I think there's different ways to think about this.
[01:32:47.280 --> 01:32:58.280] You know, I think there's a principle in medicine that most doctors try to adhere to, which is don't order a test unless there's a chance the test will change your management.
[01:33:00.040 --> 01:33:01.800] And it's easy to deviate from that.
[01:32:57.920 --> 01:33:03.160] I certainly know I do at times.
[01:33:03.560 --> 01:33:11.560] But as a general rule, I try to ask myself the question: before I order this test, how will the outcome change what I do with this patient?
[01:33:11.560 --> 01:33:24.600] So through that lens, you could make a case that the only time you should be ordering a CT angiogram is if you go through the following experiment, which is, if it comes back normal, how will it change what I do?
[01:33:24.600 --> 01:33:28.280] If it comes back abnormal, how will it change what I do?
[01:33:28.280 --> 01:33:45.960] So if you were sitting in my office and I said, well, look, Rhonda, you're 35 years old, your APO B is really high, your family history is such that people get cardiovascular disease in your family, meaning, you know, it's not like you've got a bunch of relatives who are in their 90s who have never had a cardiac event.
[01:33:45.960 --> 01:33:49.880] So you don't have some genetic protection of cardiovascular disease.
[01:33:50.360 --> 01:33:53.880] Do I need a CT angiogram in you to convince me to do anything?
[01:33:53.880 --> 01:33:57.960] Because the truth of it is at 35, your CT angiogram is going to be normal.
[01:33:57.960 --> 01:33:58.920] I mean, it might not be.
[01:33:58.920 --> 01:34:03.880] Mine wasn't at 35, but it probably will be for most people.
[01:34:04.200 --> 01:34:08.200] And if it's normal, will I then say we don't need to do anything about this?
[01:34:08.200 --> 01:34:12.680] No, because that's sort of like saying you're a smoker who has a normal CT scan.
[01:34:12.680 --> 01:34:15.160] You don't yet have lung cancer, therefore we should let you keep smoking.
[01:34:15.160 --> 01:34:16.680] No, we should stop you from smoking.
[01:34:16.680 --> 01:34:21.160] So in other words, I just wouldn't have a huge appetite for doing that test in you.
[01:34:21.480 --> 01:34:34.680] There are other patients at the other end of the spectrum where, you know, they come to me, they're 75 years old, their APO B is through the roof, but I notice like all their relatives live to be 100 and they never had heart disease.
[01:34:34.680 --> 01:34:40.360] And I look at them and I think, do I really want to put this person on lipid-lowering medicine at the age of 75?
[01:34:40.680 --> 01:34:42.520] Why don't we do a CTA?
[01:34:42.520 --> 01:34:48.480] If the CTA is normal, which by some miracle is not a very important thing, I don't think we need to do something.
[01:34:48.480 --> 01:34:54.160] There's clearly something this person has going on that is beyond our understanding of the science so far.
[01:34:54.160 --> 01:34:57.360] So in that sense, I wouldn't do anything about it.
[01:34:57.360 --> 01:35:05.680] The way I think about it is there's a two by two, which is age versus finding, positive or negative.
[01:35:05.680 --> 01:35:13.280] I think CT angiograms are mostly helpful when they have a positive finding in a young person or a negative finding in an old person.
[01:35:13.280 --> 01:35:17.280] That's where it can really cause you to act differently.
[01:35:17.280 --> 01:35:24.000] Outside of those findings, i.e., positive findings in old people are to be expected, negative findings in young people are to be expected.
[01:35:24.000 --> 01:35:28.160] I think you should just track the biomarkers of interest and go off that risk.
[01:35:28.160 --> 01:35:28.800] Okay.
[01:35:29.120 --> 01:35:31.200] I mean, like, is a 45-year-old considered?
[01:35:31.520 --> 01:35:32.880] I would still put that in the young category.
[01:35:32.880 --> 01:35:33.040] Okay.
[01:35:33.040 --> 01:35:39.280] So you think that CT angiogram would still kind of look maybe good?
[01:35:39.600 --> 01:35:40.240] It should.
[01:35:40.240 --> 01:35:44.480] And again, I would only think about it through the lens of if the patient is hesitant.
[01:35:44.880 --> 01:35:48.560] Like, so we had a new patient, you know, that started a couple of weeks ago.
[01:35:48.560 --> 01:35:51.280] He'd never had one of these tests before.
[01:35:52.560 --> 01:35:54.240] But he had a lot of risk factors, right?
[01:35:54.240 --> 01:35:57.680] Elevated Apo B, elevated LP little A.
[01:35:57.680 --> 01:35:59.680] I mean, two big risk factors.
[01:35:59.680 --> 01:36:04.800] And but insanely healthy individual, like very, very healthy individual.
[01:36:04.800 --> 01:36:08.640] So on the surface, like nobody thought anything of this person.
[01:36:10.720 --> 01:36:14.000] We decided we were going to treat him regardless, and he was completely on board with that.
[01:36:14.000 --> 01:36:16.880] But the question was, how aggressively, would we treat?
[01:36:16.880 --> 01:36:19.680] And we said, let's let the CTA decide that.
[01:36:19.680 --> 01:36:29.120] If the CTA comes back clean as a whistle, we're going to treat you to like an ApoB of 60, which is still aggressive by most people's standards.
[01:36:29.120 --> 01:36:31.320] By our standards, it's sort of middle-of-the-road aggression.
[01:36:31.640 --> 01:36:39.080] If the CTA comes back and there's a problem, meaning you have calcification and soft plaque, we're going to treat you to 30 or 40.
[01:36:39.080 --> 01:36:43.800] So there, the CTA helped us make a difference, a real treatment difference.
[01:36:43.800 --> 01:36:47.800] And this is a person who's, you know, middle-aged, so not too old, not too young.
[01:36:47.800 --> 01:36:49.080] That makes a lot of sense.
[01:36:49.640 --> 01:36:54.200] Before we, you know, kind of shift gears a little to some other things I want to ask you about.
[01:36:55.720 --> 01:36:56.520] Have you looked?
[01:36:56.520 --> 01:37:01.000] Like, I know you've mentioned, it's been many years since I've heard you talk about berberine.
[01:37:01.000 --> 01:37:08.120] But I, you know, every once in a while, I'll get a question and I decide, I want to dive into literature and see if there's anything new, right?
[01:37:08.120 --> 01:37:09.800] So that happened recently.
[01:37:09.800 --> 01:37:21.240] My team and I did a deep dive into berberine and its effect on clearing away existing plaque, on lowering, you know, LDL particle number, possibly total LDL cholesterol level.
[01:37:21.240 --> 01:37:22.680] But I was surprised.
[01:37:22.680 --> 01:37:23.720] Yeah, what did you find?
[01:37:23.720 --> 01:37:29.480] So there was a systematic review, and it was 2022, I believe.
[01:37:30.280 --> 01:37:33.400] And these are all like, we need, this is the sparse data, right?
[01:37:33.400 --> 01:37:37.480] A systematic review of what the existing literature was, which isn't a huge body of evidence.
[01:37:37.480 --> 01:37:48.680] But so there was a bunch of studies that looked at berberine and varying doses and then looking at it in conjunction with statins or comparing it to statins or comparing it to epilecebo.
[01:37:49.000 --> 01:37:54.680] And it pretty much, to me, was convincing that it was beneficial in every single scenario.
[01:37:54.680 --> 01:37:59.240] So berberine alone was lowering the LDL cholesterol.
[01:37:59.240 --> 01:38:02.200] And I can't remember if it was particle number, but it was LDL.
[01:38:02.360 --> 01:38:05.640] And it's interesting, berberine is also a mitochondrial toxin.
[01:38:05.640 --> 01:38:06.360] Really?
[01:38:06.360 --> 01:38:06.760] Yeah.
[01:38:06.760 --> 01:38:09.600] Berberine is an analog of metformin.
[01:38:09.320 --> 01:38:10.080] So.
[01:38:10.360 --> 01:38:11.960] So it's a complex one inhibitor.
[01:38:11.960 --> 01:38:12.440] Is it?
[01:38:12.440 --> 01:38:12.920] Really?
[01:38:13.240 --> 01:38:13.720] Wow.
[01:38:13.720 --> 01:38:14.880] I didn't know that.
[01:38:15.120 --> 01:38:18.080] It was like, it was to me looking really beneficial where it was like.
[01:38:14.200 --> 01:38:19.600] I'm not saying that wouldn't be.
[01:38:19.760 --> 01:38:21.040] I'm just sort of pointing out.
[01:38:14.440 --> 01:38:21.600] It's interesting.
[01:38:21.920 --> 01:38:23.120] Is there literature showing that?
[01:38:23.120 --> 01:38:26.400] Or is it like an in vitro kind of thing where it's like I don't remember?
[01:38:26.400 --> 01:38:32.640] It's been so long since I've looked at berberine, but berberine is kind of a poor man's metformin.
[01:38:32.640 --> 01:38:32.880] Okay.
[01:38:32.880 --> 01:38:34.800] Well, it was, and that's the way I thought about it.
[01:38:34.800 --> 01:38:38.080] I think I'd heard you talk about it years ago, maybe on Tim's podcast.
[01:38:38.080 --> 01:38:38.720] I don't remember.
[01:38:38.720 --> 01:38:39.600] It was a long time ago.
[01:38:40.000 --> 01:38:42.720] And that's kind of where I even first heard of berberine, was you.
[01:38:43.040 --> 01:38:45.040] And I remember because I was like going for a run.
[01:38:45.040 --> 01:38:47.840] It was when I lived in Oakland, and then I was like, berberine, what's that?
[01:38:47.840 --> 01:38:51.840] And I remember you talking about it in the context of, I think, metabolic health.
[01:38:51.840 --> 01:38:52.080] Yep.
[01:38:52.080 --> 01:38:52.560] Yep.
[01:38:52.560 --> 01:38:54.320] And kinase or something.
[01:38:54.400 --> 01:38:55.520] It should inhibit the global case.
[01:38:55.760 --> 01:38:58.240] But this data on the lipids was very interesting.
[01:38:58.240 --> 01:38:58.720] And I linked it to the list.
[01:38:58.880 --> 01:39:01.120] And what was the magnitude of effect?
[01:39:01.360 --> 01:39:02.320] I don't like you.
[01:39:03.520 --> 01:39:04.240] It's in that document.
[01:39:04.240 --> 01:39:04.880] It's linked.
[01:39:05.280 --> 01:39:06.720] The studies, the meta-analysis.
[01:39:06.720 --> 01:39:08.800] So you can look at it because I don't remember everything.
[01:39:09.440 --> 01:39:15.040] But what I do know is it also lowered the side effects of statin myopathy was one in particular.
[01:39:15.360 --> 01:39:21.600] It lowered the dose, effective dose of statins that was needed to lower the LDL cholesterol.
[01:39:21.600 --> 01:39:22.480] Very interesting, right?
[01:39:22.480 --> 01:39:26.720] And so I was like, you know, I actually ordered some berberine.
[01:39:26.720 --> 01:39:30.400] I'm like, maybe I should test this and see, you know, and it's there.
[01:39:30.400 --> 01:39:31.760] There are companies like Thorn and that.
[01:39:32.240 --> 01:39:33.040] I ordered Thorn.
[01:39:33.040 --> 01:39:34.800] Yeah, yeah, which I have no affiliation with.
[01:39:34.800 --> 01:39:36.080] I just trust their brain.
[01:39:36.160 --> 01:39:36.480] Yeah.
[01:39:36.480 --> 01:39:42.720] So, anyways, I wanted to bring that up because, you know, I know that, again, I'd heard a berberine from you like years ago.
[01:39:43.040 --> 01:39:56.160] But speaking of metabolic health, and you kind of talked about this, you know, earlier with with continuous glucose monitoring and you know measuring um you know measuring your your fasting glucose and also, you know, your response to foods.
[01:39:56.160 --> 01:41:33.360] And so, like, what, you know, glucose disposal is something that you've talked about people always hear about you know fasting glucose hb a1c like what what should those numbers be but also what is glucose disposal and why should people be paying attention to that and can cgms can they use cgms to sort of measure that yeah yeah um you know glucose disposal is is is is let's take a step back glucose regulation is just it's such a miracle of our physiology i mean there's every time i think about biology i'm really grateful that i've you know came to this field in one way or another because it's it leaves you endlessly uh at awe of what's happening so the the interplay between our endocrine system our liver our muscles in terms of how glucose is regulated is so complicated and exists on such a fine fine line that uh it is it is humbling so let's just put some of these numbers in perspective so most people who have had a blood test would recognize that a fasting blood glucose of 100 milligrams per deciliter is sort of right on the cusp of being just starting to get to be too high so what does that mean right what is 100 milligrams per deciliter well it means that in you know someone my size in all of my plasma floating around all of my body all of my blood i have five grams of glucose so do i have more than five grams of glucose in my body of course i do i have way more than that but the majority of the glucose in my body is either in my liver or in my muscles.
[01:41:33.360 --> 01:41:41.840] There's only five paltry grams, 20 calories worth of glucose in my entire circulation at this moment in time.
[01:41:41.840 --> 01:41:57.760] Now, if you assume for a moment that i'm just sitting here at rest and nothing in my body is demanding glucose, meaning my muscles aren't requiring it, the only organ that should be really demanding it at the moment is my brain.
[01:41:57.760 --> 01:42:02.960] Now, of course, my red blood cells demand it because they don't have mitochondria, so they're going to have to use glucose.
[01:42:03.200 --> 01:42:05.920] And of course, the kidney uses it and all sorts of other things.
[01:42:05.920 --> 01:42:14.800] But basically, the majority of the glucose in my bloodstream at this moment in time is being is there for the purpose of my brain.
[01:42:15.120 --> 01:42:18.320] And, you know, you can do the math on this.
[01:42:18.320 --> 01:42:19.840] Anybody can do the math on this.
[01:42:19.840 --> 01:42:24.800] Within a number of minutes, I will go through that five grams.
[01:42:24.800 --> 01:42:28.800] So where does the next drop of glucose come from?
[01:42:28.880 --> 01:42:30.400] Comes from my liver.
[01:42:30.400 --> 01:42:46.080] So my liver is constantly titrating just a little bit of glucose into my circulation to make sure that number never goes from, say, 100, where it is now, down to 50, because that would be way too low.
[01:42:46.080 --> 01:42:51.600] But it's never putting so much in that that number would be 150 or 200.
[01:42:51.600 --> 01:42:55.680] At that point, I would be full-fledged type 2 diabetes.
[01:42:55.680 --> 01:43:08.000] So the difference between you and me, if I have type 2 diabetes, is literally a teaspoon of glucose in our circulation at any point in time.
[01:43:08.000 --> 01:43:12.000] Think about how tiny a difference that is.
[01:43:12.320 --> 01:43:20.080] And that speaks to this enormous capacitor and buffer system of our liver and our muscles.
[01:43:20.080 --> 01:43:34.520] So if the liver is the thing that is responsible for the doling out of glucose into circulation, the muscle is primarily responsible for where we put glucose when it gets flooded into our system.
[01:43:34.520 --> 01:43:36.600] And that happens every time you eat.
[01:43:36.600 --> 01:43:40.600] So you eat, and again, let's just do some easy math on this.
[01:43:40.600 --> 01:43:47.320] Like you eat a bowl of pasta, like not a Peter bowl, which is like the size of my head, but just a normal size bowl.
[01:43:47.320 --> 01:43:51.320] You're easily getting 60 grams of glucose.
[01:43:51.640 --> 01:43:55.800] So you eat 60, 70, 80 grams of glucose.
[01:43:55.800 --> 01:43:57.720] Well, remember what I just said a moment ago.
[01:43:57.720 --> 01:44:03.480] Like if your blood level goes from five to 10 grams, you're hosed.
[01:44:03.480 --> 01:44:05.320] Like that's a really big problem.
[01:44:05.320 --> 01:44:07.720] Now, acutely, it's not the end of the world, right?
[01:44:08.040 --> 01:44:15.000] But a healthy person would probably never go from five to eight, more than eight grams.
[01:44:15.000 --> 01:44:19.560] So how do you get that other 60 grams of glucose away?
[01:44:19.560 --> 01:44:21.640] You have to put that into the muscles.
[01:44:21.640 --> 01:44:25.720] And so the muscle is the sink for glucose disposal.
[01:44:25.720 --> 01:44:32.200] And there are two ways that that happens, but the majority of it is an insulin-dependent way.
[01:44:32.200 --> 01:44:37.800] So insulin is released by the pancreas when glucose levels are sensed.
[01:44:37.800 --> 01:44:42.040] So the pancreas sits very high in the GI tract.
[01:44:42.360 --> 01:44:56.920] So very early in the absorption of glucose as it exits the stomach into the duodenum, does the endocrine system, vis-a-vis the beta cells, sense this increase in glucose.
[01:44:56.920 --> 01:44:58.600] The beta cells release insulin.
[01:44:58.600 --> 01:45:01.720] The insulin results in a signal.
[01:45:01.720 --> 01:45:02.520] It goes to the muscle.
[01:45:02.520 --> 01:45:04.840] So the insulin hits an insulin receptor.
[01:45:04.840 --> 01:45:16.960] The insulin receptor triggers a kinase in a cell, and that brings a glucose transporter to the surface of a muscle cell so that passively, right, without a gradient, glucose can flow from outside the cell to inside the cell.
[01:45:16.960 --> 01:45:20.480] So that's called insulin-dependent glucose disposal.
[01:45:20.480 --> 01:45:33.280] In a person who's particularly fit, there's also an insulin-independent system where just the contractile aspect of the muscle itself is enough to get glucose transporters up to the surface of the muscle.
[01:45:33.280 --> 01:45:45.280] So people who do a lot of cardio training have this capacity to, you know, and I've seen this in patients with type 1 diabetes who do a lot of training, because that's a pure experiment where you have no insulin.
[01:45:45.280 --> 01:45:50.720] You can actually see them lower their glucose without insulin just by exercising.
[01:45:50.720 --> 01:45:58.880] So the act of exercising itself can produce glucose transport across the muscle without insulin.
[01:45:58.880 --> 01:46:01.040] So how does all this figure into health?
[01:46:01.040 --> 01:46:05.200] Well, as we alluded to, glucose is toxic when you have too much of it.
[01:46:05.200 --> 01:46:07.120] Now, I'm not going to talk about acute toxicity.
[01:46:07.120 --> 01:46:15.760] So if you ever walked around with like 40 teaspoons of blood, 40 teaspoons of glucose in your bloodstream, you would go into a coma.
[01:46:15.760 --> 01:46:23.760] So there's an acute toxicity, but luckily that's very, very rare and only really would occur in somebody with ketoacidosis.
[01:46:24.560 --> 01:46:30.320] But the chronic toxicity of elevated levels of glucose is significant.
[01:46:30.320 --> 01:46:45.440] And that's where the difference between having four, five, six, seven, eight grams of glucose as the benchmark concentration is a difference in 10 years of life expectancy.
[01:46:45.760 --> 01:46:50.960] And again, like it seems hard to fathom that that makes such a difference, but it does.
[01:46:50.960 --> 01:46:52.880] And it does for several reasons.
[01:46:52.880 --> 01:47:04.520] But one of them is that glucose is involved in the process by which proteins become sticky.
[01:46:58.960 --> 01:47:16.120] And so as the proteins in our blood get glycosylated and get stickier, one, their function is lower, but two, they also tend to obscure the narrowest part of our vascular system.
[01:47:16.120 --> 01:47:24.920] So the tiniest, tiniest, tiniest capillaries become more occluded, and therefore it's harder to deliver oxygen to those tissues.
[01:47:24.920 --> 01:47:32.040] So the canary in the coal mine, believe it or not, of microvascular damage is within the eyes.
[01:47:32.040 --> 01:47:40.360] So a good ophthalmologist is generally the first doctor to tell when a person is on the road to type 2 diabetes.
[01:47:40.360 --> 01:47:49.320] Because by looking at the retina and by looking at the capillaries in the back of the eye, they're actually able to do something that no one else gets to do in the body, right?
[01:47:49.320 --> 01:47:53.800] Like we don't look directly at the vascular system elsewhere in the body.
[01:47:53.800 --> 01:47:54.760] And they get to do that.
[01:47:54.760 --> 01:47:58.040] They get to shine a light directly onto those capillary beds.
[01:47:58.040 --> 01:48:05.560] So as a general rule, elevated levels of glucose are damaging to small vessels.
[01:48:05.560 --> 01:48:10.360] Elevated levels of insulin are damaging to large blood vessels.
[01:48:10.360 --> 01:48:21.160] So the eyes, the kidneys, the microvasculature of the heart and the brain are very susceptible to high levels of glucose.
[01:48:21.160 --> 01:48:30.920] The larger blood vessels of the heart, the aorta, the iliac vessels, carotid arteries, more susceptible to the elevated levels of insulin.
[01:48:30.920 --> 01:48:40.200] And both of these things go hand in hand because, of course, as is obvious, I guess, to people now, when those glucose levels are chronically elevated, the body wants to fix it.
[01:48:40.440 --> 01:48:44.880] It wants to crank up more insulin as the solution to the resistance.
[01:48:43.800 --> 01:48:49.280] So the resistance is at the cell where the insulin signal isn't being heard.
[01:48:49.600 --> 01:48:53.360] So the pancreas just yells louder and it makes more and more insulin.
[01:48:53.360 --> 01:48:59.680] And so before you see that elevated level of glucose, you will actually see an elevated level of insulin.
[01:48:59.680 --> 01:49:05.440] So post-prandial hyperinsulinemia is the metabolic harbinger of all this stuff.
[01:49:06.400 --> 01:49:14.320] And so the major, obviously, it seems like a lifestyle factor that is regulating, you know, glucose disposal, insulin sensitivity.
[01:49:14.320 --> 01:49:20.960] I mean, it seems like both of these things are affected by the contractions of muscle and increasing those glucose transporters, right?
[01:49:21.440 --> 01:49:27.280] Exercise is probably the single most important thing we have at our disposal to increase insulin sensitivity.
[01:49:27.280 --> 01:49:29.760] And then there are other things that are very important, right?
[01:49:29.760 --> 01:49:32.160] So energy balance really matters.
[01:49:32.160 --> 01:49:33.600] Sleep really matters.
[01:49:33.600 --> 01:49:37.840] So both acute and chronic disruptions of sleep will impair that system.
[01:49:37.840 --> 01:49:39.600] It's not entirely clear why, by the way.
[01:49:39.600 --> 01:49:41.440] The experimental evidence is undeniable.
[01:49:41.440 --> 01:49:45.680] And these are experiments that are so easy to do well that they're unambiguous, right?
[01:49:45.680 --> 01:49:47.280] Where you disrupt people's sleep.
[01:49:47.280 --> 01:50:09.520] You know, you take, if you just took a normal group of people and you did like what's called a euglycemic insulin clamp, which is an experiment where you run IV glucose and IV insulin into people, and you basically run a fixed amount of insulin into somebody and then determine how much glucose you need to put in to keep their glucose level fixed.
[01:50:09.520 --> 01:50:12.240] That's called a euglycemic, keep glucose fixed.
[01:50:13.120 --> 01:50:16.080] That's the gold standard for measuring insulin sensitivity.
[01:50:16.080 --> 01:50:27.360] So you do that test on somebody, and then for a week, sleep deprive them for, you know, down to five or six, four hours a night, call it four, four would be very dramatic.
[01:50:27.680 --> 01:50:35.560] Within days, you'll see like a 50% reduction in their ability to dispose of glucose with no other difference, no dietary difference, no exercise difference.
[01:50:35.560 --> 01:50:40.040] So we don't know exactly why that's happening, but it's a very repeatable observation.
[01:50:40.040 --> 01:50:42.280] So sleep disruptions impair this.
[01:50:43.080 --> 01:50:45.640] Energy imbalance impairs this.
[01:50:45.640 --> 01:50:48.120] Hormonal changes impair this, right?
[01:50:48.120 --> 01:50:53.240] So as we age, both the reduction in estrogen and testosterone impair this.
[01:50:53.240 --> 01:50:56.120] Hypercortisolemia impairs this.
[01:50:56.440 --> 01:51:00.600] And then, of course, inactivity is the greatest thing that drives this.
[01:51:00.920 --> 01:51:05.720] I definitely didn't do the exact experiment you're describing, but I've mentioned it to you before.
[01:51:05.720 --> 01:51:11.880] I had my CGM, and when I was a new mother, it was, you know, clearly my sleep was being disrupted.
[01:51:11.880 --> 01:51:13.400] I was getting up and breastfeeding.
[01:51:13.400 --> 01:51:22.280] And, you know, I mean, it was like night and day difference in my fasting blood glucose, my glucose disposal, my postprandial levels.
[01:51:22.280 --> 01:51:25.560] I mean, it was like, we would have asked you to take that CGM off.
[01:51:25.800 --> 01:51:27.960] That would be an awful time to wear a CGM.
[01:51:27.960 --> 01:51:37.960] But I did find that my going to my HIIT class, even though I was like just dogged tired, like the last thing I wanted to do really did normalize it.
[01:51:37.960 --> 01:51:47.640] So is there a postprandial level that like, you know, let's say someone's not trying to do a low-carb diet, like they're not trying to like, because that's a whole other area, right?
[01:51:47.640 --> 01:51:56.200] But like they just, you know, they're eating maybe a more omnivore diet, more paleo-ish or Mediterranean-ish, right?
[01:51:56.520 --> 01:52:04.440] Is there a level that you think post-perennial, you know, glucose levels, like a threshold that would signal, like, oh, well, you shouldn't really be going or.
[01:52:04.440 --> 01:52:05.400] It's hard to say.
[01:52:05.400 --> 01:52:10.920] I mean, here's what I think we know more clearly.
[01:52:11.640 --> 01:52:17.600] We certainly know with more conviction that the average blood glucose, the lower it is, the better you are.
[01:52:14.920 --> 01:52:20.000] And I say that even outside of diabetic range.
[01:52:20.160 --> 01:52:28.240] Now, I don't have level one data to tell you that because the study's never been done, but I can tell you that by proxy based on hemoglobin A1C data.
[01:52:28.240 --> 01:52:35.200] So the hemoglobin A1C data make it very clear that lower is better even outside of the range of diabetes.
[01:52:35.200 --> 01:52:39.920] So diabetes is defined as a hemoglobin A1C above 6.5%.
[01:52:39.920 --> 01:52:49.040] That translates, 6.5% is an estimate of an average blood glucose of 140 milligrams per deciliter.
[01:52:49.360 --> 01:53:02.160] So assume for a moment that if you have a CGM that says 6.5%, meaning you just trigger the threshold for type 2 diabetes, your CGM would say your average blood glucose is 140 milligrams per deciliter.
[01:53:02.480 --> 01:53:04.320] Nobody disputes that that's harmful.
[01:53:04.320 --> 01:53:10.480] The question is: is it better to be at 130, 120, 110, 100?
[01:53:10.480 --> 01:53:16.000] Like, at what point does is it too low?
[01:53:16.320 --> 01:53:33.520] And what the hemoglobin A1C data would suggest is being at 5%, which is about an average of 100, is better than being at 5.5%, which is an average in the one teens.
[01:53:33.840 --> 01:53:37.760] Both of those are normal by our current definitions.
[01:53:37.760 --> 01:53:41.120] Neither of those would be pre-diabetic, even.
[01:53:41.120 --> 01:53:45.360] So 5 and 5.5 are both considered completely normal levels.
[01:53:45.360 --> 01:53:53.800] But the all-cause mortality data, or the data on all-cause mortality, suggests a better outcome if you're at 5 rather than 5.5.
[01:53:53.440 --> 01:53:54.040] Okay.
[01:53:54.320 --> 01:54:05.800] That suggests to me, by proxy at least, that an average blood glucose of 100 on a CGM would be better than that of an average blood glucose of 115.
[01:54:06.120 --> 01:54:09.640] So that's the single most important metric we care about.
[01:54:09.640 --> 01:54:12.520] We use other metrics to think about that.
[01:54:12.520 --> 01:54:32.680] So that since we can't measure insulin in real time, looking at post-prandial spikes and variability, so looking at the standard deviation, which you can get off the CGM, and just the number of times you exceed a threshold, and that threshold, you could say, maybe make it 150 or 140 milligrams per deciliter.
[01:54:32.680 --> 01:54:36.120] And you can just say, how many times in a week do you exceed that threshold?
[01:54:36.120 --> 01:54:42.040] That might give you some indirect proxy of how much insulin are you secreting in response to that.
[01:54:42.040 --> 01:54:58.120] Because, for example, if you took two people who had an average blood glucose of 110 milligrams per deciliter by CGM, but one arrived at it with levels like that and one arrived at it with levels like that, the former would be a better way to achieve that than the latter.
[01:54:58.440 --> 01:55:01.880] But there are lots of things that raise glucose that are not harmful.
[01:55:01.880 --> 01:55:12.040] For example, that HIT class that you were doing probably in the short term really spikes your glucose because your liver is really trying to meet the demands of all that exercise.
[01:55:12.040 --> 01:55:19.800] So it's putting a ton of glucose into your circulation and it's going to do the right thing, which is always err on the side of too much.
[01:55:19.800 --> 01:55:23.160] Because in the short term, it's better to have too much than too little.
[01:55:23.480 --> 01:55:31.800] So if I'm wearing a CGM doing a really hard workout, I mean, I'll see that glucose get to 160, which is higher than it will get with a meal.
[01:55:32.120 --> 01:55:33.240] That goes right back down.
[01:55:34.600 --> 01:55:37.880] So, what do you think about, by the way, this is all great info.
[01:55:37.880 --> 01:55:46.800] What do you think about, so metabolic flexibility, being the capability to shift between using glucose as a substrate and using fatty acids?
[01:55:46.800 --> 01:55:47.920] I mean, this is something.
[01:55:44.760 --> 01:55:49.200] This is the zone two thing, right?
[01:55:49.360 --> 01:55:52.080] This is exactly why we train that zone two system.
[01:55:52.080 --> 01:56:00.080] And that's why, you know, we have our patients spend 80% of their cardio training time in zone two.
[01:56:00.080 --> 01:56:03.120] That's really pushing that metabolic flexibility.
[01:56:04.400 --> 01:56:21.760] This is the training system for making sure you expand the capacity of your mitochondria to, under ever-increasing demands, have the ability to utilize fatty acids for oxidative phosphorylation and glucose for that matter.
[01:56:22.400 --> 01:56:32.480] But if you were to do, let's say you're doing more high-intensity interval training, which I do a lot of, that increases the capacity because it's such a potent stimulator of mitochondrial biogenesis.
[01:56:32.480 --> 01:56:40.720] So maybe, and I and I hesitate to say, like, I think a lot of times when I'm doing my HIIT, I'm still really using my mitochondria.
[01:56:40.720 --> 01:56:46.160] Like, you know, I'm not like doing an all-out sprint, but like, you know, I do shift into using glucose, of course.
[01:56:46.560 --> 01:56:50.720] We just think that only 20% of the cardio training volume should be there.
[01:56:50.720 --> 01:56:55.680] And the reason for that is actually kind of an empirical observation.
[01:56:55.680 --> 01:57:07.680] If you ask the question, who are the most metabolically flexible, healthiest specimens we have on this planet?
[01:57:07.680 --> 01:57:14.800] They are high-level endurance athletes, namely cross-country skiers, distance runners, and cyclists.
[01:57:14.800 --> 01:57:16.560] So, what do we know about this group?
[01:57:16.560 --> 01:57:22.640] We know that they have the highest VO2 maxes of any humans on the planet.
[01:57:22.640 --> 01:57:27.280] And we know that they are the most metabolically flexible of any humans on this planet.
[01:57:27.280 --> 01:57:34.040] Now, my experience is far more with cyclists, and so I usually just talk about this through the lens of a cyclist.
[01:57:35.560 --> 01:57:43.880] And the other thing I like about cycling compared to skiing or running is we can use wattage because we can put people on power meters and we can get the numbers.
[01:57:44.520 --> 01:57:56.200] A world-class cyclist is able to put out four watts per kilogram of power while keeping lactate below two millimole.
[01:57:56.520 --> 01:58:04.520] In fact, the best cyclists in the world are probably at about 4.2, 4.3 watts per kilo.
[01:58:04.520 --> 01:58:10.040] So, let's just do the math on that if someone's listening to this and they've ever been near a power meter.
[01:58:10.040 --> 01:58:24.280] So, if you're 80 kilos, you're 175 pounds, that means you're able to put out 330 to 340 watts, which by the way, most people who weigh 80 kilos can't do that for one minute.
[01:58:24.280 --> 01:58:26.680] Literally, they can't do that for one minute.
[01:58:26.680 --> 01:58:32.600] These people can do it for hours and keep their lactate below two millimole.
[01:58:33.240 --> 01:58:39.880] It's the single greatest demonstration of metabolic flexibility that you will ever see.
[01:58:40.200 --> 01:58:41.960] How do these people train?
[01:58:41.960 --> 01:58:47.560] Because this is, you know, this is one of the questions my patients ask me: Peter, where is this 80-20 coming from?
[01:58:47.560 --> 01:58:49.320] Where is the study that demonstrated this?
[01:58:49.320 --> 01:58:56.360] And I said, Well, the studies are all based on what do you have to do to achieve that level of performance.
[01:58:56.680 --> 01:59:14.520] So, these athletes and their coaches have all figured out that to produce the highest VO2 max and to produce the greatest degree of metabolic flexibility, you think of it as a pyramid, where the base of the pyramid is your zone two efficiency, and the peak of the pyramid is your VO2 max.
[01:59:14.640 --> 01:59:20.000] And the area, total area of the pyramid, is your cardiorespiratory engine.
[01:59:20.000 --> 01:59:25.840] So you want not a narrow base with a high peak, not a wide base with a short peak.
[01:59:25.840 --> 01:59:28.480] You want a big base, big peak.
[01:59:28.480 --> 01:59:31.120] And the way to get that is about 80-20.
[01:59:31.120 --> 01:59:37.600] If you try to do too much high-intensity, you simply don't have the aerobic base on which to build it.
[01:59:37.600 --> 01:59:41.600] So yeah, you might have more mitochondria, but they're not as efficient.
[01:59:41.600 --> 01:59:45.920] If you only do the low-intensity stuff, they're efficient, but you might not have enough.
[01:59:45.920 --> 01:59:49.920] This is a bit of an oversimplification, but you want the best of both worlds, right?
[01:59:50.560 --> 01:59:55.280] You want both the breadth and the peak, effectively.
[01:59:55.280 --> 02:00:01.840] So what we basically do with our patients is we start from a standpoint of time.
[02:00:01.840 --> 02:00:03.920] How much time are you willing to exercise a week?
[02:00:03.920 --> 02:00:05.920] I'm not going to tell you what you need to do.
[02:00:05.920 --> 02:00:08.640] Let's start with you telling me what you're willing to do.
[02:00:08.640 --> 02:00:13.920] And then the simplest approach is we'll put half of that into strength and stability, half of that into cardio.
[02:00:13.920 --> 02:00:16.000] Of the cardio, it's 80-20.
[02:00:16.000 --> 02:00:20.480] 80% of that will be zone 2, 20% of that will be VO2 max.
[02:00:20.480 --> 02:00:28.080] And VO2 max, by the way, training is pretty hard because it's slightly longer intervals than what people think of as traditional hit.
[02:00:28.080 --> 02:00:29.760] So traditional HIT works.
[02:00:29.760 --> 02:00:34.800] I'm just saying, you know, it's not the best way to get there.
[02:00:35.920 --> 02:00:37.360] It's a good way to get there.
[02:00:37.360 --> 02:00:40.000] And we know, like, even just looking at the Tabata studies, right?
[02:00:40.080 --> 02:00:42.640] Tabata is neither one or the other, right?
[02:00:42.640 --> 02:00:54.120] Like a 20 on, 10 off times eight rounds is neither a pure zone two nor it's it's it's way too hard even for vo2 max, actually.
[02:00:54.120 --> 02:01:00.120] Because VO2 max sweet spot is three to eight minutes with one to one-to-one rest to recovery.
[02:01:00.120 --> 02:01:03.240] So, three on, three off, three on, three off.
[02:01:03.480 --> 02:01:06.520] That's a lower intensity than most people are doing in a hit class.
[02:01:06.520 --> 02:01:09.720] Most people in a hit class are doing shorter intervals and pushing much harder.
[02:01:10.200 --> 02:01:20.360] I just had a talk with Marty Cabala, and I asked him that question, you know, and he was like, Rhonda, you got to do more three, because I wanted to, I was like, I want to do VO2 Max training.
[02:01:20.360 --> 02:01:21.560] Like, this is what I do.
[02:01:21.560 --> 02:01:26.760] I do a lot of the, you know, I'll do 16 rounds and I'll do 20 seconds on, 10 seconds off, right?
[02:01:26.760 --> 02:01:30.280] But my 10 seconds off are, I mean, my heart rate's still pretty high.
[02:01:30.280 --> 02:01:41.640] Like, I don't, so he's like, you, you got to do like three minutes, at least one, you know, and so I've shifted my training now to doing, and it's absolutely true.
[02:01:41.640 --> 02:01:43.000] I am not going as hard.
[02:01:43.000 --> 02:01:43.560] You can't.
[02:01:43.560 --> 02:01:46.120] Yeah, it's, you just can't go as hard.
[02:01:46.440 --> 02:01:47.000] And so.
[02:01:47.320 --> 02:01:48.200] And it's an art form.
[02:01:48.360 --> 02:01:55.960] You'll figure it out because you'll realize and you'll, you'll have to, you know, you'll be like, I went too hard and I was dead at a minute and a half.
[02:01:55.960 --> 02:01:58.360] And I was like loafing the last minute and a half.
[02:01:58.360 --> 02:02:00.120] Or I held back too much.
[02:02:00.120 --> 02:02:03.240] And by the end of the three minutes, it was like, oh, I actually could have gone harder.
[02:02:03.240 --> 02:02:03.800] And that's okay.
[02:02:03.800 --> 02:02:06.680] Like, you'll sort of figure out what that sweet spot is.
[02:02:07.640 --> 02:02:16.360] But that three to eight minutes is the optimal zone for generating VO2 max power.
[02:02:16.360 --> 02:02:16.840] Right.
[02:02:16.840 --> 02:02:17.240] Yeah.
[02:02:19.320 --> 02:02:22.120] So metabo

Prompt 6: Key Takeaways

Now please extract the key takeaways from the transcript content I provided.

Extract the most important key takeaways from this part of the conversation. Use a single sentence statement (the key takeaway) rather than milquetoast descriptions like "the hosts discuss...". 

Limit the key takeaways to a maximum of 3. The key takeaways should be insightful and knowledge-additive. 

IMPORTANT: Return ONLY valid JSON, no explanations or markdown. Ensure:
- All strings are properly quoted and escaped
- No trailing commas
- All braces and brackets are balanced
Format: {"key_takeaways": ["takeaway 1", "takeaway 2"]}

Prompt 7: Segments

Now identify 2-4 distinct topical segments from this part of the conversation.

For each segment, identify:
- Descriptive title (3-6 words)  
- START timestamp when this topic begins (HH:MM:SS format)
- Double check that the timestamp is accurate - a timestamp will NEVER be greater than the total length of the audio
- Most important Key takeaway from that segment. Key takeaway must be specific and knowledge-additive.
- Brief summary of the discussion

IMPORTANT: The timestamp should mark when the topic/segment STARTS, not a range. Look for topic transitions and conversation shifts.

Return ONLY valid JSON. Ensure all strings are properly quoted, no trailing commas:
{
  "segments": [
    {
      "segment_title": "Topic Discussion", 
      "timestamp": "01:15:30",
      "key_takeaway": "main point from this segment",
      "segment_summary": "brief description of what was discussed"
    }
  ]
}

Timestamp format: HH:MM:SS (e.g., 00:05:30, 01:22:45) marking the START of each segment.

Prompt 8: Media Mentions

Now scan the transcript content I provided for ACTUAL mentions of specific media titles:

Find explicit mentions of:
- Books (with specific titles)
- Movies (with specific titles)  
- TV Shows (with specific titles)
- Music/Songs (with specific titles)

DO NOT include:
- Websites, URLs, or web services
- Other podcasts or podcast names

IMPORTANT: 
- Only include items explicitly mentioned by name. Do not invent titles.
- Valid categories are: "Book", "Movie", "TV Show", "Music"
- Include the exact phrase where each item was mentioned
- Find the nearest proximate timestamp where it appears in the conversation
- THE TIMESTAMP OF THE MEDIA MENTION IS IMPORTANT - DO NOT INVENT TIMESTAMPS AND DO NOT MISATTRIBUTE TIMESTAMPS
- Double check that the timestamp is accurate - a timestamp will NEVER be greater than the total length of the audio
- Timestamps are given as ranges, e.g. 01:13:42.520 --> 01:13:46.720. Use the EARLIER of the 2 timestamps in the range.

Return ONLY valid JSON. Ensure all strings are properly quoted and escaped, no trailing commas:
{
  "media_mentions": [
    {
      "title": "Exact Title as Mentioned",
      "category": "Book",
      "author_artist": "N/A",
      "context": "Brief context of why it was mentioned",
      "context_phrase": "The exact sentence or phrase where it was mentioned",
      "timestamp": "estimated time like 01:15:30"
    }
  ]
}

If no media is mentioned, return: {"media_mentions": []}

Prompt 9: Context Setup

You are an expert data extractor tasked with analyzing a podcast transcript. 
I will provide you with part 3 of 4 from a podcast transcript. 
I will then ask you to extract different types of information from this content in subsequent messages. Please confirm you have received and understood the transcript content.

Transcript section:
02:01:03.480 --> 02:01:06.520] That's a lower intensity than most people are doing in a hit class.
[02:01:06.520 --> 02:01:09.720] Most people in a hit class are doing shorter intervals and pushing much harder.
[02:01:10.200 --> 02:01:20.360] I just had a talk with Marty Cabala, and I asked him that question, you know, and he was like, Rhonda, you got to do more three, because I wanted to, I was like, I want to do VO2 Max training.
[02:01:20.360 --> 02:01:21.560] Like, this is what I do.
[02:01:21.560 --> 02:01:26.760] I do a lot of the, you know, I'll do 16 rounds and I'll do 20 seconds on, 10 seconds off, right?
[02:01:26.760 --> 02:01:30.280] But my 10 seconds off are, I mean, my heart rate's still pretty high.
[02:01:30.280 --> 02:01:41.640] Like, I don't, so he's like, you, you got to do like three minutes, at least one, you know, and so I've shifted my training now to doing, and it's absolutely true.
[02:01:41.640 --> 02:01:43.000] I am not going as hard.
[02:01:43.000 --> 02:01:43.560] You can't.
[02:01:43.560 --> 02:01:46.120] Yeah, it's, you just can't go as hard.
[02:01:46.440 --> 02:01:47.000] And so.
[02:01:47.320 --> 02:01:48.200] And it's an art form.
[02:01:48.360 --> 02:01:55.960] You'll figure it out because you'll realize and you'll, you'll have to, you know, you'll be like, I went too hard and I was dead at a minute and a half.
[02:01:55.960 --> 02:01:58.360] And I was like loafing the last minute and a half.
[02:01:58.360 --> 02:02:00.120] Or I held back too much.
[02:02:00.120 --> 02:02:03.240] And by the end of the three minutes, it was like, oh, I actually could have gone harder.
[02:02:03.240 --> 02:02:03.800] And that's okay.
[02:02:03.800 --> 02:02:06.680] Like, you'll sort of figure out what that sweet spot is.
[02:02:07.640 --> 02:02:16.360] But that three to eight minutes is the optimal zone for generating VO2 max power.
[02:02:16.360 --> 02:02:16.840] Right.
[02:02:16.840 --> 02:02:17.240] Yeah.
[02:02:19.320 --> 02:02:22.120] So metabolic flexibility, obviously hugely important.
[02:02:22.120 --> 02:02:23.560] VO2 Max, hugely important.
[02:02:23.560 --> 02:02:37.320] But with respect to, I would say, like eating diet-wise, like you hear a lot of people like low-carb community, ketogenic, you know, metabolic flexibility if they're doing, does that like affect metabolic flexibility?
[02:02:37.320 --> 02:02:38.040] Like if you're doing it.
[02:02:38.120 --> 02:04:16.600] Yeah, it's tough to say there there i think there may be a bit of a confounder there so um i i used to think so um i'm not sure anymore truthfully um so so the obvious confounder there is if you're on a completely carbohydrate restricted uh diet your respiratory quotient so on a from a functional standpoint one of the ways we how do we measure what you're oxidizing so when a person does a cpat test a functional test like a vo2 max test we're we're measuring o2 consumed and co2 produced so if any have you done a vo2 max test yet i haven't okay so you'll you can you just go to any doctor or doctors don't do it no you typically go to um well when i did when i lived in san diego i used to do them with my coach so he would do them um in in austin we send people to ut like we just send people to the university and get them done it's a very inexpensive test like like a hundred bucks or something like that right so they're gonna have you do it in one of two ways which is a bike or a treadmill and i always tell patients do it in the way you train because there's a you know there's a you don't want to take a cyclist and make them do the running test or vice versa so it sounds like you're doing most of your work on a peloton so you would do it on a bike because you're going to sit on a bike and they're going to put a mask on you and it's super uncomfortable the mask has to be incredibly tight it can't have any interference from the outside world in terms of air that you're breathing can't escape and no air from the outside can get to you there are two gas sensors on the outside of the mask one for o2 one for co2 this is the bread and butter of this whole device.
[02:04:16.600 --> 02:04:20.200] If those sensors aren't calibrated correctly or they don't work, the test is meaningless.
[02:04:20.200 --> 02:04:22.120] And like one out of 10 times, they fail.
[02:04:22.120 --> 02:04:31.640] So you got to make sure whenever you're doing this test the per the tech who does it has calibrated this thing and knows what to look for if the calibration fails during the test.
[02:04:31.800 --> 02:04:34.840] We just had a patient do one recently, the test failed.
[02:04:34.840 --> 02:04:42.840] So you're going to be put on a bike and it's going to be an erg, which means unlike the Peloton where you set the resistance.
[02:04:42.840 --> 02:04:46.360] And how, like, let's say you have the resistance at 50.
[02:04:46.360 --> 02:04:48.520] Well, that doesn't determine the wattage by itself.
[02:04:48.520 --> 02:04:50.920] How fast you pedal also determines the wattage.
[02:04:50.920 --> 02:04:52.040] That's different here.
[02:04:52.040 --> 02:04:56.600] Here, the computer is telling the bike how many watts to put out.
[02:04:56.600 --> 02:05:00.520] So the faster you pedal, the less the resistance will be.
[02:05:00.520 --> 02:05:01.080] Okay.
[02:05:01.080 --> 02:05:01.480] Okay.
[02:05:01.480 --> 02:05:03.160] But it's fixed wattage.
[02:05:03.160 --> 02:05:06.600] So they might say, look, Rhonda, we're going to start you out at 50 watts, nice little warm-up.
[02:05:06.600 --> 02:05:08.440] We're going to have you spend, you know, five minutes here.
[02:05:08.440 --> 02:05:14.680] And then like three, every three minutes, we're going to go up, you know, 25 watts or something like that.
[02:05:14.840 --> 02:05:18.760] And they're, you know, within about 15 minutes, you're going to be in crunch time.
[02:05:18.760 --> 02:05:22.040] And at that point, they're probably going to increase the wattage every minute.
[02:05:22.040 --> 02:05:26.360] And you're going to, you're in the, the pain train has left the station.
[02:05:26.360 --> 02:05:29.320] Like, this is unpleasant.
[02:05:29.320 --> 02:05:30.920] And you have to keep your RPMs high.
[02:05:30.920 --> 02:05:34.840] The test is usually aborted if you can't keep your RPM above about 50 or 60.
[02:05:34.840 --> 02:05:36.920] So as you're training, keep that in mind.
[02:05:36.920 --> 02:05:40.360] These are all the things that you don't want to fail the test because you didn't know the test.
[02:05:40.600 --> 02:05:41.080] You know what I mean?
[02:05:41.800 --> 02:05:44.280] Let the physiology be the place you fail.
[02:05:44.520 --> 02:05:52.280] So make sure when you're riding that Peloton, you're really comfortable in that 80 to 100 zone of RPM.
[02:05:52.280 --> 02:05:55.000] And so what is the tech looking for?
[02:05:55.000 --> 02:05:57.320] So the tech is looking at a bunch of data.
[02:05:57.320 --> 02:06:00.840] So what they're looking for is VO2 and VCO2.
[02:06:00.840 --> 02:06:03.400] Those are the things that are being measured.
[02:06:03.400 --> 02:06:06.040] So they know your heart rate at every moment in time.
[02:06:06.040 --> 02:06:13.160] They know how many watts you're generating because you're generating by definition everything they're sending you.
[02:06:13.160 --> 02:06:18.240] And then they're measuring VO2, so ventilation rate of oxygen and VCO2, ventilation rate of CO2.
[02:06:19.280 --> 02:06:24.640] They also, at every moment in time, see the ratio of VCO2 to VO2.
[02:06:24.640 --> 02:06:27.360] That's called respiratory quotient, or RQ.
[02:06:27.360 --> 02:06:29.200] It's also known as RER.
[02:06:29.200 --> 02:06:38.480] That ratio, in any moment in time, tells you how much fat you're oxidizing versus how much glucose.
[02:06:39.120 --> 02:06:47.200] When that ratio is 0.7, you are 100% fat oxidizing.
[02:06:47.200 --> 02:06:51.600] When that ratio is 0.85, it's about 50-50.
[02:06:51.600 --> 02:06:56.640] When that ratio is 1 and above, you're all carbohydrate.
[02:06:57.920 --> 02:07:03.520] So what you'll want to see when you do the test is you won't want the report, the summary.
[02:07:03.520 --> 02:07:06.880] You will also want the raw data, which is pages and pages of a spreadsheet.
[02:07:06.880 --> 02:07:08.880] And you'll kind of go through and you can see how these things change.
[02:07:08.880 --> 02:07:11.520] So when I used to do my tests, I used to plot my own data.
[02:07:11.520 --> 02:07:16.480] I would just get the spreadsheet and I would make the fuel partitioning curve.
[02:07:16.480 --> 02:07:24.000] So what I would draw would be a curve, what I would have Excel plot for me is on the x-axis, I would have wattage, because I cared more by wattage than by heart rate.
[02:07:24.000 --> 02:07:27.280] So you have either wattage or heart rate on the x-axis.
[02:07:27.280 --> 02:07:30.480] And on the y-axis, I'd have a double y-axis.
[02:07:30.480 --> 02:07:36.080] And the y-axis would be either calories or preferably grams per minute.
[02:07:36.080 --> 02:07:40.000] And I would have carbohydrate oxidation and fat oxidation.
[02:07:40.000 --> 02:07:43.600] So fat oxidation goes down from as the test starts.
[02:07:43.600 --> 02:07:47.280] So it usually has an early peak and then comes down as intensity goes up.
[02:07:47.280 --> 02:07:50.960] And carbohydrate oxidation just rises monotonically.
[02:07:51.280 --> 02:07:54.720] And there's where those two cross.
[02:07:54.720 --> 02:07:59.960] Some people call that your anaerobic threshold, but that's where your respiratory quotient is equal.
[02:07:59.280 --> 02:08:06.840] If you've done this in calories, if you do it in grams per minute, it won't be because obviously there's way more calories in fat than oxygen.
[02:08:07.480 --> 02:08:16.760] So, one of the other metrics we care very deeply about in our patients is what is your peak fat oxidation and where does it occur?
[02:08:16.760 --> 02:08:18.360] And we plot that.
[02:08:18.360 --> 02:08:25.480] So, we plot their VO2 max, we plot their zone two, and we plot fat oxidation.
[02:08:25.480 --> 02:08:31.480] And not surprisingly, there's a family of curves that we put the patients on.
[02:08:31.480 --> 02:08:34.760] So, we say, this is what someone with type 2 diabetes looks like.
[02:08:34.760 --> 02:08:36.600] This is their fat oxidation curve.
[02:08:36.600 --> 02:08:40.360] This is what a world-class Tour de France cyclist looks like.
[02:08:40.360 --> 02:08:41.880] They couldn't be further apart.
[02:08:41.880 --> 02:08:43.560] And this is everything in between.
[02:08:43.560 --> 02:08:45.400] And where do you stack up?
[02:08:45.400 --> 02:08:52.680] So, what you want is the highest amount of fat oxidation, and you want to be able to sustain that for as long as possible.
[02:08:52.680 --> 02:09:06.280] Now, if you do this on somebody who is heavily carbohydrate-restricted, you will get an artifact of the test because their resting RQ is very, very low.
[02:09:06.280 --> 02:09:06.920] Okay.
[02:09:07.240 --> 02:09:21.320] And so it's not clear what the implications of that are, other than we typically will feed people carbohydrates before they do the test.
[02:09:21.560 --> 02:09:22.280] Like in the days that they're.
[02:09:22.440 --> 02:09:25.880] But their VO2 max won't be doesn't affect their VO2 max.
[02:09:25.880 --> 02:09:26.200] No.
[02:09:26.200 --> 02:09:35.320] Because the VO2 max is literally taking the peak VO2 that they achieve and dividing it by their weight in kilos.
[02:09:35.640 --> 02:09:38.440] What VO2 max do you aim for?
[02:09:38.440 --> 02:09:50.880] And if you can recall, I know that JAMA 2018 paper, which was probably one of the most convincing studies that VO2Max is like one of the best metrics of health and longevity.
[02:09:51.280 --> 02:09:52.720] And there was an even bigger paper that came out.
[02:09:52.880 --> 02:09:56.400] That JAMA paper had 120,000 subjects in it.
[02:09:56.400 --> 02:10:02.160] There was a JACC paper that came out a year ago that had almost a million subjects in it.
[02:10:02.160 --> 02:10:04.800] And it showed the exact same findings.
[02:10:04.800 --> 02:10:05.520] Do you know?
[02:10:05.520 --> 02:10:08.000] So the findings, if I recall, was like.
[02:10:08.240 --> 02:10:09.200] Both of them are in the book.
[02:10:09.200 --> 02:10:11.920] I think I have figures from both of them in the exercise.
[02:10:12.400 --> 02:10:13.360] You had the numbers in there?
[02:10:13.360 --> 02:10:13.600] Okay.
[02:10:14.400 --> 02:10:17.840] And that, so that was like the top, I just remember it was like the top percentile.
[02:10:17.840 --> 02:10:19.680] I mean, they had like 80% lower.
[02:10:20.240 --> 02:10:32.080] Yeah, if you compared the top, the difference in risk between someone in the bottom 25 percentile of VO2 max to the top 2.5% had a hazard ratio of five.
[02:10:32.720 --> 02:10:40.800] Meaning it's 400 times greater all-cause mortality if you're in the bottom 25% versus the top 2%.
[02:10:41.120 --> 02:10:44.320] Okay, so if I want that number, do you know it?
[02:10:44.320 --> 02:10:46.560] Or, I mean, what's like the top?
[02:10:47.120 --> 02:10:49.760] Yeah, are you 30 to 40?
[02:10:50.320 --> 02:10:51.280] I'll be 45.
[02:10:51.280 --> 02:10:53.600] Okay, so you're right in the middle of the 40 to 50.
[02:10:54.720 --> 02:10:58.960] I would guess, but the table is in my book, so I can put it that way.
[02:10:59.040 --> 02:11:04.240] Well, I would guess that it's about, it's in the high 40s.
[02:11:04.560 --> 02:11:05.120] Okay.
[02:11:05.120 --> 02:11:14.960] Yeah, so roughly probably like 46, 47, 48 milligrams, sorry, milliliters per minute per kilogram.
[02:11:17.760 --> 02:11:19.360] This is such great information.
[02:11:19.360 --> 02:11:26.960] I have other, like, there's, I want to get into some cancer hormones, especially, because I'm going to be 45.
[02:11:26.960 --> 02:11:30.040] I have a very personal, personal interest in this.
[02:11:29.520 --> 02:11:34.680] But, you know, we're talking about metabolic health.
[02:11:34.840 --> 02:11:42.360] Obviously, you've talked endlessly about the importance of metabolic health for cancer, certainly, you know, cancer prevention.
[02:11:42.360 --> 02:11:48.680] But looking at like, so the biggest risk factor for cancer is age, right?
[02:11:49.320 --> 02:11:52.920] Yes, if you, yeah, unless you include, yeah, if you don't include modifiable risk.
[02:11:52.920 --> 02:11:55.000] So, yeah, we generally talk about modifiable risk.
[02:11:55.000 --> 02:11:55.480] Okay, yes.
[02:11:55.960 --> 02:11:59.560] Age is the greatest risk for all disease, including cardiovascular disease.
[02:11:59.880 --> 02:12:01.880] The biggest modifiable risk factor.
[02:12:01.880 --> 02:12:04.120] So let's talk about modifiable risk factors, like obesity.
[02:12:04.600 --> 02:12:05.480] Smoking is number one.
[02:12:05.480 --> 02:12:05.960] Smoking.
[02:12:05.960 --> 02:12:06.120] Okay.
[02:12:06.360 --> 02:12:07.000] Still number one.
[02:12:07.480 --> 02:12:12.680] Of course, smoking, I always not be smoking, but it is easy to forget.
[02:12:12.680 --> 02:12:14.440] It's like, oh, yeah, people do still smoke.
[02:12:15.000 --> 02:12:18.840] It's hard to fathom that, but addiction is addiction.
[02:12:18.840 --> 02:12:20.360] So smoking is the number one.
[02:12:20.600 --> 02:12:24.280] Smoking is still the number one modifiable risk factor.
[02:12:24.440 --> 02:12:25.080] What's after that?
[02:12:25.080 --> 02:12:25.480] Obesity.
[02:12:25.880 --> 02:12:26.440] Obesity.
[02:12:26.920 --> 02:12:30.680] So why do you think obesity, if you were to speculate, why do you think it is?
[02:12:30.920 --> 02:12:32.840] Yeah, and I feel pretty strongly about this.
[02:12:32.840 --> 02:12:37.000] I mean, I'm happy to speculate on things, and I'm happy to acknowledge when I have no idea.
[02:12:37.000 --> 02:12:39.160] Here, I think we have a pretty good idea.
[02:12:39.160 --> 02:12:41.800] First of all, I don't think it's the excess adiposity, right?
[02:12:41.800 --> 02:12:47.560] Like, I don't think it's the extra two pounds I have on my waist that I wish I didn't have for vanity purposes.
[02:12:48.520 --> 02:13:00.360] It is the environment of growth factors that comes with obesity, namely the hyperinsulinemia, but also the chronically elevated IGF and things of that nature.
[02:13:00.360 --> 02:13:04.920] And it is the inflammatory environment that comes rife with obesity.
[02:13:04.920 --> 02:13:13.560] And again, that's not due to the excess energy that's stored within the confines of the subcutaneous storage depot.
[02:13:13.560 --> 02:13:25.360] It's due to the excess fat that spills over from that into these other areas where fat accumulation is very harmful.
[02:13:25.360 --> 02:13:36.320] So fat accumulation is not problematic, believe it or not, despite our aesthetic preferences, when it occurs in areas that we are designed to store excess energy.
[02:13:36.320 --> 02:13:44.000] It becomes problematic when it escapes those areas and gets around the viscera, gets around our organs, enters the muscle itself.
[02:13:44.000 --> 02:14:05.040] By the way, that's how it directly contributes to insulin resistance when it accumulates in the liver, accumulates around the heart, within the pancreas itself, where it serves the double role of not just creating an inflammatory environment, but also reducing the amount of insulin that the beta cell can release and also around the kidneys.
[02:14:05.040 --> 02:14:09.600] So those are the main places where even a small amount of fat, i.e.
[02:14:09.680 --> 02:14:17.120] if just 10% of your total body fat were in those places, you would be at enormous risk for cardiometabolic disease.
[02:14:17.440 --> 02:14:21.120] Yeah, I remember I've seen a few studies where it's like visceral fat.
[02:14:21.120 --> 02:14:25.760] So you're talking about the fat that's, you know, covering, surrounding your organs, you know.
[02:14:25.760 --> 02:14:30.320] That was highly correlated with an increased cancer risk.
[02:14:30.720 --> 02:14:46.160] And there was like, there was also another correlation with like there's some specific inflammatory cytokines that were being generated or, you know, associated with, I guess, I would say, with the visceral fat and the cancer incidence, which again, it's like the inflammatory environment like you're talking about.
[02:14:46.160 --> 02:14:51.600] So, so the metabolic health being important, we talked about, you know, the best, like exercise being at the top, right?
[02:14:51.600 --> 02:15:00.760] I mean, that's one of the best ways to exercise, energy balance, sleep, and then, of course, you know, management of distress, right?
[02:15:00.760 --> 02:15:04.200] Hypercortisalemia will also contribute to this significantly.
[02:14:59.920 --> 02:15:04.440] Right.
[02:15:04.680 --> 02:15:09.720] Which, of course, even doing things like exercise and getting enough sleep helped help balance those things.
[02:15:09.960 --> 02:15:11.400] Right, exactly.
[02:15:12.120 --> 02:15:21.480] When it comes to cancer prevention, you know, you talk a lot in Outlive about cancer screening, aggressive cancer screening.
[02:15:21.800 --> 02:15:30.520] So, can you talk a little bit about weighing the benefits versus the risks of that type, you know, doing more of an aggressive type of cancer screening?
[02:15:30.520 --> 02:15:42.120] Yeah, I mean, the reason I think we have to pay attention to cancer screening in such an aggressive way is that unlike cardiovascular disease, and even though we didn't really go into the pathogenesis of it today, I mean, I've covered this on other podcasts.
[02:15:42.120 --> 02:15:43.640] I'm sure you have as well.
[02:15:43.640 --> 02:15:45.320] It's very well understood.
[02:15:45.400 --> 02:15:46.920] Doesn't mean we know everything.
[02:15:47.240 --> 02:15:56.040] I'll happily spend 20 minutes telling you all the things I don't understand or that we don't understand as a community, but we have a pretty good sense of what's going on.
[02:15:56.040 --> 02:15:58.360] That's not the case in cancer.
[02:15:58.360 --> 02:16:06.520] It is still a really, really big black box to try to understand all the different ways in which people get cancer.
[02:16:06.520 --> 02:16:21.320] And if you just want proof positive on this, I bet you there's not a single person listening to this, not one, who can't tell you of at least one person they know who's been afflicted with cancer, who otherwise did everything right.
[02:16:21.320 --> 02:16:33.800] They didn't smoke, they weren't obese, they didn't have huge chemical carcinogen exposures, they lived a perfectly healthy life and they still got breast cancer, or they still got leukemia, or they still got some god-awful cancer.
[02:16:33.800 --> 02:16:48.320] So, the truth of it is in cardiovascular disease, when we sit here and talk about modifiable risk factors like lipids, smoking, blood pressure, all these things, that virtually accounts for the entirety of the disease.
[02:16:48.320 --> 02:16:54.240] In cancer, when we talk about the modifiable risk factors, it doesn't even account for half of it.
[02:16:54.240 --> 02:16:56.640] So, it's free money.
[02:16:56.640 --> 02:17:06.560] Don't leave it on the table, don't make unforced errors, don't smoke, and be metabolically healthy, but you don't want to leave it at that.
[02:17:06.560 --> 02:17:17.920] There's still way too great a chance that you're going to end up getting cancer relative to, you know, if you just take the approach of, well, I've taken care of those things, therefore I've done everything I can.
[02:17:17.920 --> 02:17:24.080] So, the missing link, how we bridge that gap, has to be through aggressive screening.
[02:17:24.080 --> 02:17:41.200] Because about the only thing you can say about cancer that is capital T true is when you treat a cancer in an early stage, you will have a better outcome than if you treat that cancer at a later stage.
[02:17:41.840 --> 02:17:46.960] And in the book, I talk about a couple of very specific examples of this where we have just overwhelming data.
[02:17:46.960 --> 02:17:49.520] I use breast and colon cancer as an example.
[02:17:49.520 --> 02:17:56.400] So, when a person has a stage three colon cancer, that's still a big cancer, right?
[02:17:56.720 --> 02:18:04.720] And it's by definition, because it's stage three, it has spread to the lymph nodes, but it has not spread visibly beyond the lymph nodes.
[02:18:04.720 --> 02:18:14.400] So, when you do a CT or an MRI on that patient, you'll see that there is no other evidence of cancer outside of the region of the resection, which is the colon and lymph nodes.
[02:18:14.400 --> 02:18:17.680] Now, you know that there's microscopically cancer elsewhere.
[02:18:17.680 --> 02:18:25.120] So, there are still millions to billions of cancer cells throughout that patient's body, almost assuredly in their liver.
[02:18:26.400 --> 02:18:29.760] But they're not in, you know, you can't see them.
[02:18:30.360 --> 02:18:42.520] If you give that patient the Folfox regimen, which is the standard chemotherapy regimen, that's three drugs, 65% of those patients will be alive in five years.
[02:18:42.840 --> 02:18:45.160] So a third of them will still die.
[02:18:45.480 --> 02:18:47.960] But two-thirds of them will live.
[02:18:48.280 --> 02:18:58.200] If that exact same patient, when you go in and you take their colon out and you take their lymph nodes out, also has visible metabolic disease in the liver, they're now stage four.
[02:18:58.520 --> 02:19:02.520] After surgery, they will go on to get the same chemotherapy.
[02:19:02.520 --> 02:19:05.560] None of those people will be alive in five years.
[02:19:06.200 --> 02:19:08.040] There is a fundamental difference.
[02:19:08.040 --> 02:19:08.520] Why?
[02:19:08.520 --> 02:19:09.880] Why that difference?
[02:19:09.880 --> 02:19:11.240] Same is true with breast cancer.
[02:19:11.240 --> 02:19:13.400] Same is true with every cancer.
[02:19:13.720 --> 02:19:29.480] The reason is the more cancer cells you have, the more heterogeneity you have around the burden of mutations in that cancer, the more capable that cancer is to mutate its way out of treatment, evade the immune system, a whole bunch of other things.
[02:19:29.800 --> 02:19:46.760] So if step number one is don't get cancer, which it should be, and we want to do everything we can to not get cancer, step number two is if you do get cancer, you want to be able to catch it as soon as possible so that you have the smallest possible burden of this disease to treat.
[02:19:46.760 --> 02:19:52.760] And by the way, you know, there's an entire argument that says, well, screening is too expensive.
[02:19:52.760 --> 02:20:01.400] It's a lot cheaper than treating late-stage cancer with very expensive drugs that do very little.
[02:20:03.000 --> 02:20:04.920] So you brought up a lot of good points, Peter.
[02:20:04.920 --> 02:20:09.640] I mean, I really like the way, like, you can do everything you can.
[02:20:09.640 --> 02:20:18.000] And, you know, like one of my favorite Peloton instructors, Leanne Hainsby, you know, she's out, she's like doing physical activity every day.
[02:20:18.000 --> 02:20:19.440] I mean, she looks amazing.
[02:20:19.440 --> 02:20:26.640] I'm sure she's, you know, not eating a terrible diet and she came down with breast cancer, was being treated and was still doing Peloton classes while she was being treated.
[02:20:26.640 --> 02:20:27.680] I mean, amazing.
[02:20:28.400 --> 02:20:36.960] But the reality is, is that they're like over a lifetime, you know, you do like there's a random amount of like things that can happen.
[02:20:36.960 --> 02:20:41.360] Let's say you're metabolically healthy and everything, like your cells are dividing, you can get a mutation.
[02:20:41.360 --> 02:20:49.200] Your immune cells will take care of it most of the time as, you know, we're progressing through life until we start to get, you know, into our what, fifth, sixth, seventh decade.
[02:20:49.200 --> 02:20:51.040] Maybe the immune system's not working as well.
[02:20:51.200 --> 02:20:52.960] I mean, there's things that you just can't control.
[02:20:52.960 --> 02:20:55.040] Like there's that, like you mentioned.
[02:20:55.040 --> 02:21:03.520] So with cancer screening, what, let's say you don't have any known genetic risk factors and there's no like family history, right?
[02:21:04.160 --> 02:21:13.520] What age would you say or what decade of life around where would you think that or how do you treat it in your clinical practice with respect to cancer screenings?
[02:21:13.920 --> 02:21:16.560] What are the major ones to do?
[02:21:16.560 --> 02:21:18.480] You said colon and breast.
[02:21:18.480 --> 02:21:19.760] Are there any others?
[02:21:19.760 --> 02:21:35.840] Yeah, so a discussion like this always begins with our patients by saying, you know, you have to understand your risk appetite as an individual and you have to understand the price you're going to pay for screening.
[02:21:36.480 --> 02:21:38.320] Because there's a couple of prices you pay.
[02:21:38.320 --> 02:21:40.000] The first is economic.
[02:21:40.320 --> 02:21:44.480] Everything we're about to talk about is going to be outside of the standard of care.
[02:21:44.480 --> 02:21:45.120] Not everything.
[02:21:45.120 --> 02:21:56.160] I mean, if you're at a certain age, your breast, you know, your mammography and your colonoscopy will be covered, but your colonoscopy won't be covered at the frequency that we're going to recommend you do it.
[02:21:56.480 --> 02:22:06.360] And even if your mammography is covered, they probably won't cover the MRI or the ultrasound that we're going to recommend because we never recommend mammography in isolation ever.
[02:22:08.200 --> 02:22:24.040] If we're doing a PSA on you and any of our metrics show more care is warranted, they're not going to cover the follow-up study, like a 4K test or a multiparametric MRI, unless your PSA is very high.
[02:22:24.360 --> 02:22:28.360] So understand there's a cost that has to go into this.
[02:22:28.360 --> 02:22:39.080] But I think there's an even bigger cost that you have to be willing to tolerate if you go down this rabbit hole, which is the cost of the false positive, the emotional cost of the false positive.
[02:22:39.400 --> 02:22:43.240] So we always kind of start by explaining how sensitivity and specificity work.
[02:22:43.240 --> 02:22:47.960] And I know a lot of people's eyes kind of glaze over and they're like, oh my God, like I don't want to hear the stats on this.
[02:22:47.960 --> 02:23:00.120] But if you don't understand what sensitivity means and you don't understand what specificity means, you can never understand the things that really do matter to anybody who gets a test, which is positive and negative predictive value.
[02:23:00.120 --> 02:23:07.960] Positive predictive value means if this test comes out positive, how likely is it that I actually have the thing it says?
[02:23:07.960 --> 02:23:12.600] Conversely, if this test comes out negative, how likely is it that I'm truly negative?
[02:23:12.600 --> 02:23:18.600] You want very high positive predictive value and very high negative predictive value.
[02:23:18.600 --> 02:23:20.360] And that's a function of three things.
[02:23:20.360 --> 02:23:29.240] The specificity of a test, which is the ability of a test to detect a condition being present if it is indeed present.
[02:23:29.240 --> 02:23:45.000] The specificity of a test, the ability of a test to conclude that something is absent, if it is indeed absent, and the prevalence of the condition being tested, meaning how likely is it that you have this before I test you?
[02:23:45.840 --> 02:23:53.760] So you can call that prevalence if you're screening, you can call it pretest probability, but the point is, this is all a Bayesian process.
[02:23:54.080 --> 02:23:57.520] So I really spend a lot of time going through this with people.
[02:23:57.840 --> 02:24:02.400] And let's just, you know, start with something as simple as mammography, right?
[02:24:02.400 --> 02:24:07.440] So, you know, so Peter, why are you saying you're not satisfied just doing mammography?
[02:24:07.440 --> 02:24:09.200] Well, here's why.
[02:24:09.200 --> 02:24:32.640] Mammography has a sensitivity of about 90% and a specificity of about 85%, which is fine, except if I'm going to do a mammography on you at this moment in time, your pretest probability for having breast cancer is pretty low, like a couple percent.
[02:24:32.960 --> 02:24:42.640] That means the positive and negative predictive value of this test in isolation are very poor, like less than 20%.
[02:24:44.240 --> 02:24:53.840] Furthermore, there are features about you personally that might make you a bad candidate for MRI in isolation.
[02:24:54.160 --> 02:24:56.400] One is you're very young.
[02:24:56.400 --> 02:24:58.400] You're not in menopause yet.
[02:24:58.400 --> 02:25:01.440] Your breast tissue is very glandular.
[02:25:01.440 --> 02:25:06.560] Now, in 40 years on a mammogram, your breasts are going to look totally different.
[02:25:06.560 --> 02:25:15.600] The mammogram will actually have an easier time seeing what's going on in your breast because there's going to be less dense glandular tissue.
[02:25:16.240 --> 02:25:21.040] The mammogram, because it's an x-ray, is really good at seeing calcified lesions.
[02:25:21.040 --> 02:25:25.040] It's really bad at seeing non-calcified lesions.
[02:25:25.040 --> 02:25:34.200] Conversely, an MRI is really, has no issue with glandular tissue, but can't see calcified lesions very well.
[02:25:34.520 --> 02:25:39.240] So we go through this analysis and you realize there's actually no perfect test for screening.
[02:25:39.240 --> 02:25:45.400] You have to stack tests on top of each other if you want to increase positive and negative predictive value.
[02:25:45.400 --> 02:25:50.760] And if you rely on any one test by itself, you're always going to have a blind spot.
[02:25:51.640 --> 02:25:53.960] The one exception to that, by the way, is a colonoscopy.
[02:25:53.960 --> 02:26:01.160] A colonoscopy is a test that has 100% sensitivity and very high specificity.
[02:26:01.640 --> 02:26:05.160] But with colonoscopy, you have a whole different risk, which is a physical risk.
[02:26:05.160 --> 02:26:08.040] There's actually a risk of harm from a colonoscopy.
[02:26:08.040 --> 02:26:10.280] Basically, three big risks.
[02:26:10.280 --> 02:26:16.280] There's the risk of dehydration, electrolyte imbalance, hypotension that comes from the bowel prep.
[02:26:16.600 --> 02:26:19.080] There's the risk of the sedation.
[02:26:19.400 --> 02:26:23.640] And then there's the risk of a perforation or bleeding, actual procedural risks.
[02:26:23.640 --> 02:26:33.400] Now, if you look at the largest study that came out on this, which was last summer in the New England Journal of Medicine, this was actually a study that was meant to show that colonoscopy wasn't worth it.
[02:26:33.720 --> 02:26:36.920] Actually, it showed something totally different in my mind, which showed how safe it was.
[02:26:36.920 --> 02:26:43.480] So it was a study of, I think, over 20,000 people and had not a single incident.
[02:26:43.480 --> 02:26:47.800] So it showed that in good hands, a colonoscopy is a very safe procedure.
[02:26:48.280 --> 02:26:52.440] But I always want to make sure people understand, like, we don't take this stuff lightly.
[02:26:52.840 --> 02:27:03.080] And there's a reason you don't do a colonoscopy three times a year, which if you did colonoscopy three times a year, you'd never get colon cancer because you'd all, you know, colon cancer always has to come from a polyp.
[02:27:03.080 --> 02:27:09.480] So if you were checking somebody three times a year, like you'd, you'd never, they would never be able to develop a polyp that you wouldn't catch.
[02:27:09.480 --> 02:27:13.400] But at that point, the risk would be just too high that something else would go wrong.
[02:27:14.040 --> 02:27:18.720] So, you know, standard recommendations used to be every 10 years starting at 50.
[02:27:19.040 --> 02:27:27.680] Current recommendations are starting at 45, and there's some controversy about whether you would do it every five to 10 years.
[02:27:27.680 --> 02:27:40.640] We typically say, with no family history or risk factors, meaning you don't have inflammatory bowel disease or Crohn's disease or things like that, we would typically say 40 and then about every three years, depending on the findings.
[02:27:40.640 --> 02:27:46.800] So sometimes the findings on a given colonoscopy will make you want to actually do a more frequent surveillance.
[02:27:46.800 --> 02:27:56.880] If you find a sessile polyp, for example, or if a patient has an incomplete bowel prep, you might decide, you know, actually, we need to do this a little more urgently and do it in a year again, as opposed to weight three.
[02:27:57.200 --> 02:27:58.240] Great information.
[02:27:58.240 --> 02:28:08.880] And with respect to the combined, you know, especially for younger individuals like younger like myself, the mammogram starting.
[02:28:08.880 --> 02:28:15.360] So I might say like, you know, at 40, I would start doing a mammo and an ultrasound every other year.
[02:28:15.360 --> 02:28:16.640] Sorry, every six months.
[02:28:16.640 --> 02:28:23.920] So you would do a mammo every year, you would an ultrasound every six months, every year, but stagger them by six months.
[02:28:23.920 --> 02:28:27.920] So if there was, if there was a high enough risk, that's probably an approach I would take.
[02:28:27.920 --> 02:28:33.280] Now, is that because there's a lifetime risk of one in eight just for on average, forget about all the mothers?
[02:28:33.440 --> 02:28:33.840] Okay.
[02:28:34.560 --> 02:28:45.360] And again, breast cancer is one of those cancers where if you treat it early, like it's it's it's absolutely a disease that that can be treated early.
[02:28:45.360 --> 02:28:49.040] If you catch this in a stage one, it's a non-fatal disease.
[02:28:49.600 --> 02:28:52.960] A stage four disease is a uniformly fatal disease.
[02:28:53.360 --> 02:28:57.280] What's the positive predictive value of catching it in stage one with the combination?
[02:28:57.840 --> 02:29:06.680] Well, so, okay, so the way to think about it is you think about it as what's the positive predictive value of the combined modalities.
[02:29:07.320 --> 02:29:11.720] And here it's a little more complicated because it depends on the hormone status.
[02:29:11.720 --> 02:29:13.320] So I'll give you an example.
[02:29:13.960 --> 02:29:14.840] Another...
[02:29:15.960 --> 02:29:18.840] thing that we use that we haven't talked about are liquid biopsies.
[02:29:19.080 --> 02:29:22.040] So we incorporate liquid biopsies into our testing.
[02:29:22.040 --> 02:29:22.760] Let's talk about them.
[02:29:22.760 --> 02:29:23.000] Yeah.
[02:29:23.000 --> 02:29:23.480] Yeah, yeah.
[02:29:23.880 --> 02:29:25.240] So have you talked about them on the podcast?
[02:29:25.240 --> 02:29:25.640] Do you listen to that?
[02:29:25.800 --> 02:29:31.000] I know, but there's a question I was going to ask you about with the GRAIL by Gallery by GRAIL.
[02:29:31.800 --> 02:29:33.080] Okay, so what does this test do?
[02:29:33.080 --> 02:29:50.120] So there are basically three things that you can figure out by looking at strands of DNA in the blood that can give you a clue as to whether or not a patient has cancer.
[02:29:50.440 --> 02:29:58.520] So let's say you collect a bunch of, you connect, you know, the GRAIL test uses 10 cc of blood, relatively paltry sum of blood.
[02:29:58.520 --> 02:30:03.080] And they look at all of the cell-free DNA.
[02:30:03.080 --> 02:30:05.880] So again, they separate the DNA that's in cells.
[02:30:05.880 --> 02:30:10.520] They don't want that, right, from the cell-free DNA.
[02:30:10.840 --> 02:30:28.520] And determine, so basically there could be known mutations that we know are cancer genes, like a K-RAS mutation or p53 mutation, where you might say, oh, well, if you see that K-RAS mutation, like there's cancer somewhere in the body.
[02:30:28.520 --> 02:30:34.840] The second thing that gives you a clue that there could be cancer in the body is the length of the DNA fragments that you see.
[02:30:35.160 --> 02:30:45.680] So, there's an, you know, this is not what GRAIL does, by the way, but there are other technologies that are looking at fragment length and using fragment length to impute the probability of cancer.
[02:30:44.920 --> 02:30:49.040] What GRAIL does is they look at a third thing, which is methylation.
[02:30:49.360 --> 02:30:52.800] So, they say, okay, well, all of this DNA is yours.
[02:30:52.800 --> 02:30:56.720] We're not going to worry about what the mutations are or what the fragment lengths are.
[02:30:56.720 --> 02:31:04.160] But what we do know is certain methylation patterns are indicative of cancer and tissue of origin.
[02:31:04.160 --> 02:31:05.680] That's a very big deal.
[02:31:05.680 --> 02:31:15.360] So, now you are doing a screen for not just does this patient likely have cancer or not, but if they do, can you tell me where that's coming from?
[02:31:15.360 --> 02:31:18.240] So, we can now go and look more closely there.
[02:31:18.560 --> 02:31:26.320] Now, there's something really interesting about how this works because it's different from any other type of screening test.
[02:31:26.320 --> 02:31:35.760] See, that MRI that we talked about, or the ultrasound, or the mammogram, or the colonoscopy for that matter, are basically morphology tests.
[02:31:35.760 --> 02:31:44.880] You're looking visually, either directly in the case of colonoscopy or indirectly in the form of a mammogram, where you have to look through the tissue.
[02:31:44.880 --> 02:31:47.760] You're looking at the morphology of a cancer.
[02:31:47.760 --> 02:31:50.560] The GRAIL test says nothing about that.
[02:31:50.560 --> 02:32:00.320] It's simply telling you: is this a cancer that is leaving its site of origin or shedding its DNA in sufficient enough quantities outside its site of origin?
[02:32:00.320 --> 02:32:05.520] So, something very interesting emerges when you take a closer look at the GRAIL data.
[02:32:05.520 --> 02:32:08.080] And this is why we use the test.
[02:32:08.080 --> 02:32:15.760] Again, I have no affiliation with GRAIL, so this is just my clinical experience and observation.
[02:32:15.760 --> 02:32:21.360] At first glance, the sensitivity of the GRAIL test for breast cancer is quite low.
[02:32:21.360 --> 02:32:30.000] The specificity is very high for GRAIL, by the way, meaning if you don't have cancer, it is very likely to tell you you don't have cancer.
[02:32:30.760 --> 02:32:37.240] The sensitivity is quite low, meaning if you have cancer, it could miss it.
[02:32:37.560 --> 02:32:39.640] And it's been tuned that way.
[02:32:39.640 --> 02:32:46.040] So the algorithm has been tuned for a very high specificity, a low sensitivity.
[02:32:46.360 --> 02:32:55.560] But if you look at breast cancer overall sensitivity, it's about 20% for stage 1, stage 2, which seems kind of abysmal.
[02:32:55.560 --> 02:33:02.760] Meaning, if you have a breast cancer that's early stage, stage 1, stage 2, there's only like a 20% chance it'll show up on the GRAIL test.
[02:33:02.760 --> 02:33:07.640] And many people, myself included, at one point, thought that doesn't justify doing the test.
[02:33:07.640 --> 02:33:11.640] I don't need a liquid biopsy to tell me I've got a stage three breast cancer.
[02:33:11.640 --> 02:33:15.720] Like I'm going to figure that out falling off a log, right?
[02:33:16.040 --> 02:33:19.960] So I need something to tell me when there's a stage one breast cancer.
[02:33:19.960 --> 02:33:31.800] But a closer look at the data showed that if you looked at ERPR negative breast cancers, stage one, stage two sensitivity was 75 to 80%.
[02:33:32.120 --> 02:33:39.480] It was only in the triple positive ERPR positive, HER2 new positive, that the sensitivity, specificity are so low.
[02:33:39.480 --> 02:33:42.600] And since that's the majority of breast cancers, it brings it down.
[02:33:42.600 --> 02:33:44.040] What does this mean?
[02:33:44.360 --> 02:33:51.800] It means that the more indolent a breast cancer is, the less likely the GRAIL test picks it up at an early stage.
[02:33:51.800 --> 02:33:56.680] But the more aggressive it is, the more likely it is to pick it up at an early stage.
[02:33:56.680 --> 02:34:02.440] The implication might be here that it's catching the cancers that matter.
[02:34:04.040 --> 02:34:11.080] And I think that's a very interesting way to combine liquid biopsies with morphologic studies.
[02:34:11.400 --> 02:34:18.000] Do you ever not combine, like, do you think doing just the liquid biopsy by itself would be a useful thing?
[02:34:18.160 --> 02:34:23.680] Or do you think really it's better with, you know, in combination with other morphology types of screening?
[02:34:23.840 --> 02:34:25.120] Yeah, it's a great question.
[02:34:25.120 --> 02:34:32.800] I mean, we don't do them in isolation because I still think we're in really early days.
[02:34:32.800 --> 02:34:37.040] And I just think a little bit of a belt and suspenders approach makes sense.
[02:34:37.680 --> 02:34:43.680] But it'll be wonderful if the day comes when all you need to do is the liquid biopsy.
[02:34:43.680 --> 02:34:48.320] And only if it comes up positive, do you need to go and do a morphologic survey?
[02:34:48.640 --> 02:34:49.920] A couple of questions.
[02:34:50.240 --> 02:34:56.480] So, you know, talking about some of the major screenings, the colonoscopy, the mammogram, you mentioned PSA.
[02:34:59.360 --> 02:35:17.520] So with like some of these, you know, types of morphology screenings, like the mammogram, for example, people are concerned, like there's a whole group of people that are very concerned about the potential, the mutagenic potential of, you know, these types of screening methods, you know, potentially causing cancer, right?
[02:35:17.520 --> 02:35:19.280] So CT scans, the x-rays.
[02:35:19.520 --> 02:35:23.520] Well, CT scans would be a very lousy way to screen for that reason, right?
[02:35:23.520 --> 02:35:26.240] The CT scan has a lot of radiation.
[02:35:26.240 --> 02:35:34.800] With the exception, the only time we justify the use of a CT scan is in a former smoker or a current smoker.
[02:35:34.800 --> 02:35:38.320] We don't have any current smokers in our practice, but we do have former smokers.
[02:35:38.320 --> 02:35:43.600] We do still use a low-dose CT for lung screening.
[02:35:44.480 --> 02:35:51.560] Remember, lung cancer risk is, lung cancer is the leading cause of cancer death globally and in the U.S.
[02:35:51.520 --> 02:35:53.200] for both men and women.
[02:35:54.160 --> 02:36:00.000] And 85% of lung cancers occur in former smokers or current smokers.
[02:36:00.920 --> 02:36:06.520] So in those people, you have to ask the question, what kind of cancers do they get?
[02:36:06.520 --> 02:36:17.080] And you basically have small cell, large cell, and squamous cell are the dominant cancers that occur in smokers.
[02:36:17.080 --> 02:36:21.160] And those are best detected on a low-dose CT scan.
[02:36:21.160 --> 02:36:32.120] Adenocarcinoma of the lung is the dominant cause of lung cancer in a non-smoker, and we can detect that equally well with an MRI.
[02:36:32.120 --> 02:36:35.960] So we don't expose a never-smoker to that risk.
[02:36:35.960 --> 02:36:43.080] Whereas to a smoker, we, or you know, a past smoker or current smoker, the risk reward trade-off is worth it.
[02:36:43.080 --> 02:36:45.880] And that's been documented really clearly in clinical trials.
[02:36:45.880 --> 02:36:49.560] Mammography has incredibly low radiation.
[02:36:50.200 --> 02:36:55.160] Not as low as like a DEXA scan or something like that, but it's still really, really low.
[02:36:56.280 --> 02:36:58.040] There's a lot of women that avoid them.
[02:36:58.520 --> 02:36:59.240] I'm sure there are.
[02:36:59.560 --> 02:37:00.120] I don't know.
[02:37:00.120 --> 02:37:03.000] Maybe the radiation has lessened over the years.
[02:37:03.560 --> 02:37:04.040] It always has.
[02:37:04.600 --> 02:37:06.040] Radiation is constantly going down.
[02:37:06.040 --> 02:37:12.680] I mean, just going back to something we spoke about earlier, 20 years ago, a C, so just let's explain what the numbers mean.
[02:37:12.680 --> 02:37:16.600] So radiation is measured in units called millisieverts.
[02:37:16.600 --> 02:37:27.240] And it's generally established that exposure to more than 50 millisieverts a year will increase your risk of mutagenesis.
[02:37:28.040 --> 02:37:31.240] So now let's put that in the context of certain things.
[02:37:31.240 --> 02:37:41.080] So living at sea level here in San Diego, just the exposure you get to the environment is about one to two millisieverts a year.
[02:37:41.080 --> 02:37:44.680] So that's two to four percent of your annual allotment.
[02:37:45.280 --> 02:37:49.040] If you live in Denver, you're doubling that.
[02:37:49.040 --> 02:37:52.560] So being one mile in the sky doubles your exposure.
[02:37:52.560 --> 02:37:58.080] But you're still, you know, you're at four to eight percent of your annual allotment.
[02:38:00.400 --> 02:38:09.840] A CT angiogram 20 years ago was 20 millisieverts, 40% of your annual radiation allotment on one test.
[02:38:09.840 --> 02:38:18.080] The last patient I sent for a CTA last week, because when we get the report, it also shows the radiation, less than one millisievert.
[02:38:18.400 --> 02:38:21.360] So mammograms are even less than that.
[02:38:21.360 --> 02:38:22.000] Yeah, yeah, yeah, yeah.
[02:38:22.160 --> 02:38:22.720] They're a fraction.
[02:38:22.960 --> 02:38:37.040] So it really is, it makes zero sense for a woman who has a lifetime risk of one in eight, and perhaps even higher if she's obese and drinks alcohol-wide, to avoid doing mammograms.
[02:38:37.040 --> 02:38:37.440] Correct.
[02:38:37.440 --> 02:38:37.680] Okay.
[02:38:39.200 --> 02:38:42.240] But again, I would never rely on a mammogram exclusively.
[02:38:42.560 --> 02:38:44.960] I would combine it with an ultrasound or the MRI.
[02:38:45.440 --> 02:38:48.080] But they're not concerned about people aren't really scared of the ultrasounds.
[02:38:48.400 --> 02:38:49.280] They're scared of mammograms.
[02:38:49.440 --> 02:38:51.600] Yeah, and MRI, of course, has a radiation.
[02:38:52.720 --> 02:38:58.960] But again, everyone has to, you know, you just have to, unfortunately, there's a lot of fear-mongering that goes on, but you just have to look at the numbers.
[02:38:58.960 --> 02:39:08.400] I mean, it's crystal clear that a mammogram has a very, very, they might be confusing it with, there was another test, I'm blanking on what it's called now because it's never done anymore.
[02:39:09.760 --> 02:39:12.400] It's called, I think it was called Molecular Breast Imaging.
[02:39:12.400 --> 02:39:15.840] It was another high, high-intensity mammogram.
[02:39:15.840 --> 02:39:17.840] It's, again, I've never seen one done.
[02:39:17.840 --> 02:39:20.160] I don't think they've been done in years.
[02:39:20.160 --> 02:39:27.280] But pre-MRI, like pre-utility for other tests, it was done, it was also about a 20 to 30 millisievert.
[02:39:29.680 --> 02:39:37.640] I'm sure there's a complete misinformation and misunderstanding where people are confusing mammogram from what's called an MBI, is what the test was called.
[02:39:37.640 --> 02:39:39.240] Well, this is good to clear up.
[02:39:40.120 --> 02:39:42.280] Because I mean, I'm not just, I'm not kidding.
[02:39:42.280 --> 02:39:46.600] Like, I know people, I know women that have this fear.
[02:39:46.600 --> 02:39:53.720] So, you know, I think stepping, sort of stepping back, just one more thing I want to ask you about is like blood cancers.
[02:39:53.720 --> 02:39:55.080] Is there any, like, what is that?
[02:39:55.240 --> 02:39:59.880] Well, liquid biopsies are very good on blood cancers, actually, because you have the highest proportion of those cells.
[02:39:59.880 --> 02:40:04.360] Like, you're going to get a much higher concentration of cell-free DNA.
[02:40:04.360 --> 02:40:16.680] So, yeah, we actually, that's actually one of the areas where I'm most excited about the liquid biopsies is on leukemias and other sort of hematologic issues, such as myeloma and things like that.
[02:40:17.000 --> 02:40:23.800] And for people listening, wondering about the cost of it, it's typically, it's like 900, like about $1,000, right?
[02:40:23.800 --> 02:40:25.240] And I don't think it's D to C.
[02:40:25.240 --> 02:40:27.720] So, meaning I think you have to go through your doctor to do it.
[02:40:27.720 --> 02:40:30.280] I don't think you can just do the test willy-nilly.
[02:40:30.280 --> 02:40:32.040] I don't think you can, yeah.
[02:40:32.200 --> 02:40:33.400] But I don't know for sure.
[02:40:33.400 --> 02:40:35.400] Yeah, I'd be surprised if you could.
[02:40:35.400 --> 02:40:43.160] So, on the breast cancer topic, you know, kind of going into another area, just I know we gotta, we got, we're, we're doing okay.
[02:40:43.160 --> 02:40:50.200] Um, but I really want to get your thoughts on this, this topic, which is, you know, broader sense hormones.
[02:40:50.520 --> 02:40:59.880] Um, but also just like if you look at the way a woman ages before menopause, I mean, she's aging slower than a man, right?
[02:40:59.880 --> 02:41:01.960] Like by several striks.
[02:41:02.200 --> 02:41:02.840] Yeah.
[02:41:03.160 --> 02:41:08.080] When she hits menopause, I mean, it's like a, you hear this quote-unquote cliff.
[02:41:08.080 --> 02:41:08.600] They fall off.
[02:41:08.600 --> 02:41:14.680] Like a woman, in terms of their aging, they fall off this cliff, but like it's no longer, I mean, it's just, they go rapidly, you know, down.
[02:41:15.040 --> 02:41:22.560] So what are, what are, let's just talk about some of the risk factors that women face, you know, after menopause and why.
[02:41:22.880 --> 02:41:32.960] Yeah, so obviously what happens in menopause is three hormones that are really important to a woman during her reproductive years go away.
[02:41:33.280 --> 02:41:35.200] And they go away in very short order.
[02:41:35.360 --> 02:41:37.680] So it can be quite dramatic.
[02:41:37.920 --> 02:41:41.600] And obviously those hormones are estrogen, progesterone, and testosterone.
[02:41:41.600 --> 02:41:54.720] I always mention testosterone because it's easily forgotten, but it's important to not forget it because a woman's concentration of testosterone in her, and by the way, testosterone declines slower than estrogen and progesterone.
[02:41:54.720 --> 02:41:56.080] Estrogen and progesterone really go down.
[02:41:56.080 --> 02:41:57.920] Testosterone kind of gradually goes down.
[02:41:57.920 --> 02:42:09.680] But like right now, we're sitting here and you're, you know, you're 45, presumably, you know, you're still in the throes of your reproductive, you know, you're at the tail end of your reproductive capacity, but you haven't hit menopause yet.
[02:42:10.320 --> 02:42:15.760] Your testosterone right now is at least 10 times higher than your estrogen level.
[02:42:15.760 --> 02:42:16.240] Wow.
[02:42:16.240 --> 02:42:18.000] In absolute quantities.
[02:42:18.000 --> 02:42:19.840] And by the way, that's the highest.
[02:42:19.840 --> 02:42:21.040] That's if you're ovulating.
[02:42:21.040 --> 02:42:24.160] So your peak estrogen is around ovulation.
[02:42:25.120 --> 02:42:32.800] If I take you in the early follicular cycle or in the luteal cycle, your testosterone could be 100 times higher than your testosterone.
[02:42:32.800 --> 02:42:34.560] So it's very important to understand.
[02:42:34.560 --> 02:42:41.360] Don't get confused by the units on the lab test because they're reporting them in nanograms per deciliter versus picograms per milliliter.
[02:42:41.360 --> 02:42:51.360] And so the estrogen number looks bigger, but in terms of absolute amounts of it, testosterone is still by far the most dominant hormone for both men and women.
[02:42:51.360 --> 02:42:55.920] So these things go away and a whole bunch of things happen.
[02:42:55.920 --> 02:43:02.440] Now, in the short run, and the things that generally get the most attention of the medical community are these vasomotor symptoms.
[02:43:02.440 --> 02:43:04.200] So the hot flashes and the night sweats.
[02:43:04.200 --> 02:43:07.400] And these are kind of the first things that women tend to notice.
[02:43:07.400 --> 02:43:12.920] I mean, they might notice that their period is becoming irregular, their cycle is lengthening, and things of that nature.
[02:43:12.920 --> 02:43:17.640] But in terms of actual symptoms that are disruptive to their quality of life, it are these vasomotor symptoms.
[02:43:17.640 --> 02:43:20.040] So hot flashes and night sweats.
[02:43:20.360 --> 02:43:26.920] It's not clear why some women get these horribly and some women actually don't get them at all.
[02:43:26.920 --> 02:43:31.640] Most women do get them to varying degrees.
[02:43:31.640 --> 02:43:34.840] And again, there's a spectrum there.
[02:43:35.160 --> 02:43:40.200] Other women will talk about things like brain fog, sleep disturbances.
[02:43:40.200 --> 02:43:47.800] And again, the sleep disturbances could be related to what we just said, because I got to think, if you're having hot flashes and night sweats, that can't be good for your sleep.
[02:43:47.800 --> 02:43:54.280] So, you know, is that sufficiently driving the sleep disturbances, or is there something else that's driving them?
[02:43:55.160 --> 02:43:59.080] As time progresses into menopause, other things will occur.
[02:43:59.080 --> 02:44:00.760] There will be sexual changes.
[02:44:00.760 --> 02:44:05.720] So vaginal atrophy, dryness, and reduction in libido.
[02:44:05.720 --> 02:44:08.360] And again, those can be related, but they can be independent.
[02:44:08.360 --> 02:44:20.680] We know testosterone plays an important role in libido, and we know that estradiol plays an important role in vaginal absence of estrogen is driving the vaginal symptoms.
[02:44:20.680 --> 02:44:31.000] So, and of course, if, and then of course, you have pain with intercourse that's a result of all of those things as well, which then feeds forward on the decreased libido.
[02:44:31.320 --> 02:44:37.960] As you go a little bit further, you start to see another major consequence of this, which is the destruction of bone.
[02:44:38.280 --> 02:44:47.440] And I use that word, I'm being a little aggressive in my language there, but the truth of it is both men and women hit peak bone density in their early 20s.
[02:44:47.440 --> 02:44:55.200] And for men, if you look at the reduction in bone mineral density from their 20s on, it's a gradual decline.
[02:44:55.200 --> 02:45:00.880] For women, it's a gradual decline until menopause, then a very straight, harsh line decline.
[02:45:00.880 --> 02:45:23.840] And when you consider the risk of falling and the impact of a broken hip or femur later in life, both in terms of mortality and morbidity, you realize that that may be the single biggest risk of menopause on women, though not appreciated in their 50s and not only showing up until their 60s.
[02:45:23.840 --> 02:45:34.560] So, taken together, all of these symptoms, in my mind, completely justify the use of HRT in any woman who is willing to undergo it.
[02:45:34.560 --> 02:45:54.480] And unfortunately, and I've talked about this a lot on my podcast, I think there has been no greater disservice brought by the medical community onto anyone, but in particular in this case, women, than the abject failure of the interpretation of the Women's Health Initiative in 2001, 2002, whenever it was first published.
[02:45:54.720 --> 02:45:58.800] That's a study that was completely misinterpreted.
[02:45:58.800 --> 02:46:11.600] The press were, I mean, out to lunch in the way they interpreted the study, and the investigators were, in my mind, equally at fault for not clarifying it.
[02:46:11.600 --> 02:46:17.840] Now, at least one member of the team who was a part of that study, Joanne Manson, has been more vocal lately.
[02:46:17.840 --> 02:46:19.040] I had her on my podcast.
[02:46:19.040 --> 02:46:25.200] She's been more vocal in acknowledging the way in which that study was misinterpreted.
[02:46:25.200 --> 02:46:42.040] But unfortunately, the damage has largely been done, both in terms of the fact that there is an entire generation of women, by my estimate and by the estimate of my analysis, my analyst's analysis, over 20 million women have been deprived of hormones who would have otherwise received them.
[02:46:42.040 --> 02:46:48.520] And we've even come up with some calculations for how many lives have been unnecessarily lost as a result of that.
[02:46:48.520 --> 02:46:55.800] And then there's the ongoing damage, which is, you know, as Mark Twain is attributed for saying this, right?
[02:46:55.880 --> 02:46:59.880] Like a lie will travel halfway around the world before the truth is tied up its shoes.
[02:46:59.880 --> 02:47:07.640] So just as you said there are women out there who say, I can't get a mammography because, oh my God, of the radiation, they may in fact be thinking of an MBI.
[02:47:07.640 --> 02:47:08.600] There's just a misunderstanding.
[02:47:08.600 --> 02:47:17.960] Well, similarly, there are still women walking around today that thinking HRT increases the risk of dying of breast cancer when it never did, and it certainly doesn't today.
[02:47:18.600 --> 02:47:22.360] So let's talk a little bit about that.
[02:47:22.360 --> 02:47:24.920] Like, I know, like, I've looked into the Women's Health Initiative.
[02:47:24.920 --> 02:47:34.280] I've heard you speak about it, and some of the major, major flaws of that study were one, being.
[02:47:35.080 --> 02:47:38.440] Well, so I want to, let's talk about what the study did, right?
[02:47:38.440 --> 02:47:49.400] So the study took two groups of women, women who had a uterus and women who didn't have a uterus, and randomized each of those groups into two separate groups, treatment versus placebo.
[02:47:49.400 --> 02:47:50.280] Why was that done?
[02:47:50.280 --> 02:48:05.240] Well, it was well understood by then, as it still remains, that in women with a uterus, failure to give progesterone with estrogen increases endometrial hyperplasia.
[02:48:05.240 --> 02:48:13.560] So, if you take a woman with a uterus and you just give her estrogen, but there's no progesterone, her endometrial lining will thicken, will thicken, will thicken.
[02:48:13.560 --> 02:48:21.920] And as the endometrial lining gets thicker, so too goes the risk of hyperplasia and ultimately what's called dysplasia, which can lead to cancer.
[02:48:14.920 --> 02:48:27.520] In other words, unopposed estrogen will increase the risk of endometrial cancer.
[02:48:27.520 --> 02:48:30.960] So, to this day, we know this and we do this.
[02:48:31.600 --> 02:48:40.000] So, if you had a uterus, you were put into a group where the treatment group was given conjugated equine estrogen and MPA.
[02:48:40.000 --> 02:48:45.840] So, that's estrogen taken from horse urine and a synthetic progestin.
[02:48:45.840 --> 02:48:48.640] And the treatment, and the placebo group was just given a placebo.
[02:48:48.640 --> 02:48:54.720] And then, in the other group, the no-uterus group, they were just given conjugated equine estrogen versus placebo.
[02:48:54.720 --> 02:48:58.240] They didn't have to be given the MPA, the synthetic estrogen.
[02:48:59.520 --> 02:49:03.760] These women were on average considerably older.
[02:49:03.760 --> 02:49:09.440] They were, I want to say, seven to ten years out of menopause at this point.
[02:49:10.640 --> 02:49:36.800] And the study was looking at a number of outcomes, but it was terminated early at about five and a half years when it was noted that the women in the CEE plus MPA group versus the placebo had a 0.1% higher risk of developing breast cancer.
[02:49:38.240 --> 02:49:46.640] Interestingly, the women in the CEE alone group had a lower risk of developing breast cancer.
[02:49:46.640 --> 02:49:56.640] So, the study was halted, and the headline read: Estrogen increases the risk of breast cancer by 25%.
[02:49:56.640 --> 02:49:59.040] Well, this wasn't correct.
[02:50:00.440 --> 02:50:13.320] It is true that in the CEE plus MPA group, that group had five cases of breast cancer per thousand women.
[02:50:13.320 --> 02:50:17.960] compared to four cases of breast cancer per thousand women in the placebo group.
[02:50:17.960 --> 02:50:22.520] And it is true that that's a 25% increase in the relative risk.
[02:50:22.520 --> 02:50:25.320] But of course, the absolute risk is 0.1%.
[02:50:25.320 --> 02:50:29.080] There was no difference in breast cancer mortality.
[02:50:29.080 --> 02:50:37.880] In other words, there was an extra one case of breast cancer, but there was no difference in breast cancer mortality.
[02:50:37.880 --> 02:50:48.520] Those data, by the way, have been updated every decade or so, and we now have like 19-year follow-up on that group, and that fact still remains true.
[02:50:48.520 --> 02:50:56.200] To this day, there is still no difference in the mortality of breast cancer in the CEE plus MPA group.
[02:50:56.520 --> 02:51:05.320] But you see, it would be impossible to make the case that estrogen is the cause there when in the other group you saw the exact opposite effect.
[02:51:05.320 --> 02:51:16.760] You saw that the CEE group alone had a lower incidence of breast cancer and eventually even a lower mortality due to breast cancer.
[02:51:17.080 --> 02:51:26.840] So I feel like, I don't know, maybe a 10th grade science student might come up with a different hypothesis than estrogen is the culprit.
[02:51:26.840 --> 02:51:29.560] In this group, you have A plus B.
[02:51:29.560 --> 02:51:31.320] In this group, you have A.
[02:51:31.320 --> 02:51:32.520] What could be the difference?
[02:51:32.520 --> 02:51:33.960] Might it be the B?
[02:51:33.960 --> 02:51:51.920] So I think most people who think about this problem today acknowledge that it's probably the MPA that was driving the very, very small, clinically insignificant, but statistically significant increase in breast cancer incidence that had no translation to a mortality difference.
[02:51:52.240 --> 02:51:54.800] And you might ask the question: well, is MPA in use today?
[02:51:54.800 --> 02:51:57.920] And the answer is pretty much by nobody.
[02:51:59.120 --> 02:52:01.360] I've never once prescribed MPA.
[02:52:01.360 --> 02:52:05.200] I've never seen a patient come to me who's taking MPA.
[02:52:05.200 --> 02:52:07.760] There probably are some patients on it, but I doubt it.
[02:52:07.760 --> 02:52:08.640] And what is MPA again?
[02:52:08.960 --> 02:52:10.160] It's a synthetic progestin.
[02:52:10.640 --> 02:52:19.280] Nowadays, women take bio-identical, micronized oral progesterone, or they use a progesterone-coated IUD.
[02:52:19.920 --> 02:52:25.280] If they don't benefit symptomatically from progesterone, progesterone is a funny hormone.
[02:52:25.280 --> 02:52:28.480] Some women really don't respond well to it.
[02:52:29.040 --> 02:52:32.000] It doesn't help their symptoms in any way, shape, or form.
[02:52:32.000 --> 02:52:33.920] And in those women, we don't even use it.
[02:52:33.920 --> 02:52:36.480] We just use a progesterone-coated IUD.
[02:52:36.480 --> 02:52:43.120] And that provides the local protection that prevents endometrial hyperplasia.
[02:52:43.840 --> 02:52:52.400] So in that sense, you know, I could dive deeper and deeper and go through the weeds on the whole study, but the punchline is very clear here, right?
[02:52:52.400 --> 02:53:00.800] Which is estrogen absolutely did not drive either the incidence of breast cancer or mortality associated with breast cancer.
[02:53:00.800 --> 02:53:03.360] And again, that was not true in 2002.
[02:53:03.360 --> 02:53:05.280] It was not true in 2006.
[02:53:05.280 --> 02:53:06.480] It is not true today.
[02:53:06.880 --> 02:53:20.560] That is one piece of the study that I didn't catch because, you know, when trying to sort of deconstruct it, it was like, okay, well, the synthetic, of course, versus bioidentical versus the age of initiation.
[02:53:20.560 --> 02:53:28.480] So, like you said, these women were like 10 years, I mean, like on average, like after menopause had hit, was another factor.
[02:53:28.480 --> 02:53:31.880] And then, you know, some of them were very, very unhealthy again.
[02:53:29.680 --> 02:53:35.720] Yeah, it was a very unhealthy population to begin with.
[02:53:36.360 --> 02:53:39.720] The other thing about it, by the way, is we don't use oral estrogen anymore.
[02:53:40.040 --> 02:53:41.480] Yeah, so that's another question.
[02:53:41.480 --> 02:53:45.800] What, so can you talk about a little bit of the differences?
[02:53:45.960 --> 02:53:56.120] Just, you know, sort of not so much into the deepness of it, but like the difference between, you know, oral estrogen, bioidentical estrogens, topical, like, you know, what?
[02:53:56.440 --> 02:54:09.080] So the only estrogens that are used today are bioidentical, which means they're estradiol and/or estriol, but there is no FDA-approved estriol product.
[02:54:09.080 --> 02:54:12.280] So there are three estrogens, E1, E2, E3.
[02:54:13.240 --> 02:54:16.680] There's some important nuance here that maybe justifies explaining.
[02:54:16.680 --> 02:54:35.640] So estradiol can be turned into estrone, which is E1, and it can be turned into E3 estriol, but E3 cannot be turned into E2 or E1.
[02:54:35.640 --> 02:54:37.640] So that's a one-way arrow.
[02:54:37.960 --> 02:54:43.640] E3 can be turned into, this is complicated.
[02:54:43.640 --> 02:54:44.280] Let me start.
[02:54:44.440 --> 02:54:50.040] E1 can be turned into a 2, 4, and 16-hydroxyestrone.
[02:54:50.040 --> 02:54:57.560] So you've got E3 that can go into an E, sorry, E1 can be turned into a 2-hydroxy, a 4-hydroxy, or a 16-hydroxy.
[02:54:57.560 --> 02:55:04.600] E3 can actually be turned into the 2-hydroxy, but not the 4-hydroxy or the 16-hydroxy.
[02:55:04.600 --> 02:55:11.080] Virtually all the breast cancer risk probably comes from the 4-hydroxyestrone.
[02:55:11.400 --> 02:55:18.080] So you can get that from estriol, pardon me, from estradiol, but you can't get it from estriol.
[02:55:13.800 --> 02:55:20.400] There is no FDA-approved product for estriol.
[02:55:21.040 --> 02:55:30.960] So if a woman is taking estriol, which she's probably taking in a topical fashion in combination with estradiol, they usually refer to that as a bi-est.
[02:55:30.960 --> 02:55:34.320] You'll hear that abbreviated bi-est, which just means biestrogen.
[02:55:34.320 --> 02:55:43.760] So they'll combine in some fraction, anywhere from 50-50 to 80-20, estradiol with estriol, and a woman will apply that topically.
[02:55:43.760 --> 02:55:45.920] But again, that's not FDA-approved.
[02:55:45.920 --> 02:55:49.600] That is something that compounding pharmacies would have to make for a physician.
[02:55:49.600 --> 02:55:55.120] In terms of FDA-approved products, you have oral estradiol, bio-identical.
[02:55:55.120 --> 02:56:01.520] We don't use it because, frankly, there's a small but non-zero increase in the risk of hypercoagulability.
[02:56:01.520 --> 02:56:03.440] It just doesn't seem like it's a risk worth taking.
[02:56:03.440 --> 02:56:16.400] Like, the only indication in my mind for oral estradiol is for women whose skin will not permit the absorption of any topical estradiol product.
[02:56:16.400 --> 02:56:20.240] Our preferred product is an estradiol patch.
[02:56:20.240 --> 02:56:22.000] We use the branded version.
[02:56:22.160 --> 02:56:27.040] Actually, when it comes to hormones, I really prefer using branded versions of an FDA-approved compound.
[02:56:27.040 --> 02:56:29.760] We prefer to use something called the Vivelle DOT.
[02:56:29.760 --> 02:56:33.120] So it's an FDA-approved estradiol patch.
[02:56:33.120 --> 02:56:34.800] A woman applies the patch.
[02:56:34.800 --> 02:56:42.480] You apply the, you know, the patch comes in different doses, and you can trim it if you want more or less estrogen, and she changes it like every three or four days.
[02:56:42.480 --> 02:56:46.720] So, you know, you'll put it on your lower back or your hip, butt, something like that, on your shoulder.
[02:56:46.960 --> 02:56:49.360] You just put it somewhere where it's not sort of intrusive.
[02:56:51.280 --> 02:56:54.640] By the way, we do notice variable absorption with sauna use.
[02:56:54.640 --> 02:57:00.440] So if the time ever comes for you to use it, we should discuss paying attention to different absorption rates.
[02:56:59.680 --> 02:57:04.440] But nevertheless, we don't have any issues with that.
[02:57:05.400 --> 02:57:12.280] There are ostroestrogen pellets that can be inserted in the sub-Q space or into the fat, really.
[02:57:12.280 --> 02:57:20.040] And they're also not FDA approved, but they're still used pretty liberally by physicians who know how to put them in.
[02:57:20.040 --> 02:57:22.120] I used to do this for my female patients.
[02:57:22.120 --> 02:57:23.480] I don't anymore.
[02:57:23.480 --> 02:57:30.280] I just tend to prefer the patch, truthfully, because it gives a more steady-state level dose of the estradiol.
[02:57:30.280 --> 02:57:32.280] And you can make adjustments easily.
[02:57:32.280 --> 02:57:33.640] With the pellets, you put it in there.
[02:57:33.640 --> 02:57:37.400] You got to wait five or six months before you figure it out again and decide what to do.
[02:57:37.400 --> 02:57:41.800] So those are basically the ways in which you would take estrogen in.
[02:57:41.800 --> 02:57:49.160] And as I said, progesterone, you would do either oral, micronized, bioidentical, or you would use a progesterone-coated IUD.
[02:57:49.160 --> 02:57:54.120] They also do make progesterone suppositories, but for most women, the compliance with that is low.
[02:57:54.120 --> 02:57:57.080] It's just messy and kind of inconvenient.
[02:57:57.560 --> 02:57:59.720] There's also topical estrogen products.
[02:57:59.720 --> 02:58:05.400] So you do have some women who say, look, I just do not want to take estrogen under any shape or form.
[02:58:05.400 --> 02:58:19.400] I don't want any, you know, I don't want any estrogen in my body, but these vasomotor, pardon me, these vaginal symptoms are problematic, then you can use vaginal estrogen cream or vaginal suppositories of estrogen.
[02:58:19.400 --> 02:58:24.680] Again, that won't give you any of the bone protection, that won't stop the night sweats or anything like that.
[02:58:24.680 --> 02:58:29.480] But using vaginal estrogen products alone will at least ameliorate the sexual side effects.
[02:58:29.800 --> 02:58:42.200] What about the difference between like multiphasic versus whatever the mono, like when you so like giving women estrogen in like more like their cycle versus like the same dose like all the time?
[02:58:43.440 --> 02:58:51.680] We we would we would kind of use we sometimes do multiphasic on progesterone in the transition of perimenopause.
[02:58:52.000 --> 02:58:54.400] We don't do it once women are fully in menopause.
[02:58:54.400 --> 02:58:57.440] When women are fully in menopause, we just sort of stay at the dose.
[02:58:57.440 --> 02:59:08.720] Again, the dose that a woman is on is a very low dose relative to her premenopausal levels as indicated by the FSH.
[02:59:08.720 --> 02:59:09.280] Do you go?
[02:59:09.280 --> 02:59:10.320] So that was another question.
[02:59:10.320 --> 02:59:12.560] Do you like let's in your mind?
[02:59:12.720 --> 02:59:33.200] Yeah, well like determined, let's say a woman is either premenopausal or perimenopausal, like I guess postmenopausal too, but determining like measuring your estrogen, measuring your progesterone, measuring your testosterone, when in this cycle to do it and what are the level, like what to you would say, okay, this woman's transitioning to perimenopause?
[02:59:33.840 --> 02:59:36.480] You know, is there a let like a threshold levels?
[02:59:36.480 --> 02:59:38.720] Yeah, we look at day five.
[02:59:38.720 --> 02:59:42.480] So if day one is the day the period starts, regardless, right?
[02:59:42.480 --> 02:59:45.920] Even if it's just a bit of spotting, whatever it is, like that's that's the starting point.
[02:59:45.920 --> 02:59:50.080] On day five, somewhere between day five and day seven, we just like to do it on day five.
[02:59:50.480 --> 02:59:53.440] You look at estradiol levels and FSH levels.
[02:59:53.440 --> 02:59:55.680] That is your canary in the coal mine.
[02:59:55.680 --> 03:00:05.120] As that FSH level on day five starts to climb and that estradiol will start to come down, but it's mostly the rise in FSH, that's how you know you're getting closer and closer to the cliff.
[03:00:05.120 --> 03:00:12.960] Now, there's actually some interesting data that's looking at AMH levels and anti-malarian hormone MRI.
[03:00:13.040 --> 03:00:16.880] So this is basically telling you how many eggs you have left, how many follicles you have left.
[03:00:16.880 --> 03:00:26.160] So, this is something that fertility docs are constantly looking at in women who are, you know, struggling with fertility or deciding if they can still do, you know, have kids or go through IVF.
[03:00:26.160 --> 03:00:36.280] So, there may be some also some insight that comes from AMH, but typically watching the rising FSH on day five is what's telling you this is coming.
[03:00:36.600 --> 03:00:38.360] And then, of course, you marry that to symptoms.
[03:00:38.360 --> 03:00:44.440] So, I typically do not treat women until they're symptomatic in perimenopause.
[03:00:44.440 --> 03:00:51.800] So, we'll look at their labs and I'll say, you know, Rhonda, look, you're getting closer to something.
[03:00:51.800 --> 03:00:53.320] Let's just be on guard for it.
[03:00:53.320 --> 03:00:58.840] And then, you know, maybe six months later, you'll say, all right, I'm having some hot flashes and night sweats.
[03:00:58.840 --> 03:01:00.040] Well, okay, good.
[03:01:00.440 --> 03:01:02.680] And you, by the way, you still may be ovulating.
[03:01:02.920 --> 03:01:05.560] You know, this can, this is what perimenopause looks like, right?
[03:01:05.560 --> 03:01:07.320] So to me, that's when you start treating.
[03:01:07.320 --> 03:01:09.800] And you can get away with much lower doses.
[03:01:10.760 --> 03:01:20.760] But the point I wanted to make is: once you're in full-fledged menopause, like we're only giving you enough estrogen to get your FSH down to about 25.
[03:01:21.080 --> 03:01:23.960] You now never have an FSH above 25.
[03:01:23.960 --> 03:01:28.680] So remember, FSH and estrogen work in opposition to each other.
[03:01:28.680 --> 03:01:32.520] So the lower your FSH, the higher your estradiol.
[03:01:32.840 --> 03:01:40.520] You right now, with your regular cycle, you've probably never seen an FSH above 12.
[03:01:40.520 --> 03:01:45.480] Just to give you a sense, at your lowest estrogen right now, your highest FSH is 12.
[03:01:45.480 --> 03:01:58.440] When you're in menopause, you're going to be managed to an FSH of about 25 to 35, which means your estradiol is going to be lower than it is at any point in your cycle today.
[03:01:58.440 --> 03:02:05.080] But that's sufficient to take care of all of your symptoms and preserve your bone density.
[03:02:05.720 --> 03:02:16.880] So, preserving bone, preserving bone density, obviously symptoms, but preserving bone density, also lowering cardiovascular risk, lowering Alzheimer's risk.
[03:02:14.760 --> 03:02:19.120] Alzheimer's is less clear, Rhonda.
[03:02:19.360 --> 03:02:31.040] The data right now suggests the following: late initiation of HRT may be counterproductive for AD risk, may actually increase AD risk.
[03:02:31.600 --> 03:02:38.960] Early initiation appears to potentially only be beneficial in E4 women, but not E3 women.
[03:02:38.960 --> 03:02:39.520] Okay.
[03:02:39.520 --> 03:02:46.480] So, for you, I would say doubly beneficial to initiate at the time of menopause because of your E4.
[03:02:46.480 --> 03:02:46.880] Got it.
[03:02:46.880 --> 03:02:47.920] That's really good to know.
[03:02:47.920 --> 03:02:54.880] And also, defining what is early and late, like, you know, so that, you know, there was a study, there's a couple of studies.
[03:02:54.880 --> 03:02:57.520] One was the elite study, and one was the DOPS.
[03:02:57.520 --> 03:03:02.400] So, like, I don't know, it was like early intervention for estradiol or something.
[03:03:03.200 --> 03:03:07.760] And then there was another one that was the Danish osteoporosis prevention study.
[03:03:07.760 --> 03:03:16.400] And both of those studies, in the DOPS one, the initiation of the, they did estradiol.
[03:03:16.400 --> 03:03:21.200] I think they did like triphasic or something, but also they did the progesterone.
[03:03:21.200 --> 03:03:22.720] So I had progesterone as well.
[03:03:23.200 --> 03:03:38.320] It was like the cardiovascular disease risk or mortality went down, the B venous thromboembulism, like the things that happen that can increase with menopause went down over the follow-up, which was 16 years or something.
[03:03:38.640 --> 03:03:48.080] But these women only took it for 11 years, and they started at age either between t

Prompt 10: Key Takeaways

Now please extract the key takeaways from the transcript content I provided.

Extract the most important key takeaways from this part of the conversation. Use a single sentence statement (the key takeaway) rather than milquetoast descriptions like "the hosts discuss...". 

Limit the key takeaways to a maximum of 3. The key takeaways should be insightful and knowledge-additive. 

IMPORTANT: Return ONLY valid JSON, no explanations or markdown. Ensure:
- All strings are properly quoted and escaped
- No trailing commas
- All braces and brackets are balanced
Format: {"key_takeaways": ["takeaway 1", "takeaway 2"]}

Prompt 11: Segments

Now identify 2-4 distinct topical segments from this part of the conversation.

For each segment, identify:
- Descriptive title (3-6 words)  
- START timestamp when this topic begins (HH:MM:SS format)
- Double check that the timestamp is accurate - a timestamp will NEVER be greater than the total length of the audio
- Most important Key takeaway from that segment. Key takeaway must be specific and knowledge-additive.
- Brief summary of the discussion

IMPORTANT: The timestamp should mark when the topic/segment STARTS, not a range. Look for topic transitions and conversation shifts.

Return ONLY valid JSON. Ensure all strings are properly quoted, no trailing commas:
{
  "segments": [
    {
      "segment_title": "Topic Discussion", 
      "timestamp": "01:15:30",
      "key_takeaway": "main point from this segment",
      "segment_summary": "brief description of what was discussed"
    }
  ]
}

Timestamp format: HH:MM:SS (e.g., 00:05:30, 01:22:45) marking the START of each segment.

Prompt 12: Media Mentions

Now scan the transcript content I provided for ACTUAL mentions of specific media titles:

Find explicit mentions of:
- Books (with specific titles)
- Movies (with specific titles)  
- TV Shows (with specific titles)
- Music/Songs (with specific titles)

DO NOT include:
- Websites, URLs, or web services
- Other podcasts or podcast names

IMPORTANT: 
- Only include items explicitly mentioned by name. Do not invent titles.
- Valid categories are: "Book", "Movie", "TV Show", "Music"
- Include the exact phrase where each item was mentioned
- Find the nearest proximate timestamp where it appears in the conversation
- THE TIMESTAMP OF THE MEDIA MENTION IS IMPORTANT - DO NOT INVENT TIMESTAMPS AND DO NOT MISATTRIBUTE TIMESTAMPS
- Double check that the timestamp is accurate - a timestamp will NEVER be greater than the total length of the audio
- Timestamps are given as ranges, e.g. 01:13:42.520 --> 01:13:46.720. Use the EARLIER of the 2 timestamps in the range.

Return ONLY valid JSON. Ensure all strings are properly quoted and escaped, no trailing commas:
{
  "media_mentions": [
    {
      "title": "Exact Title as Mentioned",
      "category": "Book",
      "author_artist": "N/A",
      "context": "Brief context of why it was mentioned",
      "context_phrase": "The exact sentence or phrase where it was mentioned",
      "timestamp": "estimated time like 01:15:30"
    }
  ]
}

If no media is mentioned, return: {"media_mentions": []}

Prompt 13: Context Setup

You are an expert data extractor tasked with analyzing a podcast transcript. 
I will provide you with part 4 of 4 from a podcast transcript. 
I will then ask you to extract different types of information from this content in subsequent messages. Please confirm you have received and understood the transcript content.

Transcript section:
 all of your symptoms and preserve your bone density.
[03:02:05.720 --> 03:02:16.880] So, preserving bone, preserving bone density, obviously symptoms, but preserving bone density, also lowering cardiovascular risk, lowering Alzheimer's risk.
[03:02:14.760 --> 03:02:19.120] Alzheimer's is less clear, Rhonda.
[03:02:19.360 --> 03:02:31.040] The data right now suggests the following: late initiation of HRT may be counterproductive for AD risk, may actually increase AD risk.
[03:02:31.600 --> 03:02:38.960] Early initiation appears to potentially only be beneficial in E4 women, but not E3 women.
[03:02:38.960 --> 03:02:39.520] Okay.
[03:02:39.520 --> 03:02:46.480] So, for you, I would say doubly beneficial to initiate at the time of menopause because of your E4.
[03:02:46.480 --> 03:02:46.880] Got it.
[03:02:46.880 --> 03:02:47.920] That's really good to know.
[03:02:47.920 --> 03:02:54.880] And also, defining what is early and late, like, you know, so that, you know, there was a study, there's a couple of studies.
[03:02:54.880 --> 03:02:57.520] One was the elite study, and one was the DOPS.
[03:02:57.520 --> 03:03:02.400] So, like, I don't know, it was like early intervention for estradiol or something.
[03:03:03.200 --> 03:03:07.760] And then there was another one that was the Danish osteoporosis prevention study.
[03:03:07.760 --> 03:03:16.400] And both of those studies, in the DOPS one, the initiation of the, they did estradiol.
[03:03:16.400 --> 03:03:21.200] I think they did like triphasic or something, but also they did the progesterone.
[03:03:21.200 --> 03:03:22.720] So I had progesterone as well.
[03:03:23.200 --> 03:03:38.320] It was like the cardiovascular disease risk or mortality went down, the B venous thromboembulism, like the things that happen that can increase with menopause went down over the follow-up, which was 16 years or something.
[03:03:38.640 --> 03:03:48.080] But these women only took it for 11 years, and they started at age either between the age of 45 and 58.
[03:03:48.080 --> 03:03:51.800] So perimenopause is in there, and also just, you know, you know, a few years ago.
[03:03:52.160 --> 03:03:54.640] This is to me the biggest unknown question, Rhonda.
[03:03:54.640 --> 03:03:56.320] And we don't know the answer.
[03:03:56.320 --> 03:04:03.560] And what's what I find very frustrating is we're not going to know the answer because nobody's going to do the study.
[03:04:04.440 --> 03:04:17.560] I am as comfortable with anything in medicine as I am that initiating HRT at the time of menopause does not increase a woman's risk of heart disease, breast cancer, or anything else.
[03:04:17.560 --> 03:04:19.320] In fact, it reduces her risk.
[03:04:19.320 --> 03:04:23.240] It clearly reduces her risk of heart disease, dementia, and BMD.
[03:04:23.240 --> 03:04:26.840] And it's either protective or neutral on cancer.
[03:04:27.240 --> 03:04:28.040] It was neutral on cancer.
[03:04:28.440 --> 03:04:30.760] It's protective or neutral on cancer.
[03:04:30.760 --> 03:04:33.560] I am very confident of all of those things.
[03:04:33.560 --> 03:04:35.720] Here's the thing we don't know.
[03:04:36.040 --> 03:04:38.520] What do you do 10 years later?
[03:04:38.520 --> 03:04:40.440] What do you do when she's 60?
[03:04:40.440 --> 03:04:41.400] Right.
[03:04:41.720 --> 03:04:51.320] And again, if you look at the HRT data from the Women's Health Initiative with all of its flaws, the answer would be you should probably stop.
[03:04:51.640 --> 03:04:57.560] But again, that study is so flawed on so many levels that I'm not sure.
[03:04:57.560 --> 03:05:06.680] And here's where I would argue: there's one area where you absolutely know things will get worse when you stop the estrogen, and that's bone density.
[03:05:06.680 --> 03:05:09.720] So the other things are a little less clear to me.
[03:05:11.720 --> 03:05:25.160] There's some opacity around what will happen to cardiovascular disease risk, dementia disease risk, and cancer disease risk if you start appropriately initiated HRT after 10 or 15 years.
[03:05:25.160 --> 03:05:29.240] But what is unambiguously clear is her bones are going to get brittle again.
[03:05:29.240 --> 03:05:33.000] Because the moment you take the estrogen away, bone density goes down.
[03:05:33.000 --> 03:05:38.440] Estrogen is the most important hormone in men and women for the regulation of BMD.
[03:05:38.760 --> 03:05:46.080] It is the chemical transduction system that turns force into bone building.
[03:05:46.400 --> 03:06:00.000] So we have basically strain gauges in our bones that are sensing forces on the bones, and that force is being turned via estrogen into a chemical signal to osteoblast and osteoclast to promote bone building.
[03:06:00.000 --> 03:06:01.920] And once estrogen goes down, that goes away.
[03:06:01.920 --> 03:06:08.560] So if you take the estrogen off a woman 10 years post-menopause, she will once again go into a rapid state of decline.
[03:06:08.560 --> 03:06:14.800] Now, she's still better off because she'll still be further ahead than where she is if you put her in decline 10 years sooner.
[03:06:14.800 --> 03:06:24.480] So, you know, I've had arguments with people on the anti-HRT side, and they say, you should never use estrogen for treating BMD because we have bisphosphonates.
[03:06:24.480 --> 03:06:27.520] And I say, first of all, you only use bisphosphonates for three to five years.
[03:06:27.520 --> 03:06:31.120] Two, they suck, meaning they're not as good as estrogen.
[03:06:31.120 --> 03:06:34.960] And third, you can use estrogen for longer.
[03:06:34.960 --> 03:06:39.120] And they say, well, yeah, but once you take it off, it still goes down.
[03:06:39.120 --> 03:06:40.640] And it's like, yeah, but it's a new baseline.
[03:06:40.640 --> 03:06:41.120] And it's a high-tech.
[03:06:41.280 --> 03:06:42.240] It's like waiting to retire.
[03:06:42.240 --> 03:06:46.640] Like you're going to have more in your retirement fund if you retire at 70 versus 60.
[03:06:47.600 --> 03:06:48.880] This is the big question.
[03:06:48.880 --> 03:07:20.000] Because, I mean, and my, and again, we've done a back of the envelope calculation that would suggest even if the risk of Alzheimer's disease or heart disease or cancer, even if you lost any protection from HRT and maybe had a slight increase in risk, given how big their risk of falling is, you might still end up being neutral risk, carrying out HRT indefinitely.
[03:07:20.320 --> 03:07:22.400] So this is where, you know, the lifestyle factors.
[03:07:22.480 --> 03:07:23.680] Which is quality of life.
[03:07:23.680 --> 03:07:24.000] Right.
[03:07:24.240 --> 03:07:42.840] But this is probably where lifestyle factors do play somewhat of a role as well, because if you have, obviously, if you've been doing resistance training up until that point and continuing it, you're building not only bone, you've certainly built up a lot of bone density reserve earlier in life, but muscle mass helps, right?
[03:07:42.840 --> 03:07:51.400] And then let me throw this at you because I've thought a lot about the nuclear hormone, nuclear hormones, basically.
[03:07:51.800 --> 03:07:54.280] So vitamin D is the one that I've really focused on.
[03:07:54.280 --> 03:08:01.480] And when I was doing a lot of research on it, so nuclear hormones, you know, we have steroid hormones, nuclear steroid hormones, I should say, sorry.
[03:08:01.480 --> 03:08:04.120] So we have estrogen, testosterone, vitamin D is one.
[03:08:04.120 --> 03:08:09.720] So these are binding to a receptor that, you know, in some cases, the receptor complexes with other ones.
[03:08:09.720 --> 03:08:18.280] It goes into the nucleus of a cell, which is where all the DNA is, and it goes down to the level of genes and it recognizes a little sequence of genes.
[03:08:18.280 --> 03:08:21.800] So in the case of estrogen, it's called an estrogen response element, an ERE.
[03:08:21.800 --> 03:08:25.400] In the case of vitamin D, it's called a VDRE, vitamin D response element.
[03:08:25.720 --> 03:08:33.880] There's a lot of overlap between vitamin D and the estrogen in terms of the genes they're regulating.
[03:08:33.880 --> 03:08:48.360] And so I'm wondering if avoiding vitamin D deficiency also becomes one of those important lifestyle factors because in some cases, obviously vitamin D also plays a role in bone metabolism, right?
[03:08:48.680 --> 03:08:57.080] But independent of that, also just looking at the crosstalk of the genes that vitamin D and estrogen are regulate, and they're like, they're both.
[03:08:57.080 --> 03:09:05.560] And the response elements are, they're different, but they're somewhat, I'm looking at that and it's like, oh, I wonder if there's like, that seems like you might be able to compensate a little.
[03:09:05.560 --> 03:09:12.120] So it's kind of another interesting, in addition to being, you know, physically active, resistance training, one of the most important things, right?
[03:09:12.360 --> 03:09:14.120] But also, like, I did a lot of jump roping.
[03:09:14.120 --> 03:09:16.480] I was a star jump roper as a kid.
[03:09:14.840 --> 03:09:21.760] Lots and lots of jumping rope, which there is evidence that that also builds bone density.
[03:09:22.080 --> 03:09:23.440] So I want to ask you a question about this.
[03:09:23.440 --> 03:09:38.400] So, what do we know about the relationship between call it naturally acquired vitamin D through sunlight versus supplementation of vitamin D exogenously through a supplement?
[03:09:38.880 --> 03:09:44.000] Do we have any reason to believe that those are different at the same level of vitamin D?
[03:09:44.320 --> 03:09:47.840] In the same, like in terms of like how vitamin D is acting.
[03:09:47.840 --> 03:09:51.520] So the thing is, is that when you're in sunlight, like there's other things going on.
[03:09:51.760 --> 03:09:52.560] Right, that's my point.
[03:09:52.560 --> 03:09:55.120] Like if you're outsourcing sunlight, you're more active.
[03:09:55.120 --> 03:09:56.240] And you're nitric oxide.
[03:09:56.240 --> 03:09:59.760] Like there's like other things that you're getting from the sunlight.
[03:09:59.760 --> 03:10:01.840] So there's a confounder there.
[03:10:02.000 --> 03:10:16.960] But I mean, like with respect to, let's say, forget every, like, let's say you finally, you, you convert the vitamin D3 into the 25-hydroxy vitamin D into the 125, you know, at that level, it's, it is the same, like, you know, to some degree.
[03:10:16.960 --> 03:10:28.000] I mean, that's not, when it's, when it's binding to the vitamin D receptor, like the actual 125 hydroxy vitamin D, which is the active steroid hormone, it's the same.
[03:10:28.800 --> 03:10:39.600] Now, with respect to like, you know, your body regulates how much vitamin D3 is converted or is released in the bloodstream and converted into 25 hydroxy vitamin D at the level of sun exposure.
[03:10:39.600 --> 03:10:44.000] So at a certain level, you're not making the vitamin D3 when you've gotten so much of it.
[03:10:44.000 --> 03:10:45.760] That's how you avoid toxicity, right?
[03:10:45.760 --> 03:10:47.440] Like you're not, you're not going to keep.
[03:10:47.600 --> 03:10:51.440] Yeah, what's the highest level of vitamin D a person can ever get to naturally?
[03:10:51.440 --> 03:11:00.680] Meaning, if you just like took an individual and put them in the sun, put, you know, shorts only, no shirt, go out there and work in the sun for all summer.
[03:11:00.840 --> 03:11:01.480] Like, how high?
[03:11:01.480 --> 03:11:05.560] Like, how high were my vitamin D levels when I was in high school working construction?
[03:11:05.560 --> 03:11:22.440] I know, I, I, I know there's like data out there where people have looked at like, you know, you know, people that are that are like out in the they're out they're outside all the time, but they're all they're honestly often looking at people like in the tropics and stuff that have more melanin.
[03:11:22.680 --> 03:11:23.160] Yeah, yeah.
[03:11:23.160 --> 03:11:26.840] Yeah, which again, so it might depend also on that.
[03:11:27.000 --> 03:11:36.200] But that would be an interesting at least way to say, like, if the body has a built-in mechanism to say, I'm not going to let you make more vitamin D than this, supplementing above that would be a bad idea.
[03:11:36.200 --> 03:11:36.920] And it is, yeah.
[03:11:36.920 --> 03:11:40.680] Like, and so that's why looking at measuring that threshold is.
[03:11:41.720 --> 03:11:46.440] I think going above 60 nanograms per milliliter is probably still okay.
[03:11:46.440 --> 03:11:54.600] Like going to 80, you know, like there's studies looking at 80 and it's still associated with lower all-cause mortality.
[03:11:55.400 --> 03:12:04.680] And in fact, I mean, honestly, if you start to look at some of the literature, you have to take a really high dose daily for like a decade to start getting like the high calcium.
[03:12:04.680 --> 03:12:16.280] But like the problem is that when you absorb, when you have a lot of vitamin D, you absorb more dietary calcium and you also absorb more phosphorus and calcium plus phosphorus can precipitate, right?
[03:12:16.280 --> 03:12:22.040] And so like there's so many factors involved, but I think most people are not supplementing.
[03:12:22.040 --> 03:12:29.560] Like there's some people that are crazily supplementing and it's like they just think more of everything is good, but I don't think most people are doing that.
[03:12:29.560 --> 03:12:33.200] Like I don't think taking 5,000, 7,000 IEs, for most people.
[03:12:33.200 --> 03:12:35.640] Some people have to take more than that because they have SNPs, right?
[03:12:35.640 --> 03:12:40.520] And you've probably seen it in your patients where it's like, they got to take a high level just to get up to 30 or 40.
[03:12:41.000 --> 03:12:52.720] This, by the way, is why I think all these vitamin D trials, the mega trials, are so flawed: they're always doing it on the basis of A, they're taking too low a dose and they're doing it based on dose, not level.
[03:12:52.880 --> 03:13:06.320] Like to me, the dispositive study on this would be: take a whole bunch of people whose vitamin D is 30, give half of them a placebo, give half of them whatever vitamin D is necessary to get them to 60 or 80.
[03:13:06.320 --> 03:13:07.520] 80, yeah, get something higher.
[03:13:07.520 --> 03:13:08.960] Yeah, create separation.
[03:13:10.160 --> 03:13:12.560] But be like, do it the way we do blood pressure trials.
[03:13:12.560 --> 03:13:16.160] When we do a blood pressure trial, we don't say you're going to take a fixed dose of a med.
[03:13:16.160 --> 03:13:19.920] We give you whatever dose of the med is necessary to change the blood pressure.
[03:13:19.920 --> 03:13:28.240] So we're comparing two blood pressure levels, not placebo versus 10 milligrams of a drug that for one guy is too much and for one guy is too little.
[03:13:28.240 --> 03:13:39.040] And yet this isn't done in vitamin D, and I find it infuriating that we have no really good, reliable RCT data on what seems like a juggular question.
[03:13:39.040 --> 03:13:43.920] Are you better off with a vitamin D level of 80 than you are of 30?
[03:13:43.920 --> 03:13:55.840] I mean, again, we think the answer is yes, but the evidence-based medicine crowd will tell you no, because this trial that gave people 2,000 IU for 10 minutes found no difference.
[03:13:55.840 --> 03:13:56.160] Right.
[03:13:56.160 --> 03:14:02.000] Or they measured maybe, if they measured anyone's level, they measured like 10% of the population.
[03:14:02.000 --> 03:14:02.400] Yes, exactly.
[03:14:02.480 --> 03:14:03.680] Like the most recent study.
[03:14:03.680 --> 03:14:05.600] We only got a level on 10% of people.
[03:14:06.080 --> 03:14:09.840] With like, you know, the fact of the matter is so many people do have these SNPs too.
[03:14:10.160 --> 03:14:12.720] And I remember having an email dialogue with Joanne Manson.
[03:14:12.720 --> 03:14:14.400] This was years ago when I was postdoc.
[03:14:14.400 --> 03:14:17.200] And she was, I think at the time, she was doing the vital study.
[03:14:17.200 --> 03:14:18.240] It hadn't been published yet.
[03:14:18.240 --> 03:14:22.880] And it was like, please, please, can you get the SNP data in there?
[03:14:22.880 --> 03:14:24.320] Can you measure the levels?
[03:14:24.320 --> 03:14:28.000] Like, do everything, you know, like, it's so important.
[03:14:28.160 --> 03:14:29.120] But I'm with you on that.
[03:14:29.440 --> 03:14:31.800] I think what is clear is avoiding deficiency.
[03:14:31.800 --> 03:14:32.760] And I do say that a lot.
[03:14:33.160 --> 03:14:34.040] And where are you drawing the line?
[03:14:34.280 --> 03:14:35.640] Is 30 or 40 where you?
[03:14:29.840 --> 03:14:36.360] I say 30.
[03:14:36.600 --> 03:14:43.560] I mean, it does depend on: are you looking at what the Endocrine Society says is more of an adequate level or inadequate?
[03:14:43.640 --> 03:14:50.680] Are you looking at deficiency where you're like literally your bone health isn't good?
[03:14:51.960 --> 03:14:54.600] But for me, I want to know the same thing.
[03:14:54.760 --> 03:14:58.920] I'm always kind of like hovering around 50, 60, but I'm like, should I be at 80?
[03:14:58.920 --> 03:14:59.320] Yeah.
[03:14:59.800 --> 03:15:01.480] And I don't know.
[03:15:01.640 --> 03:15:04.040] So it's always like, okay, well, I'll err on the side of caution.
[03:15:04.360 --> 03:15:05.320] Err on the side of caution.
[03:15:05.320 --> 03:15:06.760] Certainly avoiding deficiency.
[03:15:07.640 --> 03:15:25.320] But even with respect to all these genes I'm talking about, what if there's some crosstalk with there is crosstalk, but what if there's some way that having a level of vitamin D, 50 or 60 nanograms per milliliter, does help alleviate some of the effects of having no estrogen?
[03:15:25.800 --> 03:15:26.520] We don't really know.
[03:15:26.520 --> 03:15:27.320] That's interesting.
[03:15:27.400 --> 03:15:29.320] It is, especially when you look at the mechanism.
[03:15:29.320 --> 03:15:41.000] And like I said, I spent a lot of time looking at these response elements and looking at the fact that estrogen can actually compensate for vitamin D deficiency in some cases with certain genes too.
[03:15:41.000 --> 03:15:42.120] And it goes both ways.
[03:15:42.120 --> 03:15:48.040] So I'm like, well, I feel like that should be an important component in the equation, right?
[03:15:48.840 --> 03:15:50.120] But I'm with you on the 10.
[03:15:50.120 --> 03:16:05.800] Like, even the studies I was talking about where there was protective effects against, you know, in the cardiovascular health, in cancer prevention with hormone replacement therapy, when initiated, like, you know, within a close range, like not greater than six years.
[03:16:05.800 --> 03:16:06.760] So it's six years or less.
[03:16:06.760 --> 03:16:10.120] So if you're doing it seven years, that's not part of the study.
[03:16:10.440 --> 03:16:12.840] They only did it for like 10 or 11 years and they stopped.
[03:16:13.400 --> 03:16:17.040] And it's like, well, what happens then when you're 65?
[03:16:17.040 --> 03:16:23.600] And if you started at 55, you know, like, so we don't know the question to that, I mean, the answer to that either.
[03:16:24.240 --> 03:16:25.680] But I'm happy that you're thinking about it.
[03:16:25.920 --> 03:16:26.080] So.
[03:16:26.320 --> 03:16:33.120] Oh, you know, one thing maybe even before we go to male hormones that I didn't mention on the female side was testosterone.
[03:16:33.600 --> 03:16:39.360] And this is, you know, I mentioned earlier, of course, the abundance of testosterone in a woman prior to menopause.
[03:16:39.360 --> 03:16:47.680] But what's far less studied is the impact of testosterone replacement in women post-menopause.
[03:16:47.680 --> 03:16:50.000] And this is something that is being studied.
[03:16:50.960 --> 03:17:00.240] So by the time this podcast comes out, there'll be a couple of podcasts I've released on the topic of sexual health, but through the lens of both male and female.
[03:17:00.400 --> 03:17:05.040] So Sharon Parrish and Mo Cara will be the two folks that I've discussed with on that.
[03:17:05.040 --> 03:17:08.080] And Mo's actually involved, he's at Baylor in Texas.
[03:17:08.080 --> 03:17:15.600] He's involved in a study that is looking at the use of testosterone replacement in women for sexual function.
[03:17:15.600 --> 03:17:27.040] So both Mo and Sharon talk extensively about the importance of testosterone in sexual function, specifically around libido and orgasmic function, along with arousal.
[03:17:27.040 --> 03:17:33.520] So this is like, I mean, I've said this before, you know, I said it, I think, to them on the podcast.
[03:17:33.520 --> 03:17:38.240] It's rare that I go into a podcast with so little information on a topic.
[03:17:38.240 --> 03:17:43.200] Usually I like, you know, like you, like, you know all the answers to the questions you're asking me because you've prepared for it, right?
[03:17:43.200 --> 03:17:48.240] But, you know, usually when I'm going into a podcast, I kind of know what's going on.
[03:17:48.240 --> 03:17:53.680] But I was blown away in my discussions with Mo and Sharon on these topics.
[03:17:53.680 --> 03:18:03.800] So the long and short of it is we have become much more liberal in our use of testosterone in women for any sort of sexual side effects.
[03:18:04.120 --> 03:18:12.200] Also, keep in mind, we've talked about it, but the importance of maintaining muscle mass as you age is imperative, just as imperative for women as it is for men.
[03:18:12.200 --> 03:18:14.520] And testosterone is the dominant hormone there.
[03:18:14.520 --> 03:18:19.240] So again, when people hear this, they kind of think, what are we talking about, like anabolic steroids?
[03:18:19.240 --> 03:18:21.880] And it's like, well, yeah, testosterone is an anabolic steroid.
[03:18:21.880 --> 03:18:26.440] What we're talking about is replacing women to the levels that they were at in their 30s and 40s.
[03:18:26.440 --> 03:18:37.000] These are very, very low levels of testosterone, typically about one-tenth the dose that men take to also have a physiologic replacement.
[03:18:37.000 --> 03:18:41.080] And that's about 1/10th the level that bodybuilders would take.
[03:18:41.080 --> 03:18:48.680] So we're not talking about huge amounts of testosterone, but just restoring someone to physiologic levels can have profound impacts.
[03:18:48.680 --> 03:18:54.120] But is that in combination with also giving these women the estrogen progesterone?
[03:18:54.360 --> 03:18:58.600] Because what would happen if you just were doing the testosterone?
[03:18:58.600 --> 03:19:07.000] And let's say a woman was 10 years out, missed the whole window.
[03:19:09.240 --> 03:19:13.560] And this is something that people have asked me: what do I do?
[03:19:13.560 --> 03:19:20.680] Like, how do I, you know, get some benefits, you know, without actually taking, you know, estrogen and progesterone?
[03:19:20.920 --> 03:19:22.280] Would you also give that person?
[03:19:22.520 --> 03:19:23.800] So there's two questions here.
[03:19:23.800 --> 03:19:24.760] There are, yeah.
[03:19:25.560 --> 03:19:26.360] Great question.
[03:19:28.040 --> 03:19:29.560] We handle each of those.
[03:19:29.560 --> 03:19:31.960] I hate to say this because it sounds like such an obvious cliche.
[03:19:31.960 --> 03:19:34.440] We handle each of those on a case-by-case basis.
[03:19:34.760 --> 03:19:37.240] So I won't sugarcoat it.
[03:19:37.240 --> 03:19:42.920] Like, we're not very comfortable doing, initiating HRT in women who are 10 years out.
[03:19:42.920 --> 03:19:52.800] But at the same time, we realize there are a lot of women who are 60 today who went through menopause at the height of the stupidity around the WHI.
[03:19:52.800 --> 03:19:58.720] And as a result of that, like they're worse off today than they would have been had they been on the appropriate hormones 10 years ago.
[03:19:58.720 --> 03:20:03.360] And we have to make a very difficult decision about whether it's worth additional risk.
[03:20:03.360 --> 03:20:06.720] And I say that because we don't know what the risk is.
[03:20:07.360 --> 03:20:19.120] And so the way we handle that is we basically try to figure out what is your risk of AD, ASCBD, and cancer, specifically breast cancer, as it stands now.
[03:20:19.440 --> 03:20:36.880] And, you know, for example, if a woman is especially high risk for one of those things, particularly AD, if she's a 3-3 or even a 3-4-4-4, and/or if she's very high risk of breast cancer, we might be a little bit more reluctant to do so.
[03:20:37.200 --> 03:20:44.000] Or if we do it, we do it at an even lower dose than we normally would, and we have to increase our surveillance around those things.
[03:20:44.320 --> 03:20:46.400] So not an easy question.
[03:20:46.400 --> 03:20:54.000] To your other question, would we be comfortable using testosterone in isolation without opposition?
[03:20:54.640 --> 03:21:00.720] I would say at this point, I'm not, I'm not, I don't think I know the answer to that question yet.
[03:21:01.360 --> 03:21:07.280] And I think that that's something that would need further study before we could sort of make a clear recommendation.
[03:21:07.920 --> 03:21:14.720] In the cases of the, in your clinical practice, you're handling the hormone replacement therapy.
[03:21:14.880 --> 03:21:16.480] Is testosterone part of that equation?
[03:21:16.480 --> 03:21:19.080] Or do you ask, is it like a more of a symptom thing?
[03:21:19.080 --> 03:21:24.920] Like my libido is down, even though I'm also on estrogen with it's not a standard.
[03:21:25.120 --> 03:21:27.120] Yeah, it's not, nothing is standard, right?
[03:21:27.120 --> 03:21:28.320] Everything is bespoke.
[03:21:28.320 --> 03:21:31.560] And I think that that's just really important for anybody listening to this, right?
[03:21:31.560 --> 03:21:35.560] It's like you don't want to go to somebody who's does paint by numbers.
[03:21:29.840 --> 03:21:37.240] You know, paint by numbers is a bad approach.
[03:21:37.400 --> 03:21:38.760] Everybody's on this, everybody's on that.
[03:21:38.760 --> 03:21:39.400] No, no, no.
[03:21:39.400 --> 03:21:43.480] It's like, you know, some women do not absorb testosterone very well.
[03:21:43.480 --> 03:21:47.320] Pardon me, do not absorb estrogen very well from a cream.
[03:21:47.320 --> 03:21:50.680] Some, you know, might end up requiring to take it orally.
[03:21:50.680 --> 03:21:54.200] Some much prefer a cream, some prefer a patch.
[03:21:54.200 --> 03:21:57.960] Some can tolerate, some only need this dose, some need that dose.
[03:21:57.960 --> 03:22:00.360] Some need a very small amount of oral progesterone.
[03:22:00.360 --> 03:22:05.800] You do need at least 100 milligrams to oppose the estrogen at the endometrial level.
[03:22:05.800 --> 03:22:09.000] So somewhere between 100 and 200 is probably necessary.
[03:22:09.000 --> 03:22:11.800] Some can't tolerate it at all, and you have to use the IUD.
[03:22:11.800 --> 03:22:14.680] When it comes to testosterone, there's lots of ways to deliver it, right?
[03:22:14.680 --> 03:22:20.200] So one of the most interesting ways that's being studied now is using an FDA-approved product.
[03:22:20.200 --> 03:22:31.480] It's not approved for this use, so it's called Natesto, and it's an intranasal testosterone spray that is FDA-approved for male use for testosterone replacement therapy.
[03:22:32.440 --> 03:22:34.120] But it's being used off-label.
[03:22:34.120 --> 03:22:38.120] It's also being tested in a clinical trial for libido in women.
[03:22:38.120 --> 03:22:39.800] It has a higher acting.
[03:22:39.800 --> 03:22:46.360] So another point to think about here is where the testosterone, where the androgen receptors are, factors into it.
[03:22:46.360 --> 03:22:59.480] So the intranasal testosterone probably is more rapid acting in terms of sex drive and libido, whereas the intravaginal testosterone for women increases orgasmic function.
[03:22:59.480 --> 03:23:06.120] So even the way in which you use testosterone can impact function and what your indication is.
[03:23:07.400 --> 03:23:14.840] And a question I have is, well, one of the questions I had regarding men had to do with the types of testosterone you're administering.
[03:23:15.040 --> 03:23:25.120] But taking a step back, you hear a lot about low T, low T, and there's this controversy around it.
[03:23:25.120 --> 03:23:26.720] Like, what defines low T?
[03:23:26.720 --> 03:23:27.840] Is it a level?
[03:23:27.840 --> 03:23:30.480] Is it a combination of levels and symptoms?
[03:23:31.200 --> 03:23:37.600] So, how are, like, we're looking at menopause in women, we're talking about an average age of about 51 or something like that, right?
[03:23:38.240 --> 03:23:43.360] Men, let's take the same period of life from men, okay, 50s.
[03:23:43.680 --> 03:23:46.960] Do they start to experience like a decrease in testosterone?
[03:23:47.440 --> 03:23:51.680] Yeah, but it's more gradual, and it starts, frankly, in your 20s and 30s.
[03:23:52.320 --> 03:23:58.720] So, male testosterone probably peaks in the 20s, and it's just a slow, steady decline.
[03:23:59.760 --> 03:24:08.800] It's not like in the case of women where they, you know, they go through puberty, they have these hormones that are cyclical, and then fall off a cliff.
[03:24:08.800 --> 03:24:14.320] With men, it's sort of you go through puberty, you kind of peak, and then you're on a slow decline down.
[03:24:14.640 --> 03:24:16.480] So, you're right.
[03:24:16.480 --> 03:24:29.360] Low T is really a combination of levels and symptoms, and it's really important to remember that symptoms matter because levels are really, well, how can I put it delicately?
[03:24:29.360 --> 03:24:33.520] I mean, just not as helpful as we'd like to believe they are.
[03:24:33.840 --> 03:24:36.720] And it actually comes back to something you talked about a minute ago, right?
[03:24:36.720 --> 03:24:39.760] Which is how do these hormones work?
[03:24:39.760 --> 03:24:51.680] These hormones work by binding to androgen receptors, and the testosterone-androgen receptor complex has to make its way into the nucleus where it impacts transcription factors.
[03:24:51.680 --> 03:25:01.640] Now, we know that not all men have the same density of androgen receptors, and we know that not all androgen receptors function in the exact same way.
[03:25:01.640 --> 03:25:09.960] So, we have this problem, which is we sit here and we measure testosterone levels in men, and maybe we measure bioavailable or free testosterone, but those are just estimates.
[03:25:09.960 --> 03:25:13.640] They aren't actually telling you free testosterone level.
[03:25:13.880 --> 03:25:18.600] You're measuring total testosterone, you're measuring sex hormone binding globulin, you're measuring albumin.
[03:25:18.600 --> 03:25:28.760] You use those to estimate the free amount of testosterone, but that's still an estimate, kind of like LDLC calculated by the Friedwald formula is an estimate.
[03:25:28.760 --> 03:25:36.440] And then you sort of have to guess: well, maybe their androgen receptors are saturated, maybe they're not.
[03:25:36.440 --> 03:25:54.600] But if you're giving a guy testosterone in the presence of mild to low T, you're assuming his androgen receptors are not saturated, and therefore giving him more testosterone will lead to an increased saturation of the AR and will lead to more nuclear transcription.
[03:25:54.600 --> 03:25:57.160] But we have no way of measuring that.
[03:25:57.160 --> 03:26:07.960] And so, what I always say to patients is: I got to see a certain set of symptoms in combination with a biochemical set of labs that makes sense.
[03:26:07.960 --> 03:26:13.320] And then we have to test it out, but it's not going to be a placebo test, so we're going to have a placebo effect.
[03:26:13.320 --> 03:26:22.360] And then, if the response we see isn't a hell yes, I think we should pull it all off and see if we notice a response in the deficit.
[03:26:22.360 --> 03:26:24.520] And I'm looking for symptoms as follows, right?
[03:26:24.520 --> 03:26:27.080] So, I'm looking for some signs and some symptoms.
[03:26:27.080 --> 03:26:28.440] Most of it is symptoms.
[03:26:28.440 --> 03:26:33.160] So, it's reduction in libido, reduction in energy, mood.
[03:26:33.480 --> 03:26:43.400] And then, on the signs, we're kind of looking for insulin resistance, difficulty putting on muscle mass, and difficulty recovering from exercise.
[03:26:43.400 --> 03:26:45.760] Those are kind of your big ones.
[03:26:44.760 --> 03:26:51.920] And some combination of those signs and symptoms, coupled with a biochemical story that's plausible.
[03:26:52.240 --> 03:27:03.280] So, you know, your total testosterone might be below the 30th percentile or even 40th percentile, and your free is commensurate with that, even though, again, that's an estimate.
[03:27:03.280 --> 03:27:06.320] There's probably reason in my book to initiate.
[03:27:07.600 --> 03:27:12.080] And is there a level that you decide to go to?
[03:27:12.080 --> 03:27:15.920] Like, so, I mean, is there like a threshold where it's like, this is too much testosterone?
[03:27:16.080 --> 03:27:19.040] Yeah, it's actually kind of like what we were talking about on the vitamin D front.
[03:27:19.040 --> 03:27:21.360] Like, don't be too incremental.
[03:27:21.360 --> 03:27:22.640] You're not going to get the answer.
[03:27:22.640 --> 03:27:32.080] So, if, and again, each lab is going to have different scales, but in the lab, we use the fifth percentile of total testosterone.
[03:27:32.080 --> 03:27:36.240] Well, let's do free testosterone because we actually, even though free is an estimate, we kind of look more closely at free.
[03:27:36.240 --> 03:27:45.520] So, approximately the fifth percentile is five nanograms per deciliter, and the 95th percentile is about 24 nanograms per deciliter.
[03:27:45.520 --> 03:27:48.160] So, call it five to 25, basically.
[03:27:48.480 --> 03:27:58.640] So, if a guy is at eight and we have the case to make that he's going to, we should try TRT, I'm not going to take him to 12.
[03:27:58.640 --> 03:27:59.760] It's incremental.
[03:27:59.760 --> 03:28:04.240] Like, I'm going to take him from eight to 20 and see if something matters.
[03:28:04.320 --> 03:28:21.440] And if he says to me at 20, I don't feel any different, and we take it away and he says, I don't feel any different, unless we were only treating this for insulin resistance and muscle mass, those were the only things, in which case I would say we still say the course and see if those things get better.
[03:28:21.440 --> 03:28:36.360] But if he, you know, if we were doing this because there was, you know, some of the other actual symptoms, then I would say that, look, this guy might have been already saturated at eight nanograms per deciliter where he started, and all that additional testosterone may have done him no good.
[03:28:36.680 --> 03:28:45.640] Whereas somebody else might have been woefully under saturated, and when you increased him by 150%, you actually got benefit from it.
[03:28:45.960 --> 03:28:50.040] Does the like injection versus like a gel, does that matter?
[03:28:50.760 --> 03:28:53.480] We're very biased towards injections.
[03:28:53.720 --> 03:28:56.040] I think they're far more consistent.
[03:28:56.840 --> 03:29:02.680] I think you have variable absorption, and it doesn't just vary by individual, it varies by time of day.
[03:29:02.680 --> 03:29:12.360] So, you know, for example, like if you're if you just finished a workout and you're sweating and you even if you go and have a shower, you're still kind of in a less absorptive state than maybe if you're cold.
[03:29:13.320 --> 03:29:15.720] You know, what part of your body do you put it on?
[03:29:15.720 --> 03:29:17.640] Do you have to exfoliate the skin first?
[03:29:17.640 --> 03:29:19.000] Do you have hair on the skin?
[03:29:19.000 --> 03:29:21.800] You know, you want to put it on an area that doesn't have hair.
[03:29:21.800 --> 03:29:23.400] There's just more issues with it.
[03:29:23.960 --> 03:29:26.760] So we recommend an injection.
[03:29:26.760 --> 03:29:33.400] We also recommend instead of doing it every two weeks, which is standard, doing it twice a week at obviously a much lower dose.
[03:29:33.400 --> 03:29:38.600] So typical dose would be somewhere between 80 and 100 milligrams of testosterone a week.
[03:29:38.600 --> 03:29:42.040] So it would be 40 to 50 milligrams twice a week.
[03:29:42.040 --> 03:29:47.720] And that produces just a much more steady level because you're really trying to get the steadiest level possible.
[03:29:47.720 --> 03:30:00.520] And the problem with doing it every two weeks, which was usually done in the days when people would go to their doctor to get the injection and you wanted to minimize the inconvenience of that, you're just supra physiologic for four or five days.
[03:30:00.520 --> 03:30:05.240] Then you're kind of physiologic, and then you're actually backed down to being very sub-physiologic before the dose.
[03:30:05.240 --> 03:30:06.360] So we'd like to avoid that.
[03:30:06.760 --> 03:30:12.600] Is there any, like, what's the relationship between testosterone replacement therapy and like the prostate?
[03:30:13.320 --> 03:30:14.480] Yeah, very well studied.
[03:30:14.720 --> 03:30:16.960] So a couple things we know as clear as day, right?
[03:30:14.280 --> 03:30:21.520] So we know that the lower the testosterone, the higher the risk of high-grade prostate cancer.
[03:30:14.680 --> 03:30:27.600] So again, contrary to popular belief, testosterone replacement therapy does not increase the risk of prostate cancer.
[03:30:28.880 --> 03:30:33.600] But what it does do is potentially increase BPH, benign prostatic hypertrophy.
[03:30:33.600 --> 03:30:36.560] So it does increase the size of the prostate potentially.
[03:30:36.880 --> 03:30:39.280] So one needs to be mindful of that.
[03:30:39.280 --> 03:30:41.520] And also, there are side effects of testosterone, right?
[03:30:41.520 --> 03:30:50.160] It will drive hair loss in an individual who's susceptible to hair loss through the sort of androgen pathways there.
[03:30:50.480 --> 03:30:53.120] It can increase acne in a susceptible individual.
[03:30:53.120 --> 03:31:02.160] Again, these things are typically more the type of side effects that people talk about when testosterone is being used in supraphysiologic levels.
[03:31:02.160 --> 03:31:11.040] So I'm just trying to think the last time we saw a patient who had acne, I'll probably see it once a year.
[03:31:11.600 --> 03:31:14.320] So these are really infrequent side effects.
[03:31:14.480 --> 03:31:18.000] But we do have a lot of patients who are concerned about hair loss.
[03:31:18.000 --> 03:31:23.040] And so we say, look, I mean, there are strategies around that.
[03:31:23.040 --> 03:31:26.400] Of course, you can take a 5-alpha reductase inhibitor.
[03:31:26.560 --> 03:31:32.320] So those are drugs that block the conversion of testosterone to dihydrotestosterone, which is a more potent androgen.
[03:31:32.320 --> 03:31:36.480] And that's the androgen that's driving androgen-specific hair loss.
[03:31:38.400 --> 03:31:40.720] Or they might say, you know, like I've had patients say, oh, you know what?
[03:31:40.720 --> 03:31:45.120] Like my hair matters more to me than my testosterone, and I don't want to testosterone.
[03:31:45.840 --> 03:31:48.560] So, those are the things that we just kind of want to point out.
[03:31:49.200 --> 03:32:04.760] The only other thing that's worth noting is I do believe that in a susceptible individual, in the short run, there's probably a slight increase in their risk of cardiovascular events with testosterone, and it's probably borne through an increase in blood pressure.
[03:32:05.080 --> 03:32:12.760] So, there was a very large study that looked at kind of high-risk men, and they were given testosterone.
[03:32:12.760 --> 03:32:22.440] And at one year post-initiation of TRT, there was a slight increase in the risk of major adverse cardiac events in the testosterone group compared to the placebo group.
[03:32:22.440 --> 03:32:33.560] That vanished at two and three years, almost suggesting that the highest-risk men, probably those that were closest to having an event, were actually pushed over the edge a little bit.
[03:32:33.560 --> 03:32:39.480] Again, I would probably attribute that to an increase in blood pressure as the thing that was potentially driving it.
[03:32:39.480 --> 03:32:46.920] So, you know, we're not keen to put guys on testosterone until we have the house in order with respect to everything else.
[03:32:47.480 --> 03:32:50.840] What sort of blood pressure do you, like, levels do you like to?
[03:32:51.080 --> 03:32:52.280] We're very aggressive, right?
[03:32:52.280 --> 03:33:01.560] I mean, if you look at the sprint trial, I think it's very clear that 120 over 80 or better is the place to be, and that's better than 130 over 85, which used to be the standard.
[03:33:01.560 --> 03:33:02.600] For hypertension, right?
[03:33:02.600 --> 03:33:03.160] That's right.
[03:33:03.480 --> 03:33:03.960] Okay.
[03:33:03.960 --> 03:33:05.880] So, we're very aggressive.
[03:33:06.360 --> 03:33:17.800] The good news with blood pressure, unlike the lipid, you know, we spent a lot of time talking about lipids, and a listener may come away from that thinking, okay, there's some dietary stuff, but you guys didn't talk about exercise, and you're right.
[03:33:17.800 --> 03:33:19.560] Exercise doesn't move lipids that much.
[03:33:19.560 --> 03:33:24.040] Like, you're going to be, you're heading down the path of pharmacology much sooner on the lipid front.
[03:33:24.040 --> 03:33:32.120] But blood pressure is just as big a risk factor for cardiovascular disease as lipids, and it's way more amenable to, I hate the word, but lifestyle intervention.
[03:33:32.120 --> 03:33:36.600] You know, losing weight and exercising will fix a lot of people's blood pressure.
[03:33:36.600 --> 03:33:37.480] Not everybody.
[03:33:37.480 --> 03:33:44.440] We have some very lean, fit, healthy people in our practice who still have essential hypertension, and it has to be lowered pharmacologically.
[03:33:44.440 --> 03:33:54.560] But for many people, losing 20 pounds and exercising, especially cardio, is going to do amazing things on their blood pressure.
[03:33:54.560 --> 03:34:00.960] Have you looked at, so I have a relative who exercises, good diet.
[03:34:00.960 --> 03:34:06.320] Like the only thing that lowers her blood pressure is hot tubs.
[03:34:06.560 --> 03:34:07.200] Interesting.
[03:34:07.200 --> 03:34:08.400] In addition to the exercise.
[03:34:08.400 --> 03:34:08.880] Interesting.
[03:34:08.880 --> 03:34:13.200] And it's like very, she's also a very high stress, like so she's, which is obviously.
[03:34:13.520 --> 03:34:14.800] I wonder if, it's funny.
[03:34:14.800 --> 03:34:24.800] I wonder if it's the impact of, you know, whether it be sauna or hot tub on hypercortisolemia that might be having the indirect effect on blood pressure.
[03:34:24.800 --> 03:34:27.120] Because she is absolutely prone to high cortisol.
[03:34:27.360 --> 03:34:28.800] She's like, it's a very high stress.
[03:34:28.800 --> 03:34:34.560] And the other thing is, you know, so Dan, he also, I mean, he exercises a lot.
[03:34:34.880 --> 03:34:36.480] Like we have the same diet.
[03:34:37.040 --> 03:34:42.560] My blood pressure, I mean, like, I've got phenomenal blood pressure, like always, always, I mean, like, really low.
[03:34:42.560 --> 03:34:46.640] Like, I'm actually on the side of like, I need to make sure I'm not like too low.
[03:34:46.640 --> 03:34:46.800] Yeah.
[03:34:47.760 --> 03:34:54.320] But he, at times, like, when measuring it at home, by the way, people at home should just get an automated cuff, right?
[03:34:54.320 --> 03:34:55.440] I mean, like, absolutely.
[03:34:55.440 --> 03:34:56.240] I mean, it's just yeah.
[03:34:56.240 --> 03:35:01.040] And then when you finish this story, I'll walk through to make sure everybody's measuring correctly because it's very important.
[03:35:01.280 --> 03:35:02.240] Yes, please do.
[03:35:03.280 --> 03:35:06.080] He has hemochromatosis.
[03:35:06.080 --> 03:35:06.480] Okay.
[03:35:06.800 --> 03:35:11.840] And there's some other relatives that had it and noticed that their blood pressure was high.
[03:35:12.000 --> 03:35:17.440] Like we're talking people that are like very physically doing lots of these are like running marathons.
[03:35:17.440 --> 03:35:20.000] They're doing, you know, like they're very, super healthy.
[03:35:20.000 --> 03:35:25.120] And donating blood seemed to help normalize the blood pressure for whatever reason.
[03:35:25.120 --> 03:35:25.520] I don't know.
[03:35:26.080 --> 03:35:28.880] Which is important for obviously getting rid of the iron and hemochromatosis.
[03:35:28.880 --> 03:35:29.400] Right.
[03:35:29.120 --> 03:35:32.760] But the other thing that's really helped, so Dan is doing that now.
[03:35:33.080 --> 03:35:42.680] But the other thing that seems to really help him, I mean, he does sauna, hot tubs, exercise, you know, and there'll be times when he's in his office working and he's like 135 systolic.
[03:35:42.680 --> 03:35:44.040] And it's like, what in the world?
[03:35:44.040 --> 03:35:45.800] That's crazy, right?
[03:35:46.760 --> 03:35:48.680] Green shakes help him.
[03:35:48.680 --> 03:35:51.560] So like tons of like nitrates.
[03:35:51.560 --> 03:35:54.040] So a bunch of like green vegetables.
[03:35:54.040 --> 03:35:56.200] And these are like nasty tasting shakes.
[03:35:56.200 --> 03:35:57.720] These aren't like good tasting ones.
[03:35:57.960 --> 03:35:58.760] Not AG.
[03:35:58.760 --> 03:35:59.400] No.
[03:36:00.840 --> 03:36:03.480] And that will help him as well.
[03:36:03.480 --> 03:36:07.640] So yeah, exercise is very important, but like there's also like.
[03:36:07.880 --> 03:36:10.120] Has he tried like cocaflavonoids, things like that?
[03:36:10.120 --> 03:36:12.120] You know, we, I was, I give that to him.
[03:36:12.120 --> 03:36:13.080] So another story.
[03:36:13.080 --> 03:36:14.280] No, I wasn't doing that.
[03:36:14.520 --> 03:36:17.480] We haven't been doing that because we take a lot of our vitamins at night.
[03:36:17.480 --> 03:36:19.160] We do take some fish oil in the morning.
[03:36:19.160 --> 03:36:27.640] I did mention that to him because another story, my mother, who is sedentary, she's lost a lot of weight, but she's still overweight.
[03:36:28.200 --> 03:36:31.880] She, you know, she, she, she's losing the weight was great.
[03:36:31.880 --> 03:36:33.800] I mean, she's lost like 75 pounds.
[03:36:33.800 --> 03:36:35.240] Like, she's lost a lot of weight.
[03:36:35.320 --> 03:36:40.520] You look at the pictures, it's like years to her life have been extended just by that alone.
[03:36:40.920 --> 03:36:48.680] But I can't, like, I can get her in the sauna sometimes, but it's still, it's still like a little bit more of an effort.
[03:36:49.000 --> 03:36:52.920] But one thing about her is she will take the vitamins I give her.
[03:36:52.920 --> 03:36:57.000] And she's got, she's homozygous for MTHFR.
[03:36:57.000 --> 03:37:08.360] If she's not taking a high-dose like B supplement along with like methyl folate, like her homocysteine will go high and her blood pressure goes up.
[03:37:08.360 --> 03:37:13.880] And she had stopped taking all those because she wasn't over my house all the time when I was giving it to her every day.
[03:37:13.880 --> 03:37:27.280] And so I got her, you know, this like sort of like battery of supplements that I was giving her, including all the methyl folate and lowering her, things that were lowering her homocysteine, along with magnesium and cocoflavanol.
[03:37:27.280 --> 03:37:28.880] So I was giving her Cocovia.
[03:37:29.360 --> 03:37:31.120] She was getting four of those pills.
[03:37:31.120 --> 03:37:32.960] She gets four and she still takes them.
[03:37:32.960 --> 03:37:37.360] Her blood pressure went from like 155 to like 125.
[03:37:37.360 --> 03:37:42.400] Okay, her doctors are like, they wanted to get her on anti-hypertension treatment before she came to me.
[03:37:42.400 --> 03:37:44.720] And it's like, and this has been like months now.
[03:37:45.840 --> 03:37:47.680] It's happy, you know, she measures it at home.
[03:37:47.680 --> 03:37:48.960] She takes, she does logs.
[03:37:48.960 --> 03:37:54.480] I mean, so I'm very happy about that, you know, the fact that she's been able to do that.
[03:37:55.280 --> 03:37:59.920] But again, it just, it shows that there are, they definitely are lifestyle factors.
[03:37:59.920 --> 03:38:09.440] I know you hate that word, but, you know, exercise being one of the main ones, but there are people also that in addition to being very physically active, like they still get high blood pressure, you know?
[03:38:09.680 --> 03:38:09.920] Yeah.
[03:38:09.920 --> 03:38:22.880] And there, and, and, you know, I don't think we have the outcome data to look at the direct impact of cocoflavonoids or all the suite of B vitamins that are necessary to lower homocysteine and their impact on blood pressure.
[03:38:22.880 --> 03:38:23.920] But here's what we do know.
[03:38:23.920 --> 03:38:29.520] And again, this is mechanistic, and it's very strong mechanistic, but that doesn't necessarily equate to outcomes.
[03:38:29.520 --> 03:38:40.240] But we know that as homocysteine is elevated, it impairs the clearance of something called asymmetric and symmetric dimethylarginine.
[03:38:40.240 --> 03:38:42.800] I don't know if you've talked about ADMA and SDMA.
[03:38:42.800 --> 03:38:48.960] And ADMA and SDMA directly and indirectly inhibit nitric oxide synthase.
[03:38:49.280 --> 03:38:56.000] So we know that homocysteine is associated with poor outcomes in cardiovascular disease.
[03:38:56.400 --> 03:39:11.080] And I think that this mechanism of homocysteine impairing the clearance of ADMA and SDMA is the mechanistic link because when you directly inhibit nitric oxide synthase in the endothelium, you are preventing the creation of nitric oxide.
[03:39:11.080 --> 03:39:16.200] And of course, that's what cocoflavanols actually do the opposite of that.
[03:39:16.200 --> 03:39:27.400] So I think the one-two punch of lowering homocysteine and raising nitric oxide synthase activity via cocoflavanol could certainly explain a reduction in blood pressure.
[03:39:27.400 --> 03:39:28.200] That's really interesting.
[03:39:28.360 --> 03:39:35.240] I was giving her the cocoflavanol just because I had seen the studies on increased blood flow, and I'm like, okay, we need that, you know, like we need that.
[03:39:35.480 --> 03:39:36.600] Measuring blood pressure.
[03:39:36.840 --> 03:39:44.920] Yeah, so this was established really clearly through the sprint trial, and this has basically been now kind of the gold standard for how we use an automated cuff.
[03:39:44.920 --> 03:40:00.360] So that trial was done by having individuals sit for five minutes, check a blood pressure, no stimulation during that time, so not talking, not looking at a phone, not doing anything, and then repeat that two more times.
[03:40:00.360 --> 03:40:12.840] So it's a 15, I'm not suggesting this is what Dan does or what anybody does, but just so you understand at the level of how the trials are done, you're sitting for 15 minutes, having a check at 5, 10, and 15 minutes.
[03:40:12.840 --> 03:40:23.560] You're sitting like this, the cuff is two inches above the elbow, and the cuff is right at the level of the right atrium.
[03:40:23.560 --> 03:40:28.680] So, you know, you're, and by the way, if anybody wants to do this experiment at home, it's really interesting to do.
[03:40:29.080 --> 03:40:36.840] Put an automated cuff on your arm and put your arm here, put your arm above your head, and put your arm in the right spot, and look at how big a difference you get.
[03:40:36.840 --> 03:40:39.640] So, measurement errors are a huge problem.
[03:40:39.640 --> 03:40:41.880] Being overstimulated is a huge problem.
[03:40:41.880 --> 03:40:45.000] So, you really want to make sure you're getting an accurate reading of that blood pressure.
[03:40:45.760 --> 03:40:53.200] And we have our patients do that twice a day, you know, an early in the day and a late in the day check.
[03:40:53.200 --> 03:40:56.560] And then, you know, we just have everybody do that for two weeks to start.
[03:40:56.560 --> 03:40:58.880] And that's what's considered your blood pressure.
[03:40:58.880 --> 03:41:04.320] So, you know, the idea that you're going to walk into the doctor's office and get a blood pressure is not valuable for most people.
[03:41:04.320 --> 03:41:07.360] So, when someone says, what's your blood pressure?
[03:41:07.360 --> 03:41:15.040] It should be, what's the average of those two weeks of twice-daily checks done where you take the five-minute protocol and test perfectly?
[03:41:15.040 --> 03:41:18.480] And I think everybody listening to this should know that number.
[03:41:18.480 --> 03:41:19.440] Yeah, that's great.
[03:41:19.440 --> 03:41:22.480] I'm going to like, I'm going to do it.
[03:41:23.920 --> 03:41:27.280] Peter, so this has been amazing.
[03:41:27.280 --> 03:41:30.160] I mean, so much information, actionable information.
[03:41:30.160 --> 03:41:35.440] A lot of people listening here, they want medicine 3.0.
[03:41:35.440 --> 03:41:37.840] They want aggressive prevention.
[03:41:39.360 --> 03:41:49.200] Do you have some tool, like some pointers, maybe some strategies that people can work within the existing healthcare system to kind of like help them?
[03:41:49.200 --> 03:42:01.120] Like, how can they, you know, get some of these tests that we've talked about, whether it's through Boston Heart or, you know, doing the Grail, working with their physicians to like being able to order them?
[03:42:01.120 --> 03:42:06.960] You know, like, how can people try to get as close as they can to medicine 3.0?
[03:42:07.600 --> 03:42:10.960] I mean, we've, I hate to sound like a shameless plug.
[03:42:10.960 --> 03:42:15.840] We've created something to help do this because, you know, I've talked here about our practice.
[03:42:15.840 --> 03:42:17.440] Our practice is super small.
[03:42:18.880 --> 03:42:34.600] It's just never, there's no desire to scale this practice, and we will never be able to meet the demand of the, you know, the people that want to come in and the amount of room that we can make because it's just not, the model doesn't make sense, right?
[03:42:29.600 --> 03:42:36.920] It's, it's too labor-intensive the way we're doing it.
[03:42:37.240 --> 03:42:43.160] But the good news is, like, I really don't think you need to be my patient to get the benefits of what we do.
[03:42:43.160 --> 03:42:52.760] I really think you can get most of these benefits if, first and foremost, you are a really thoughtful consumer of your own healthcare information.
[03:42:52.760 --> 03:42:56.040] So, to that end, we've created this product called Early.
[03:42:56.440 --> 03:43:03.400] It is, I mean, it's going to be fully released next year, but it's having a limited release this year.
[03:43:03.400 --> 03:43:08.200] So, we released it for four days in the spring just to our subscribers.
[03:43:10.120 --> 03:43:12.040] The reception to that has been very positive.
[03:43:12.040 --> 03:43:15.800] It's going to be released again once more this year just to people on a wait list.
[03:43:15.800 --> 03:43:19.560] So, anybody who goes to, I'm ashamed to say I don't know the website.
[03:43:19.560 --> 03:43:22.680] I think it's early.com, but maybe it's earlymedical.com.
[03:43:22.840 --> 03:43:23.640] Yeah, I don't know.
[03:43:23.640 --> 03:43:24.440] Google Early Medical.
[03:43:24.600 --> 03:43:25.560] Yeah, yeah, something like that.
[03:43:25.720 --> 03:43:30.200] And there's a waitlist, and those who sign up on the waitlist will be offered the next window.
[03:43:30.200 --> 03:43:32.360] It'll be a very short window in the fall.
[03:43:32.360 --> 03:43:35.480] And basically, that program does everything, right?
[03:43:35.480 --> 03:43:42.440] It walks you through everything, how to operationalize everything that I've written about in the book or that we're talking about here today.
[03:43:42.440 --> 03:43:47.320] It also allows you to directly go to any lab you want.
[03:43:47.320 --> 03:43:53.240] And we've, and we have no affiliation with any of these people, so we don't want to make any money on how these labs are done.
[03:43:53.240 --> 03:43:58.280] But you can run our panel at Boston Heart and get all these results.
[03:43:58.280 --> 03:44:02.360] And then we sort of, you know, give you our dashboard on how to walk through these.
[03:44:02.360 --> 03:44:04.840] We give you the, these are the ranges.
[03:44:05.080 --> 03:44:12.360] And what I hope to be able to do, because so far, a lot of people who are buying this product from us are physicians.
[03:44:12.360 --> 03:44:25.600] What I really hope will eventually happen is we'll have a critical enough mass of both people who are buying this who want this kind of medicine and physicians who are buying this who want to practice this kind of medicine that there could be sort of a match made here.
[03:44:25.920 --> 03:44:32.080] And, you know, the good news is I think a lot of physicians really want to practice this way.
[03:44:32.720 --> 03:44:37.280] And the challenge of practicing this way is you just have to get re-educated.
[03:44:37.280 --> 03:44:38.720] And that takes a little bit of time.
[03:44:38.720 --> 03:44:40.480] And that's why we've put this together, right?
[03:44:40.720 --> 03:44:44.640] We've sort of taken two and a half years to build this program, this curriculum.
[03:44:44.640 --> 03:44:46.080] And it's an investment.
[03:44:46.080 --> 03:45:00.960] I make no, you know, it's probably 30 hours of video plus tons of downloadable material that are, you know, lead you through a bunch of exercises you have to do, like how to take a correct family history, like what to really look for in your family history.
[03:45:01.600 --> 03:45:05.920] Stuff like we're talking about, the blood pressure stuff, how to check the labs and all those things.
[03:45:05.920 --> 03:45:21.760] So, you know, I think that that's, I think that's the way to, maybe not at the societal level, you know, I don't have the policy solution for how to fix medicine, but I think at the individual 11, at the individual level, just sort of taking control over it and saying, okay, I'm done with medicine 2.0.
[03:45:21.760 --> 03:45:23.440] It's time to go to medicine 3.0.
[03:45:23.440 --> 03:45:30.960] And medicine 3.0 is really about highly preventive, super early, personalized care.
[03:45:31.600 --> 03:45:39.440] There are a couple of personal questions that I'm going to ask you just at the very end of this that I know people are also very interested in.
[03:45:39.440 --> 03:45:54.440] One being your ideal, your ideal diet and exercise routine and other factors that you're doing for longevity, or maybe for the day or for the week, whichever way you kind of bunch them in.
[03:45:54.320 --> 03:45:59.680] Like, like what's ideal for you for you to, you know, improve your longevity.
[03:45:59.680 --> 03:46:00.760] I know that's a very general way.
[03:46:01.000 --> 03:46:02.440] With respect to nutrition and exercise?
[03:45:59.760 --> 03:46:07.320] Nutrition, exercise, and anything else, sleep, like, you know, sauna, whatever, whatever's your ideal like program.
[03:46:07.640 --> 03:46:08.680] Full suite, yeah.
[03:46:09.320 --> 03:46:10.600] Well, I will say this.
[03:46:11.000 --> 03:46:17.160] I'm sure that everything I'm about to say is going to make me sound really rigid, and people are going to be like, that guy's a psycho.
[03:46:17.160 --> 03:46:21.080] So I'm always a little hesitant when in talking about what I do.
[03:46:21.480 --> 03:46:23.400] Well, people want to know what you do.
[03:46:23.720 --> 03:46:24.200] Okay.
[03:46:24.760 --> 03:46:30.200] So look, probably compared to most people, I am considered quite regimented.
[03:46:31.080 --> 03:46:34.040] I'm way less regimented than I used to be.
[03:46:34.920 --> 03:46:37.400] But nevertheless, here's sort of how I think about things.
[03:46:37.400 --> 03:46:39.640] So let's start with sleep.
[03:46:40.440 --> 03:46:50.920] I really take my sleep seriously and I'm, you know, someone who believes, who functions best with a consistent bedtime and wake-up time.
[03:46:50.920 --> 03:46:57.960] So I am in bed usually for eight hours a night, and that's typically 10 to 6.
[03:46:58.280 --> 03:47:02.440] And that usually results in probably seven and a half hours of sleep.
[03:47:03.400 --> 03:47:06.920] I'm going to just rattle off the names of things I use because I don't have any affiliation with these things.
[03:47:06.920 --> 03:47:09.320] So I use 8 Sleep as my mattress cover.
[03:47:09.320 --> 03:47:11.160] I love what these guys have done.
[03:47:11.400 --> 03:47:16.680] It's a fantastic cooling product, and it's made an enormous difference for me.
[03:47:16.680 --> 03:47:18.440] I've been using it for the last three years.
[03:47:18.440 --> 03:47:20.440] Most of our patients are using it.
[03:47:20.440 --> 03:47:23.080] There are other products out there, and I've tried them, and they're good.
[03:47:23.080 --> 03:47:25.320] This one, I just happen to fancy the most.
[03:47:25.320 --> 03:47:26.040] Agreed.
[03:47:28.040 --> 03:47:33.400] I'm also very particular about what I'm doing before bed and what I'm not doing before bed.
[03:47:33.400 --> 03:47:36.280] So I really, and I'm not perfect with this.
[03:47:36.280 --> 03:47:44.680] I'm not perfect with any of these things, Rhonda, but I really go out of my way to not look at anything that's going to activate me.
[03:47:44.680 --> 03:47:48.160] So I try not to look at email for a couple hours before bed.
[03:47:44.840 --> 03:47:49.520] In fact, I have two separate phones.
[03:47:49.840 --> 03:47:54.080] I have like my regular phone that has email and social media and junk on it.
[03:47:54.080 --> 03:47:57.120] And then I have what I call my bat phone that literally has nothing.
[03:47:57.120 --> 03:48:08.560] It's just, it has like the remote to the TV, you know, and it has like a phone and email, but like, oh, sorry, a phone and text, but only like two people know the number, my wife and my daughter.
[03:48:08.560 --> 03:48:10.720] And that's about it.
[03:48:10.720 --> 03:48:11.280] And the camera.
[03:48:11.280 --> 03:48:15.840] So it's basically an excuse to have a camera and a phone if I'm going someplace and I don't want my phone with me.
[03:48:16.160 --> 03:48:19.680] So that's kind of the phone that's with me if I'm watching TV downstairs or something like that.
[03:48:19.680 --> 03:48:23.600] But I can't even be tempted to look at social media or look at email.
[03:48:23.600 --> 03:48:29.600] So it's all in this spirit of like turning the system down before bed.
[03:48:30.480 --> 03:48:35.920] Even little things like I'll brush and floss my teeth before I go in the sauna because I sauna before bed as well.
[03:48:35.920 --> 03:48:41.360] So that once I'm done with that sauna and shower, like I'm just going straight into bed.
[03:48:42.000 --> 03:48:45.680] So for me, that's also a very productive sleep trick.
[03:48:45.680 --> 03:48:47.680] There's certain supplements that I use to sleep as well.
[03:48:47.680 --> 03:48:59.600] So I'm a fan of glycine, ashwagandha, magnesium L3N8, and just straight mag oxide as well.
[03:48:59.600 --> 03:49:03.200] I don't use melatonin or phosphatidylserine unless I'm jet lagging.
[03:49:03.200 --> 03:49:06.320] If I'm time zone hopping, I'll use those as well.
[03:49:07.200 --> 03:49:08.400] So that's sleep.
[03:49:09.360 --> 03:49:13.360] On the nutrition side, I don't follow any particular diet.
[03:49:13.680 --> 03:49:16.560] I guess you could say I eat what would be called a balanced diet.
[03:49:16.560 --> 03:49:28.320] So, I'm an omnivore who will probably always struggle with food in the sense that, like, if left to my own devices, I would eat everything and too much of it.
[03:49:28.320 --> 03:49:30.760] So, I do need to be mindful about what I eat.
[03:49:30.760 --> 03:49:32.200] So, what do I pay attention to?
[03:49:29.680 --> 03:49:34.760] So, I just generally pay attention to not eating junk.
[03:49:34.920 --> 03:49:38.360] That's that's like the most important credo of my diet, I would say.
[03:49:38.360 --> 03:49:40.360] And I say this as someone who's done everything, right?
[03:49:40.360 --> 03:49:50.360] Like, I've been vegan, I've been keto, I've been like the most, you know, you know, hardcore fasting, intermittent fasting, time-restricted eating.
[03:49:50.360 --> 03:49:58.120] Like, I've done, there's no diet I don't think I've done for long periods of time, and I have found benefit in one form or another from various different aspects of these things.
[03:49:58.120 --> 03:50:07.880] But, you know, right now I'm mostly optimized around energy balance, which, you know, stay in energy balance, and protein intake.
[03:50:07.880 --> 03:50:15.960] And so, most of my conscious effort around my diet goes into making sure I'm getting 40 to 50 grams of protein four times a day.
[03:50:16.920 --> 03:50:30.280] And a lot of times, at least two of those are in meals that are just like just venison or just eggs or something where it's just a protein and there's not a lot of other stuff in it.
[03:50:31.160 --> 03:50:35.720] I do make sure I stop eating at least three hours before bed.
[03:50:35.720 --> 03:50:40.200] It really makes a difference going back to sleep that I go to bed a little hungry.
[03:50:40.520 --> 03:50:46.600] If I ever go to bed with my belly too, too full, it feels nice, but I don't sleep as well.
[03:50:46.600 --> 03:50:49.640] So, I really try to err on the side of going to bed a little hungry.
[03:50:49.640 --> 03:50:52.760] And that's, you know, I'm really lucky because we have young kids, so we eat early.
[03:50:52.760 --> 03:50:53.960] So, we're eating at six.
[03:50:53.960 --> 03:51:01.560] So, I'm going to bed typically with four hours between when I last ate and when I go to sleep.
[03:51:01.560 --> 03:51:03.080] We can talk about alcohol.
[03:51:04.600 --> 03:51:12.760] I'm in the camp that believes there is absolutely no benefit to alcohol at any dose from a purely, you know, biochemical standpoint.
[03:51:13.320 --> 03:51:18.880] However, I acknowledge that there are probably some pro-social benefits to it, and I happen to really, really like alcohol.
[03:51:19.200 --> 03:51:24.640] So I probably have, well, I don't know, it depends.
[03:51:24.640 --> 03:51:30.560] I mean, anywhere from zero to seven or eight drinks in a week.
[03:51:31.680 --> 03:51:38.240] Probably, I don't think there's a time that I can recall in the last five, six years where I've had more than two drinks in a day.
[03:51:38.240 --> 03:51:40.240] And I also try to do my drinking early.
[03:51:40.240 --> 03:51:43.760] Now, by that, I don't mean two in the afternoon, but I mean with dinner.
[03:51:43.760 --> 03:51:49.440] So that again, alcohol is completely, functionally, the alcohol doesn't factor into my sleep.
[03:51:49.440 --> 03:51:54.640] And I know this because I track all these things and I know exactly how alcohol negatively impacts sleep in me.
[03:51:54.640 --> 03:52:04.400] And I know that as long as I have that drinking done by six or seven, it doesn't show up anywhere on any metric that I'm tracking with respect to sleep.
[03:52:04.400 --> 03:52:09.760] Okay, exercise, most important thing from a physiologic standpoint for me.
[03:52:09.760 --> 03:52:15.840] I exercise every day and it's an, you know, it's much of what I do revolves around it.
[03:52:15.840 --> 03:52:45.680] So even here being in San Diego this week, I mean, it's like I have a membership at a great gym every time I'm here and I just know that I'm going to get up first thing in the morning and I'm going to go and I'm going to do my workouts and they're going to be completely, you know, they're not going to be the exact same workouts I'd be doing at home, but I'm still generally doing, you know, four hours of zone two a week with one sort of higher intensity workout that's geared towards VO2 max a week and then four strength training sessions a week.
[03:52:45.680 --> 03:52:48.720] So that's kind of the foundational pillar of everything I do.
[03:52:48.720 --> 03:52:56.080] And then there's other things that get layered on top of that, like rucking and recreational activities that are also physical as well.
[03:52:56.800 --> 03:53:03.800] So, and then the last thing I guess I would say on that, which we didn't talk about, but it's an equally important part of this, is mental health.
[03:53:03.800 --> 03:53:06.760] So, everything that we've talked about factors into.
[03:53:07.000 --> 03:53:15.640] So, the right sleep, the right nutrition, exercise, all of that factors into creating, you know, what I kind of describe as a wider buffer zone around distress tolerance.
[03:53:15.640 --> 03:53:27.720] And then, you know, therapy, which I do at least one session a week, sometimes two, plus journaling and, you know, doing something called dialectical behavioral therapy.
[03:53:27.720 --> 03:53:33.960] These things have been, you know, enormously important at increasing kind of the quality of my life in the past five years.
[03:53:34.600 --> 03:53:35.560] That's amazing.
[03:53:35.560 --> 03:53:37.800] I mean, thank you so much, Peter.
[03:53:37.800 --> 03:53:44.360] So if people want to, I mean, people definitely are going to want to hear more from you.
[03:53:44.360 --> 03:53:47.480] You've got a podcast, The Drive I mentioned, it's everywhere.
[03:53:47.480 --> 03:53:49.560] It's on YouTube, Spotify, iTunes.
[03:53:49.560 --> 03:53:51.960] You've got a book that is a must-read.
[03:53:51.960 --> 03:53:52.440] I read it.
[03:53:52.440 --> 03:53:53.720] It took me about seven hours.
[03:53:53.720 --> 03:53:54.680] I did a flight.
[03:53:54.680 --> 03:53:57.480] I mean, it was, but there were parts where I was like, I know this is a good idea.
[03:53:57.720 --> 03:54:04.120] I know what Peter has, his thoughts on this, and I was 2xing it, you know, whatever you want to call it.
[03:54:04.120 --> 03:54:07.000] But yeah, I was like, oh, you audio read it, you mean?
[03:54:07.000 --> 03:54:07.640] No, no.
[03:54:08.280 --> 03:54:09.160] I read it, read it.
[03:54:09.160 --> 03:54:10.520] And you read it in seven hours.
[03:54:10.680 --> 03:54:11.880] I did, but like I said, there.
[03:54:11.960 --> 03:54:13.000] You're a fast reader.
[03:54:13.000 --> 03:54:20.680] Well, I think the more important factor was I'm very familiar with your thoughts and lots of things.
[03:54:20.680 --> 03:54:24.280] There were things where I was like, I know, because I know, and I'm just skimming this part.
[03:54:24.920 --> 03:54:26.600] And then there were things that were a little bit more.
[03:54:26.600 --> 03:54:28.200] So phenomenal book.
[03:54:28.200 --> 03:54:33.960] I mean, lots of important, lots of things we talked about today, but even more and lots of applications there.
[03:54:33.960 --> 03:54:35.560] So it's called Outlive.
[03:54:35.720 --> 03:54:39.720] I went to a spa the other day and I saw it right there and I was like, awesome.
[03:54:40.400 --> 03:54:43.400] But you've got a website, I mean, peteratia.com.
[03:54:43.400 --> 03:54:46.000] Yeah, I think PeterArtea MD.com is the website.
[03:54:46.000 --> 03:54:49.040] That's where people can sign up for our newsletter, which comes out every Sunday.
[03:54:44.920 --> 03:54:55.280] And then I think earlymedical.com is a separate website where that other thing exists.
[03:54:55.760 --> 03:54:58.080] So question for you: when are you going to write a book?
[03:54:58.480 --> 03:55:01.520] Has this ever, is this ever something you've thought about?
[03:55:01.520 --> 03:55:02.720] I've thought about it.
[03:55:02.720 --> 03:55:05.840] I'm not sure that I want to go there.
[03:55:05.920 --> 03:55:24.080] I mean, I can't imagine the work, like, because your book was, I mean, it was impressive, you know, and to write a book in the scientific world like that that people are excited about, can understand, I mean, it's, it's really challenging.
[03:55:24.080 --> 03:55:30.320] So yeah, I mean, I guess all of those things are true.
[03:55:30.320 --> 03:55:35.040] And yet, I think as I stand here on this side of it, I can say I think there are benefits to it.
[03:55:35.280 --> 03:55:44.560] I don't want to talk you into doing something that's really hard because it is, but, you know, like Andrew Huberman is working on a book and, you know, it's hard.
[03:55:44.560 --> 03:55:45.040] He knows it.
[03:55:45.760 --> 03:55:50.640] But books do communicate in a way that podcasts don't.
[03:55:51.040 --> 03:55:53.680] And they reach different audiences too.
[03:55:53.680 --> 03:56:02.720] So there was a part of me throughout the process that was kind of like, because I started the book two years before I started podcasting.
[03:56:02.720 --> 03:56:07.840] And then as I'm into the book and podcasting, there was a lot of time when I thought, why am I doing this?
[03:56:07.840 --> 03:56:09.920] Like, this is such a waste of time.
[03:56:09.920 --> 03:56:12.640] Like, this is taking so much time.
[03:56:12.640 --> 03:56:16.400] And I could cover all of this material in 10 podcasts.
[03:56:16.400 --> 03:56:21.840] Like, the book could be summarized into 10 really well thought out podcasts.
[03:56:22.960 --> 03:56:25.360] But now that it's all said and done, I realize a couple things.
[03:56:25.360 --> 03:56:28.480] One, writing sharpens your thinking so much.
[03:56:29.200 --> 03:56:34.280] And I'm not saying that your thinking isn't sharp or that my thinking wasn't sharp, but there's just no two ways about it.
[03:56:34.440 --> 03:56:42.280] Like as I sit here talking, I'm sort of blabbering, but like when you have to write it down, you really have to get clear on what you're saying.
[03:56:43.560 --> 03:56:56.520] And as I said, there's, you know, there's probably somebody out there, more than somebody, there's probably a lot of people out there who would get to know who you are and what your message is going to be that wouldn't figure it out from a podcast.
[03:56:56.520 --> 03:57:01.560] So, you know, maybe there's a bunch of listeners who are saying, yeah, Peter, tell her, tell her, tell her.
[03:57:01.560 --> 03:57:05.720] So, but I think there'd be a lot of people who would love it if you wrote a book if you decided to make that commitment.
[03:57:06.040 --> 03:57:07.800] It's good to hear that from you for sure.
[03:57:08.120 --> 03:57:12.280] Especially being on the other side of it, you know, because you often wonder, was it worth it?
[03:57:12.280 --> 03:57:18.120] You know, like, Peter, there are other things that we didn't get to discuss, believe it or not.
[03:57:18.760 --> 03:57:21.240] So let's please do this again.
[03:57:21.560 --> 03:57:31.880] My podcast, your podcast, I want to do both because, you know, there's just, there's so much to dive into and we have so much overlap in our interests that it's always a pleasure to talk with you.
[03:57:31.880 --> 03:57:33.960] And so thank you again.
[03:57:33.960 --> 03:57:36.600] Really, really enjoyed this conversation.
[03:57:36.600 --> 03:57:43.160] Well, thank you for having me and thank you for pouring through the book and coming up with so many awesome topics to get through.
[03:57:43.160 --> 03:57:45.720] And it's funny that we barely go through half of them.
[03:57:46.680 --> 03:57:47.800] Thank you so much to Dr.
[03:57:47.800 --> 03:57:52.200] Peter Attia for his relentless pursuit of strategies to extend health span.
[03:57:52.200 --> 03:57:57.640] As a companion to today's episode, I've created a free evidence-based blueprint that you can download.
[03:57:57.640 --> 03:58:05.720] In this guide, which you can find at bdnfprotocols.com, you will find protocols designed to improve cognitive function and delay brain aging.
[03:58:05.720 --> 03:58:24.400] This guide explores modifiable lifestyle factors, the tactics, strategies, and things you can do, particularly when it comes to exercise, nutrition, and even supplementation, to improve cognition and enhance neuroprotection, many of which are at least partially mediated through increases in brain-derived neurotrophic factor levels.
[03:58:24.400 --> 03:58:28.400] In this guide, you will also find a section entitled Rhonda's Protocols.
[03:58:28.400 --> 03:58:40.000] These protocols are either practices I actively engage in or strategies I'm currently exploring, curated specifically for their promising potential for beneficial cognitive and neuroprotective impact.
[03:58:40.000 --> 03:58:44.640] These protocols are detailed and specific, everything you'd look for in a blueprint.
[03:58:44.640 --> 03:58:52.080] So, if you're looking to dive deeper into these insights and start applying them, head over to bdnfprotocols.com to get your free guide.
[03:58:52.080 --> 03:58:57.440] It's a valuable tool for anyone committed to optimizing their brain health and longevity.
[03:58:57.440 --> 03:59:00.800] Once again, that's bdnfprotocols.com.

Prompt 14: Key Takeaways

Now please extract the key takeaways from the transcript content I provided.

Extract the most important key takeaways from this part of the conversation. Use a single sentence statement (the key takeaway) rather than milquetoast descriptions like "the hosts discuss...". 

Limit the key takeaways to a maximum of 3. The key takeaways should be insightful and knowledge-additive. 

IMPORTANT: Return ONLY valid JSON, no explanations or markdown. Ensure:
- All strings are properly quoted and escaped
- No trailing commas
- All braces and brackets are balanced
Format: {"key_takeaways": ["takeaway 1", "takeaway 2"]}

Prompt 15: Segments

Now identify 2-4 distinct topical segments from this part of the conversation.

For each segment, identify:
- Descriptive title (3-6 words)  
- START timestamp when this topic begins (HH:MM:SS format)
- Double check that the timestamp is accurate - a timestamp will NEVER be greater than the total length of the audio
- Most important Key takeaway from that segment. Key takeaway must be specific and knowledge-additive.
- Brief summary of the discussion

IMPORTANT: The timestamp should mark when the topic/segment STARTS, not a range. Look for topic transitions and conversation shifts.

Return ONLY valid JSON. Ensure all strings are properly quoted, no trailing commas:
{
  "segments": [
    {
      "segment_title": "Topic Discussion", 
      "timestamp": "01:15:30",
      "key_takeaway": "main point from this segment",
      "segment_summary": "brief description of what was discussed"
    }
  ]
}

Timestamp format: HH:MM:SS (e.g., 00:05:30, 01:22:45) marking the START of each segment.

Prompt 16: Media Mentions

Now scan the transcript content I provided for ACTUAL mentions of specific media titles:

Find explicit mentions of:
- Books (with specific titles)
- Movies (with specific titles)  
- TV Shows (with specific titles)
- Music/Songs (with specific titles)

DO NOT include:
- Websites, URLs, or web services
- Other podcasts or podcast names

IMPORTANT: 
- Only include items explicitly mentioned by name. Do not invent titles.
- Valid categories are: "Book", "Movie", "TV Show", "Music"
- Include the exact phrase where each item was mentioned
- Find the nearest proximate timestamp where it appears in the conversation
- THE TIMESTAMP OF THE MEDIA MENTION IS IMPORTANT - DO NOT INVENT TIMESTAMPS AND DO NOT MISATTRIBUTE TIMESTAMPS
- Double check that the timestamp is accurate - a timestamp will NEVER be greater than the total length of the audio
- Timestamps are given as ranges, e.g. 01:13:42.520 --> 01:13:46.720. Use the EARLIER of the 2 timestamps in the range.

Return ONLY valid JSON. Ensure all strings are properly quoted and escaped, no trailing commas:
{
  "media_mentions": [
    {
      "title": "Exact Title as Mentioned",
      "category": "Book",
      "author_artist": "N/A",
      "context": "Brief context of why it was mentioned",
      "context_phrase": "The exact sentence or phrase where it was mentioned",
      "timestamp": "estimated time like 01:15:30"
    }
  ]
}

If no media is mentioned, return: {"media_mentions": []}

Full Transcript

[00:00:00.160 --> 00:00:01.920] Welcome to the Found My Fitness Podcast.
[00:00:01.920 --> 00:00:03.760] I'm your host, Rhonda Patrick.
[00:00:03.760 --> 00:00:05.280] Today's episode features Dr.
[00:00:05.280 --> 00:00:06.640] Peter Attia.
[00:00:06.640 --> 00:00:06.960] Dr.
[00:00:06.960 --> 00:00:13.520] Peter Attia is a highly respected expert in preventative medicine with a special focus on applied science of longevity.
[00:00:13.520 --> 00:00:21.360] His deep engagement with the topic of longevity is the cornerstone of his New York Times best-selling book, Outlive: The Science and Art of Longevity.
[00:00:21.360 --> 00:00:21.680] Dr.
[00:00:21.680 --> 00:00:31.120] Atia also extends his expertise into his clinical practice, Early Medical, and shares his knowledge through his popular podcast, many of you are already aware of, The Drive.
[00:00:31.120 --> 00:00:42.640] In this episode, you will learn why APOB is a superior predictor of cardiovascular disease over LDL particle number and managing the four main factors that elevate APOB.
[00:00:42.640 --> 00:00:46.800] Why APOB exists in humans when it doesn't in most species?
[00:00:46.800 --> 00:00:56.880] Whether or not low LDL is a risk factor for cancer, and a variety of other surprising facts about LDL biology you really can't find anywhere else.
[00:00:56.880 --> 00:01:00.240] Peter's opinion on APOB reference ranges.
[00:01:00.240 --> 00:01:18.880] Whether there is an APOB level low enough that it is impossible to die from atherosclerosis, which dietary factors increase APOB, how statins and other lipid-lowering pharmacotherapies work, including their side effects and costs, and what the alternatives are.
[00:01:18.880 --> 00:01:22.160] The pros and cons of different statin alternatives.
[00:01:22.480 --> 00:01:36.800] How increased muscle mass helps achieve lower blood sugar levels, which may play a pivotal role in reducing overall mortality, and the potential for glycemic control to be suboptimal well before doctors identify it.
[00:01:36.800 --> 00:01:42.080] Peter's 80% zone 2, 20% BO2 max training protocol.
[00:01:42.080 --> 00:01:46.400] The dangers of visceral fat and why it correlates with increased cancer risk.
[00:01:46.400 --> 00:01:53.360] Peter outlines the benefits and risks of aggressive cancer screening and offers insights on optimal screening timing.
[00:01:53.360 --> 00:01:58.480] He also clears up misconceptions about the radiation used in mammograms.
[00:01:58.480 --> 00:02:10.840] The hormonal changes of menopause and their significant impact on women's health, along with how hormone replacement therapy influences the risk of dementia, cancer, and heart disease in women.
[00:02:10.840 --> 00:02:15.000] Vitamin D, sunlight versus supplementing in optimal levels.
[00:02:15.000 --> 00:02:24.840] Why symptoms of low testosterone are often more important than actual levels when deciding whether or not to go on testosterone replacement therapy.
[00:02:24.840 --> 00:02:31.000] Why Peter's recommended testosterone replacement therapy dosing schedule differs from the standard.
[00:02:31.000 --> 00:02:37.880] Peter's protocol for treating low testosterone and why testosterone replacement therapy isn't always the right answer.
[00:02:37.880 --> 00:02:43.480] Methods for lowering blood pressure, exercise, nitrates, hot tub, and cocoflavanols.
[00:02:43.480 --> 00:02:50.600] Peter's exercise, sleep, nutrition, and alcohol routines for optimizing longevity, and so much more.
[00:02:50.600 --> 00:02:52.360] Before we dive into our discussion with Dr.
[00:02:52.360 --> 00:02:57.000] Peter Artea, I'd like to highlight a valuable resource available for you.
[00:02:57.000 --> 00:03:05.560] It's a comprehensive report I've compiled focusing on evidence-based strategies to optimize cognition and slow down brain aging.
[00:03:05.560 --> 00:03:19.560] This report delves deep into the best exercise practices for boosting brain-derived neurotrophic factor, a key neurotrophic factor integral to learning, memory, mood regulation, and combating brain aging.
[00:03:19.560 --> 00:03:38.120] Additionally, it encompasses a range of lifestyle approaches, including specific protocols for heat exposure through sauna or hot baths, along with detailed guidance on omega-3 and polyphenol intake, all targeted at elevating brain-derived neurotrophic factor levels.
[00:03:38.120 --> 00:03:45.280] You can find that detailed protocols report at bdnfprotocols.com.
[00:03:41.480 --> 00:03:46.320] Once again, that's bdnfprotocols.com.
[00:03:50.640 --> 00:03:52.800] And now on to the podcast with Dr.
[00:03:52.800 --> 00:03:54.560] Peter Atia.
[00:03:54.880 --> 00:03:55.600] Hi, everyone.
[00:03:55.600 --> 00:03:58.080] I'm sitting here with the amazing Dr.
[00:03:58.080 --> 00:03:59.680] Peter Atia.
[00:03:59.680 --> 00:04:02.640] Many of you don't need an intro to him.
[00:04:02.640 --> 00:04:14.640] He has changed our understanding of the scientific literature, preventative medicine with respect to longevity, improving health span.
[00:04:14.640 --> 00:04:21.200] He's a number one New York Times best-selling author of the book Outlive, amazing book.
[00:04:21.200 --> 00:04:29.840] Also, he has a very popular podcast on health and medicine, one of the few podcasts that I listen to called The Drive.
[00:04:29.840 --> 00:04:34.880] And he's also a renowned speaker, so public speaking, he does a lot of that as well.
[00:04:34.880 --> 00:04:38.320] And you can find a lot of lectures he's given on YouTube.
[00:04:38.320 --> 00:04:43.360] So I'm very excited to be sitting here with you today, Peter, and having this conversation.
[00:04:43.360 --> 00:04:46.560] You were on the podcast many years ago, about eight years ago.
[00:04:46.560 --> 00:04:49.040] Yeah, I was going to say, like probably 2016, right?
[00:04:49.040 --> 00:04:50.160] I think it was earlier.
[00:04:50.240 --> 00:04:50.640] You might have been.
[00:04:51.600 --> 00:04:56.800] You might have been one of the first, I don't know, six or seven guests.
[00:04:56.800 --> 00:04:59.760] I mean, you were like one of the first guests that I had on the podcast.
[00:04:59.760 --> 00:05:00.640] So it was a long time ago.
[00:05:00.640 --> 00:05:02.000] You were still at New C.
[00:05:02.080 --> 00:05:02.240] Yep.
[00:05:03.040 --> 00:05:04.240] So it was a while ago.
[00:05:04.240 --> 00:05:05.840] Well, thank you for having me back.
[00:05:06.400 --> 00:05:18.800] So let's dive into maybe a general question that I kind of have for you, which is what ignited your interest in the field of longevity?
[00:05:19.120 --> 00:05:25.840] I mean, I think it's a it was kind of an intersection of two things, but I think the critical spark was the birth of my daughter.
[00:05:26.400 --> 00:05:48.520] And I write about this a little bit in the book, but you know I think you know I'm in my mid-30s she's born and all of a sudden that became a manner in which I contemplated my own mortality and it's not like I hadn't been aware or had been blind to my family history, but I have a very bad family history for cardiovascular disease.
[00:05:48.520 --> 00:06:00.040] And so now the idea that I had this daughter and boy, she was like, I mean, I just adored her more than I could have imagined during my wife's pregnancy.
[00:06:00.040 --> 00:06:01.400] It was so real.
[00:06:01.400 --> 00:06:16.120] And I also kind of realized, like, you know, if I don't figure out what's going on here, I'm going to potentially leave this planet sooner than I would like and therefore leave her and potentially other kids to come along.
[00:06:16.120 --> 00:06:26.040] So it was really those two things that really catapulted me into, at the time, just trying to understand everything I could with respect to cardiovascular disease.
[00:06:26.040 --> 00:06:27.960] That became my initial obsession.
[00:06:27.960 --> 00:06:30.760] So it was really less about longevity and more about that.
[00:06:30.760 --> 00:06:39.880] But of course, once you dive into that, you realize, well, you know, what does it benefit you if you figure out how to not die of heart disease, but you die of some other thing?
[00:06:40.040 --> 00:06:46.520] Or what does it, you know, eventually, what does it benefit you to delay your death, but have a lousy quality of life?
[00:06:46.520 --> 00:06:49.720] So then, you know, all of these things just came as an evolution out of that.
[00:06:49.720 --> 00:06:55.000] It's funny because I actually have a very similar story about the birth of my son.
[00:06:55.000 --> 00:07:12.280] And my, I mean, I remember times like, you know, within the first couple of years of my son being born, going for my long runs and stopping in the middle of my run and literally bawling my eyes out because I knew there was a time that I was going to be gone and he was going to be without me.
[00:07:12.280 --> 00:07:15.000] And it was so hard to think about that.
[00:07:16.560 --> 00:07:27.760] And so, you know, like everything that you just said completely resonates with me, where it's like, I want to be around when my grandkids are, you know, getting older.
[00:07:27.760 --> 00:07:30.400] I want to be not only around, but I want to be jumping rope with them.
[00:07:30.400 --> 00:07:32.320] I want to teach them to jump rope.
[00:07:32.320 --> 00:07:36.320] And so, like, all of those things have sort of crossed my mind at the same time.
[00:07:37.200 --> 00:07:58.640] With respect to the cardiovascular disease that you mentioned, and you talk about this in the book as well, there's a statistic that I've read from the National Health Statistics website, which is that every 33 seconds, someone dies from cardiovascular disease in the United States.
[00:07:58.960 --> 00:08:05.760] So, when people hear the word cardiovascular disease, I mean, at least even me, when I, cardiovascular disease, what is that?
[00:08:05.760 --> 00:08:06.560] What does it mean?
[00:08:06.560 --> 00:08:08.320] Where is atherosclerosis coming to play?
[00:08:08.320 --> 00:08:10.160] Where does coronary heart disease?
[00:08:10.160 --> 00:08:12.160] What is cardiovascular disease?
[00:08:12.480 --> 00:08:19.040] I mean, you could define it very broadly and include valvular disease and cardiomyopathies and all of those things.
[00:08:19.040 --> 00:08:35.920] But when we talk about ASCBD, atherosclerotic cardiovascular disease, which is the leading cause of death in the United States and globally, it's leading cause of death for men and women, what we're referring to is the disease of coronary arteries that leads to ischemia.
[00:08:35.920 --> 00:08:52.640] And, you know, just to take a step back for a moment, when you think about all of these chronic diseases, which I'm sure we'll get into today, cancer, neurodegenerative diseases, et cetera, things that you and I have spoken about a lot, including when you were on my podcast, it's important to understand that this is the disease for which we have the clearest understanding.
[00:08:52.640 --> 00:09:01.880] So, you know, our understanding of what initiates and propagates cancer is very small compared to our understanding on the cardiovascular front.
[00:09:02.120 --> 00:09:05.080] Our understanding of this on the neurodegenerative side is also quite small.
[00:08:59.840 --> 00:09:07.080] There are still many things we don't understand.
[00:09:07.400 --> 00:09:19.000] So, you know, everything we're about to talk about on the cardiovascular side should be at least thought of in the context of how wonderful is it that we understand these things because we have the most tools for prevention here.
[00:09:19.000 --> 00:09:26.920] So, with that said, what we're really talking about that does the lion's share of killing, and again, I'll bracket for a moment that there are other things.
[00:09:26.920 --> 00:09:33.880] There are people that are dying from, you know, cardiomyopathies, there are people that are dying from valvular cardiovascular disease and things of that nature.
[00:09:34.200 --> 00:09:41.720] But the majority of what's happening is a disease that leads to plaque formation inside of coronary arteries.
[00:09:41.720 --> 00:09:50.680] And we can go as deep or as shallow as you want into that and why that happens and how that's a function of endothelial injury, lipoprotein burden, and inflammation.
[00:09:50.680 --> 00:09:58.440] But this leads to a reduction in blood flow to key parts of the heart, muscle.
[00:09:58.440 --> 00:10:01.480] And when that happens, the heart undergoes an ischemic event.
[00:10:01.480 --> 00:10:04.760] Now, sometimes that can be chronic, and sometimes that can be acute.
[00:10:04.760 --> 00:10:11.880] And if an acute event occurs in a region where enough muscle of the heart is compromised, that's going to result in sudden death.
[00:10:11.880 --> 00:10:13.080] That's a heart attack.
[00:10:13.080 --> 00:10:20.520] And it's important to understand that a little, when I was in medical school, it was more than 50%.
[00:10:20.520 --> 00:10:24.120] It's now a little less than 50%, but it's still a very high number.
[00:10:24.120 --> 00:10:30.760] A little less than 50% of people's first brush with a symptom of coronary artery disease is sudden death.
[00:10:31.000 --> 00:10:35.240] That's worth repeating because we couldn't, I remember, I still remember being asked this question in medical school.
[00:10:35.240 --> 00:10:46.480] You know, you're sitting there as a first-year medical student in cardiovascular pathology class, and the pathologist said, what's the single most common presenting feature for someone having cardiovascular disease the first time?
[00:10:46.480 --> 00:10:50.160] And everyone was like, chest pain, shortness of breath, you know, rattling off all the usual stuff.
[00:10:50.160 --> 00:10:51.760] He goes, no, sudden death.
[00:10:53.040 --> 00:10:59.040] Again, today it's not quite 50%, but that's a very sobering statistic.
[00:10:59.360 --> 00:11:00.400] Absolutely.
[00:11:00.800 --> 00:11:10.080] I do want to dive into some of the major causes of the atherosclerosis and the atheroscleric cardiovascular disease that you're talking about.
[00:11:10.080 --> 00:11:19.760] So, lipoproteins, you mentioned, and most people know, they hear about lipoproteins, they hear about LDL or HDL.
[00:11:20.320 --> 00:11:25.440] But APOB, why should people know about ApoB?
[00:11:26.080 --> 00:11:32.000] Well, again, I think it's worth maybe just getting everybody on the same page with cholesterol.
[00:11:32.000 --> 00:11:32.800] Let's start with that, right?
[00:11:32.800 --> 00:11:39.200] So, everybody's heard of cholesterol, and I think most people would probably even have kind of a negative valence when they think about it.
[00:11:39.200 --> 00:11:41.280] It's like cholesterol is a bad thing.
[00:11:41.280 --> 00:11:43.920] So, it's worth explaining that that's not really true, right?
[00:11:43.920 --> 00:11:47.040] Cholesterol is an essential thing, right?
[00:11:47.040 --> 00:11:49.360] So, without cholesterol, we wouldn't be alive.
[00:11:49.360 --> 00:11:58.400] And, you know, there are really rare, fortunately, genetic conditions in which cholesterol synthesis is compromised, and those tend to be fatal in utero.
[00:11:58.400 --> 00:12:08.080] So, if an organism can't make enough cholesterol, it ceases to exist because cholesterol is the thing that gives every cell fluidity, the membrane of every cell fluidity.
[00:12:08.080 --> 00:12:11.040] And it's the precursor to some of the most important hormones we make.
[00:12:11.040 --> 00:12:19.520] So, in the case of us as humans, right, testosterone, estrogen, progesterone, cortisol, these essential hormones are all made from cholesterol.
[00:12:19.520 --> 00:12:24.640] So, every cell in the body, with the exception of red blood cells, makes plenty of cholesterol.
[00:12:24.640 --> 00:12:28.840] The lion's share of it is probably done by the liver and the steroidal tissues.
[00:12:29.160 --> 00:12:33.000] And we have to figure out a way to move this stuff around the body.
[00:12:28.800 --> 00:12:35.320] And the highway system of the body is the blood.
[00:12:35.480 --> 00:12:37.720] And the blood, of course, is water.
[00:12:37.720 --> 00:12:46.680] So if we want to move things that are water-soluble throughout the body, like proteins and ions, it's easy because they dissolve freely in water and they move around.
[00:12:46.680 --> 00:12:57.160] But when you want to move something around water that is not water-soluble, such as cholesterol as a lipid, you have to wrap it in something that is water-soluble.
[00:12:57.160 --> 00:12:59.960] And that something is the lipoprotein.
[00:13:00.280 --> 00:13:07.000] And the big protein on the surface of that sphere is called an apolipoprotein.
[00:13:07.000 --> 00:13:11.400] And there are, broadly speaking, two classes of apolipoproteins.
[00:13:11.400 --> 00:13:14.120] There are the A class and the B class.
[00:13:14.760 --> 00:13:20.920] So some of the lipoproteins are wrapped in an apolipoprotein called ApoB100.
[00:13:20.920 --> 00:13:23.320] And we just abbreviate that to ApoB.
[00:13:23.320 --> 00:13:26.120] But I'll just say it this one time and we'll never talk about it again.
[00:13:26.120 --> 00:13:31.640] There's also an ApoB48 that wraps another type of lipoprotein called a chylomicron.
[00:13:31.640 --> 00:13:35.480] We won't talk about that again because it doesn't really factor into cardiovascular disease.
[00:13:35.480 --> 00:13:56.440] So ApoB is short for apolipoprotein B100, which is the structural apoprotein that sits on low-density lipoproteins, abbreviated LDLs, intermediate density lipoproteins, abbreviated IDLs, very low density lipoproteins, abbreviated VLDLs.
[00:13:56.440 --> 00:14:07.320] The APO A's, and this is big A, never to be confused with apo-little A, which we may talk about, those wrap the family of high-density lipoproteins.
[00:14:07.320 --> 00:14:11.880] They're much more complicated than Apo-Bs, believe it or not, and there are many of them.
[00:14:12.200 --> 00:14:14.920] But nevertheless, broadly speaking, that's what's going on.
[00:14:15.840 --> 00:14:18.720] So, why do we care about all this stuff?
[00:14:18.720 --> 00:14:37.040] Well, in the 1950s, when it became clear that cholesterol was playing a role in cardiovascular disease, The first observation was people with very, very, very high total cholesterol, because at the time that was all that could be measured, was total cholesterol.
[00:14:37.040 --> 00:14:46.160] By the way, what that meant was the total amount of cholesterol in all of your lipoproteins, in your HDLs, in your LDLs, and in your VLDLs.
[00:14:46.160 --> 00:14:52.480] Those three lipoproteins constitute the amount of total cholesterol you have in the lipoproteins.
[00:14:52.480 --> 00:14:54.480] We can come back to this idea because it's important.
[00:14:54.480 --> 00:14:58.160] That represents about 10% of the total cholesterol in your body.
[00:14:58.800 --> 00:15:06.320] The total cholesterol concentration was loosely correlated with cardiovascular outcomes, but only at extremes.
[00:15:06.320 --> 00:15:16.880] Meaning, if you took people whose total cholesterol was in the top 5% and compared them to people whose total cholesterol was in the bottom 5%, there was a clear association with cardiovascular disease.
[00:15:16.880 --> 00:15:30.000] March forward many, many decades, we came to realize that actually this low-density lipoprotein, which is a subset of your total cholesterol, but it's the cholesterol contained within the low-density lipoproteins, that's much more strongly associated.
[00:15:30.320 --> 00:15:39.280] And what we now know is the case is there's an even better way to predict risk than just saying how much cholesterol is contained within the low-density lipoproteins.
[00:15:39.280 --> 00:15:46.000] A better way to predict risk is to add up the concentration of all the APOB particles.
[00:15:46.000 --> 00:16:00.000] So that number, APOB, measured in milligrams per deciliter, is the concentration of the entire burden of particles that are capable of undergoing something that I'm sure we'll talk about, which is the initiation and progression of atherosclerosis.
[00:16:00.440 --> 00:16:09.560] So how, how, the APOB number, can you talk about how that, so you mentioned LDL, total, total LDL cholesterol?
[00:16:09.880 --> 00:16:13.720] That number is like some is like determined by some equation, right?
[00:16:14.120 --> 00:16:16.360] Well, it can be, but it can also be measured directly.
[00:16:16.360 --> 00:16:17.000] Yeah, so there's.
[00:16:17.160 --> 00:16:18.440] Would that be particle number though?
[00:16:19.080 --> 00:16:19.240] No?
[00:16:19.960 --> 00:16:21.560] So there's two ways to go about doing this.
[00:16:21.560 --> 00:16:29.080] So in the olden days, and unfortunately many labs still do this, they rely on an equation called the Friederwald equation.
[00:16:29.080 --> 00:16:32.520] So total cholesterol is relatively easy to measure.
[00:16:33.400 --> 00:16:41.480] So you draw the plasma, you spin it down, and you basically lyse all of the lipoproteins, and you can measure total cholesterol.
[00:16:41.480 --> 00:16:50.840] So if you just basically apply something to lyse all of the proteins, you'll say, all of the lipoproteins, you'll say total cholesterol is 200 milligrams per deciliter.
[00:16:51.160 --> 00:16:54.040] Then they directly also measure two other things.
[00:16:54.040 --> 00:17:04.120] They can directly measure total triglyceride concentration, and using a separate assay, they can measure the total concentration of cholesterol within the HDL particles.
[00:17:04.440 --> 00:17:10.200] So now you've measured total cholesterol, HDL cholesterol, and triglyceride.
[00:17:10.200 --> 00:17:23.400] The Friederwald equation stems from an observation that kind of sort of on average sometimes, VLDL cholesterol is approximately one-fifth the triglyceride concentration.
[00:17:23.400 --> 00:17:27.960] So the Friederwald equation is quite literally used to estimate LDL as follows.
[00:17:27.960 --> 00:17:38.600] LDL cholesterol is estimated as total cholesterol, less HDL cholesterol, less triglyceride concentration divided by five, if you're doing everything in milligrams per deciliter.
[00:17:38.600 --> 00:17:41.720] And unfortunately, most labs still do that.
[00:17:41.720 --> 00:17:55.760] So when you look at your cholesterol report, it'll say LDLC, it'll give a number, and unless it says direct, you can assume they've done the Friederwald equation, which is, I've seen that wrong more often than I've seen it right.
[00:17:56.080 --> 00:17:58.320] A good lab will do a direct assay.
[00:17:58.320 --> 00:18:05.760] They will actually measure LDL concentration and they will give you in milligrams per deciliter the total concentration of LDL C.
[00:18:06.080 --> 00:18:10.960] That is still an inferior predictor of risk relative to APOB.
[00:18:10.960 --> 00:18:11.440] Yes, okay.
[00:18:11.440 --> 00:18:18.480] So let's, the reason I wanted to mention that LDLC is because, as you mentioned, many labs do measure it indirectly.
[00:18:18.480 --> 00:18:21.600] And there are many types of LDL, right?
[00:18:21.600 --> 00:18:23.920] So there are different densities and sizes.
[00:18:23.920 --> 00:18:34.080] So I'm curious about what your thoughts are on the different sizes of like more atherogenic sizes of LDL, such as the smaller dense particles.
[00:18:34.080 --> 00:18:43.280] And, you know, like how you view that, like the different particle sizes and the particle number, and then, of course, APOB.
[00:18:43.280 --> 00:18:44.160] So like the whole.
[00:18:44.800 --> 00:18:50.240] I mean, there's been a big evolution in the way we've practiced medicine in our practice with respect to this.
[00:18:50.240 --> 00:19:16.960] So 10 years ago, we were looking at LDL particle number, which both the MESA population, so the multi-ethnic study of atherosclerosis, and the Framingham offspring population have both demonstrated unequivocally that when you compared LDL particle number to LDL cholesterol, LDL particle number always predicted risk better than LDL cholesterol.
[00:19:16.960 --> 00:19:18.400] So, how would you do this?
[00:19:18.400 --> 00:19:27.360] You would follow people longitudinally for cardiovascular events, and you would do this in sort of a like a cumulative incidence graph.
[00:19:27.360 --> 00:19:42.440] So, on the x-axis, you have time, on the y-axis, you have incidence of cardiovascular disease, and you plot out everybody as a function of whether LDL-C was higher or lower as a percentile than LDLP.
[00:19:42.440 --> 00:19:49.080] So, LDLP stands for the number of particles, LDLC is the concentration of cholesterol.
[00:19:49.080 --> 00:19:50.840] And this was again unequivocally the case.
[00:19:50.840 --> 00:19:53.400] Particle number always predicted better.
[00:19:53.400 --> 00:19:55.320] So, how do you count the number of particles?
[00:19:55.320 --> 00:19:57.240] Well, it turns out there are different ways to do this.
[00:19:57.240 --> 00:19:59.240] You can do this using NMR.
[00:19:59.560 --> 00:20:02.920] So, nuclear magnetic resonance is like how an MRI works.
[00:20:02.920 --> 00:20:04.440] So, it's applying a magnetic field.
[00:20:04.440 --> 00:20:11.400] It's basically doing, I mean, this is being a little cheeky, but it's sort of like doing an MRI on the blood, and you can count the number of particles that way.
[00:20:11.400 --> 00:20:15.880] That's not actually the gold standard, but that's the way it's most commonly done in clinical practice.
[00:20:15.880 --> 00:20:17.960] It can also be done with ion motility.
[00:20:18.280 --> 00:20:23.880] We switched from NMR to ion motility for LDLP because it was more accurate.
[00:20:23.880 --> 00:20:30.200] But ultimately, and this is now about five years ago, we actually switched to APOB, which was superior on all fronts.
[00:20:30.200 --> 00:20:31.960] And here's the reason why.
[00:20:32.280 --> 00:20:35.160] First of all, there are different ways in labs to do this.
[00:20:35.160 --> 00:20:40.760] So, LabCorp, for example, and Boston Heart have different magnets and different algorithms for how they run their LDLP.
[00:20:40.760 --> 00:20:44.920] So, if you run an LDLP on each of those labs, you'll get a different number.
[00:20:44.920 --> 00:20:46.520] That's a bit disturbing to me.
[00:20:46.520 --> 00:20:53.960] I want to know that the APOB that I get at one lab is the same as the APOB I get at another lab, and it's standardized across all fronts.
[00:20:53.960 --> 00:21:02.200] But there's a more important reason why I favor APOB over LDLP, and that is it encompasses the total atherogenic burden.
[00:21:02.200 --> 00:21:14.120] And you can get burned and fooled by patients who have very high VLDL, meaning they have a high burden of very low density lipoproteins, even if their LDL burden is low.
[00:21:14.480 --> 00:21:26.000] So I won't go into it because it's so nerdy, it's not worth getting this deep in the weeds, but there are certain genetic conditions where people have completely normal LDL, but very elevated VLDL.
[00:21:26.000 --> 00:21:28.560] And they have a very high atherogenic risk.
[00:21:28.560 --> 00:21:32.240] And you will miss that if you're looking at LDLP or LDLC.
[00:21:32.240 --> 00:21:34.640] You will not miss that if you're looking at APOB.
[00:21:35.280 --> 00:21:48.560] What about the fact that if small dense LDL, which has been shown to be more athergenic, so APOB does become, so you mentioned the structural role of APOB in the lipoproteins, it's very important.
[00:21:48.560 --> 00:21:56.560] It also plays a role, as you mentioned, in allowing the lipids to be soluble in the plasma, right?
[00:21:57.520 --> 00:22:00.480] But it plays a role also in recycling.
[00:22:00.480 --> 00:22:04.960] So it gets, you know, it interacts with the LDL receptor and can be taken back up into the liver.
[00:22:05.200 --> 00:22:12.000] The small dense LDL particles, APOB is somewhat obscured as the LDL particle gets smaller in size and more dense.
[00:22:12.000 --> 00:22:12.960] Therefore, it's not taken.
[00:22:13.200 --> 00:22:13.760] Harder to clear.
[00:22:13.760 --> 00:22:15.200] Harder to clear, exactly.
[00:22:15.520 --> 00:22:23.120] So what about in the case, and the reason I'm asking is because, as you mentioned, ApoB is on VLDL, IDL, LDL, right?
[00:22:23.440 --> 00:22:34.160] But there's different sizes of these LDL, and the larger, more buoyant LDL is better than having a higher proportion of the smaller dense LDL.
[00:22:34.480 --> 00:22:37.680] Right, that's why ApoB, but ApoB captures that risk, right?
[00:22:37.680 --> 00:22:49.840] So in other words, this is another reason why I think that APOB is the great equalizer, because once you have the APOB concentration, you're accounting for the fact that clearance is going down.
[00:22:49.840 --> 00:22:59.360] I mean, the one way to think about this is anytime you see an elevated APOB, it always comes back to something on the clearance side is not working.
[00:22:59.400 --> 00:23:07.480] Now, there are really, broadly speaking, when I talk about this with patients, I go through the four sort of pillars of what elevates APOB.
[00:23:07.480 --> 00:23:15.000] So it can be driven by cholesterol synthesis, and we can talk about that because it's going to factor into dietary choices, for example.
[00:23:15.000 --> 00:23:19.080] So how certain dietary patterns will lead to higher LDL than others.
[00:23:19.080 --> 00:23:22.360] It's impacted by cholesterol reabsorption.
[00:23:22.360 --> 00:23:29.800] So we can talk about what the life cycle of cholesterol is, but again, it's, you know, we make it and we reabsorb it and it gets circulated.
[00:23:29.800 --> 00:23:32.120] It can have to do with triglyceride burden.
[00:23:32.120 --> 00:23:38.760] So this is where insulin resistance really factors into how APOB can go up.
[00:23:38.760 --> 00:23:41.000] And ultimately, it comes down to clearance.
[00:23:41.000 --> 00:23:50.760] And clearance has everything to do with the presentation of the LDL receptor on the liver, the confirmation of it, the number of them, and how long they survive on the liver.
[00:23:50.760 --> 00:23:56.520] And all of these things have an enormous effect, some of which we can manipulate with drugs.
[00:23:56.520 --> 00:24:05.000] So for example, all drugs that are used to treat LDL in some way or another, indirectly or directly, impact the LDL receptor.
[00:24:05.000 --> 00:24:12.360] Some do it really directly, like a PC-SK9 inhibitor directly does that by targeting a protein that breaks down LDL receptors.
[00:24:13.000 --> 00:24:24.840] So anyway, a long-winded way of saying, and this is another advantage of APOB, is it allows you to, in one measurement, capture all of that risk.
[00:24:24.840 --> 00:24:36.280] Because if you have small, if you have, you know, two individuals, like if you're just using LDLP as your risk, you might miss some of the elevated VLDLs.
[00:24:36.280 --> 00:24:40.040] If you're looking at LDLC, you'll clearly miss some of the size issues.
[00:24:40.360 --> 00:24:42.680] That should be captured in LDLP.
[00:24:43.320 --> 00:24:53.120] But again, I guess maybe what you're asking is, if you have a low APOB, but they're all small, is that worse than having a low APOB where they're all big?
[00:24:53.120 --> 00:24:59.200] And the answer is probably, but you'll also see that in...
[00:24:59.840 --> 00:25:04.480] Like there are other metrics that are kind of coming on board now, which are looking at LDL triglyceride levels.
[00:25:04.480 --> 00:25:08.320] So you can look at the degree to which the LDLs are cholesterol depleted.
[00:25:08.320 --> 00:25:10.080] And that can also give you a sense of risk.
[00:25:10.080 --> 00:25:12.320] The question is, is that a first or second order term?
[00:25:12.320 --> 00:25:15.200] And I think the first order term is still going to be the number of particles.
[00:25:15.200 --> 00:25:18.480] That's the biggest driver of risk.
[00:25:18.480 --> 00:25:19.840] And everything else factors into it.
[00:25:19.840 --> 00:25:26.000] In other words, that's not an independent risk because it's driven by the residence time of the LDL, which is driven by the clearance rate.
[00:25:26.320 --> 00:25:29.120] So let's talk about like the number.
[00:25:29.120 --> 00:25:37.920] So the LDL, sorry, the APOB number, because like if most people go to a standard lab and they measure their APOB, there's a reference range.
[00:25:37.920 --> 00:25:42.000] And it says, you know, okay, if you're less than 80 milligrams per deciliter.
[00:25:42.160 --> 00:25:42.960] You're excellent.
[00:25:42.960 --> 00:25:44.160] Then you're okay.
[00:25:45.440 --> 00:25:48.240] Where does that number come from?
[00:25:48.240 --> 00:25:55.680] And, you know, what, like, has anyone measured APOB levels across the lifespan?
[00:25:55.680 --> 00:26:01.280] Do we know, like, is there a correlation with APOB levels and the beginnings of atherosclerosis?
[00:26:01.280 --> 00:26:02.880] Has someone done those studies?
[00:26:02.880 --> 00:26:04.240] You know, that sort of thing.
[00:26:04.240 --> 00:26:11.360] Yeah, so the reference ranges are purely population-based distribution questions.
[00:26:11.360 --> 00:26:25.200] So every lab will have a different way of doing this, but a general, you know, sort of philosophy for labs is, you know, let, you know, so for the lab we use, and by the way, we completely ignore these reference ranges, but they're there.
[00:26:25.200 --> 00:26:25.920] We can't avoid them.
[00:26:25.920 --> 00:26:26.240] They're there.
[00:26:26.240 --> 00:26:29.720] And we explain to our patients that we're going to editorialize on top of them.
[00:26:29.720 --> 00:26:33.400] But, you know, the reference lab we use will say APOB below 80 is wonderful.
[00:26:29.360 --> 00:26:36.680] Well, 80 just happens to be the 20th percentile of the population.
[00:26:37.000 --> 00:26:44.200] It will say 80 to 100 is intermediate, or 80 to 120, it says is intermediate risk, and above 120 is very high risk.
[00:26:44.200 --> 00:26:53.800] So for the lab we use, we know that 80 is the 20th percentile, 120 is the 80th percentile or the 60th percentile, I can't remember.
[00:26:54.040 --> 00:26:59.080] So it's literally just putting you up against a population distribution, and that's it.
[00:26:59.080 --> 00:27:02.520] Now, our philosophy on APOB is completely different.
[00:27:02.520 --> 00:27:11.160] And as you may recall, I devote actually quite a bit of real estate to this in the book because I think it is such an important concept.
[00:27:11.160 --> 00:27:47.160] And it is, in my opinion, certainly top three failures of Medicine 2.0 is in failing to appreciate the point I'm about to make, which is that once you understand the causality of APOB, meaning once you understand that APOB is not just associated with cardiovascular disease, but it's causally linked to it, meaning it causes ASCVD, to get into this discussion about managing 10-year risk, thinking about being in this percent versus this percent makes no sense.
[00:27:47.160 --> 00:27:51.000] When you have causal things that cause disease, you eliminate them.
[00:27:51.000 --> 00:27:54.760] And the analogy I use is cigarettes with lung cancer.
[00:27:54.760 --> 00:28:00.760] So nobody disputes that cigarettes are causally linked to lung cancer.
[00:28:00.760 --> 00:28:01.240] They are.
[00:28:01.240 --> 00:28:04.840] It's as clear as, you know, Tuesday follows Monday.
[00:28:05.160 --> 00:28:13.800] But people forget that, you know, causality doesn't mean everybody who smokes will get lung cancer, and it doesn't mean that every person with lung cancer smoked.
[00:28:13.800 --> 00:28:20.240] So you don't need to be necessary and sufficient, necessary or sufficient to still be causal.
[00:28:20.560 --> 00:28:28.160] But our approach to patients who smoke is very clear, which is never smoke.
[00:28:28.160 --> 00:28:31.040] And if you do smoke, stop immediately.
[00:28:31.360 --> 00:28:39.920] Do we look at people who smoke and say, well, once your 10-year risk of lung cancer reaches this threshold, we're going to tell you to stop smoking.
[00:28:39.920 --> 00:28:48.320] Or once your PAC year smoking is above the 50th percentile or the 80th percentile, we're going to tell you to stop.
[00:28:48.320 --> 00:28:49.440] Absolutely not.
[00:28:49.440 --> 00:28:52.000] You immediately eliminate smoking.
[00:28:52.000 --> 00:29:06.640] And so similarly, it makes no sense that we would look at a causal driver of ASCBD in the case of APOB and kind of take an approach of, well, being at the 20th percentile or the 30th percentile, the 40th percentile is acceptable.
[00:29:06.640 --> 00:29:08.240] None of those things really make sense.
[00:29:08.240 --> 00:29:10.640] You have something that is causing the disease.
[00:29:10.640 --> 00:29:15.440] You should eliminate it as soon as possible because it is an area under the curve problem.
[00:29:15.440 --> 00:29:18.960] So atherosclerosis begins at birth.
[00:29:19.920 --> 00:29:31.120] When you do autopsies on people who are very young, in fact, I in the book include a photo of a guy who, you know, a man, I forget, I think maybe 26 years old who was a victim of a homicide or something.
[00:29:31.120 --> 00:29:33.920] So an completely unrelated death.
[00:29:34.480 --> 00:29:37.840] But you look at the autopsy sections of his coronary arteries.
[00:29:37.840 --> 00:29:40.560] I mean, he already had very advanced atherosclerosis.
[00:29:40.560 --> 00:29:42.640] Now, it wasn't clinically relevant.
[00:29:42.640 --> 00:29:45.520] It wasn't going to kill him anytime soon.
[00:29:45.520 --> 00:29:50.800] But the point is, this is a disease that takes decades to progress.
[00:29:51.120 --> 00:29:58.560] And one of the biggest drivers of it, in addition to things like high blood pressure and smoking and insulin resistance, is APOB.
[00:29:58.880 --> 00:30:13.080] So to be able to take that off the table sooner rather than later is going to certainly have the potential to take atherosclerosis off its pedestal at the top of the list of killing.
[00:30:13.400 --> 00:30:19.320] And so what do you, I mean, take, you obviously can't take it off the table completely, right?
[00:30:19.320 --> 00:30:20.760] We need ApoB.
[00:30:20.760 --> 00:30:23.320] But what can you do?
[00:30:23.320 --> 00:30:24.600] So let's think about it.
[00:30:24.600 --> 00:30:28.600] Yeah, so let's start with what we know.
[00:30:28.600 --> 00:30:31.000] Apo B rises with age.
[00:30:31.320 --> 00:30:31.960] Right.
[00:30:33.240 --> 00:30:35.240] We don't really know.
[00:30:35.240 --> 00:30:37.800] There are probably a lot of little reasons.
[00:30:38.360 --> 00:30:51.400] So there are, you know, endocrine changes, insulin resistance, senescence that, you know, might involve the decreased life of LDL receptors.
[00:30:51.400 --> 00:30:53.400] There's no clear reason, actually.
[00:30:53.400 --> 00:30:56.200] What about, so you were talking about clearance versus synthesis.
[00:30:56.200 --> 00:31:01.640] And I remember our mutual friend Ron Krause, like I've had, you know, many conversations with him.
[00:31:01.640 --> 00:31:03.800] I did my postdoc down the hall from his lab.
[00:31:03.800 --> 00:31:04.440] Right.
[00:31:05.240 --> 00:31:13.000] And I remember him telling me that, you know, ApoB, you're basically, your liver is constantly producing it.
[00:31:13.000 --> 00:31:16.200] You're making VLDL, just churning it out, right?
[00:31:16.200 --> 00:31:17.000] And it's just going, going.
[00:31:17.400 --> 00:31:19.800] And we also make LDL de novo, by the way.
[00:31:19.800 --> 00:31:20.200] Right.
[00:31:20.200 --> 00:31:23.240] Yeah, there's a de novo pathway plus the VLDL to LDL pathway.
[00:31:23.800 --> 00:31:38.360] But that, you know, the thing is, is that, you know, he was saying, well, from an evolutionary perspective, you're making this VLDL because, as you mentioned, you know, it's transporting things throughout the body to other organs, right?
[00:31:38.360 --> 00:31:41.400] Cholesterol, triglycerides, fatty acids.
[00:31:41.400 --> 00:31:45.520] It's also transporting, and this is where I was so intrigued, inflammatory proteins.
[00:31:44.920 --> 00:31:50.320] So, cytokines, Sirakoprotein also are being transported through VLDL.
[00:31:50.640 --> 00:32:00.560] Now, that was important pre-antibiotics, pre-everything that we do now to combat infectious disease and viruses and bacteria, parasites, whatever.
[00:32:01.120 --> 00:32:06.080] But before that time, that VLDL did serve that purpose too.
[00:32:06.080 --> 00:32:13.760] And that's why he thinks it's kind of a relic left over where the reason why we're constantly making is because it's a very large protein in size.
[00:32:13.760 --> 00:32:19.120] It's like tens of millions of the unit versus like 50,000 or something.
[00:32:19.120 --> 00:32:19.840] It's very big.
[00:32:19.840 --> 00:32:22.080] And so it takes time to make it.
[00:32:22.720 --> 00:32:30.320] And so I was thinking, well, like inflammation also does make it go up even further at the level of synthesis.
[00:32:30.320 --> 00:32:39.120] I don't know exactly the clearance, you know, how it's regulating clearance, but do you think the aging process is mostly affecting the clearance of it?
[00:32:39.120 --> 00:32:39.440] Or?
[00:32:40.240 --> 00:32:41.520] My intuition is yes.
[00:32:41.520 --> 00:32:50.320] My intuition is that it's primarily impacted on the clearance level, which is going to be, again, some facet of LDLR, LDLR meeting LDL receptor.
[00:32:50.320 --> 00:33:10.160] So is it we are making less of them, they are surviving less, the proteins that, you know, and that can basically done, there are many ways to regulate that process, but that's my intuition: it's less a conformational change in the LDLR and more a number of them and/or a reduced amount of time that they stay present.
[00:33:10.160 --> 00:33:25.840] One thing I'll add on the evolutionary front, you know, I had a guy named John Castellan on my podcast a few months ago, and he he proposed a really interesting idea, which completely makes sense evolutionarily, which you you could argue sort of like we don't really need APOB.
[00:33:25.840 --> 00:35:03.760] Like, this is the other thing: like, most species don't have apo b they don't require ldl but how i mean they have cholesterol but they don't they don't they don't require transporting all these you know you can do it with hdl you can transport everything with hdl yeah okay yeah they don't need the ldl i thought hdl was always going in reverse like it was bringing everything back to the no it's actually much more complicated i mean and in us ldl is doing the majority of what's called reverse cholesterol transport so rct which is kind of like the good movement of cholesterol you sort of think of the bad movement as taking cholesterol into the arteries the good movement is taking it back to the liver in us ldl is doing the majority of that so hdls are typically transferring their cholesterol to ldls and ldls are bringing them back to the liver um but john made an interesting point right which is that you know in in sort of following up on what you said the evolutionary cost of making cholesterol is enormous i mean it's a very labor intensive step right i can't remember the number of atps that are required to make a molecule of cholesterol but it's in the tens right like it could be 40 or something to that effect and so we evolved to have a system that prioritized having a lot of cholesterol being able to keep a lot of it around um because again this was an energy conserving system now this serves us no benefit today because today we can make plenty of it and we are we are in an energy abundant environment which we were not in you know hundreds of thousands of years ago.
[00:35:03.760 --> 00:35:15.600] And so this is a bit of an unfortunate vestige of our past it much in the way that a lot of the things that lead to insulin resistance are a vestige to things that were once very valuable.
[00:35:15.600 --> 00:35:25.840] I mean, the things that allowed us to leap up out of the swan with our swamp with big brains was primarily our capacity to store excess energy in a way that even primates can't.
[00:35:26.160 --> 00:35:29.520] Again, it served us really well until 150 years ago.
[00:35:29.520 --> 00:35:33.040] And I think the same is probably true of cholesterol and APOB.
[00:35:33.040 --> 00:35:36.400] So going back to your question, how much APOB is enough?
[00:35:36.400 --> 00:35:39.760] Well, it turns out you don't really need any of it to be perfectly fine.
[00:35:39.760 --> 00:35:48.240] So if you look at a child, they're born with an LDL cholesterol or APOB level, typically below 20 milligrams per deciliter.
[00:35:48.240 --> 00:35:54.480] So a kid, if you think about it, has the greatest need for growth, right?
[00:35:54.480 --> 00:36:08.720] Like, so you think about the cholesterol demand of myelinating the entire central nervous system, all of the enormous explosion of steroidal tissue, all of these things are done with lipoprotein levels that are incredibly low.
[00:36:08.720 --> 00:36:16.480] Again, what we call physiologic levels of LDL cholesterol and APOB are on the order of 10 to 30 milligrams per deciliter.
[00:36:16.480 --> 00:36:22.160] And yet there are no negative consequences to such low levels of that lipoprotein burden.
[00:36:22.160 --> 00:36:27.840] And it's only when we get, you know, when we become teenagers and in our 20s that we start to see those numbers go up.
[00:36:27.840 --> 00:36:34.400] And again, that's really just reflected by a reduction in clearance, then some need for additional LDL.
[00:36:34.400 --> 00:36:34.960] We don't have it.
[00:36:34.960 --> 00:36:39.120] The majority of what we need is actually, you know, before the age of 20.
[00:36:39.440 --> 00:36:52.560] Do you think, so like if you were to then estimate or speculate a level of APOB that you could say safely, well, I guess there's two things.
[00:36:52.560 --> 00:36:56.800] One, you're not going to die of atherosclerosis if you maintain a level below.
[00:36:57.040 --> 00:37:17.720] Yeah, so Peter Libby from the Brigham, who's one of the authorities on this topic, has argued, and I reference him in my book, that if you had an APO B level below about 30 milligrams per deciliter, 20 to 30 milligrams per deciliter, it wouldn't be possible to develop atherosclerosis.
[00:37:18.360 --> 00:37:20.840] What about not dying from atherosclerosis?
[00:37:20.920 --> 00:37:24.680] Like, what about if it's the major cause of death globally?
[00:37:24.680 --> 00:37:25.320] Yep.
[00:37:25.320 --> 00:37:31.160] And let's say like what it takes to get down to 30 probably is pretty aggressive.
[00:37:31.480 --> 00:37:36.680] Yeah, most people cannot get down to 30 without a pharmacologic intervention.
[00:37:36.680 --> 00:37:37.000] Yeah.
[00:37:37.480 --> 00:37:42.760] Do you think that you would die of atherosclerosis if you had, you know.
[00:37:42.760 --> 00:37:43.560] If you're at 60.
[00:37:43.560 --> 00:37:44.120] 60.
[00:37:44.440 --> 00:37:46.200] Well, it comes down to a couple of other things.
[00:37:46.200 --> 00:37:48.840] So the first thing is, how long are you at 60?
[00:37:48.840 --> 00:37:58.760] So if you say I've never exceeded 60, that's very different from saying, hey, I showed up and I was at 120 and you now lowered me to 60.
[00:37:58.760 --> 00:38:12.840] So again, I think of, you know, I imagine like everybody walks around and you've got a graph that on the x-axis is time and on the y-axis is APOB and you have a curve and you want to figure out what the area under that curve is.
[00:38:12.840 --> 00:38:15.400] And we want to minimize the area under that curve.
[00:38:15.400 --> 00:38:20.280] So if you took exactly so if you took, so again, very similar to smoking, right?
[00:38:20.440 --> 00:38:24.200] We talk about risk in pack years of smoking.
[00:38:24.200 --> 00:38:35.240] So if a person smokes a pack a day for 20 years or two packs a day for 10 years, you know, you have a way of kind of comparing apples to apples on those things.
[00:38:35.560 --> 00:38:42.760] So, to have a lifetime ceiling of 60 would also be a very, very low-risk individual.
[00:38:42.760 --> 00:38:48.640] 60 milligrams per deciliter is about the fifth percentile at the adult population level.
[00:38:48.960 --> 00:38:51.440] So, then that comes back to my question.
[00:38:51.840 --> 00:38:56.800] Sorry, one of the things I would add across the lifespan: when, like, when do you start measuring this?
[00:38:56.800 --> 00:39:01.520] Like, people aren't measuring their APOB in their teenage or 20.
[00:39:01.760 --> 00:39:09.360] Yeah, I mean, I would argue we should be, but I want to go back and say one other thing about your question, which I should have mentioned earlier, which is it also depends on other risk factors.
[00:39:09.360 --> 00:39:22.560] So, there are really four big things that are driving risk causally: APOB is one, insulin resistance is one, hypertension is one, and smoking is one.
[00:39:22.560 --> 00:39:24.720] Those are the big four.
[00:39:25.040 --> 00:39:33.920] So, you have to take everything we're saying on the APOB front and acknowledge that those other things are also causally linked to ASCBD.
[00:39:34.240 --> 00:39:39.600] So, again, it's a difficult situation to imagine, but it's certainly at least theoretically plausible.
[00:39:39.600 --> 00:39:46.720] You have somebody whose APOB is at 60, but they have uncontrolled hypertension, type 2 diabetes, and they smoke.
[00:39:47.040 --> 00:39:49.920] I mean, you could certainly arrive at that situation pharmacologically.
[00:39:49.920 --> 00:39:52.640] You're probably not going to arrive at that situation naturally.
[00:39:53.120 --> 00:39:55.360] Would I say that that person is free and clear?
[00:39:55.360 --> 00:39:56.640] No, I wouldn't.
[00:39:56.640 --> 00:40:04.480] So, we, you know, at the outset, I mentioned how the, you know, the downside of talking about ASCBD is it's the number one killer.
[00:40:04.480 --> 00:40:10.480] I mean, it's, you know, in fact, when you talk about it globally, the gap between ASCBD and cancer is even bigger.
[00:40:10.480 --> 00:40:14.320] It's like 19 million people annually to 12 or 13 million for cancer.
[00:40:14.320 --> 00:40:16.160] I mean, it's an enormous difference.
[00:40:16.800 --> 00:40:27.920] But the good news is, our understanding mechanistically of what drives this is so clear, and our tools for prevention are some of the best and most benign.
[00:40:28.240 --> 00:40:28.880] Okay.
[00:40:29.200 --> 00:40:38.040] So, let's say that a person is relatively healthy, you know, they're committed to exerciser, they're not insulin resistant.
[00:40:38.120 --> 00:40:44.280] I do want to talk about hypertension and insulin resistance, but okay, a healthy, generalized quote-unquote healthy person, right?
[00:40:45.000 --> 00:40:47.320] Wants to lower their APOB.
[00:40:47.640 --> 00:40:50.520] They want to try everything through diet, through lifestyle.
[00:40:50.520 --> 00:40:56.120] And you mentioned there are some major lifestyle dietary factors that can increase APOB.
[00:40:56.120 --> 00:40:57.240] So let's talk about those.
[00:40:57.240 --> 00:40:57.800] What are the major?
[00:40:58.120 --> 00:41:01.160] So the big two are anything that contributes to insulin resistance.
[00:41:01.160 --> 00:41:02.120] So we'll start with that.
[00:41:02.120 --> 00:41:07.560] And that does so mostly through the VLDL triglyceride pathway.
[00:41:07.560 --> 00:41:11.560] So we talked earlier about it, how there are really two ways we make LDL.
[00:41:11.560 --> 00:41:15.240] We make LDL directly, but most of the LDL is made through VLDL.
[00:41:15.240 --> 00:41:23.560] So if you're exporting a lot of VLDL, what you're doing is both making a lot of that lipoprotein, but you also have a lot of triglyceride in it.
[00:41:23.560 --> 00:41:28.760] Now, something I didn't mention a moment ago that's worth restating or stating in the first place.
[00:41:28.760 --> 00:41:35.000] The LDL is carrying around both cholesterol and triglyceride.
[00:41:35.320 --> 00:41:40.120] And the more cholesterol there is, all things equal, the more LDL you need.
[00:41:40.120 --> 00:41:42.600] But the same is true with triglyceride.
[00:41:42.920 --> 00:41:55.400] So the first mechanism in which we see a very clear relationship between diet and APOB is the higher the burden of triglycerides, the higher the burden of APOB.
[00:41:55.720 --> 00:42:25.600] To state this another way, if you take two people who have the exact same level of LDL cholesterol and the same total cholesterol, but one has very high triglycerides and one has very low triglycerides, the former is going to have a much higher APOB and therefore be at a much higher risk of atherosclerosis because they have more cargo and therefore require more ships in the analogy of cargo being cholesterol and triglycerides and the ships being the lipoproteins.
[00:42:25.600 --> 00:42:30.640] So step number one is lower the triglyceride as much as possible.
[00:42:30.640 --> 00:42:36.480] And the triglyceride being low is an enormous proxy for insulin sensitivity.
[00:42:36.480 --> 00:42:44.400] So this is one of the important ways in which managing insulin resistance is a key to keeping APOB in check.
[00:42:44.400 --> 00:42:46.240] And of course there are other issues as well.
[00:42:46.240 --> 00:42:56.320] So insulin and glucose by themselves, when elevated, also create problems at the endothelial level, which becomes another mechanism by which this is problematic.
[00:42:57.840 --> 00:43:06.960] It's pretty clearly observed from a dietary pattern perspective that carbohydrate restriction is the most effective tool at triglyceride reduction.
[00:43:07.280 --> 00:43:12.640] All carbohydrates, I mean like vegetables, fruits, yeah, refined and starchy carbohydrates.
[00:43:12.640 --> 00:43:13.520] Yeah.
[00:43:13.520 --> 00:43:25.200] So, but that actually feeds really nicely into the next observation, which is what's the next dietary pattern that impacts APOB, and that's saturated fat consumption.
[00:43:25.520 --> 00:43:28.560] And the reasons for that are twofold.
[00:43:28.560 --> 00:43:34.080] So the first is that saturated fat directly impacts cholesterol synthesis.
[00:43:34.080 --> 00:43:44.240] Now, this is not true equally of all saturated fats, but we don't really have great data on if certain saturated fats have a greater impact on cholesterol synthesis relative to others.
[00:43:44.240 --> 00:43:49.920] For example, a C16 might be potentially more so than a C18 or a C19.
[00:43:49.920 --> 00:43:52.160] But again, what foods would you find a C16 versus?
[00:43:52.240 --> 00:43:58.080] Oh, like a C16 would be more in, I believe, like a coconut oil or a palm oil or something like that.
[00:43:58.080 --> 00:43:58.800] Versus.
[00:43:58.960 --> 00:44:08.200] Also, by the way, you would also see that more a C16, like a palmitate, would be more of a synthesis, would be more of a saturated fat you see in response to insulin resistance.
[00:44:08.200 --> 00:44:11.960] So it would actually be a de novo saturated fat synthesis.
[00:44:11.960 --> 00:44:16.600] So perhaps, so I think that's a big part of it.
[00:44:16.600 --> 00:44:18.200] I think cholesterol synthesis is a big part of it.
[00:44:18.200 --> 00:44:33.640] I think a bigger part of it might be that excess saturated fat inhibits the sterile binding, the sterile regulatory binding protein in the liver that results in fewer LDL receptors being made.
[00:44:33.960 --> 00:44:40.280] So saturated fat therefore has two things that it's doing that are driving up APOB.
[00:44:40.280 --> 00:44:44.520] And the susceptibility of this varies from different individuals.
[00:44:44.520 --> 00:44:48.440] So I was on a ketogenic diet for three years.
[00:44:48.440 --> 00:44:50.920] I was not one of the people who seemed to suffer from this.
[00:44:50.920 --> 00:45:05.320] So even on a ketogenic diet where I was getting 80% of my calories from fat and probably half of that was saturated fat, I did not have any sort of obnoxious increase in my APOB or LDLC or any of these metrics.
[00:45:05.320 --> 00:45:10.120] Similarly, we have some patients who are on very low carb, very high fat diets.
[00:45:10.120 --> 00:45:16.040] Some of them have completely normal levels of lipids and some of them have lipids that go absolutely haywire.
[00:45:16.040 --> 00:45:26.760] So it's not entirely clear what the difference is, but clearly there are different genes that will allow certain people to metabolize that saturated fat safely while others do not.
[00:45:26.760 --> 00:45:39.000] So I'm not in the camp that believes that, and there is an entire camp of people who believe this, that if you're on a low-carb, high-fat diet, and your APOB and LDL-C go through the roof, it's not problematic.
[00:45:39.160 --> 00:45:40.280] I don't believe that at all.
[00:45:40.280 --> 00:45:43.720] I think that that's a very bold claim, and I would not be willing to play that game.
[00:45:43.720 --> 00:45:59.840] I think if your ApoB goes haywire, even if you're very insulin-sensitive, and even if you're in energy balance and all the other wonderful things that might come with your ketogenic diet, I think you have to pay very close attention to if your lipids get out of whack.
[00:45:59.840 --> 00:46:04.240] So, those are basically your big manipulations dietary-wise.
[00:46:04.240 --> 00:46:11.600] It's the composition of fat, the quantity and composition of fat, and the dietary choices that address insulin sensitivity.
[00:46:11.600 --> 00:46:23.760] So, in the people that, let's say, they're eating a higher saturated fat diet, if they swap that out with monounsaturated fat or even polyunsaturated fat, which some camps also like to demonize the kind of polyunsaturated fat.
[00:46:24.320 --> 00:46:28.000] But if you swap that out, their Apo B levels are not.
[00:46:28.720 --> 00:46:43.600] In our experience, about half of the people who have this hyper-response to saturated fat, if you iso-calorically shift them to high monounsaturated fat, you fix the problem.
[00:46:43.920 --> 00:46:44.960] Yeah, okay.
[00:46:44.960 --> 00:46:47.280] It starts to get into a little bit of an issue, right?
[00:46:47.280 --> 00:46:52.160] Which is, and this is where you have to remember what problem you're solving.
[00:46:52.160 --> 00:47:00.000] So, for some people, that's an easy switch, you know, because they were kind of, some people tend to go out of their way to try to eat as much saturated fat as possible.
[00:47:00.000 --> 00:47:00.640] I'm not sure why.
[00:47:00.640 --> 00:47:08.240] Like, they sort of, you know, they're like, okay, well, I'm doing this, you know, ketogenic diet, and I'm just going to basically eat coconut oil and palm oil.
[00:47:08.240 --> 00:47:09.200] Like, it's my job.
[00:47:09.200 --> 00:47:10.080] Yeah, yeah, yeah, yeah.
[00:47:10.400 --> 00:47:14.240] And so, for those people, you just got to say, dude, like, stop doing that.
[00:47:14.240 --> 00:47:17.680] Just like use olive oil on your salad and like, let's be reasonable.
[00:47:17.680 --> 00:47:18.960] And then it fixes everything.
[00:47:19.200 --> 00:47:22.640] But for other people, you know, it's it just can't be addressed.
[00:47:22.640 --> 00:47:26.080] And I've heard other people say, oh, you know, this is crazy.
[00:47:26.080 --> 00:47:31.800] Like, we know that, you know, excessive fat restriction in the diet will lower cholesterol.
[00:47:29.840 --> 00:47:32.280] And that's true.
[00:47:32.440 --> 00:47:40.600] I mean, if you go on a really draconian fat-lowering diet, you will lower your cholesterol.
[00:47:41.560 --> 00:47:49.960] My view clinically is that makes very little sense because that usually comes with a whole bunch of other issues.
[00:47:49.960 --> 00:48:02.360] So a lot of times when I see people on these excessively restrictive fat lowering diets, they actually become insulin resistant, a lot of them, because they're really over-consuming a lot of poor quality carbs.
[00:48:02.600 --> 00:48:06.680] And they're suffering other consequences of really low fat intake.
[00:48:06.680 --> 00:48:09.640] Now, again, this doesn't mean that a low-fat diet is necessarily problematic.
[00:48:09.640 --> 00:48:17.960] The devil's in the details here, just like the devil's in the details on what constitutes a reasonable versus an unreasonable low-carb diet.
[00:48:17.960 --> 00:48:26.920] But the point I try to make to people is I believe that using nutrition to solve the lipid problem is not a good solution.
[00:48:26.920 --> 00:48:30.280] I think use nutrition to solve the nutrition problem.
[00:48:30.280 --> 00:48:44.280] Use nutrition to address energy balance, protein needs, anabolic structure, energy, all of these other things, and let your lipids fall where they may, because this is one of the few areas in medicine where we have amazing pharmacologic tools.
[00:48:44.280 --> 00:48:47.640] Most of medicine doesn't really have great pharmacology if you stop to think about it.
[00:48:47.640 --> 00:48:56.200] Like we don't have great, there's nothing pharmacologically that's adding brilliance to our Alzheimer's prevention strategy or our cancer prevention strategy.
[00:48:56.200 --> 00:49:01.080] I mean, we have some stuff, but it's nothing compared to what we can do with blood pressure and lipid management.
[00:49:01.080 --> 00:49:14.960] So I always say it's hard enough to find the right diet that's going to work for you in terms of your ability to be compliant with it, your ability to be within energy balance, which is the single most important thing, your ability to be insulin sensitive, your ability to get adequate amounts of protein.
[00:49:14.440 --> 00:49:19.120] If you solve that with a low-fat diet that also happens to keep your lipids low, great.
[00:49:19.440 --> 00:49:28.320] But if you solve that with a higher fat diet that does everything perfect for you except your lipids go haywire, don't put your head in the sand and act like having lipids that have gone haywire is a good thing.
[00:49:28.320 --> 00:49:34.160] No, just acknowledge it's not a good thing, but we can fix it with, again, myriad tools that didn't exist 20 years ago.
[00:49:35.520 --> 00:49:41.280] Are there people that are genetically have genetically low APOB?
[00:49:41.600 --> 00:49:45.040] And if so, what's their cardiovascular mortality?
[00:49:45.040 --> 00:49:46.400] They're all-cause mortality.
[00:49:47.040 --> 00:49:48.640] Yeah, so there are people.
[00:49:48.800 --> 00:50:05.680] So it turns out APOB and LDLC are highly genetic, which is what has allowed us to do the Mendelian randomization studies that act as one of the, you know, there are basically three cornerstones of data that make it unambiguously clear of the relationship between LDL or APOB and ASCVD.
[00:50:05.680 --> 00:50:11.200] So you have all of the epidemiologic data, which again, epidemiology is rife with problems.
[00:50:11.200 --> 00:50:18.640] But, you know, when the data is pretty much all in the same direction and you have the dose effect and all these other things, it becomes quite helpful.
[00:50:18.640 --> 00:50:23.280] You have all the clinical trial data, which I would divide into primary and secondary prevention data.
[00:50:23.280 --> 00:50:46.080] And then you have the Mendelian randomization data, which again, for listeners, is basically anytime there is a biologic variable of interest that is under a high degree of genetic control and produces a high degree of variability in the population, you can look at how nature has basically randomized it across people and you can look at outcomes of interest.
[00:50:46.080 --> 00:51:03.640] So, in the case of LDLC, because we know it is highly genetic, right, this is clear in that, and I don't just mean in extreme cases, but just across a population, you can see that lower lifelong exposure to APOB or LDL produces lower ASCVD risk over a lifetime.
[00:51:03.960 --> 00:51:10.680] So, using this, we can say there are people at really low and high extremes.
[00:51:10.680 --> 00:51:25.880] So, at the high extreme, you have the people who have what's called familial hypercholesteria, which is a genetically heterogeneous disease, meaning there are literally thousands of mutations that result in a similar phenotype.
[00:51:25.880 --> 00:51:33.800] The phenotype is defined as having an LDL cholesterol off-medication of more than 190 milligrams per deciliter, and there's a couple of other criteria.
[00:51:33.800 --> 00:51:39.000] But just to give you a sense of how high the LDL needs to be to meet that criteria.
[00:51:39.640 --> 00:51:45.720] At the other end of the spectrum, we have these people with very, very low LDLC or APOB.
[00:51:45.720 --> 00:51:53.720] And the most interesting group of these are the people who are folks that have a hypo-functioning gene for PCSK9.
[00:51:53.720 --> 00:52:01.320] So, Helen Hobbes made this discovery in probably the early 2000s.
[00:52:01.560 --> 00:52:04.520] My vague recollection, I remember reading this paper when it came out.
[00:52:04.520 --> 00:52:06.200] It was a really mind-boggling paper.
[00:52:06.200 --> 00:52:17.080] Call it like somewhere in 2004, 2005, 2006, somewhere in that neighborhood, which is, hey, there are these people walking around with LDLC of like 10 to 20 milligrams per deciliter.
[00:52:17.800 --> 00:52:18.840] And these are adults, right?
[00:52:18.840 --> 00:52:21.240] So normally we just never see that in adults.
[00:52:21.240 --> 00:52:22.760] And they weren't doing anything different, right?
[00:52:22.760 --> 00:52:27.320] They just, like they weren't on some crazy diet or clearly weren't taking any medication.
[00:52:27.320 --> 00:52:35.160] And these people were found to have a mutation in their PCSK9 gene that rendered a hypofunctioning protein.
[00:52:35.160 --> 00:52:39.080] And PCSK9 is a protein that degrades LDL receptors.
[00:52:39.080 --> 00:52:51.440] Now, another subset of these people, their mirror opposites, were discovered several years earlier, which had a hyper-functioning PCSK9 gene, or a gene that produced a hyperfunctioning protein.
[00:52:51.440 --> 00:52:54.160] And these people had sky-high LDL cholesterol.
[00:52:54.160 --> 00:52:58.320] They were a subset of the familial hypercholesterolemia syndromes.
[00:52:58.320 --> 00:52:59.200] And these people weren't.
[00:52:59.200 --> 00:53:04.720] And what was interesting to note is that they just didn't develop cardiovascular disease.
[00:53:04.720 --> 00:53:12.960] So I can't tell you what their life expectancy is because I haven't looked at those data.
[00:53:12.960 --> 00:53:19.520] But what I did confirm is they have no increase in the incidence of any other disease.
[00:53:19.520 --> 00:53:26.400] So in other words, they're absent ASCVD, but they don't make up for it with more cancer or more neurodegenerative disease or more diabetes.
[00:53:27.360 --> 00:53:29.600] That's interesting for a couple of reasons.
[00:53:29.600 --> 00:53:43.440] One, you see on Twitter a lot, you know, the very, very, you know, just the hyper-focused, very low-carb community that's like, you know, they share studies about, oh, low cholesterol.
[00:53:43.440 --> 00:53:46.320] People with low cholesterol have a higher all-cause mortality.
[00:53:46.320 --> 00:53:49.920] They're more likely to die from, you know, all these different causes of death.
[00:53:50.320 --> 00:54:04.000] Yeah, the problem with those studies is, I mean, I'll only address this once because I've done so much addressing this that I realize you can only waste so much time preaching to an audience that actually has no interest in understanding the truth.
[00:54:04.320 --> 00:54:18.960] But just to give you an example of the type of biases that creep into those studies, when you look at people who have very low LDL cholesterol, you're sampling a subset of people who are at very high risk for a disease, typically two diseases, right?
[00:54:18.960 --> 00:54:26.800] When you have very high LDL, you are at risk of ASCVD, cerebrovascular disease, and Alzheimer's disease and all causes of dementia.
[00:54:26.800 --> 00:54:35.000] So, therefore, the people who are at high risk for those are typically the people at a population level who have the lowest level because they're being treated the most aggressively.
[00:54:29.680 --> 00:54:37.080] So, this is kind of the problem with that stuff.
[00:54:37.720 --> 00:54:39.160] I'll give you an example.
[00:54:39.160 --> 00:54:41.880] There's a clear association in the epidemiology.
[00:54:41.880 --> 00:54:48.440] It doesn't come up often, but it's come up from time to time that the lower the LDL cholesterol, the higher the risk of cancer.
[00:54:48.760 --> 00:54:58.200] This is a great example of when Mendelian randomization becomes very valuable because you can actually go back and look at the genes that are controlling LDL.
[00:54:58.200 --> 00:55:08.920] You can look at how those are spread out, and you can ask the question: once you just look at the random assignment of those genes that control LDL cholesterol, does that have any bearing on cancer outcome?
[00:55:08.920 --> 00:55:11.640] And the answer is unequivocally, no, it does not.
[00:55:11.640 --> 00:55:24.120] So, when you do the MR, you get the answer that the EPI is clearly confounding with something else, which is, in other words, low LDL at the population level is a proxy for other illness.
[00:55:24.120 --> 00:55:25.240] This is the issue here.
[00:55:25.240 --> 00:55:26.360] Yes, thank you.
[00:55:27.320 --> 00:55:32.920] The other interesting point was with the actual gene that you were mentioning, the PCS canine, right?
[00:55:32.920 --> 00:55:44.920] So, when you were talking about we have pharmacological interventions that do very nicely lower APOB, one of them is PCS canine inhibitors.
[00:55:44.920 --> 00:55:45.400] Exactly.
[00:55:45.480 --> 00:55:47.400] Came right out of Helen Hobbes' observation.
[00:55:47.720 --> 00:56:01.160] So, I want to, let's, you know, let's touch on the pharmacological treatments, but also the PCS canine inhibitors, they're not necessarily available to everyone at the start, right out the gate.
[00:56:01.160 --> 00:56:18.880] And then I want to get your thoughts on some of the base editing trials that have started looking at literally like you're doing a gene edit, you know, and you're changing, you know, a nucleotide to essentially make a PC or the people that you're talking about walking around, right?
[00:56:18.880 --> 00:56:20.640] With no ASCB.
[00:56:20.640 --> 00:56:21.280] Yeah.
[00:56:14.840 --> 00:56:22.240] So.
[00:56:23.120 --> 00:56:27.120] Okay, so let's maybe just talk broadly about what the different pharmacologic strategies are, right?
[00:56:27.120 --> 00:56:40.800] So the very first drug that was ever used to lower lipids was a drug called, oh God, I'm always blanked on the name of this, like triperanol.
[00:56:41.120 --> 00:56:43.440] So this was done in the 1950s.
[00:56:43.440 --> 00:56:44.880] Yeah, well, there's a reason you never heard of it, right?
[00:56:44.880 --> 00:56:46.640] So it turned out to be a really bad drug.
[00:56:46.640 --> 00:56:53.040] So there used to be a day when, again, in the 1950s and 1960s, we just didn't know what the hell was going on.
[00:56:53.040 --> 00:56:56.960] So the idea was if you came up with any drug that lowered cholesterol, it must be a good thing.
[00:56:56.960 --> 00:57:07.600] Well, it turned out this drug lowered cholesterol by inhibiting an enzyme that was the final enzyme in the step that we used to make cholesterol.
[00:57:07.600 --> 00:57:16.800] So we make cholesterol using two pathways, but one of the pathways results in a molecule called desmosterol, which gets converted into cholesterol.
[00:57:16.800 --> 00:57:21.440] So there's an enzyme that facilitates that, and this drug blocked that enzyme.
[00:57:21.440 --> 00:57:24.080] And as a result, cholesterol levels went down.
[00:57:24.080 --> 00:57:29.040] And although no one was really paying attention at the time, desmosterol levels went sky high.
[00:57:29.040 --> 00:57:31.280] And it lowered cholesterol.
[00:57:31.280 --> 00:57:33.600] So on the basis of that, this drug was approved.
[00:57:33.600 --> 00:57:37.280] And back at the time, that was the only thing you were monitoring, was total cholesterol.
[00:57:37.600 --> 00:57:42.960] But it was found that the patients on this drug, even though they had lower cholesterol, had a higher incidence of heart attacks.
[00:57:42.960 --> 00:57:45.520] So the drug was ultimately pulled in the 1960s.
[00:57:45.520 --> 00:57:54.560] We now know today that it was almost assuredly the case that the desmosterol was even more athergenic than the cholesterol, or at least as atherogenic.
[00:57:54.560 --> 00:58:01.960] So, fast forward to the 1980s, the next class of drugs is developed called bile acid sequesterants.
[00:57:59.680 --> 00:58:06.840] We didn't really get into the life cycle of cholesterol, so it might be worth doing that now because it'll make sense in the context of the drugs.
[00:58:07.000 --> 00:58:09.720] So, every cell in the body is making cholesterol.
[00:58:10.040 --> 00:58:13.080] So, just think path one: synthesis of cholesterol.
[00:58:13.080 --> 00:58:16.520] If you synthesize less cholesterol, that's one way to lower it.
[00:58:16.520 --> 00:58:20.200] As you noted, all that cholesterol is making its way back to the liver.
[00:58:20.200 --> 00:58:28.600] When the liver gets a hold of all that cholesterol, it's putting a lot of it into bile, and we're using bile acids to digest food.
[00:58:28.600 --> 00:58:34.440] So, as bile via the bile duct is entering the small intestine, it is full of cholesterol.
[00:58:34.760 --> 00:58:38.840] The body reabsorbs much of that cholesterol.
[00:58:38.840 --> 00:58:46.840] So, each of the enterocytes, which are the gut cells that line your intestine, they have a couple of transporters on them.
[00:58:46.840 --> 00:58:54.600] So, one of the transporters on them, it's called a Neiman-Pixie 1-like one transporter, it absorbs all of the sterols.
[00:58:54.600 --> 00:58:59.160] And this is, I use the word sterol very carefully to distinguish it here from just cholesterol.
[00:58:59.160 --> 00:59:04.680] This is zoosterol and plant sterol, which is, or an animal sterol, which is called cholesterol.
[00:59:04.680 --> 00:59:05.960] It absorbs that all.
[00:59:06.280 --> 00:59:13.640] There are basically regulatory steps inside the cell that determine how much of that should be kept and how much should be excreted.
[00:59:13.640 --> 00:59:17.560] And a fraction of that then gets excreted through an ATP binding cassette.
[00:59:17.560 --> 00:59:22.040] So, point being, that's a second point of regulation at the absorption site.
[00:59:22.040 --> 00:59:25.080] But again, this is not the cholesterol we eat.
[00:59:25.080 --> 00:59:28.840] This is un-esterified cholesterol that's easy to get in and out of the body.
[00:59:28.840 --> 00:59:31.480] Esterified cholesterol can't be absorbed.
[00:59:31.480 --> 00:59:33.720] And most of the cholesterol we eat is esterified.
[00:59:33.720 --> 00:59:35.880] That's why we just poop it out.
[00:59:37.240 --> 00:59:48.560] So, bile acid sequesterants, which were the first version of drugs, the second version, I guess, of drugs to lower cholesterol, which are not used today, blocked that process in a very crude mechanical way.
[00:59:48.800 --> 00:59:53.200] They sequestered the bile acids and dragged all the cholesterol out the GI tract.
[00:59:53.200 --> 00:59:59.840] They were not a very successful class of drugs, and not the least of which because the side effects were pretty bad.
[00:59:59.840 --> 01:00:10.320] So, it really wasn't until the mid to late 80s, probably I think 1987, if my memory serves me correctly, that the first statin came to be developed.
[01:00:10.320 --> 01:00:22.240] And that was the real turning point in basically the pharmacologic tool that became valuable against ASCBD.
[01:00:22.320 --> 01:00:31.520] Now, the first, second, and third generation statins of that era are no longer in use today because their side effect profile was very harsh relative to what we can do today.
[01:00:31.520 --> 01:00:38.240] So, there are currently seven statins in existence, and each of them offers some strengths and advantages over others.
[01:00:38.240 --> 01:00:40.000] And they're not a benign class of drugs.
[01:00:40.000 --> 01:00:42.560] So, to be clear, they're an effective class of drug.
[01:00:42.560 --> 01:00:45.680] They're very effective at lowering LDL cholesterol.
[01:00:45.680 --> 01:00:50.960] They work by inhibiting the first committed step of cholesterol synthesis.
[01:00:50.960 --> 01:00:54.240] They do that everywhere, but primarily in the liver.
[01:00:54.240 --> 01:01:01.680] And the response of the liver when cholesterol synthesis is being shut down, the liver says, I got to get more cholesterol in here.
[01:01:01.680 --> 01:01:02.480] And what does it do?
[01:01:02.480 --> 01:01:06.000] It puts a whole bunch more LDL receptors all over the liver.
[01:01:06.000 --> 01:01:11.440] And that's what's primarily driving down LDL in the presence of a statin.
[01:01:11.760 --> 01:01:13.360] But the side effects are what?
[01:01:13.360 --> 01:01:17.200] Well, about 7% of people develop muscle aches on statins.
[01:01:17.200 --> 01:01:22.240] So, that's a, if you think about how many people are on those drugs or how many people are prescribed those drugs, that's a huge number of people.
[01:01:22.240 --> 01:01:24.720] The good news is that's a completely reversible side effect.
[01:01:24.720 --> 01:01:31.080] So, you put a person on a statin, they experience muscle soreness, you take them off, it's gone within a week or two.
[01:01:32.200 --> 01:01:37.880] The other big side effect, the one that I probably think about the most, is insulin resistance.
[01:01:37.880 --> 01:01:46.200] So, a very small set of subset of people, about 0.4% of people put on a statin, might go on to develop type 2 diabetes as a result of it.
[01:01:46.200 --> 01:01:54.040] Now, I think any doctor who lets a patient get to the point where they get type 2 diabetes because of their statin hasn't been paying attention.
[01:01:54.040 --> 01:01:58.360] We want to know the minute you're becoming insulin-resistant in response to the statin.
[01:01:58.360 --> 01:01:59.720] And those data are less clear.
[01:01:59.720 --> 01:02:13.720] You don't know exactly how many people are getting insulin-resistant, but this is a reason to be paying attention to bigger markers and more important markers than just hemoglobin A1C trips over the threshold of 6.5%, you have type 2 diabetes.
[01:02:13.720 --> 01:02:16.760] Here, you want to be able to say: is the hemoglobin A1C moving?
[01:02:16.760 --> 01:02:19.400] What's happening to the fasting insulin and glucose and these other markers?
[01:02:19.400 --> 01:02:21.000] Does a patient wear a CGM?
[01:02:21.000 --> 01:02:28.280] One of the reasons we like CGMs on patients when we put them on statins is we have a historical level of what their glucose control looks like.
[01:02:28.280 --> 01:02:41.960] And if all of a sudden their baseline average glucose goes up by 10 milligrams per deciliter, which I've seen in patients on a statin, I know it's, you know, that's not just a quick dietary trigger, especially when you take them off the statin and it comes right back down to normal.
[01:02:41.960 --> 01:02:47.640] So, even though they haven't become, you know, they haven't gone to the level of being diabetic, they're clearly becoming insulin-resistant.
[01:02:47.640 --> 01:02:54.120] And the third thing we see with statins is change in or an increase in the transaminases or the liver function tests.
[01:02:54.200 --> 01:02:59.720] Liver function test is a bit of a misnomer because the transaminases really tell us more about inflammation than function.
[01:02:59.720 --> 01:03:11.400] So, all that said, statins are still kind of, you know, they're doing the lion's share of the work in this area, but by no means should we say that that's the only thing that we have at our disposal.
[01:03:11.400 --> 01:03:13.320] About 20 years ago, another drug called azetamine.
[01:03:13.480 --> 01:03:15.000] Can I interrupt for a second and ask you about statins?
[01:03:15.280 --> 01:03:15.680] Yeah, you can.
[01:03:15.680 --> 01:03:16.000] Of course.
[01:03:16.320 --> 01:03:18.400] Because I have some questions about them.
[01:03:18.400 --> 01:03:26.400] So I'll never forget this conversation that, again, I had with our mutual friend Ron Kraus because he worked down the hall.
[01:03:26.400 --> 01:03:27.520] I worked down the hall from him.
[01:03:27.520 --> 01:03:29.840] And I collaborated with some of his postdocs.
[01:03:29.840 --> 01:03:43.920] And, you know, they would come over and show me data and we would talk because I had a lot of experience in assaying mitochondrial function and mitochondrial biology during graduate school.
[01:03:43.920 --> 01:03:46.640] And I remember saying this to Ron.
[01:03:46.640 --> 01:03:58.800] I'm like, you know, so statins are affecting the HMG CoA pathway that you mentioned, the cholesterol synthesis, which also is important for the synthesis of ubiquinol, right?
[01:03:58.800 --> 01:04:02.480] This is an important, or CoQ10, as I should probably call it.
[01:04:02.640 --> 01:04:04.720] This is important for mitochondrial function.
[01:04:04.720 --> 01:04:15.520] I mean, it's necessary for mitochondrial function for transferring electrons across the electron transport chain, which is essentially coupling the oxygen we breathe with the food that we eat to make energy.
[01:04:15.520 --> 01:04:20.320] And I remember saying, oh, so statins have a side effect of targeting mitochondria.
[01:04:20.320 --> 01:04:24.160] And he said to me, no, it's a direct effect.
[01:04:24.160 --> 01:04:33.760] So what are your thoughts on how statins are affecting mitochondria and through this pathway?
[01:04:33.760 --> 01:04:40.320] And obviously, you might mention supplementation with a reduced form of ubiquinol, right?
[01:04:40.560 --> 01:04:45.360] Measuring mitochondrial function in terms of BO2 max, something.
[01:04:46.240 --> 01:04:49.920] So it's a great question, actually, and something I have thought a lot about.
[01:04:50.720 --> 01:04:54.800] So the literature has nothing to offer here, unfortunately.
[01:04:55.040 --> 01:05:00.200] So I wish I could say, you know, Rhonda, the answer is this, because here's what the literature says.
[01:05:00.200 --> 01:05:02.200] Here's what I can tell you.
[01:04:59.360 --> 01:05:04.440] And this is not going to be a satisfying answer.
[01:05:04.760 --> 01:05:12.280] If there is an impact on mitochondrial function with statin use, it's very small.
[01:05:12.280 --> 01:05:21.800] based on what I consider to be the single best measurement we have to measure mitochondrial function, which is zone 2 testing with lactate production.
[01:05:22.120 --> 01:05:30.840] So I know you know what this is because we talk about this stuff all day long, but just for folks listening, this requires a little bit of explanation, but it's very important.
[01:05:30.840 --> 01:05:33.080] And I think it's, I'm glad you brought this up.
[01:05:33.080 --> 01:05:35.800] So everybody understands what the mitochondria do.
[01:05:36.040 --> 01:05:40.360] If they're listeners of your podcast, we don't need to explain the mitochondria.
[01:05:40.360 --> 01:05:45.320] But it's important to understand that a functional test is a very important test in medicine.
[01:05:45.320 --> 01:05:47.480] We don't have many functional tests, right?
[01:05:47.480 --> 01:05:50.600] Most of the things we talk about are biomarkers.
[01:05:50.920 --> 01:05:54.600] And by themselves, they don't tell you a huge amount of information.
[01:05:54.600 --> 01:05:57.560] They tend to be quite static and not dynamic.
[01:05:57.880 --> 01:06:10.440] But we understand that the healthier an individual is, the more they can rely on their mitochondria for ATP generation under increasing demands of the cell.
[01:06:10.440 --> 01:06:13.480] This is one of the hallmarks of health.
[01:06:13.480 --> 01:06:20.360] And by extension, one of the hallmarks of aging and one of the hallmarks of disease is an inability to do that.
[01:06:20.360 --> 01:06:32.600] Meaning, as the ATP demand on a cell goes up, there is an earlier and earlier shift to glycolysis as opposed to oxidative phosphorylation.
[01:06:32.600 --> 01:06:35.560] So, how do we, how can we measure that clinically?
[01:06:35.560 --> 01:06:41.800] Well, we can put a person in, because we can't, you know, rather than test a cell, let's test the whole organism, right?
[01:06:41.800 --> 01:06:45.200] So, we put a person in sort of an ergometer, right?
[01:06:45.200 --> 01:06:58.480] So, on a treadmill or on a bike or under some sort of demand where we can control the work that they have to do, and we can drive up the amount of work they do while sampling lactate.
[01:06:58.480 --> 01:07:00.080] And why does that, what does that tell us?
[01:07:00.080 --> 01:07:07.360] Well, just to remind everybody, you know, glucose enters a cell and it basically has two fates, right?
[01:07:07.360 --> 01:07:10.960] So, glucose will be converted into pyruvate regardless.
[01:07:10.960 --> 01:07:19.360] It has the fate at which oxygen is plentiful and the body has the time to make a lot of ATP where it goes into the mitochondria.
[01:07:19.360 --> 01:07:27.520] And it has the less efficient but quicker way to get ATP, which is converting lactate, pardon me, pyruvate into lactate.
[01:07:27.520 --> 01:07:33.520] So, this is the glycolytic pathway versus the oxidative phosphorylitic pathway.
[01:07:34.800 --> 01:07:39.680] The longer a cell can stay in that mitochondrial space, the better it is.
[01:07:39.680 --> 01:07:46.320] It makes way more ATP and it accumulates less lactate and hydrogen ion.
[01:07:46.320 --> 01:07:56.080] And the more lactate and hydrogen ion you accumulate, eventually the cell becomes effectively poisoned by that hydrogen ion, and it becomes very difficult for a muscular cell to contract.
[01:07:56.080 --> 01:07:59.200] So, we use this test with patients.
[01:07:59.200 --> 01:08:01.840] This is one of the most important metrics we care about.
[01:08:01.840 --> 01:08:18.720] Literally, it would be in the top 10 things we care about for our patients, which is how many watts can you produce on a bike, or how many METs can you exercise at on a treadmill or whatever vehicle you're using while keeping lactate below about 2 millimole.
[01:08:18.720 --> 01:08:30.000] 2 millimole is about the threshold beyond which you are now shifting away from the maximum capacity of the mitochondria to undergo this process.
[01:08:31.080 --> 01:08:39.480] Okay, all of this is to say I have clearly seen the effect of a drug like metformin at impacting that.
[01:08:39.800 --> 01:08:43.000] Metformin, which is a mitochondrial toxin, right?
[01:08:43.000 --> 01:08:47.320] Metformin impairs complex one of the mitochondria.
[01:08:47.320 --> 01:08:54.120] We immediately see a change in the lactate performance curve of an individual on metformin.
[01:08:54.120 --> 01:08:57.560] We see a complete reduction in their zone 2 output.
[01:08:57.560 --> 01:09:00.600] They hit that lactate of 2 much sooner.
[01:09:00.600 --> 01:09:09.560] We also see an increase, not big, but significant, meaning clinically significant, in their fasting, resting, lactate level.
[01:09:09.560 --> 01:09:13.160] So all things equal, their lactate is just getting higher.
[01:09:13.480 --> 01:09:17.160] To me, by the way, I don't know if that's necessarily harmful.
[01:09:17.160 --> 01:09:22.120] I don't think it's a good idea, which is why I don't believe in metformin as a girro-protective agent.
[01:09:22.120 --> 01:09:28.360] I think metformin is a good drug for someone who's diabetic, if they can't exercise enough and they can't get into energy balance.
[01:09:28.920 --> 01:09:34.120] But I don't think metformin is a great drug for someone like you or someone like me.
[01:09:35.400 --> 01:09:38.040] We don't see this with statins.
[01:09:38.360 --> 01:09:41.880] So if it's happening, it's dose-dependent or not.
[01:09:42.200 --> 01:09:42.920] Just don't see it.
[01:09:42.920 --> 01:09:45.160] Yeah, just don't see it.
[01:09:45.160 --> 01:09:48.680] So it could be happening, but we don't have the resolution to measure it.
[01:09:48.920 --> 01:09:55.080] So that's why I'm saying, like, I think one always has to have the humility, which I hope I have, to say, look, I don't know.
[01:09:55.400 --> 01:10:00.520] But what I do know is if there's an effect there, it's really small.
[01:10:00.520 --> 01:10:08.520] Now, you mentioned ubiquinol or CoQ10, and there are two states of it, ubiquinol and ubiquinone, but ubiquinol would be the state we would want to consider here.
[01:10:08.520 --> 01:10:16.960] There have been a number of clinical trials looking at using or supplementing ubiquinol with patients taking statins.
[01:10:16.960 --> 01:10:22.400] They have mostly done this to assess the muscle soreness issue.
[01:10:22.400 --> 01:10:30.320] So they've mostly done this as a way to ask the question: can you reduce the insulin, the incidence rather, of muscle soreness with statins?
[01:10:30.320 --> 01:10:32.640] I haven't looked at those literature in a couple of years.
[01:10:32.640 --> 01:10:36.080] The last I looked at them, there was still no difference.
[01:10:37.040 --> 01:10:45.440] That said, we have patients that really feel strongly about taking ubiquinol when they're on a statin, and I don't have any issue with that.
[01:10:45.840 --> 01:10:47.600] I don't think there's any harm in taking it.
[01:10:47.600 --> 01:10:49.120] I really don't think there is.
[01:10:50.320 --> 01:10:53.440] And if there's a chance of benefit, then I would say let's take it.
[01:10:53.440 --> 01:11:01.840] But again, unless something has happened in the last couple of years that I'm unaware of, I don't think we have great data that ubiquinol offsets that.
[01:11:01.840 --> 01:11:10.560] And more importantly, to your point, it's not clear to me that that effect translates to a functional deficit in the mitochondria.
[01:11:10.880 --> 01:11:20.320] When you're measuring, so using the zone 2, you know, lactate threshold training to kind of measure mitochondrial function.
[01:11:21.920 --> 01:11:27.760] So buying the lactate meter, Nova Biomedical or something like that.
[01:11:28.240 --> 01:11:29.520] It's like a yellow-purple one.
[01:11:29.840 --> 01:11:35.440] I got it per year recommendation, but for people listening, if they want to get one.
[01:11:35.440 --> 01:11:45.040] But also knowing how, because there's, when you go to like any sort of, if you were to go talk to an exercise physiologist and you say lactate threshold, like they kind of know.
[01:11:45.360 --> 01:11:46.160] And they're going to push you up.
[01:11:46.200 --> 01:11:48.480] The lactate threshold is a different number.
[01:11:48.480 --> 01:11:48.640] Right.
[01:11:48.640 --> 01:11:50.480] So this is like lower level.
[01:11:51.040 --> 01:11:52.320] This is below your lactate threshold.
[01:11:52.560 --> 01:11:53.520] Yeah, this is lower.
[01:11:53.520 --> 01:11:56.320] So how do people know?
[01:11:56.320 --> 01:12:02.120] Let's like, let's say they have a Peloton at home, okay, and they get on their Peloton and they want to do a zone two test.
[01:12:02.120 --> 01:12:02.760] Okay.
[01:12:03.800 --> 01:12:15.080] Can you somehow use a percent max rate, heart rate, sorry, max heart rate proxy to kind of know like there are lots of different ways to estimate this.
[01:12:15.080 --> 01:12:23.160] And to be clear, like I'm one of the very few people that is checking his lactate every, you know, every day that he's on his bike, which is four days a week for me.
[01:12:23.160 --> 01:12:29.400] And by the way, I'm also doing it while using all the other metrics that I'll explain in a moment.
[01:12:29.400 --> 01:12:38.440] Mostly just in an ever, never-ending quest to just have as much data as possible to understand when is lactate the best predictor?
[01:12:38.440 --> 01:12:40.280] When was RPE the best predictor?
[01:12:40.280 --> 01:12:42.120] When was heart rate the best predictor?
[01:12:42.120 --> 01:12:44.120] When was absolute wattage the best predictor?
[01:12:44.120 --> 01:12:46.440] Like there's a lot of stuff going on here.
[01:12:46.440 --> 01:12:54.280] So first thing I always say to people, namely my patients, when they say, I don't want to get that lactate meter, I don't want to be poking myself in the finger.
[01:12:54.280 --> 01:12:55.640] I'm like, great, don't.
[01:12:55.640 --> 01:12:56.680] You don't have to.
[01:12:56.680 --> 01:13:01.880] There are like other ways that you can pretty much approximate your zone two output.
[01:13:01.880 --> 01:13:07.720] And the only reason I brought up the whole lactate testing is it is the gold standard and it is the most objective way to do this.
[01:13:07.720 --> 01:13:12.840] And therefore, if I'm trying to really understand the impact of say metformin or astatin, that's what I want to do.
[01:13:12.840 --> 01:13:19.080] But let's put that aside for a moment and answer the relevant question, which is, hey, how does someone exercise in this zone?
[01:13:19.400 --> 01:13:26.600] I think the most important tool for virtually anybody is rate of perceived exertion.
[01:13:26.600 --> 01:13:29.240] I think that will almost never let you down.
[01:13:29.880 --> 01:13:37.480] In fact, I would argue that for a really, really out-of-shape individual, rate of perceived exertion is even better than lactate.
[01:13:37.800 --> 01:13:44.640] And the reason for that is you take somebody who's got, for example, type 2 diabetes, their resting lactate may already be at 2.
[01:13:44.200 --> 01:13:47.680] So in those patients, we actually never use lactate.
[01:13:47.840 --> 01:13:54.320] Until you get somebody to a certain level of fitness, we only use rate of perceived exertion, and we will provide heart rate guidance.
[01:13:54.320 --> 01:13:56.560] So here's two ways to think about it.
[01:13:57.840 --> 01:14:02.960] RPE, rate of perceived exertion, we give people the test, which is the talk test.
[01:14:02.960 --> 01:14:13.280] So when you are in zone two, you should be able to speak to somebody, but it should be uncomfortable and not something you want to do.
[01:14:13.280 --> 01:14:16.800] If you can't speak, you're out of zone two.
[01:14:17.600 --> 01:14:20.080] If you can't speak in a full sentence, you're not in zone two anymore.
[01:14:20.560 --> 01:14:22.080] You're north of zone two.
[01:14:22.080 --> 01:14:25.840] If you can speak the way you and I are speaking now, you're not working hard enough.
[01:14:25.840 --> 01:14:27.760] You're too far below it.
[01:14:27.760 --> 01:14:40.080] So there is that sweet spot where if you're on that Peloton and the phone rings and you answer it, the person knows you're exercising and you're going to let them do most of the talking.
[01:14:40.080 --> 01:14:45.360] But if they ask you a question and you have to answer it, you'll answer it and you can speak in a full sentence, but you're not that comfortable.
[01:14:45.360 --> 01:14:48.480] That's the single most important thing people need to understand about it.
[01:14:48.480 --> 01:14:59.120] As far as what heart rate guidance comes with it, Philmafitone uses a test that I think is a pretty good starting place, which is 180 minus your age.
[01:14:59.440 --> 01:15:03.600] Now, the fitter you are, the less relevant that becomes.
[01:15:03.600 --> 01:15:09.840] So I'm 50, so that would put me at 130, but I can tell you my zone two is above 130.
[01:15:09.840 --> 01:15:14.320] So if you're fitter, you may add five to 10 to that.
[01:15:16.000 --> 01:15:26.320] I use another app that checks my HRV every single morning, and it predicts my zone two as a result of my HRV.
[01:15:26.320 --> 01:15:42.040] And so every day, what I'm doing is I'm looking at the heart rate predicted by the app, which can vary by as much as 10 beats per minute based on how much I slept, the quality of my sleep, how sore I am, a subjective measurement of how much I want to train that day, and my HRV.
[01:15:42.040 --> 01:15:44.760] So it's a Morpheus.
[01:15:44.760 --> 01:15:45.560] Morpheus.
[01:15:45.560 --> 01:15:45.960] Yeah.
[01:15:46.520 --> 01:15:49.080] So, and I have no affiliation with them or anything like that.
[01:15:49.080 --> 01:16:03.800] So, basically, so this morning I got up, my HRV was, I don't even remember, 78 milliseconds, slept seven hours, 15 minutes, good quality sleep, not sore, felt good.
[01:16:03.800 --> 01:16:06.040] So, I actually had a pretty high target today.
[01:16:06.040 --> 01:16:09.720] My target today was 141, the heart rate.
[01:16:09.720 --> 01:16:12.760] On a day, that's about as high as it will predict me to be.
[01:16:13.080 --> 01:16:17.240] On a day when everything sucks, it might tell me as low as 129.
[01:16:17.560 --> 01:16:21.640] Usually, it's about 136, 137, 138, is where it's predicting.
[01:16:21.640 --> 01:16:24.920] And that's generally aligning with where my lactate is.
[01:16:25.560 --> 01:16:28.520] That'll generally put me at a lactate of about 1.9.
[01:16:29.480 --> 01:16:32.680] And then, on top of that, I'm paying attention to the wattage, so I kind of know where to be.
[01:16:32.680 --> 01:16:36.440] But again, for somebody just starting out, RPE is all you need to know.
[01:16:36.440 --> 01:16:38.520] 180 minus your age is good.
[01:16:38.520 --> 01:16:49.000] And then, if a person is fit enough that they truly know their maximum heart rate, we tell them to start at somewhere between 75 and 80 percent of that number.
[01:16:49.320 --> 01:16:50.840] Great recommendations.
[01:16:51.000 --> 01:17:02.760] So, if a person is specifically trying to do this functional mitochondrial test, how long should they be in that zone two before they can measure their lactate?
[01:17:02.920 --> 01:17:06.360] We like to see people there for 30 to 45 minutes before we do it.
[01:17:06.360 --> 01:17:08.440] Yeah, so a true, true steady state.
[01:17:08.440 --> 01:17:09.320] Awesome.
[01:17:10.200 --> 01:17:18.960] So, I kind of want to, the other, going back, circling back to the statins, and here's my question to you.
[01:17:14.840 --> 01:17:19.200] Okay.
[01:17:20.320 --> 01:17:41.040] What questions do you think I should be asking and looking in the literature to convince myself that, let's say, a lipophilic statin that could, you know, cross the blood-brain barrier, get into the brain, inhibit, you know, HEM-CoA in the brain, particularly at higher doses.
[01:17:41.040 --> 01:17:54.000] But generally speaking, what question should I be asking myself to convince myself that it's not going to put me at a higher risk for both of the neurodegenerative disease that I'm terrified about?
[01:17:54.000 --> 01:17:55.360] One, Alzheimer's disease.
[01:17:55.360 --> 01:18:00.080] I have a genetic, it's family history, genetic risk factor, and Parkinson's disease, family history.
[01:18:00.560 --> 01:18:04.080] Both of those diseases have been associated with statin use.
[01:18:04.080 --> 01:18:10.800] They've also been, the literature, as you know, is, you know, you can find what you want, right?
[01:18:11.120 --> 01:18:13.680] So do you have any, you know, advice?
[01:18:13.920 --> 01:18:18.800] Yeah, I did a recent AMA on this, although it might not be out yet.
[01:18:18.800 --> 01:18:22.400] I lose track of when I record them and when they come out, so I apologize if it hasn't come out yet.
[01:18:23.600 --> 01:18:28.960] But I did an entire AMA on this topic because it is so important.
[01:18:28.960 --> 01:18:32.240] And I think it's, as you said, it's so confusing.
[01:18:32.880 --> 01:18:34.960] So I was actually surprised to learn this.
[01:18:35.520 --> 01:18:42.000] I was surprised to learn that there has never been, I shouldn't have been surprised, but regardless, here's what it is.
[01:18:42.000 --> 01:18:52.240] There has never been a study done that has looked at the use of statins and the incidence of Alzheimer's disease or dementia as a primary outcome.
[01:18:52.240 --> 01:18:53.600] Why is that important?
[01:18:53.600 --> 01:19:02.040] It's important because in clinical research, the primary outcome is the only thing you can really take to the bank because that's what the study is powered to detect.
[01:19:02.680 --> 01:19:24.200] There are more than a dozen, probably less than 25, so a big number of studies, call it 15, 16, that have used statins, have had a primary outcome of ASC V D, but a secondary outcome of dementia or Alzheimer's disease.
[01:19:24.200 --> 01:19:27.240] And I looked at every single one of those.
[01:19:27.880 --> 01:19:41.080] And I can tell you that every single one of those found neutral to benefit of statin use on the incidence of dementia and the incidence of Alzheimer's disease.
[01:19:41.080 --> 01:19:46.120] So that includes vascular dementia, I mean, that sort of makes more sense.
[01:19:46.360 --> 01:19:47.560] Parkinson's disease.
[01:19:47.560 --> 01:19:49.800] Have you seen, have you looked at the literature on that?
[01:19:50.120 --> 01:19:55.720] So Parkinson's is a little bit more confusing because the literature is way more sparse.
[01:19:56.360 --> 01:20:01.480] But I do want to go back and talk about Alzheimer's disease because I think there's an important caveat to everything I just said.
[01:20:01.480 --> 01:20:05.400] What I basically, oh, the other point I want to make, Rhonda, this actually surprised me.
[01:20:05.400 --> 01:20:16.600] There was no difference between hydrophobic and hydrophilic statins with respect to the difference whatsoever.
[01:20:16.600 --> 01:20:20.920] So counterintuitive, but no difference whatsoever.
[01:20:22.200 --> 01:20:29.000] So even though, again, you might think, well, gosh, you know, a statin that gets in the brain should have more of an impact, but it didn't.
[01:20:29.000 --> 01:20:29.800] It didn't seem to have.
[01:20:29.880 --> 01:20:35.960] Is there a difference in those two types of statins with respect to the diabetes, increased diabetes risk that you're talking about?
[01:20:36.600 --> 01:20:37.880] That's a really good question.
[01:20:38.680 --> 01:20:41.000] I didn't look at that in, and that wasn't looked at in this.
[01:20:41.480 --> 01:20:52.400] Yeah, here's what I can tell you: the highest incidence of diabetes is probably with atorvastatin, but that might also be because atorvastatin is the most widely used.
[01:20:52.400 --> 01:21:00.800] Like, I don't, we basically, first of all, there's only four statins that I think are even worth prescribing these days, maybe only three.
[01:21:00.800 --> 01:21:02.880] And I treat them all equally in terms of risk.
[01:21:02.880 --> 01:21:07.520] In other words, I would assume anytime you put somebody on a statin, you should be looking for any of the side effects.
[01:21:07.520 --> 01:21:13.840] And I don't particularly, because again, you might say at the population level, it's different, but at the individual level, who cares?
[01:21:14.320 --> 01:21:15.440] It's either one or zero.
[01:21:15.440 --> 01:21:16.560] You're going to get it or you're not.
[01:21:16.800 --> 01:21:17.520] What statins are those?
[01:21:18.080 --> 01:21:29.360] The ones that we would prescribe would be resuvastatin or atorvastatin or lipitor, patavastatin, livolo, and sometimes we use prevastatin or prevacol, but pretty rarely.
[01:21:30.080 --> 01:21:31.840] So usually those would be the big four.
[01:21:31.840 --> 01:21:41.520] Now, here's what I would say, and this is something that we spend an awful lot of time looking at in our practice.
[01:21:41.520 --> 01:21:50.880] And actually, just last week, Tom Dayspring gave us an internal presentation that was so incredible.
[01:21:51.360 --> 01:22:03.040] It was months in the making, looking at the relationship between statin use and desmosterol levels and dementia risk.
[01:22:03.040 --> 01:22:06.560] So you may recall a moment ago I mentioned desmosterol.
[01:22:06.560 --> 01:22:10.640] So desmosterol is, well, let's back up.
[01:22:10.640 --> 01:22:14.000] Remember how I said there were two cholesterol synthesis pathways?
[01:22:14.000 --> 01:22:22.240] Well, in the CNS, really only you have one pathway, and it's the pathway that goes through desmosterol to cholesterol.
[01:22:22.240 --> 01:22:30.000] So, desmosterol levels are actually a decent proxy for brain cholesterol synthesis.
[01:22:30.840 --> 01:22:40.200] Lithosterol, which is the penultimate molecule in the other pathway, is more of a proxy for peripheral cholesterol synthesis.
[01:22:40.520 --> 01:22:41.160] Are these measured?
[01:22:41.240 --> 01:22:42.440] You can measure these on a like.
[01:22:42.600 --> 01:22:44.760] They're very difficult to measure in most labs.
[01:22:44.760 --> 01:22:46.440] We use a lab that measures them.
[01:22:46.440 --> 01:22:53.240] So, we measure desmosterol and lithosterol in every patient with every blood draw.
[01:22:53.240 --> 01:22:55.240] Unfortunately, this is not standard of care.
[01:22:55.240 --> 01:22:56.920] Most labs can't measure this.
[01:22:56.920 --> 01:22:58.120] Boston Heart does this.
[01:22:58.120 --> 01:23:00.120] So, that's why we use Boston Heart.
[01:23:02.360 --> 01:23:15.960] There are enough data suggesting that if desmosterol levels are very low, the risk of AD does indeed go up, and the risk of dementia beyond AD goes up.
[01:23:16.600 --> 01:23:35.400] So, this is kind of what I would describe as personalized medicine/slash medicine 3.0 at its finest, which is you have to treat every patient individually, and we're doubly careful in patients with an APOE4 gene and/or a family history.
[01:23:35.400 --> 01:23:40.520] And in those patients, based on the literature, and I'd be happy to send you Tom's presentation.
[01:23:40.520 --> 01:23:43.320] He would not have a hard time with me sharing that, even though it was kind of an internal presentation.
[01:23:43.320 --> 01:23:49.720] In fact, I could share with you the recording Tom made because we recorded the internal meeting because it was so valuable.
[01:23:50.040 --> 01:23:52.760] But basically, the cutoff we use is 0.8.
[01:23:52.760 --> 01:24:04.520] So, if desmosterol falls below 0.8 milligrams per deciliter, we think the risk of dementia is sufficiently high enough that we would abort the use of the statin.
[01:24:04.840 --> 01:24:05.960] Very good information.
[01:24:05.960 --> 01:24:10.160] And you think there is a correlation with APOE status on that?
[01:24:10.640 --> 01:24:13.720] No one has done that study yet.
[01:24:14.120 --> 01:24:15.040] In your clinical practice.
[01:24:14.440 --> 01:24:18.240] But in our clinical practice, we just decided, like, why would we take the risk?
[01:24:18.720 --> 01:24:27.440] But yes, no one has done the study to show our desmosterol levels lower in ApoE4 individuals.
[01:24:27.440 --> 01:24:32.160] That's actually a very testable hypothesis, and it makes a lot of sense.
[01:24:32.160 --> 01:24:38.400] Because we know APOE is heavily involved in cholesterol activity in the brain.
[01:24:38.720 --> 01:24:50.160] And so it wouldn't be surprising to me if, you know, if you put people into three buckets, zero alleles, one allele, or two allele, E4 alleles, and then just looked at desmosterol levels.
[01:24:50.160 --> 01:24:53.760] Like that would be a very easy, mindless study to do.
[01:24:53.760 --> 01:24:57.920] Just a survey, like just a quick, is there a correlation, yes or no?
[01:24:58.960 --> 01:25:01.760] So that's one thing I'd love to know the answer to.
[01:25:02.240 --> 01:25:10.160] But even absent that knowledge, our view is there's simply no reason to take the risk.
[01:25:10.480 --> 01:25:20.560] You know, earlier I said it makes no sense to go on some crazy, obscure diet that has a whole bunch of unintensed consequences just to control your lipids.
[01:25:20.560 --> 01:25:22.880] Well, I would make the exact same statement here.
[01:25:22.880 --> 01:25:31.120] It makes no sense to get all, to take unnecessary risks with statins in a higher-risk individual when we have these other tools.
[01:25:31.120 --> 01:25:36.320] We have, as we talked about or we will talk about, azetamide, PCSK9 inhibitors, bempidoic acid.
[01:25:36.320 --> 01:25:41.360] These are unbelievable tools that have no bearing on brain cholesterol synthesis.
[01:25:41.360 --> 01:25:50.960] But Peter, aren't people that have an APOE4 allele more likely to be prescribed statins based on their LDL particle number by their physician?
[01:25:50.960 --> 01:25:53.760] Because the physician doesn't look at their none of this.
[01:25:53.760 --> 01:25:54.640] This isn't personalized.
[01:25:54.640 --> 01:25:55.920] It's not medicine 3.0, right?
[01:25:56.480 --> 01:25:56.880] Yep.
[01:25:56.880 --> 01:25:58.320] No, it's very frustrating.
[01:25:58.800 --> 01:26:05.720] And it's also frustrating that of those three drugs that are an alternative to statins, two of them are still very expensive.
[01:26:06.280 --> 01:26:09.400] Okay, so the three drugs, I know the PCSK9 inhibitor.
[01:26:09.400 --> 01:26:09.880] Yep.
[01:26:10.920 --> 01:26:18.920] Highly effective, insanely safe, zero side effects, cheaper than when they came out.
[01:26:18.920 --> 01:26:21.480] So they were approved in 2015.
[01:26:21.880 --> 01:26:25.640] And we have long-term data with the people walking around with a natural mutation, right?
[01:26:26.200 --> 01:26:27.000] Just amazing.
[01:26:27.000 --> 01:26:27.640] Yeah, exactly.
[01:26:27.640 --> 01:26:29.000] We have the natural experiment.
[01:26:29.000 --> 01:26:31.480] We have all of the data from these drugs.
[01:26:31.800 --> 01:26:39.160] And these drugs have been tested in really good trials, and they've gone head to head with every drug, and they always win, and there's no side effects.
[01:26:39.400 --> 01:26:40.440] But they're expensive, right?
[01:26:40.600 --> 01:26:43.960] It's a $500 a month drug in the United States.
[01:26:43.960 --> 01:26:46.680] It's cheaper outside of this country, so everything's better out of the U.S.
[01:26:46.680 --> 01:26:47.960] when it comes to drug pricing.
[01:26:47.960 --> 01:26:53.560] But in the U.S., you're talking about $500 a month for that drug if it's not covered by your insurance company.
[01:26:53.560 --> 01:26:54.200] Right.
[01:26:54.760 --> 01:26:58.120] And if you can get a doctor to say, I'm going to prescribe it to you.
[01:26:58.120 --> 01:26:58.520] I mean, like.
[01:26:58.920 --> 01:27:06.120] I mean, at this point, a doctor who's not willing to prescribe a PCSK9 inhibitor just is a fool.
[01:27:07.080 --> 01:27:23.240] So it's just a question of the cost, because unfortunately, most insurance companies will not cover it unless you meet certain criteria, such as having familial hypercholesteromia or having already had a cardiac event, like a heart attack, and not being able to tolerate a statin.
[01:27:23.240 --> 01:27:24.360] Or what about myopathy?
[01:27:24.360 --> 01:27:25.640] Like if you have muscle.
[01:27:25.800 --> 01:27:25.960] Yes.
[01:27:26.120 --> 01:27:32.600] Significant myopathy on multiple statins, but you'd also have to be at high enough risk to justify it.
[01:27:32.600 --> 01:27:35.400] So, insurance companies are going to go out of their way to not pay for this.
[01:27:36.200 --> 01:27:37.560] Then you have azetamib.
[01:27:37.640 --> 01:27:40.280] Now, azetamib is relatively inexpensive.
[01:27:40.280 --> 01:27:42.120] It's just not as potent.
[01:27:42.120 --> 01:27:50.000] So, azetamib also effectively serves to increase the LDL receptors on the liver, but it does so by impairing cholesterol reabsorption.
[01:27:50.080 --> 01:27:54.000] So, it blocks one of those two transporters I was talking about in the gut, the first one.
[01:27:54.000 --> 01:28:05.520] And by blocking that, the body is absorbing way less of its own cholesterol, and the liver senses that, and the liver says, Hey, I got to get more cholesterol, puts more LDL receptors on, pulls it out of circulation.
[01:28:06.800 --> 01:28:08.160] It's not as potent.
[01:28:08.160 --> 01:28:19.360] And as a monotherapy, the only times we see really head-over-heels responses are in patients who have defective ATP binding cassettes in their gut.
[01:28:19.360 --> 01:28:23.600] And we measure that by looking at phytosterol levels.
[01:28:23.600 --> 01:28:28.720] So, we measure two things: one is called cytosterol, one is called compesterol.
[01:28:28.720 --> 01:28:29.840] Those are phytosterols.
[01:28:29.840 --> 01:28:32.000] So, these are cholesterol we don't make.
[01:28:32.000 --> 01:28:33.520] It's zoosterol.
[01:28:33.680 --> 01:28:36.000] Pardon me, it's phytosterol, not zoosterol.
[01:28:36.000 --> 01:28:45.360] And so, when we measure those levels, we know that it speaks to how much plant sterol is being absorbed and not being excreted.
[01:28:45.360 --> 01:28:53.520] And so, when patients have really, really high levels of phytosterols, you know they have a defective ATP binding cassette.
[01:28:53.520 --> 01:28:57.120] And those patients respond really well to azetamib.
[01:28:57.520 --> 01:28:59.440] It's like a blockbuster in those people.
[01:28:59.440 --> 01:29:00.080] Wow.
[01:29:00.080 --> 01:29:04.320] Is that a common, you know, single nucleotide polymorphism?
[01:29:05.920 --> 01:29:08.800] You know, it depends how extreme it is.
[01:29:08.800 --> 01:29:24.960] So, it's not uncommon to see people who are above the 90th percentile, but I've only seen like probably three people that have a level that is so high you'd actually be concerned with it, just in and of itself.
[01:29:24.960 --> 01:29:29.400] Meaning, like the actual level, because phytosterols are actually more atherogenic than cholesterol.
[01:29:28.960 --> 01:29:33.560] And that's also like Boston Hart measured all these phytosterols.
[01:29:29.120 --> 01:29:34.120] Okay.
[01:29:35.000 --> 01:29:37.240] They're more atherogenic than cholesterol.
[01:29:37.240 --> 01:29:37.720] Yeah.
[01:29:38.040 --> 01:29:41.160] They're more prone to oxidation, more inflammatory.
[01:29:41.160 --> 01:29:43.800] Are they being carried in lipoproteins?
[01:29:43.800 --> 01:29:46.680] They're oxidized.
[01:29:46.680 --> 01:29:47.480] Are they oxidized?
[01:29:47.480 --> 01:29:48.440] They're more oxidized?
[01:29:48.440 --> 01:29:49.400] They're more oxidizable.
[01:29:49.400 --> 01:29:55.800] And this is, by the way, is a reason that we don't favor the practice of using phytosterols to lower cholesterol.
[01:29:55.800 --> 01:30:01.880] So there are a lot of sort of over-the-counter treatments where people use phytosterols to lower their cholesterol.
[01:30:01.880 --> 01:30:03.080] And it does.
[01:30:03.400 --> 01:30:17.160] So if you ingest a ton of phytosterols, you will out-compete cholesterol at that enterocyte, and your body will regulate, and you'll end up net reabsorbing less total cholesterol.
[01:30:18.280 --> 01:30:29.000] The problem with that is if you have a defective ATP binding cassette, which again, it's not that uncommon that you do, you will end up really absorbing a lot of those phytosterols.
[01:30:29.000 --> 01:30:40.840] And again, so this is sort of an example of that desmosterol point earlier where you can lower cholesterol, but if you're really raising desmosterol too much, it can be more atherogenic than cholesterol in the first place.
[01:30:40.840 --> 01:30:42.760] So desmosterol has shown up twice today.
[01:30:42.760 --> 01:30:45.320] It showed up in a good sense and in a bad sense.
[01:30:45.320 --> 01:30:54.120] So too much of it, if you're using a drug that blocks the enzyme that comes after it, that was the thing that was producing too much atherosclerosis in the 60s.
[01:30:54.120 --> 01:31:03.000] Too little of it could be a marker of too little cholesterol synthesis in the brain, and that can be a whole problem in and of itself.
[01:31:03.000 --> 01:31:12.040] The final drug, so we can just wrap this up because I'm sure the listeners are tired of hearing about this stuff, is a drug called bempidoic acid that is a pro-drug.
[01:31:12.040 --> 01:31:13.800] So, it's a very elegant drug.
[01:31:13.800 --> 01:31:23.920] It's taken as a pill, but it's ineffective until it's metabolized by the liver, and in the liver, it then inhibits cholesterol synthesis.
[01:31:23.920 --> 01:31:30.320] What makes this drug special is, unlike statins, this drug only works in the liver.
[01:31:30.320 --> 01:31:38.480] So, statins work throughout the body, they do most of their work in the liver, but technically every cell is impacted by a statin.
[01:31:38.480 --> 01:31:41.680] Only hepatocytes are impacted by bempidoic acid.
[01:31:41.680 --> 01:31:43.040] And it lowers APOB.
[01:31:43.360 --> 01:31:43.840] Same way.
[01:31:43.840 --> 01:31:45.200] Lowers cholesterol synthesis.
[01:31:45.280 --> 01:31:53.440] Liver says, I need more cholesterol, puts more LDL receptors up, pulls more LDL in, LDL and cholesterol go down, but no side effects.
[01:31:53.440 --> 01:31:54.560] No type 2 diabetes.
[01:31:54.720 --> 01:31:55.360] Nothing.
[01:31:55.520 --> 01:31:56.560] Nothing, nothing.
[01:31:56.560 --> 01:31:59.360] It's just, it's only acting in the liver.
[01:31:59.680 --> 01:32:03.280] Well, that sounds same problem as PCSK9 inhibitor.
[01:32:03.280 --> 01:32:05.440] It's a $500 a month drug.
[01:32:05.440 --> 01:32:06.000] Okay.
[01:32:06.000 --> 01:32:06.560] Yep.
[01:32:06.560 --> 01:32:08.880] So, again, we'd have every.
[01:32:09.200 --> 01:32:17.600] Look, honestly, at this point, like, if money were no issue, you'd probably just be on PCSK9 inhibitors, azetamib, and bempidoic acid.
[01:32:17.600 --> 01:32:19.040] I mean, eventually we'll get there, right?
[01:32:19.040 --> 01:32:20.800] Yeah, we just have to come down in price.
[01:32:21.120 --> 01:32:34.080] For people that want a more clear picture of the plaque accumulation in their arteries and their vascular system, the best way to do it, I think I've heard about CT angiogram.
[01:32:34.080 --> 01:32:34.480] Okay.
[01:32:34.480 --> 01:32:43.520] And is that something, you know, like you think people should start at a certain age, or certainly if they have measured their, you know, APOB?
[01:32:43.920 --> 01:32:46.800] Yeah, I mean, you know, I think there's different ways to think about this.
[01:32:47.280 --> 01:32:58.280] You know, I think there's a principle in medicine that most doctors try to adhere to, which is don't order a test unless there's a chance the test will change your management.
[01:33:00.040 --> 01:33:01.800] And it's easy to deviate from that.
[01:32:57.920 --> 01:33:03.160] I certainly know I do at times.
[01:33:03.560 --> 01:33:11.560] But as a general rule, I try to ask myself the question: before I order this test, how will the outcome change what I do with this patient?
[01:33:11.560 --> 01:33:24.600] So through that lens, you could make a case that the only time you should be ordering a CT angiogram is if you go through the following experiment, which is, if it comes back normal, how will it change what I do?
[01:33:24.600 --> 01:33:28.280] If it comes back abnormal, how will it change what I do?
[01:33:28.280 --> 01:33:45.960] So if you were sitting in my office and I said, well, look, Rhonda, you're 35 years old, your APO B is really high, your family history is such that people get cardiovascular disease in your family, meaning, you know, it's not like you've got a bunch of relatives who are in their 90s who have never had a cardiac event.
[01:33:45.960 --> 01:33:49.880] So you don't have some genetic protection of cardiovascular disease.
[01:33:50.360 --> 01:33:53.880] Do I need a CT angiogram in you to convince me to do anything?
[01:33:53.880 --> 01:33:57.960] Because the truth of it is at 35, your CT angiogram is going to be normal.
[01:33:57.960 --> 01:33:58.920] I mean, it might not be.
[01:33:58.920 --> 01:34:03.880] Mine wasn't at 35, but it probably will be for most people.
[01:34:04.200 --> 01:34:08.200] And if it's normal, will I then say we don't need to do anything about this?
[01:34:08.200 --> 01:34:12.680] No, because that's sort of like saying you're a smoker who has a normal CT scan.
[01:34:12.680 --> 01:34:15.160] You don't yet have lung cancer, therefore we should let you keep smoking.
[01:34:15.160 --> 01:34:16.680] No, we should stop you from smoking.
[01:34:16.680 --> 01:34:21.160] So in other words, I just wouldn't have a huge appetite for doing that test in you.
[01:34:21.480 --> 01:34:34.680] There are other patients at the other end of the spectrum where, you know, they come to me, they're 75 years old, their APO B is through the roof, but I notice like all their relatives live to be 100 and they never had heart disease.
[01:34:34.680 --> 01:34:40.360] And I look at them and I think, do I really want to put this person on lipid-lowering medicine at the age of 75?
[01:34:40.680 --> 01:34:42.520] Why don't we do a CTA?
[01:34:42.520 --> 01:34:48.480] If the CTA is normal, which by some miracle is not a very important thing, I don't think we need to do something.
[01:34:48.480 --> 01:34:54.160] There's clearly something this person has going on that is beyond our understanding of the science so far.
[01:34:54.160 --> 01:34:57.360] So in that sense, I wouldn't do anything about it.
[01:34:57.360 --> 01:35:05.680] The way I think about it is there's a two by two, which is age versus finding, positive or negative.
[01:35:05.680 --> 01:35:13.280] I think CT angiograms are mostly helpful when they have a positive finding in a young person or a negative finding in an old person.
[01:35:13.280 --> 01:35:17.280] That's where it can really cause you to act differently.
[01:35:17.280 --> 01:35:24.000] Outside of those findings, i.e., positive findings in old people are to be expected, negative findings in young people are to be expected.
[01:35:24.000 --> 01:35:28.160] I think you should just track the biomarkers of interest and go off that risk.
[01:35:28.160 --> 01:35:28.800] Okay.
[01:35:29.120 --> 01:35:31.200] I mean, like, is a 45-year-old considered?
[01:35:31.520 --> 01:35:32.880] I would still put that in the young category.
[01:35:32.880 --> 01:35:33.040] Okay.
[01:35:33.040 --> 01:35:39.280] So you think that CT angiogram would still kind of look maybe good?
[01:35:39.600 --> 01:35:40.240] It should.
[01:35:40.240 --> 01:35:44.480] And again, I would only think about it through the lens of if the patient is hesitant.
[01:35:44.880 --> 01:35:48.560] Like, so we had a new patient, you know, that started a couple of weeks ago.
[01:35:48.560 --> 01:35:51.280] He'd never had one of these tests before.
[01:35:52.560 --> 01:35:54.240] But he had a lot of risk factors, right?
[01:35:54.240 --> 01:35:57.680] Elevated Apo B, elevated LP little A.
[01:35:57.680 --> 01:35:59.680] I mean, two big risk factors.
[01:35:59.680 --> 01:36:04.800] And but insanely healthy individual, like very, very healthy individual.
[01:36:04.800 --> 01:36:08.640] So on the surface, like nobody thought anything of this person.
[01:36:10.720 --> 01:36:14.000] We decided we were going to treat him regardless, and he was completely on board with that.
[01:36:14.000 --> 01:36:16.880] But the question was, how aggressively, would we treat?
[01:36:16.880 --> 01:36:19.680] And we said, let's let the CTA decide that.
[01:36:19.680 --> 01:36:29.120] If the CTA comes back clean as a whistle, we're going to treat you to like an ApoB of 60, which is still aggressive by most people's standards.
[01:36:29.120 --> 01:36:31.320] By our standards, it's sort of middle-of-the-road aggression.
[01:36:31.640 --> 01:36:39.080] If the CTA comes back and there's a problem, meaning you have calcification and soft plaque, we're going to treat you to 30 or 40.
[01:36:39.080 --> 01:36:43.800] So there, the CTA helped us make a difference, a real treatment difference.
[01:36:43.800 --> 01:36:47.800] And this is a person who's, you know, middle-aged, so not too old, not too young.
[01:36:47.800 --> 01:36:49.080] That makes a lot of sense.
[01:36:49.640 --> 01:36:54.200] Before we, you know, kind of shift gears a little to some other things I want to ask you about.
[01:36:55.720 --> 01:36:56.520] Have you looked?
[01:36:56.520 --> 01:37:01.000] Like, I know you've mentioned, it's been many years since I've heard you talk about berberine.
[01:37:01.000 --> 01:37:08.120] But I, you know, every once in a while, I'll get a question and I decide, I want to dive into literature and see if there's anything new, right?
[01:37:08.120 --> 01:37:09.800] So that happened recently.
[01:37:09.800 --> 01:37:21.240] My team and I did a deep dive into berberine and its effect on clearing away existing plaque, on lowering, you know, LDL particle number, possibly total LDL cholesterol level.
[01:37:21.240 --> 01:37:22.680] But I was surprised.
[01:37:22.680 --> 01:37:23.720] Yeah, what did you find?
[01:37:23.720 --> 01:37:29.480] So there was a systematic review, and it was 2022, I believe.
[01:37:30.280 --> 01:37:33.400] And these are all like, we need, this is the sparse data, right?
[01:37:33.400 --> 01:37:37.480] A systematic review of what the existing literature was, which isn't a huge body of evidence.
[01:37:37.480 --> 01:37:48.680] But so there was a bunch of studies that looked at berberine and varying doses and then looking at it in conjunction with statins or comparing it to statins or comparing it to epilecebo.
[01:37:49.000 --> 01:37:54.680] And it pretty much, to me, was convincing that it was beneficial in every single scenario.
[01:37:54.680 --> 01:37:59.240] So berberine alone was lowering the LDL cholesterol.
[01:37:59.240 --> 01:38:02.200] And I can't remember if it was particle number, but it was LDL.
[01:38:02.360 --> 01:38:05.640] And it's interesting, berberine is also a mitochondrial toxin.
[01:38:05.640 --> 01:38:06.360] Really?
[01:38:06.360 --> 01:38:06.760] Yeah.
[01:38:06.760 --> 01:38:09.600] Berberine is an analog of metformin.
[01:38:09.320 --> 01:38:10.080] So.
[01:38:10.360 --> 01:38:11.960] So it's a complex one inhibitor.
[01:38:11.960 --> 01:38:12.440] Is it?
[01:38:12.440 --> 01:38:12.920] Really?
[01:38:13.240 --> 01:38:13.720] Wow.
[01:38:13.720 --> 01:38:14.880] I didn't know that.
[01:38:15.120 --> 01:38:18.080] It was like, it was to me looking really beneficial where it was like.
[01:38:14.200 --> 01:38:19.600] I'm not saying that wouldn't be.
[01:38:19.760 --> 01:38:21.040] I'm just sort of pointing out.
[01:38:14.440 --> 01:38:21.600] It's interesting.
[01:38:21.920 --> 01:38:23.120] Is there literature showing that?
[01:38:23.120 --> 01:38:26.400] Or is it like an in vitro kind of thing where it's like I don't remember?
[01:38:26.400 --> 01:38:32.640] It's been so long since I've looked at berberine, but berberine is kind of a poor man's metformin.
[01:38:32.640 --> 01:38:32.880] Okay.
[01:38:32.880 --> 01:38:34.800] Well, it was, and that's the way I thought about it.
[01:38:34.800 --> 01:38:38.080] I think I'd heard you talk about it years ago, maybe on Tim's podcast.
[01:38:38.080 --> 01:38:38.720] I don't remember.
[01:38:38.720 --> 01:38:39.600] It was a long time ago.
[01:38:40.000 --> 01:38:42.720] And that's kind of where I even first heard of berberine, was you.
[01:38:43.040 --> 01:38:45.040] And I remember because I was like going for a run.
[01:38:45.040 --> 01:38:47.840] It was when I lived in Oakland, and then I was like, berberine, what's that?
[01:38:47.840 --> 01:38:51.840] And I remember you talking about it in the context of, I think, metabolic health.
[01:38:51.840 --> 01:38:52.080] Yep.
[01:38:52.080 --> 01:38:52.560] Yep.
[01:38:52.560 --> 01:38:54.320] And kinase or something.
[01:38:54.400 --> 01:38:55.520] It should inhibit the global case.
[01:38:55.760 --> 01:38:58.240] But this data on the lipids was very interesting.
[01:38:58.240 --> 01:38:58.720] And I linked it to the list.
[01:38:58.880 --> 01:39:01.120] And what was the magnitude of effect?
[01:39:01.360 --> 01:39:02.320] I don't like you.
[01:39:03.520 --> 01:39:04.240] It's in that document.
[01:39:04.240 --> 01:39:04.880] It's linked.
[01:39:05.280 --> 01:39:06.720] The studies, the meta-analysis.
[01:39:06.720 --> 01:39:08.800] So you can look at it because I don't remember everything.
[01:39:09.440 --> 01:39:15.040] But what I do know is it also lowered the side effects of statin myopathy was one in particular.
[01:39:15.360 --> 01:39:21.600] It lowered the dose, effective dose of statins that was needed to lower the LDL cholesterol.
[01:39:21.600 --> 01:39:22.480] Very interesting, right?
[01:39:22.480 --> 01:39:26.720] And so I was like, you know, I actually ordered some berberine.
[01:39:26.720 --> 01:39:30.400] I'm like, maybe I should test this and see, you know, and it's there.
[01:39:30.400 --> 01:39:31.760] There are companies like Thorn and that.
[01:39:32.240 --> 01:39:33.040] I ordered Thorn.
[01:39:33.040 --> 01:39:34.800] Yeah, yeah, which I have no affiliation with.
[01:39:34.800 --> 01:39:36.080] I just trust their brain.
[01:39:36.160 --> 01:39:36.480] Yeah.
[01:39:36.480 --> 01:39:42.720] So, anyways, I wanted to bring that up because, you know, I know that, again, I'd heard a berberine from you like years ago.
[01:39:43.040 --> 01:39:56.160] But speaking of metabolic health, and you kind of talked about this, you know, earlier with with continuous glucose monitoring and you know measuring um you know measuring your your fasting glucose and also, you know, your response to foods.
[01:39:56.160 --> 01:41:33.360] And so, like, what, you know, glucose disposal is something that you've talked about people always hear about you know fasting glucose hb a1c like what what should those numbers be but also what is glucose disposal and why should people be paying attention to that and can cgms can they use cgms to sort of measure that yeah yeah um you know glucose disposal is is is is let's take a step back glucose regulation is just it's such a miracle of our physiology i mean there's every time i think about biology i'm really grateful that i've you know came to this field in one way or another because it's it leaves you endlessly uh at awe of what's happening so the the interplay between our endocrine system our liver our muscles in terms of how glucose is regulated is so complicated and exists on such a fine fine line that uh it is it is humbling so let's just put some of these numbers in perspective so most people who have had a blood test would recognize that a fasting blood glucose of 100 milligrams per deciliter is sort of right on the cusp of being just starting to get to be too high so what does that mean right what is 100 milligrams per deciliter well it means that in you know someone my size in all of my plasma floating around all of my body all of my blood i have five grams of glucose so do i have more than five grams of glucose in my body of course i do i have way more than that but the majority of the glucose in my body is either in my liver or in my muscles.
[01:41:33.360 --> 01:41:41.840] There's only five paltry grams, 20 calories worth of glucose in my entire circulation at this moment in time.
[01:41:41.840 --> 01:41:57.760] Now, if you assume for a moment that i'm just sitting here at rest and nothing in my body is demanding glucose, meaning my muscles aren't requiring it, the only organ that should be really demanding it at the moment is my brain.
[01:41:57.760 --> 01:42:02.960] Now, of course, my red blood cells demand it because they don't have mitochondria, so they're going to have to use glucose.
[01:42:03.200 --> 01:42:05.920] And of course, the kidney uses it and all sorts of other things.
[01:42:05.920 --> 01:42:14.800] But basically, the majority of the glucose in my bloodstream at this moment in time is being is there for the purpose of my brain.
[01:42:15.120 --> 01:42:18.320] And, you know, you can do the math on this.
[01:42:18.320 --> 01:42:19.840] Anybody can do the math on this.
[01:42:19.840 --> 01:42:24.800] Within a number of minutes, I will go through that five grams.
[01:42:24.800 --> 01:42:28.800] So where does the next drop of glucose come from?
[01:42:28.880 --> 01:42:30.400] Comes from my liver.
[01:42:30.400 --> 01:42:46.080] So my liver is constantly titrating just a little bit of glucose into my circulation to make sure that number never goes from, say, 100, where it is now, down to 50, because that would be way too low.
[01:42:46.080 --> 01:42:51.600] But it's never putting so much in that that number would be 150 or 200.
[01:42:51.600 --> 01:42:55.680] At that point, I would be full-fledged type 2 diabetes.
[01:42:55.680 --> 01:43:08.000] So the difference between you and me, if I have type 2 diabetes, is literally a teaspoon of glucose in our circulation at any point in time.
[01:43:08.000 --> 01:43:12.000] Think about how tiny a difference that is.
[01:43:12.320 --> 01:43:20.080] And that speaks to this enormous capacitor and buffer system of our liver and our muscles.
[01:43:20.080 --> 01:43:34.520] So if the liver is the thing that is responsible for the doling out of glucose into circulation, the muscle is primarily responsible for where we put glucose when it gets flooded into our system.
[01:43:34.520 --> 01:43:36.600] And that happens every time you eat.
[01:43:36.600 --> 01:43:40.600] So you eat, and again, let's just do some easy math on this.
[01:43:40.600 --> 01:43:47.320] Like you eat a bowl of pasta, like not a Peter bowl, which is like the size of my head, but just a normal size bowl.
[01:43:47.320 --> 01:43:51.320] You're easily getting 60 grams of glucose.
[01:43:51.640 --> 01:43:55.800] So you eat 60, 70, 80 grams of glucose.
[01:43:55.800 --> 01:43:57.720] Well, remember what I just said a moment ago.
[01:43:57.720 --> 01:44:03.480] Like if your blood level goes from five to 10 grams, you're hosed.
[01:44:03.480 --> 01:44:05.320] Like that's a really big problem.
[01:44:05.320 --> 01:44:07.720] Now, acutely, it's not the end of the world, right?
[01:44:08.040 --> 01:44:15.000] But a healthy person would probably never go from five to eight, more than eight grams.
[01:44:15.000 --> 01:44:19.560] So how do you get that other 60 grams of glucose away?
[01:44:19.560 --> 01:44:21.640] You have to put that into the muscles.
[01:44:21.640 --> 01:44:25.720] And so the muscle is the sink for glucose disposal.
[01:44:25.720 --> 01:44:32.200] And there are two ways that that happens, but the majority of it is an insulin-dependent way.
[01:44:32.200 --> 01:44:37.800] So insulin is released by the pancreas when glucose levels are sensed.
[01:44:37.800 --> 01:44:42.040] So the pancreas sits very high in the GI tract.
[01:44:42.360 --> 01:44:56.920] So very early in the absorption of glucose as it exits the stomach into the duodenum, does the endocrine system, vis-a-vis the beta cells, sense this increase in glucose.
[01:44:56.920 --> 01:44:58.600] The beta cells release insulin.
[01:44:58.600 --> 01:45:01.720] The insulin results in a signal.
[01:45:01.720 --> 01:45:02.520] It goes to the muscle.
[01:45:02.520 --> 01:45:04.840] So the insulin hits an insulin receptor.
[01:45:04.840 --> 01:45:16.960] The insulin receptor triggers a kinase in a cell, and that brings a glucose transporter to the surface of a muscle cell so that passively, right, without a gradient, glucose can flow from outside the cell to inside the cell.
[01:45:16.960 --> 01:45:20.480] So that's called insulin-dependent glucose disposal.
[01:45:20.480 --> 01:45:33.280] In a person who's particularly fit, there's also an insulin-independent system where just the contractile aspect of the muscle itself is enough to get glucose transporters up to the surface of the muscle.
[01:45:33.280 --> 01:45:45.280] So people who do a lot of cardio training have this capacity to, you know, and I've seen this in patients with type 1 diabetes who do a lot of training, because that's a pure experiment where you have no insulin.
[01:45:45.280 --> 01:45:50.720] You can actually see them lower their glucose without insulin just by exercising.
[01:45:50.720 --> 01:45:58.880] So the act of exercising itself can produce glucose transport across the muscle without insulin.
[01:45:58.880 --> 01:46:01.040] So how does all this figure into health?
[01:46:01.040 --> 01:46:05.200] Well, as we alluded to, glucose is toxic when you have too much of it.
[01:46:05.200 --> 01:46:07.120] Now, I'm not going to talk about acute toxicity.
[01:46:07.120 --> 01:46:15.760] So if you ever walked around with like 40 teaspoons of blood, 40 teaspoons of glucose in your bloodstream, you would go into a coma.
[01:46:15.760 --> 01:46:23.760] So there's an acute toxicity, but luckily that's very, very rare and only really would occur in somebody with ketoacidosis.
[01:46:24.560 --> 01:46:30.320] But the chronic toxicity of elevated levels of glucose is significant.
[01:46:30.320 --> 01:46:45.440] And that's where the difference between having four, five, six, seven, eight grams of glucose as the benchmark concentration is a difference in 10 years of life expectancy.
[01:46:45.760 --> 01:46:50.960] And again, like it seems hard to fathom that that makes such a difference, but it does.
[01:46:50.960 --> 01:46:52.880] And it does for several reasons.
[01:46:52.880 --> 01:47:04.520] But one of them is that glucose is involved in the process by which proteins become sticky.
[01:46:58.960 --> 01:47:16.120] And so as the proteins in our blood get glycosylated and get stickier, one, their function is lower, but two, they also tend to obscure the narrowest part of our vascular system.
[01:47:16.120 --> 01:47:24.920] So the tiniest, tiniest, tiniest capillaries become more occluded, and therefore it's harder to deliver oxygen to those tissues.
[01:47:24.920 --> 01:47:32.040] So the canary in the coal mine, believe it or not, of microvascular damage is within the eyes.
[01:47:32.040 --> 01:47:40.360] So a good ophthalmologist is generally the first doctor to tell when a person is on the road to type 2 diabetes.
[01:47:40.360 --> 01:47:49.320] Because by looking at the retina and by looking at the capillaries in the back of the eye, they're actually able to do something that no one else gets to do in the body, right?
[01:47:49.320 --> 01:47:53.800] Like we don't look directly at the vascular system elsewhere in the body.
[01:47:53.800 --> 01:47:54.760] And they get to do that.
[01:47:54.760 --> 01:47:58.040] They get to shine a light directly onto those capillary beds.
[01:47:58.040 --> 01:48:05.560] So as a general rule, elevated levels of glucose are damaging to small vessels.
[01:48:05.560 --> 01:48:10.360] Elevated levels of insulin are damaging to large blood vessels.
[01:48:10.360 --> 01:48:21.160] So the eyes, the kidneys, the microvasculature of the heart and the brain are very susceptible to high levels of glucose.
[01:48:21.160 --> 01:48:30.920] The larger blood vessels of the heart, the aorta, the iliac vessels, carotid arteries, more susceptible to the elevated levels of insulin.
[01:48:30.920 --> 01:48:40.200] And both of these things go hand in hand because, of course, as is obvious, I guess, to people now, when those glucose levels are chronically elevated, the body wants to fix it.
[01:48:40.440 --> 01:48:44.880] It wants to crank up more insulin as the solution to the resistance.
[01:48:43.800 --> 01:48:49.280] So the resistance is at the cell where the insulin signal isn't being heard.
[01:48:49.600 --> 01:48:53.360] So the pancreas just yells louder and it makes more and more insulin.
[01:48:53.360 --> 01:48:59.680] And so before you see that elevated level of glucose, you will actually see an elevated level of insulin.
[01:48:59.680 --> 01:49:05.440] So post-prandial hyperinsulinemia is the metabolic harbinger of all this stuff.
[01:49:06.400 --> 01:49:14.320] And so the major, obviously, it seems like a lifestyle factor that is regulating, you know, glucose disposal, insulin sensitivity.
[01:49:14.320 --> 01:49:20.960] I mean, it seems like both of these things are affected by the contractions of muscle and increasing those glucose transporters, right?
[01:49:21.440 --> 01:49:27.280] Exercise is probably the single most important thing we have at our disposal to increase insulin sensitivity.
[01:49:27.280 --> 01:49:29.760] And then there are other things that are very important, right?
[01:49:29.760 --> 01:49:32.160] So energy balance really matters.
[01:49:32.160 --> 01:49:33.600] Sleep really matters.
[01:49:33.600 --> 01:49:37.840] So both acute and chronic disruptions of sleep will impair that system.
[01:49:37.840 --> 01:49:39.600] It's not entirely clear why, by the way.
[01:49:39.600 --> 01:49:41.440] The experimental evidence is undeniable.
[01:49:41.440 --> 01:49:45.680] And these are experiments that are so easy to do well that they're unambiguous, right?
[01:49:45.680 --> 01:49:47.280] Where you disrupt people's sleep.
[01:49:47.280 --> 01:50:09.520] You know, you take, if you just took a normal group of people and you did like what's called a euglycemic insulin clamp, which is an experiment where you run IV glucose and IV insulin into people, and you basically run a fixed amount of insulin into somebody and then determine how much glucose you need to put in to keep their glucose level fixed.
[01:50:09.520 --> 01:50:12.240] That's called a euglycemic, keep glucose fixed.
[01:50:13.120 --> 01:50:16.080] That's the gold standard for measuring insulin sensitivity.
[01:50:16.080 --> 01:50:27.360] So you do that test on somebody, and then for a week, sleep deprive them for, you know, down to five or six, four hours a night, call it four, four would be very dramatic.
[01:50:27.680 --> 01:50:35.560] Within days, you'll see like a 50% reduction in their ability to dispose of glucose with no other difference, no dietary difference, no exercise difference.
[01:50:35.560 --> 01:50:40.040] So we don't know exactly why that's happening, but it's a very repeatable observation.
[01:50:40.040 --> 01:50:42.280] So sleep disruptions impair this.
[01:50:43.080 --> 01:50:45.640] Energy imbalance impairs this.
[01:50:45.640 --> 01:50:48.120] Hormonal changes impair this, right?
[01:50:48.120 --> 01:50:53.240] So as we age, both the reduction in estrogen and testosterone impair this.
[01:50:53.240 --> 01:50:56.120] Hypercortisolemia impairs this.
[01:50:56.440 --> 01:51:00.600] And then, of course, inactivity is the greatest thing that drives this.
[01:51:00.920 --> 01:51:05.720] I definitely didn't do the exact experiment you're describing, but I've mentioned it to you before.
[01:51:05.720 --> 01:51:11.880] I had my CGM, and when I was a new mother, it was, you know, clearly my sleep was being disrupted.
[01:51:11.880 --> 01:51:13.400] I was getting up and breastfeeding.
[01:51:13.400 --> 01:51:22.280] And, you know, I mean, it was like night and day difference in my fasting blood glucose, my glucose disposal, my postprandial levels.
[01:51:22.280 --> 01:51:25.560] I mean, it was like, we would have asked you to take that CGM off.
[01:51:25.800 --> 01:51:27.960] That would be an awful time to wear a CGM.
[01:51:27.960 --> 01:51:37.960] But I did find that my going to my HIIT class, even though I was like just dogged tired, like the last thing I wanted to do really did normalize it.
[01:51:37.960 --> 01:51:47.640] So is there a postprandial level that like, you know, let's say someone's not trying to do a low-carb diet, like they're not trying to like, because that's a whole other area, right?
[01:51:47.640 --> 01:51:56.200] But like they just, you know, they're eating maybe a more omnivore diet, more paleo-ish or Mediterranean-ish, right?
[01:51:56.520 --> 01:52:04.440] Is there a level that you think post-perennial, you know, glucose levels, like a threshold that would signal, like, oh, well, you shouldn't really be going or.
[01:52:04.440 --> 01:52:05.400] It's hard to say.
[01:52:05.400 --> 01:52:10.920] I mean, here's what I think we know more clearly.
[01:52:11.640 --> 01:52:17.600] We certainly know with more conviction that the average blood glucose, the lower it is, the better you are.
[01:52:14.920 --> 01:52:20.000] And I say that even outside of diabetic range.
[01:52:20.160 --> 01:52:28.240] Now, I don't have level one data to tell you that because the study's never been done, but I can tell you that by proxy based on hemoglobin A1C data.
[01:52:28.240 --> 01:52:35.200] So the hemoglobin A1C data make it very clear that lower is better even outside of the range of diabetes.
[01:52:35.200 --> 01:52:39.920] So diabetes is defined as a hemoglobin A1C above 6.5%.
[01:52:39.920 --> 01:52:49.040] That translates, 6.5% is an estimate of an average blood glucose of 140 milligrams per deciliter.
[01:52:49.360 --> 01:53:02.160] So assume for a moment that if you have a CGM that says 6.5%, meaning you just trigger the threshold for type 2 diabetes, your CGM would say your average blood glucose is 140 milligrams per deciliter.
[01:53:02.480 --> 01:53:04.320] Nobody disputes that that's harmful.
[01:53:04.320 --> 01:53:10.480] The question is: is it better to be at 130, 120, 110, 100?
[01:53:10.480 --> 01:53:16.000] Like, at what point does is it too low?
[01:53:16.320 --> 01:53:33.520] And what the hemoglobin A1C data would suggest is being at 5%, which is about an average of 100, is better than being at 5.5%, which is an average in the one teens.
[01:53:33.840 --> 01:53:37.760] Both of those are normal by our current definitions.
[01:53:37.760 --> 01:53:41.120] Neither of those would be pre-diabetic, even.
[01:53:41.120 --> 01:53:45.360] So 5 and 5.5 are both considered completely normal levels.
[01:53:45.360 --> 01:53:53.800] But the all-cause mortality data, or the data on all-cause mortality, suggests a better outcome if you're at 5 rather than 5.5.
[01:53:53.440 --> 01:53:54.040] Okay.
[01:53:54.320 --> 01:54:05.800] That suggests to me, by proxy at least, that an average blood glucose of 100 on a CGM would be better than that of an average blood glucose of 115.
[01:54:06.120 --> 01:54:09.640] So that's the single most important metric we care about.
[01:54:09.640 --> 01:54:12.520] We use other metrics to think about that.
[01:54:12.520 --> 01:54:32.680] So that since we can't measure insulin in real time, looking at post-prandial spikes and variability, so looking at the standard deviation, which you can get off the CGM, and just the number of times you exceed a threshold, and that threshold, you could say, maybe make it 150 or 140 milligrams per deciliter.
[01:54:32.680 --> 01:54:36.120] And you can just say, how many times in a week do you exceed that threshold?
[01:54:36.120 --> 01:54:42.040] That might give you some indirect proxy of how much insulin are you secreting in response to that.
[01:54:42.040 --> 01:54:58.120] Because, for example, if you took two people who had an average blood glucose of 110 milligrams per deciliter by CGM, but one arrived at it with levels like that and one arrived at it with levels like that, the former would be a better way to achieve that than the latter.
[01:54:58.440 --> 01:55:01.880] But there are lots of things that raise glucose that are not harmful.
[01:55:01.880 --> 01:55:12.040] For example, that HIT class that you were doing probably in the short term really spikes your glucose because your liver is really trying to meet the demands of all that exercise.
[01:55:12.040 --> 01:55:19.800] So it's putting a ton of glucose into your circulation and it's going to do the right thing, which is always err on the side of too much.
[01:55:19.800 --> 01:55:23.160] Because in the short term, it's better to have too much than too little.
[01:55:23.480 --> 01:55:31.800] So if I'm wearing a CGM doing a really hard workout, I mean, I'll see that glucose get to 160, which is higher than it will get with a meal.
[01:55:32.120 --> 01:55:33.240] That goes right back down.
[01:55:34.600 --> 01:55:37.880] So, what do you think about, by the way, this is all great info.
[01:55:37.880 --> 01:55:46.800] What do you think about, so metabolic flexibility, being the capability to shift between using glucose as a substrate and using fatty acids?
[01:55:46.800 --> 01:55:47.920] I mean, this is something.
[01:55:44.760 --> 01:55:49.200] This is the zone two thing, right?
[01:55:49.360 --> 01:55:52.080] This is exactly why we train that zone two system.
[01:55:52.080 --> 01:56:00.080] And that's why, you know, we have our patients spend 80% of their cardio training time in zone two.
[01:56:00.080 --> 01:56:03.120] That's really pushing that metabolic flexibility.
[01:56:04.400 --> 01:56:21.760] This is the training system for making sure you expand the capacity of your mitochondria to, under ever-increasing demands, have the ability to utilize fatty acids for oxidative phosphorylation and glucose for that matter.
[01:56:22.400 --> 01:56:32.480] But if you were to do, let's say you're doing more high-intensity interval training, which I do a lot of, that increases the capacity because it's such a potent stimulator of mitochondrial biogenesis.
[01:56:32.480 --> 01:56:40.720] So maybe, and I and I hesitate to say, like, I think a lot of times when I'm doing my HIIT, I'm still really using my mitochondria.
[01:56:40.720 --> 01:56:46.160] Like, you know, I'm not like doing an all-out sprint, but like, you know, I do shift into using glucose, of course.
[01:56:46.560 --> 01:56:50.720] We just think that only 20% of the cardio training volume should be there.
[01:56:50.720 --> 01:56:55.680] And the reason for that is actually kind of an empirical observation.
[01:56:55.680 --> 01:57:07.680] If you ask the question, who are the most metabolically flexible, healthiest specimens we have on this planet?
[01:57:07.680 --> 01:57:14.800] They are high-level endurance athletes, namely cross-country skiers, distance runners, and cyclists.
[01:57:14.800 --> 01:57:16.560] So, what do we know about this group?
[01:57:16.560 --> 01:57:22.640] We know that they have the highest VO2 maxes of any humans on the planet.
[01:57:22.640 --> 01:57:27.280] And we know that they are the most metabolically flexible of any humans on this planet.
[01:57:27.280 --> 01:57:34.040] Now, my experience is far more with cyclists, and so I usually just talk about this through the lens of a cyclist.
[01:57:35.560 --> 01:57:43.880] And the other thing I like about cycling compared to skiing or running is we can use wattage because we can put people on power meters and we can get the numbers.
[01:57:44.520 --> 01:57:56.200] A world-class cyclist is able to put out four watts per kilogram of power while keeping lactate below two millimole.
[01:57:56.520 --> 01:58:04.520] In fact, the best cyclists in the world are probably at about 4.2, 4.3 watts per kilo.
[01:58:04.520 --> 01:58:10.040] So, let's just do the math on that if someone's listening to this and they've ever been near a power meter.
[01:58:10.040 --> 01:58:24.280] So, if you're 80 kilos, you're 175 pounds, that means you're able to put out 330 to 340 watts, which by the way, most people who weigh 80 kilos can't do that for one minute.
[01:58:24.280 --> 01:58:26.680] Literally, they can't do that for one minute.
[01:58:26.680 --> 01:58:32.600] These people can do it for hours and keep their lactate below two millimole.
[01:58:33.240 --> 01:58:39.880] It's the single greatest demonstration of metabolic flexibility that you will ever see.
[01:58:40.200 --> 01:58:41.960] How do these people train?
[01:58:41.960 --> 01:58:47.560] Because this is, you know, this is one of the questions my patients ask me: Peter, where is this 80-20 coming from?
[01:58:47.560 --> 01:58:49.320] Where is the study that demonstrated this?
[01:58:49.320 --> 01:58:56.360] And I said, Well, the studies are all based on what do you have to do to achieve that level of performance.
[01:58:56.680 --> 01:59:14.520] So, these athletes and their coaches have all figured out that to produce the highest VO2 max and to produce the greatest degree of metabolic flexibility, you think of it as a pyramid, where the base of the pyramid is your zone two efficiency, and the peak of the pyramid is your VO2 max.
[01:59:14.640 --> 01:59:20.000] And the area, total area of the pyramid, is your cardiorespiratory engine.
[01:59:20.000 --> 01:59:25.840] So you want not a narrow base with a high peak, not a wide base with a short peak.
[01:59:25.840 --> 01:59:28.480] You want a big base, big peak.
[01:59:28.480 --> 01:59:31.120] And the way to get that is about 80-20.
[01:59:31.120 --> 01:59:37.600] If you try to do too much high-intensity, you simply don't have the aerobic base on which to build it.
[01:59:37.600 --> 01:59:41.600] So yeah, you might have more mitochondria, but they're not as efficient.
[01:59:41.600 --> 01:59:45.920] If you only do the low-intensity stuff, they're efficient, but you might not have enough.
[01:59:45.920 --> 01:59:49.920] This is a bit of an oversimplification, but you want the best of both worlds, right?
[01:59:50.560 --> 01:59:55.280] You want both the breadth and the peak, effectively.
[01:59:55.280 --> 02:00:01.840] So what we basically do with our patients is we start from a standpoint of time.
[02:00:01.840 --> 02:00:03.920] How much time are you willing to exercise a week?
[02:00:03.920 --> 02:00:05.920] I'm not going to tell you what you need to do.
[02:00:05.920 --> 02:00:08.640] Let's start with you telling me what you're willing to do.
[02:00:08.640 --> 02:00:13.920] And then the simplest approach is we'll put half of that into strength and stability, half of that into cardio.
[02:00:13.920 --> 02:00:16.000] Of the cardio, it's 80-20.
[02:00:16.000 --> 02:00:20.480] 80% of that will be zone 2, 20% of that will be VO2 max.
[02:00:20.480 --> 02:00:28.080] And VO2 max, by the way, training is pretty hard because it's slightly longer intervals than what people think of as traditional hit.
[02:00:28.080 --> 02:00:29.760] So traditional HIT works.
[02:00:29.760 --> 02:00:34.800] I'm just saying, you know, it's not the best way to get there.
[02:00:35.920 --> 02:00:37.360] It's a good way to get there.
[02:00:37.360 --> 02:00:40.000] And we know, like, even just looking at the Tabata studies, right?
[02:00:40.080 --> 02:00:42.640] Tabata is neither one or the other, right?
[02:00:42.640 --> 02:00:54.120] Like a 20 on, 10 off times eight rounds is neither a pure zone two nor it's it's it's way too hard even for vo2 max, actually.
[02:00:54.120 --> 02:01:00.120] Because VO2 max sweet spot is three to eight minutes with one to one-to-one rest to recovery.
[02:01:00.120 --> 02:01:03.240] So, three on, three off, three on, three off.
[02:01:03.480 --> 02:01:06.520] That's a lower intensity than most people are doing in a hit class.
[02:01:06.520 --> 02:01:09.720] Most people in a hit class are doing shorter intervals and pushing much harder.
[02:01:10.200 --> 02:01:20.360] I just had a talk with Marty Cabala, and I asked him that question, you know, and he was like, Rhonda, you got to do more three, because I wanted to, I was like, I want to do VO2 Max training.
[02:01:20.360 --> 02:01:21.560] Like, this is what I do.
[02:01:21.560 --> 02:01:26.760] I do a lot of the, you know, I'll do 16 rounds and I'll do 20 seconds on, 10 seconds off, right?
[02:01:26.760 --> 02:01:30.280] But my 10 seconds off are, I mean, my heart rate's still pretty high.
[02:01:30.280 --> 02:01:41.640] Like, I don't, so he's like, you, you got to do like three minutes, at least one, you know, and so I've shifted my training now to doing, and it's absolutely true.
[02:01:41.640 --> 02:01:43.000] I am not going as hard.
[02:01:43.000 --> 02:01:43.560] You can't.
[02:01:43.560 --> 02:01:46.120] Yeah, it's, you just can't go as hard.
[02:01:46.440 --> 02:01:47.000] And so.
[02:01:47.320 --> 02:01:48.200] And it's an art form.
[02:01:48.360 --> 02:01:55.960] You'll figure it out because you'll realize and you'll, you'll have to, you know, you'll be like, I went too hard and I was dead at a minute and a half.
[02:01:55.960 --> 02:01:58.360] And I was like loafing the last minute and a half.
[02:01:58.360 --> 02:02:00.120] Or I held back too much.
[02:02:00.120 --> 02:02:03.240] And by the end of the three minutes, it was like, oh, I actually could have gone harder.
[02:02:03.240 --> 02:02:03.800] And that's okay.
[02:02:03.800 --> 02:02:06.680] Like, you'll sort of figure out what that sweet spot is.
[02:02:07.640 --> 02:02:16.360] But that three to eight minutes is the optimal zone for generating VO2 max power.
[02:02:16.360 --> 02:02:16.840] Right.
[02:02:16.840 --> 02:02:17.240] Yeah.
[02:02:19.320 --> 02:02:22.120] So metabolic flexibility, obviously hugely important.
[02:02:22.120 --> 02:02:23.560] VO2 Max, hugely important.
[02:02:23.560 --> 02:02:37.320] But with respect to, I would say, like eating diet-wise, like you hear a lot of people like low-carb community, ketogenic, you know, metabolic flexibility if they're doing, does that like affect metabolic flexibility?
[02:02:37.320 --> 02:02:38.040] Like if you're doing it.
[02:02:38.120 --> 02:04:16.600] Yeah, it's tough to say there there i think there may be a bit of a confounder there so um i i used to think so um i'm not sure anymore truthfully um so so the obvious confounder there is if you're on a completely carbohydrate restricted uh diet your respiratory quotient so on a from a functional standpoint one of the ways we how do we measure what you're oxidizing so when a person does a cpat test a functional test like a vo2 max test we're we're measuring o2 consumed and co2 produced so if any have you done a vo2 max test yet i haven't okay so you'll you can you just go to any doctor or doctors don't do it no you typically go to um well when i did when i lived in san diego i used to do them with my coach so he would do them um in in austin we send people to ut like we just send people to the university and get them done it's a very inexpensive test like like a hundred bucks or something like that right so they're gonna have you do it in one of two ways which is a bike or a treadmill and i always tell patients do it in the way you train because there's a you know there's a you don't want to take a cyclist and make them do the running test or vice versa so it sounds like you're doing most of your work on a peloton so you would do it on a bike because you're going to sit on a bike and they're going to put a mask on you and it's super uncomfortable the mask has to be incredibly tight it can't have any interference from the outside world in terms of air that you're breathing can't escape and no air from the outside can get to you there are two gas sensors on the outside of the mask one for o2 one for co2 this is the bread and butter of this whole device.
[02:04:16.600 --> 02:04:20.200] If those sensors aren't calibrated correctly or they don't work, the test is meaningless.
[02:04:20.200 --> 02:04:22.120] And like one out of 10 times, they fail.
[02:04:22.120 --> 02:04:31.640] So you got to make sure whenever you're doing this test the per the tech who does it has calibrated this thing and knows what to look for if the calibration fails during the test.
[02:04:31.800 --> 02:04:34.840] We just had a patient do one recently, the test failed.
[02:04:34.840 --> 02:04:42.840] So you're going to be put on a bike and it's going to be an erg, which means unlike the Peloton where you set the resistance.
[02:04:42.840 --> 02:04:46.360] And how, like, let's say you have the resistance at 50.
[02:04:46.360 --> 02:04:48.520] Well, that doesn't determine the wattage by itself.
[02:04:48.520 --> 02:04:50.920] How fast you pedal also determines the wattage.
[02:04:50.920 --> 02:04:52.040] That's different here.
[02:04:52.040 --> 02:04:56.600] Here, the computer is telling the bike how many watts to put out.
[02:04:56.600 --> 02:05:00.520] So the faster you pedal, the less the resistance will be.
[02:05:00.520 --> 02:05:01.080] Okay.
[02:05:01.080 --> 02:05:01.480] Okay.
[02:05:01.480 --> 02:05:03.160] But it's fixed wattage.
[02:05:03.160 --> 02:05:06.600] So they might say, look, Rhonda, we're going to start you out at 50 watts, nice little warm-up.
[02:05:06.600 --> 02:05:08.440] We're going to have you spend, you know, five minutes here.
[02:05:08.440 --> 02:05:14.680] And then like three, every three minutes, we're going to go up, you know, 25 watts or something like that.
[02:05:14.840 --> 02:05:18.760] And they're, you know, within about 15 minutes, you're going to be in crunch time.
[02:05:18.760 --> 02:05:22.040] And at that point, they're probably going to increase the wattage every minute.
[02:05:22.040 --> 02:05:26.360] And you're going to, you're in the, the pain train has left the station.
[02:05:26.360 --> 02:05:29.320] Like, this is unpleasant.
[02:05:29.320 --> 02:05:30.920] And you have to keep your RPMs high.
[02:05:30.920 --> 02:05:34.840] The test is usually aborted if you can't keep your RPM above about 50 or 60.
[02:05:34.840 --> 02:05:36.920] So as you're training, keep that in mind.
[02:05:36.920 --> 02:05:40.360] These are all the things that you don't want to fail the test because you didn't know the test.
[02:05:40.600 --> 02:05:41.080] You know what I mean?
[02:05:41.800 --> 02:05:44.280] Let the physiology be the place you fail.
[02:05:44.520 --> 02:05:52.280] So make sure when you're riding that Peloton, you're really comfortable in that 80 to 100 zone of RPM.
[02:05:52.280 --> 02:05:55.000] And so what is the tech looking for?
[02:05:55.000 --> 02:05:57.320] So the tech is looking at a bunch of data.
[02:05:57.320 --> 02:06:00.840] So what they're looking for is VO2 and VCO2.
[02:06:00.840 --> 02:06:03.400] Those are the things that are being measured.
[02:06:03.400 --> 02:06:06.040] So they know your heart rate at every moment in time.
[02:06:06.040 --> 02:06:13.160] They know how many watts you're generating because you're generating by definition everything they're sending you.
[02:06:13.160 --> 02:06:18.240] And then they're measuring VO2, so ventilation rate of oxygen and VCO2, ventilation rate of CO2.
[02:06:19.280 --> 02:06:24.640] They also, at every moment in time, see the ratio of VCO2 to VO2.
[02:06:24.640 --> 02:06:27.360] That's called respiratory quotient, or RQ.
[02:06:27.360 --> 02:06:29.200] It's also known as RER.
[02:06:29.200 --> 02:06:38.480] That ratio, in any moment in time, tells you how much fat you're oxidizing versus how much glucose.
[02:06:39.120 --> 02:06:47.200] When that ratio is 0.7, you are 100% fat oxidizing.
[02:06:47.200 --> 02:06:51.600] When that ratio is 0.85, it's about 50-50.
[02:06:51.600 --> 02:06:56.640] When that ratio is 1 and above, you're all carbohydrate.
[02:06:57.920 --> 02:07:03.520] So what you'll want to see when you do the test is you won't want the report, the summary.
[02:07:03.520 --> 02:07:06.880] You will also want the raw data, which is pages and pages of a spreadsheet.
[02:07:06.880 --> 02:07:08.880] And you'll kind of go through and you can see how these things change.
[02:07:08.880 --> 02:07:11.520] So when I used to do my tests, I used to plot my own data.
[02:07:11.520 --> 02:07:16.480] I would just get the spreadsheet and I would make the fuel partitioning curve.
[02:07:16.480 --> 02:07:24.000] So what I would draw would be a curve, what I would have Excel plot for me is on the x-axis, I would have wattage, because I cared more by wattage than by heart rate.
[02:07:24.000 --> 02:07:27.280] So you have either wattage or heart rate on the x-axis.
[02:07:27.280 --> 02:07:30.480] And on the y-axis, I'd have a double y-axis.
[02:07:30.480 --> 02:07:36.080] And the y-axis would be either calories or preferably grams per minute.
[02:07:36.080 --> 02:07:40.000] And I would have carbohydrate oxidation and fat oxidation.
[02:07:40.000 --> 02:07:43.600] So fat oxidation goes down from as the test starts.
[02:07:43.600 --> 02:07:47.280] So it usually has an early peak and then comes down as intensity goes up.
[02:07:47.280 --> 02:07:50.960] And carbohydrate oxidation just rises monotonically.
[02:07:51.280 --> 02:07:54.720] And there's where those two cross.
[02:07:54.720 --> 02:07:59.960] Some people call that your anaerobic threshold, but that's where your respiratory quotient is equal.
[02:07:59.280 --> 02:08:06.840] If you've done this in calories, if you do it in grams per minute, it won't be because obviously there's way more calories in fat than oxygen.
[02:08:07.480 --> 02:08:16.760] So, one of the other metrics we care very deeply about in our patients is what is your peak fat oxidation and where does it occur?
[02:08:16.760 --> 02:08:18.360] And we plot that.
[02:08:18.360 --> 02:08:25.480] So, we plot their VO2 max, we plot their zone two, and we plot fat oxidation.
[02:08:25.480 --> 02:08:31.480] And not surprisingly, there's a family of curves that we put the patients on.
[02:08:31.480 --> 02:08:34.760] So, we say, this is what someone with type 2 diabetes looks like.
[02:08:34.760 --> 02:08:36.600] This is their fat oxidation curve.
[02:08:36.600 --> 02:08:40.360] This is what a world-class Tour de France cyclist looks like.
[02:08:40.360 --> 02:08:41.880] They couldn't be further apart.
[02:08:41.880 --> 02:08:43.560] And this is everything in between.
[02:08:43.560 --> 02:08:45.400] And where do you stack up?
[02:08:45.400 --> 02:08:52.680] So, what you want is the highest amount of fat oxidation, and you want to be able to sustain that for as long as possible.
[02:08:52.680 --> 02:09:06.280] Now, if you do this on somebody who is heavily carbohydrate-restricted, you will get an artifact of the test because their resting RQ is very, very low.
[02:09:06.280 --> 02:09:06.920] Okay.
[02:09:07.240 --> 02:09:21.320] And so it's not clear what the implications of that are, other than we typically will feed people carbohydrates before they do the test.
[02:09:21.560 --> 02:09:22.280] Like in the days that they're.
[02:09:22.440 --> 02:09:25.880] But their VO2 max won't be doesn't affect their VO2 max.
[02:09:25.880 --> 02:09:26.200] No.
[02:09:26.200 --> 02:09:35.320] Because the VO2 max is literally taking the peak VO2 that they achieve and dividing it by their weight in kilos.
[02:09:35.640 --> 02:09:38.440] What VO2 max do you aim for?
[02:09:38.440 --> 02:09:50.880] And if you can recall, I know that JAMA 2018 paper, which was probably one of the most convincing studies that VO2Max is like one of the best metrics of health and longevity.
[02:09:51.280 --> 02:09:52.720] And there was an even bigger paper that came out.
[02:09:52.880 --> 02:09:56.400] That JAMA paper had 120,000 subjects in it.
[02:09:56.400 --> 02:10:02.160] There was a JACC paper that came out a year ago that had almost a million subjects in it.
[02:10:02.160 --> 02:10:04.800] And it showed the exact same findings.
[02:10:04.800 --> 02:10:05.520] Do you know?
[02:10:05.520 --> 02:10:08.000] So the findings, if I recall, was like.
[02:10:08.240 --> 02:10:09.200] Both of them are in the book.
[02:10:09.200 --> 02:10:11.920] I think I have figures from both of them in the exercise.
[02:10:12.400 --> 02:10:13.360] You had the numbers in there?
[02:10:13.360 --> 02:10:13.600] Okay.
[02:10:14.400 --> 02:10:17.840] And that, so that was like the top, I just remember it was like the top percentile.
[02:10:17.840 --> 02:10:19.680] I mean, they had like 80% lower.
[02:10:20.240 --> 02:10:32.080] Yeah, if you compared the top, the difference in risk between someone in the bottom 25 percentile of VO2 max to the top 2.5% had a hazard ratio of five.
[02:10:32.720 --> 02:10:40.800] Meaning it's 400 times greater all-cause mortality if you're in the bottom 25% versus the top 2%.
[02:10:41.120 --> 02:10:44.320] Okay, so if I want that number, do you know it?
[02:10:44.320 --> 02:10:46.560] Or, I mean, what's like the top?
[02:10:47.120 --> 02:10:49.760] Yeah, are you 30 to 40?
[02:10:50.320 --> 02:10:51.280] I'll be 45.
[02:10:51.280 --> 02:10:53.600] Okay, so you're right in the middle of the 40 to 50.
[02:10:54.720 --> 02:10:58.960] I would guess, but the table is in my book, so I can put it that way.
[02:10:59.040 --> 02:11:04.240] Well, I would guess that it's about, it's in the high 40s.
[02:11:04.560 --> 02:11:05.120] Okay.
[02:11:05.120 --> 02:11:14.960] Yeah, so roughly probably like 46, 47, 48 milligrams, sorry, milliliters per minute per kilogram.
[02:11:17.760 --> 02:11:19.360] This is such great information.
[02:11:19.360 --> 02:11:26.960] I have other, like, there's, I want to get into some cancer hormones, especially, because I'm going to be 45.
[02:11:26.960 --> 02:11:30.040] I have a very personal, personal interest in this.
[02:11:29.520 --> 02:11:34.680] But, you know, we're talking about metabolic health.
[02:11:34.840 --> 02:11:42.360] Obviously, you've talked endlessly about the importance of metabolic health for cancer, certainly, you know, cancer prevention.
[02:11:42.360 --> 02:11:48.680] But looking at like, so the biggest risk factor for cancer is age, right?
[02:11:49.320 --> 02:11:52.920] Yes, if you, yeah, unless you include, yeah, if you don't include modifiable risk.
[02:11:52.920 --> 02:11:55.000] So, yeah, we generally talk about modifiable risk.
[02:11:55.000 --> 02:11:55.480] Okay, yes.
[02:11:55.960 --> 02:11:59.560] Age is the greatest risk for all disease, including cardiovascular disease.
[02:11:59.880 --> 02:12:01.880] The biggest modifiable risk factor.
[02:12:01.880 --> 02:12:04.120] So let's talk about modifiable risk factors, like obesity.
[02:12:04.600 --> 02:12:05.480] Smoking is number one.
[02:12:05.480 --> 02:12:05.960] Smoking.
[02:12:05.960 --> 02:12:06.120] Okay.
[02:12:06.360 --> 02:12:07.000] Still number one.
[02:12:07.480 --> 02:12:12.680] Of course, smoking, I always not be smoking, but it is easy to forget.
[02:12:12.680 --> 02:12:14.440] It's like, oh, yeah, people do still smoke.
[02:12:15.000 --> 02:12:18.840] It's hard to fathom that, but addiction is addiction.
[02:12:18.840 --> 02:12:20.360] So smoking is the number one.
[02:12:20.600 --> 02:12:24.280] Smoking is still the number one modifiable risk factor.
[02:12:24.440 --> 02:12:25.080] What's after that?
[02:12:25.080 --> 02:12:25.480] Obesity.
[02:12:25.880 --> 02:12:26.440] Obesity.
[02:12:26.920 --> 02:12:30.680] So why do you think obesity, if you were to speculate, why do you think it is?
[02:12:30.920 --> 02:12:32.840] Yeah, and I feel pretty strongly about this.
[02:12:32.840 --> 02:12:37.000] I mean, I'm happy to speculate on things, and I'm happy to acknowledge when I have no idea.
[02:12:37.000 --> 02:12:39.160] Here, I think we have a pretty good idea.
[02:12:39.160 --> 02:12:41.800] First of all, I don't think it's the excess adiposity, right?
[02:12:41.800 --> 02:12:47.560] Like, I don't think it's the extra two pounds I have on my waist that I wish I didn't have for vanity purposes.
[02:12:48.520 --> 02:13:00.360] It is the environment of growth factors that comes with obesity, namely the hyperinsulinemia, but also the chronically elevated IGF and things of that nature.
[02:13:00.360 --> 02:13:04.920] And it is the inflammatory environment that comes rife with obesity.
[02:13:04.920 --> 02:13:13.560] And again, that's not due to the excess energy that's stored within the confines of the subcutaneous storage depot.
[02:13:13.560 --> 02:13:25.360] It's due to the excess fat that spills over from that into these other areas where fat accumulation is very harmful.
[02:13:25.360 --> 02:13:36.320] So fat accumulation is not problematic, believe it or not, despite our aesthetic preferences, when it occurs in areas that we are designed to store excess energy.
[02:13:36.320 --> 02:13:44.000] It becomes problematic when it escapes those areas and gets around the viscera, gets around our organs, enters the muscle itself.
[02:13:44.000 --> 02:14:05.040] By the way, that's how it directly contributes to insulin resistance when it accumulates in the liver, accumulates around the heart, within the pancreas itself, where it serves the double role of not just creating an inflammatory environment, but also reducing the amount of insulin that the beta cell can release and also around the kidneys.
[02:14:05.040 --> 02:14:09.600] So those are the main places where even a small amount of fat, i.e.
[02:14:09.680 --> 02:14:17.120] if just 10% of your total body fat were in those places, you would be at enormous risk for cardiometabolic disease.
[02:14:17.440 --> 02:14:21.120] Yeah, I remember I've seen a few studies where it's like visceral fat.
[02:14:21.120 --> 02:14:25.760] So you're talking about the fat that's, you know, covering, surrounding your organs, you know.
[02:14:25.760 --> 02:14:30.320] That was highly correlated with an increased cancer risk.
[02:14:30.720 --> 02:14:46.160] And there was like, there was also another correlation with like there's some specific inflammatory cytokines that were being generated or, you know, associated with, I guess, I would say, with the visceral fat and the cancer incidence, which again, it's like the inflammatory environment like you're talking about.
[02:14:46.160 --> 02:14:51.600] So, so the metabolic health being important, we talked about, you know, the best, like exercise being at the top, right?
[02:14:51.600 --> 02:15:00.760] I mean, that's one of the best ways to exercise, energy balance, sleep, and then, of course, you know, management of distress, right?
[02:15:00.760 --> 02:15:04.200] Hypercortisalemia will also contribute to this significantly.
[02:14:59.920 --> 02:15:04.440] Right.
[02:15:04.680 --> 02:15:09.720] Which, of course, even doing things like exercise and getting enough sleep helped help balance those things.
[02:15:09.960 --> 02:15:11.400] Right, exactly.
[02:15:12.120 --> 02:15:21.480] When it comes to cancer prevention, you know, you talk a lot in Outlive about cancer screening, aggressive cancer screening.
[02:15:21.800 --> 02:15:30.520] So, can you talk a little bit about weighing the benefits versus the risks of that type, you know, doing more of an aggressive type of cancer screening?
[02:15:30.520 --> 02:15:42.120] Yeah, I mean, the reason I think we have to pay attention to cancer screening in such an aggressive way is that unlike cardiovascular disease, and even though we didn't really go into the pathogenesis of it today, I mean, I've covered this on other podcasts.
[02:15:42.120 --> 02:15:43.640] I'm sure you have as well.
[02:15:43.640 --> 02:15:45.320] It's very well understood.
[02:15:45.400 --> 02:15:46.920] Doesn't mean we know everything.
[02:15:47.240 --> 02:15:56.040] I'll happily spend 20 minutes telling you all the things I don't understand or that we don't understand as a community, but we have a pretty good sense of what's going on.
[02:15:56.040 --> 02:15:58.360] That's not the case in cancer.
[02:15:58.360 --> 02:16:06.520] It is still a really, really big black box to try to understand all the different ways in which people get cancer.
[02:16:06.520 --> 02:16:21.320] And if you just want proof positive on this, I bet you there's not a single person listening to this, not one, who can't tell you of at least one person they know who's been afflicted with cancer, who otherwise did everything right.
[02:16:21.320 --> 02:16:33.800] They didn't smoke, they weren't obese, they didn't have huge chemical carcinogen exposures, they lived a perfectly healthy life and they still got breast cancer, or they still got leukemia, or they still got some god-awful cancer.
[02:16:33.800 --> 02:16:48.320] So, the truth of it is in cardiovascular disease, when we sit here and talk about modifiable risk factors like lipids, smoking, blood pressure, all these things, that virtually accounts for the entirety of the disease.
[02:16:48.320 --> 02:16:54.240] In cancer, when we talk about the modifiable risk factors, it doesn't even account for half of it.
[02:16:54.240 --> 02:16:56.640] So, it's free money.
[02:16:56.640 --> 02:17:06.560] Don't leave it on the table, don't make unforced errors, don't smoke, and be metabolically healthy, but you don't want to leave it at that.
[02:17:06.560 --> 02:17:17.920] There's still way too great a chance that you're going to end up getting cancer relative to, you know, if you just take the approach of, well, I've taken care of those things, therefore I've done everything I can.
[02:17:17.920 --> 02:17:24.080] So, the missing link, how we bridge that gap, has to be through aggressive screening.
[02:17:24.080 --> 02:17:41.200] Because about the only thing you can say about cancer that is capital T true is when you treat a cancer in an early stage, you will have a better outcome than if you treat that cancer at a later stage.
[02:17:41.840 --> 02:17:46.960] And in the book, I talk about a couple of very specific examples of this where we have just overwhelming data.
[02:17:46.960 --> 02:17:49.520] I use breast and colon cancer as an example.
[02:17:49.520 --> 02:17:56.400] So, when a person has a stage three colon cancer, that's still a big cancer, right?
[02:17:56.720 --> 02:18:04.720] And it's by definition, because it's stage three, it has spread to the lymph nodes, but it has not spread visibly beyond the lymph nodes.
[02:18:04.720 --> 02:18:14.400] So, when you do a CT or an MRI on that patient, you'll see that there is no other evidence of cancer outside of the region of the resection, which is the colon and lymph nodes.
[02:18:14.400 --> 02:18:17.680] Now, you know that there's microscopically cancer elsewhere.
[02:18:17.680 --> 02:18:25.120] So, there are still millions to billions of cancer cells throughout that patient's body, almost assuredly in their liver.
[02:18:26.400 --> 02:18:29.760] But they're not in, you know, you can't see them.
[02:18:30.360 --> 02:18:42.520] If you give that patient the Folfox regimen, which is the standard chemotherapy regimen, that's three drugs, 65% of those patients will be alive in five years.
[02:18:42.840 --> 02:18:45.160] So a third of them will still die.
[02:18:45.480 --> 02:18:47.960] But two-thirds of them will live.
[02:18:48.280 --> 02:18:58.200] If that exact same patient, when you go in and you take their colon out and you take their lymph nodes out, also has visible metabolic disease in the liver, they're now stage four.
[02:18:58.520 --> 02:19:02.520] After surgery, they will go on to get the same chemotherapy.
[02:19:02.520 --> 02:19:05.560] None of those people will be alive in five years.
[02:19:06.200 --> 02:19:08.040] There is a fundamental difference.
[02:19:08.040 --> 02:19:08.520] Why?
[02:19:08.520 --> 02:19:09.880] Why that difference?
[02:19:09.880 --> 02:19:11.240] Same is true with breast cancer.
[02:19:11.240 --> 02:19:13.400] Same is true with every cancer.
[02:19:13.720 --> 02:19:29.480] The reason is the more cancer cells you have, the more heterogeneity you have around the burden of mutations in that cancer, the more capable that cancer is to mutate its way out of treatment, evade the immune system, a whole bunch of other things.
[02:19:29.800 --> 02:19:46.760] So if step number one is don't get cancer, which it should be, and we want to do everything we can to not get cancer, step number two is if you do get cancer, you want to be able to catch it as soon as possible so that you have the smallest possible burden of this disease to treat.
[02:19:46.760 --> 02:19:52.760] And by the way, you know, there's an entire argument that says, well, screening is too expensive.
[02:19:52.760 --> 02:20:01.400] It's a lot cheaper than treating late-stage cancer with very expensive drugs that do very little.
[02:20:03.000 --> 02:20:04.920] So you brought up a lot of good points, Peter.
[02:20:04.920 --> 02:20:09.640] I mean, I really like the way, like, you can do everything you can.
[02:20:09.640 --> 02:20:18.000] And, you know, like one of my favorite Peloton instructors, Leanne Hainsby, you know, she's out, she's like doing physical activity every day.
[02:20:18.000 --> 02:20:19.440] I mean, she looks amazing.
[02:20:19.440 --> 02:20:26.640] I'm sure she's, you know, not eating a terrible diet and she came down with breast cancer, was being treated and was still doing Peloton classes while she was being treated.
[02:20:26.640 --> 02:20:27.680] I mean, amazing.
[02:20:28.400 --> 02:20:36.960] But the reality is, is that they're like over a lifetime, you know, you do like there's a random amount of like things that can happen.
[02:20:36.960 --> 02:20:41.360] Let's say you're metabolically healthy and everything, like your cells are dividing, you can get a mutation.
[02:20:41.360 --> 02:20:49.200] Your immune cells will take care of it most of the time as, you know, we're progressing through life until we start to get, you know, into our what, fifth, sixth, seventh decade.
[02:20:49.200 --> 02:20:51.040] Maybe the immune system's not working as well.
[02:20:51.200 --> 02:20:52.960] I mean, there's things that you just can't control.
[02:20:52.960 --> 02:20:55.040] Like there's that, like you mentioned.
[02:20:55.040 --> 02:21:03.520] So with cancer screening, what, let's say you don't have any known genetic risk factors and there's no like family history, right?
[02:21:04.160 --> 02:21:13.520] What age would you say or what decade of life around where would you think that or how do you treat it in your clinical practice with respect to cancer screenings?
[02:21:13.920 --> 02:21:16.560] What are the major ones to do?
[02:21:16.560 --> 02:21:18.480] You said colon and breast.
[02:21:18.480 --> 02:21:19.760] Are there any others?
[02:21:19.760 --> 02:21:35.840] Yeah, so a discussion like this always begins with our patients by saying, you know, you have to understand your risk appetite as an individual and you have to understand the price you're going to pay for screening.
[02:21:36.480 --> 02:21:38.320] Because there's a couple of prices you pay.
[02:21:38.320 --> 02:21:40.000] The first is economic.
[02:21:40.320 --> 02:21:44.480] Everything we're about to talk about is going to be outside of the standard of care.
[02:21:44.480 --> 02:21:45.120] Not everything.
[02:21:45.120 --> 02:21:56.160] I mean, if you're at a certain age, your breast, you know, your mammography and your colonoscopy will be covered, but your colonoscopy won't be covered at the frequency that we're going to recommend you do it.
[02:21:56.480 --> 02:22:06.360] And even if your mammography is covered, they probably won't cover the MRI or the ultrasound that we're going to recommend because we never recommend mammography in isolation ever.
[02:22:08.200 --> 02:22:24.040] If we're doing a PSA on you and any of our metrics show more care is warranted, they're not going to cover the follow-up study, like a 4K test or a multiparametric MRI, unless your PSA is very high.
[02:22:24.360 --> 02:22:28.360] So understand there's a cost that has to go into this.
[02:22:28.360 --> 02:22:39.080] But I think there's an even bigger cost that you have to be willing to tolerate if you go down this rabbit hole, which is the cost of the false positive, the emotional cost of the false positive.
[02:22:39.400 --> 02:22:43.240] So we always kind of start by explaining how sensitivity and specificity work.
[02:22:43.240 --> 02:22:47.960] And I know a lot of people's eyes kind of glaze over and they're like, oh my God, like I don't want to hear the stats on this.
[02:22:47.960 --> 02:23:00.120] But if you don't understand what sensitivity means and you don't understand what specificity means, you can never understand the things that really do matter to anybody who gets a test, which is positive and negative predictive value.
[02:23:00.120 --> 02:23:07.960] Positive predictive value means if this test comes out positive, how likely is it that I actually have the thing it says?
[02:23:07.960 --> 02:23:12.600] Conversely, if this test comes out negative, how likely is it that I'm truly negative?
[02:23:12.600 --> 02:23:18.600] You want very high positive predictive value and very high negative predictive value.
[02:23:18.600 --> 02:23:20.360] And that's a function of three things.
[02:23:20.360 --> 02:23:29.240] The specificity of a test, which is the ability of a test to detect a condition being present if it is indeed present.
[02:23:29.240 --> 02:23:45.000] The specificity of a test, the ability of a test to conclude that something is absent, if it is indeed absent, and the prevalence of the condition being tested, meaning how likely is it that you have this before I test you?
[02:23:45.840 --> 02:23:53.760] So you can call that prevalence if you're screening, you can call it pretest probability, but the point is, this is all a Bayesian process.
[02:23:54.080 --> 02:23:57.520] So I really spend a lot of time going through this with people.
[02:23:57.840 --> 02:24:02.400] And let's just, you know, start with something as simple as mammography, right?
[02:24:02.400 --> 02:24:07.440] So, you know, so Peter, why are you saying you're not satisfied just doing mammography?
[02:24:07.440 --> 02:24:09.200] Well, here's why.
[02:24:09.200 --> 02:24:32.640] Mammography has a sensitivity of about 90% and a specificity of about 85%, which is fine, except if I'm going to do a mammography on you at this moment in time, your pretest probability for having breast cancer is pretty low, like a couple percent.
[02:24:32.960 --> 02:24:42.640] That means the positive and negative predictive value of this test in isolation are very poor, like less than 20%.
[02:24:44.240 --> 02:24:53.840] Furthermore, there are features about you personally that might make you a bad candidate for MRI in isolation.
[02:24:54.160 --> 02:24:56.400] One is you're very young.
[02:24:56.400 --> 02:24:58.400] You're not in menopause yet.
[02:24:58.400 --> 02:25:01.440] Your breast tissue is very glandular.
[02:25:01.440 --> 02:25:06.560] Now, in 40 years on a mammogram, your breasts are going to look totally different.
[02:25:06.560 --> 02:25:15.600] The mammogram will actually have an easier time seeing what's going on in your breast because there's going to be less dense glandular tissue.
[02:25:16.240 --> 02:25:21.040] The mammogram, because it's an x-ray, is really good at seeing calcified lesions.
[02:25:21.040 --> 02:25:25.040] It's really bad at seeing non-calcified lesions.
[02:25:25.040 --> 02:25:34.200] Conversely, an MRI is really, has no issue with glandular tissue, but can't see calcified lesions very well.
[02:25:34.520 --> 02:25:39.240] So we go through this analysis and you realize there's actually no perfect test for screening.
[02:25:39.240 --> 02:25:45.400] You have to stack tests on top of each other if you want to increase positive and negative predictive value.
[02:25:45.400 --> 02:25:50.760] And if you rely on any one test by itself, you're always going to have a blind spot.
[02:25:51.640 --> 02:25:53.960] The one exception to that, by the way, is a colonoscopy.
[02:25:53.960 --> 02:26:01.160] A colonoscopy is a test that has 100% sensitivity and very high specificity.
[02:26:01.640 --> 02:26:05.160] But with colonoscopy, you have a whole different risk, which is a physical risk.
[02:26:05.160 --> 02:26:08.040] There's actually a risk of harm from a colonoscopy.
[02:26:08.040 --> 02:26:10.280] Basically, three big risks.
[02:26:10.280 --> 02:26:16.280] There's the risk of dehydration, electrolyte imbalance, hypotension that comes from the bowel prep.
[02:26:16.600 --> 02:26:19.080] There's the risk of the sedation.
[02:26:19.400 --> 02:26:23.640] And then there's the risk of a perforation or bleeding, actual procedural risks.
[02:26:23.640 --> 02:26:33.400] Now, if you look at the largest study that came out on this, which was last summer in the New England Journal of Medicine, this was actually a study that was meant to show that colonoscopy wasn't worth it.
[02:26:33.720 --> 02:26:36.920] Actually, it showed something totally different in my mind, which showed how safe it was.
[02:26:36.920 --> 02:26:43.480] So it was a study of, I think, over 20,000 people and had not a single incident.
[02:26:43.480 --> 02:26:47.800] So it showed that in good hands, a colonoscopy is a very safe procedure.
[02:26:48.280 --> 02:26:52.440] But I always want to make sure people understand, like, we don't take this stuff lightly.
[02:26:52.840 --> 02:27:03.080] And there's a reason you don't do a colonoscopy three times a year, which if you did colonoscopy three times a year, you'd never get colon cancer because you'd all, you know, colon cancer always has to come from a polyp.
[02:27:03.080 --> 02:27:09.480] So if you were checking somebody three times a year, like you'd, you'd never, they would never be able to develop a polyp that you wouldn't catch.
[02:27:09.480 --> 02:27:13.400] But at that point, the risk would be just too high that something else would go wrong.
[02:27:14.040 --> 02:27:18.720] So, you know, standard recommendations used to be every 10 years starting at 50.
[02:27:19.040 --> 02:27:27.680] Current recommendations are starting at 45, and there's some controversy about whether you would do it every five to 10 years.
[02:27:27.680 --> 02:27:40.640] We typically say, with no family history or risk factors, meaning you don't have inflammatory bowel disease or Crohn's disease or things like that, we would typically say 40 and then about every three years, depending on the findings.
[02:27:40.640 --> 02:27:46.800] So sometimes the findings on a given colonoscopy will make you want to actually do a more frequent surveillance.
[02:27:46.800 --> 02:27:56.880] If you find a sessile polyp, for example, or if a patient has an incomplete bowel prep, you might decide, you know, actually, we need to do this a little more urgently and do it in a year again, as opposed to weight three.
[02:27:57.200 --> 02:27:58.240] Great information.
[02:27:58.240 --> 02:28:08.880] And with respect to the combined, you know, especially for younger individuals like younger like myself, the mammogram starting.
[02:28:08.880 --> 02:28:15.360] So I might say like, you know, at 40, I would start doing a mammo and an ultrasound every other year.
[02:28:15.360 --> 02:28:16.640] Sorry, every six months.
[02:28:16.640 --> 02:28:23.920] So you would do a mammo every year, you would an ultrasound every six months, every year, but stagger them by six months.
[02:28:23.920 --> 02:28:27.920] So if there was, if there was a high enough risk, that's probably an approach I would take.
[02:28:27.920 --> 02:28:33.280] Now, is that because there's a lifetime risk of one in eight just for on average, forget about all the mothers?
[02:28:33.440 --> 02:28:33.840] Okay.
[02:28:34.560 --> 02:28:45.360] And again, breast cancer is one of those cancers where if you treat it early, like it's it's it's absolutely a disease that that can be treated early.
[02:28:45.360 --> 02:28:49.040] If you catch this in a stage one, it's a non-fatal disease.
[02:28:49.600 --> 02:28:52.960] A stage four disease is a uniformly fatal disease.
[02:28:53.360 --> 02:28:57.280] What's the positive predictive value of catching it in stage one with the combination?
[02:28:57.840 --> 02:29:06.680] Well, so, okay, so the way to think about it is you think about it as what's the positive predictive value of the combined modalities.
[02:29:07.320 --> 02:29:11.720] And here it's a little more complicated because it depends on the hormone status.
[02:29:11.720 --> 02:29:13.320] So I'll give you an example.
[02:29:13.960 --> 02:29:14.840] Another...
[02:29:15.960 --> 02:29:18.840] thing that we use that we haven't talked about are liquid biopsies.
[02:29:19.080 --> 02:29:22.040] So we incorporate liquid biopsies into our testing.
[02:29:22.040 --> 02:29:22.760] Let's talk about them.
[02:29:22.760 --> 02:29:23.000] Yeah.
[02:29:23.000 --> 02:29:23.480] Yeah, yeah.
[02:29:23.880 --> 02:29:25.240] So have you talked about them on the podcast?
[02:29:25.240 --> 02:29:25.640] Do you listen to that?
[02:29:25.800 --> 02:29:31.000] I know, but there's a question I was going to ask you about with the GRAIL by Gallery by GRAIL.
[02:29:31.800 --> 02:29:33.080] Okay, so what does this test do?
[02:29:33.080 --> 02:29:50.120] So there are basically three things that you can figure out by looking at strands of DNA in the blood that can give you a clue as to whether or not a patient has cancer.
[02:29:50.440 --> 02:29:58.520] So let's say you collect a bunch of, you connect, you know, the GRAIL test uses 10 cc of blood, relatively paltry sum of blood.
[02:29:58.520 --> 02:30:03.080] And they look at all of the cell-free DNA.
[02:30:03.080 --> 02:30:05.880] So again, they separate the DNA that's in cells.
[02:30:05.880 --> 02:30:10.520] They don't want that, right, from the cell-free DNA.
[02:30:10.840 --> 02:30:28.520] And determine, so basically there could be known mutations that we know are cancer genes, like a K-RAS mutation or p53 mutation, where you might say, oh, well, if you see that K-RAS mutation, like there's cancer somewhere in the body.
[02:30:28.520 --> 02:30:34.840] The second thing that gives you a clue that there could be cancer in the body is the length of the DNA fragments that you see.
[02:30:35.160 --> 02:30:45.680] So, there's an, you know, this is not what GRAIL does, by the way, but there are other technologies that are looking at fragment length and using fragment length to impute the probability of cancer.
[02:30:44.920 --> 02:30:49.040] What GRAIL does is they look at a third thing, which is methylation.
[02:30:49.360 --> 02:30:52.800] So, they say, okay, well, all of this DNA is yours.
[02:30:52.800 --> 02:30:56.720] We're not going to worry about what the mutations are or what the fragment lengths are.
[02:30:56.720 --> 02:31:04.160] But what we do know is certain methylation patterns are indicative of cancer and tissue of origin.
[02:31:04.160 --> 02:31:05.680] That's a very big deal.
[02:31:05.680 --> 02:31:15.360] So, now you are doing a screen for not just does this patient likely have cancer or not, but if they do, can you tell me where that's coming from?
[02:31:15.360 --> 02:31:18.240] So, we can now go and look more closely there.
[02:31:18.560 --> 02:31:26.320] Now, there's something really interesting about how this works because it's different from any other type of screening test.
[02:31:26.320 --> 02:31:35.760] See, that MRI that we talked about, or the ultrasound, or the mammogram, or the colonoscopy for that matter, are basically morphology tests.
[02:31:35.760 --> 02:31:44.880] You're looking visually, either directly in the case of colonoscopy or indirectly in the form of a mammogram, where you have to look through the tissue.
[02:31:44.880 --> 02:31:47.760] You're looking at the morphology of a cancer.
[02:31:47.760 --> 02:31:50.560] The GRAIL test says nothing about that.
[02:31:50.560 --> 02:32:00.320] It's simply telling you: is this a cancer that is leaving its site of origin or shedding its DNA in sufficient enough quantities outside its site of origin?
[02:32:00.320 --> 02:32:05.520] So, something very interesting emerges when you take a closer look at the GRAIL data.
[02:32:05.520 --> 02:32:08.080] And this is why we use the test.
[02:32:08.080 --> 02:32:15.760] Again, I have no affiliation with GRAIL, so this is just my clinical experience and observation.
[02:32:15.760 --> 02:32:21.360] At first glance, the sensitivity of the GRAIL test for breast cancer is quite low.
[02:32:21.360 --> 02:32:30.000] The specificity is very high for GRAIL, by the way, meaning if you don't have cancer, it is very likely to tell you you don't have cancer.
[02:32:30.760 --> 02:32:37.240] The sensitivity is quite low, meaning if you have cancer, it could miss it.
[02:32:37.560 --> 02:32:39.640] And it's been tuned that way.
[02:32:39.640 --> 02:32:46.040] So the algorithm has been tuned for a very high specificity, a low sensitivity.
[02:32:46.360 --> 02:32:55.560] But if you look at breast cancer overall sensitivity, it's about 20% for stage 1, stage 2, which seems kind of abysmal.
[02:32:55.560 --> 02:33:02.760] Meaning, if you have a breast cancer that's early stage, stage 1, stage 2, there's only like a 20% chance it'll show up on the GRAIL test.
[02:33:02.760 --> 02:33:07.640] And many people, myself included, at one point, thought that doesn't justify doing the test.
[02:33:07.640 --> 02:33:11.640] I don't need a liquid biopsy to tell me I've got a stage three breast cancer.
[02:33:11.640 --> 02:33:15.720] Like I'm going to figure that out falling off a log, right?
[02:33:16.040 --> 02:33:19.960] So I need something to tell me when there's a stage one breast cancer.
[02:33:19.960 --> 02:33:31.800] But a closer look at the data showed that if you looked at ERPR negative breast cancers, stage one, stage two sensitivity was 75 to 80%.
[02:33:32.120 --> 02:33:39.480] It was only in the triple positive ERPR positive, HER2 new positive, that the sensitivity, specificity are so low.
[02:33:39.480 --> 02:33:42.600] And since that's the majority of breast cancers, it brings it down.
[02:33:42.600 --> 02:33:44.040] What does this mean?
[02:33:44.360 --> 02:33:51.800] It means that the more indolent a breast cancer is, the less likely the GRAIL test picks it up at an early stage.
[02:33:51.800 --> 02:33:56.680] But the more aggressive it is, the more likely it is to pick it up at an early stage.
[02:33:56.680 --> 02:34:02.440] The implication might be here that it's catching the cancers that matter.
[02:34:04.040 --> 02:34:11.080] And I think that's a very interesting way to combine liquid biopsies with morphologic studies.
[02:34:11.400 --> 02:34:18.000] Do you ever not combine, like, do you think doing just the liquid biopsy by itself would be a useful thing?
[02:34:18.160 --> 02:34:23.680] Or do you think really it's better with, you know, in combination with other morphology types of screening?
[02:34:23.840 --> 02:34:25.120] Yeah, it's a great question.
[02:34:25.120 --> 02:34:32.800] I mean, we don't do them in isolation because I still think we're in really early days.
[02:34:32.800 --> 02:34:37.040] And I just think a little bit of a belt and suspenders approach makes sense.
[02:34:37.680 --> 02:34:43.680] But it'll be wonderful if the day comes when all you need to do is the liquid biopsy.
[02:34:43.680 --> 02:34:48.320] And only if it comes up positive, do you need to go and do a morphologic survey?
[02:34:48.640 --> 02:34:49.920] A couple of questions.
[02:34:50.240 --> 02:34:56.480] So, you know, talking about some of the major screenings, the colonoscopy, the mammogram, you mentioned PSA.
[02:34:59.360 --> 02:35:17.520] So with like some of these, you know, types of morphology screenings, like the mammogram, for example, people are concerned, like there's a whole group of people that are very concerned about the potential, the mutagenic potential of, you know, these types of screening methods, you know, potentially causing cancer, right?
[02:35:17.520 --> 02:35:19.280] So CT scans, the x-rays.
[02:35:19.520 --> 02:35:23.520] Well, CT scans would be a very lousy way to screen for that reason, right?
[02:35:23.520 --> 02:35:26.240] The CT scan has a lot of radiation.
[02:35:26.240 --> 02:35:34.800] With the exception, the only time we justify the use of a CT scan is in a former smoker or a current smoker.
[02:35:34.800 --> 02:35:38.320] We don't have any current smokers in our practice, but we do have former smokers.
[02:35:38.320 --> 02:35:43.600] We do still use a low-dose CT for lung screening.
[02:35:44.480 --> 02:35:51.560] Remember, lung cancer risk is, lung cancer is the leading cause of cancer death globally and in the U.S.
[02:35:51.520 --> 02:35:53.200] for both men and women.
[02:35:54.160 --> 02:36:00.000] And 85% of lung cancers occur in former smokers or current smokers.
[02:36:00.920 --> 02:36:06.520] So in those people, you have to ask the question, what kind of cancers do they get?
[02:36:06.520 --> 02:36:17.080] And you basically have small cell, large cell, and squamous cell are the dominant cancers that occur in smokers.
[02:36:17.080 --> 02:36:21.160] And those are best detected on a low-dose CT scan.
[02:36:21.160 --> 02:36:32.120] Adenocarcinoma of the lung is the dominant cause of lung cancer in a non-smoker, and we can detect that equally well with an MRI.
[02:36:32.120 --> 02:36:35.960] So we don't expose a never-smoker to that risk.
[02:36:35.960 --> 02:36:43.080] Whereas to a smoker, we, or you know, a past smoker or current smoker, the risk reward trade-off is worth it.
[02:36:43.080 --> 02:36:45.880] And that's been documented really clearly in clinical trials.
[02:36:45.880 --> 02:36:49.560] Mammography has incredibly low radiation.
[02:36:50.200 --> 02:36:55.160] Not as low as like a DEXA scan or something like that, but it's still really, really low.
[02:36:56.280 --> 02:36:58.040] There's a lot of women that avoid them.
[02:36:58.520 --> 02:36:59.240] I'm sure there are.
[02:36:59.560 --> 02:37:00.120] I don't know.
[02:37:00.120 --> 02:37:03.000] Maybe the radiation has lessened over the years.
[02:37:03.560 --> 02:37:04.040] It always has.
[02:37:04.600 --> 02:37:06.040] Radiation is constantly going down.
[02:37:06.040 --> 02:37:12.680] I mean, just going back to something we spoke about earlier, 20 years ago, a C, so just let's explain what the numbers mean.
[02:37:12.680 --> 02:37:16.600] So radiation is measured in units called millisieverts.
[02:37:16.600 --> 02:37:27.240] And it's generally established that exposure to more than 50 millisieverts a year will increase your risk of mutagenesis.
[02:37:28.040 --> 02:37:31.240] So now let's put that in the context of certain things.
[02:37:31.240 --> 02:37:41.080] So living at sea level here in San Diego, just the exposure you get to the environment is about one to two millisieverts a year.
[02:37:41.080 --> 02:37:44.680] So that's two to four percent of your annual allotment.
[02:37:45.280 --> 02:37:49.040] If you live in Denver, you're doubling that.
[02:37:49.040 --> 02:37:52.560] So being one mile in the sky doubles your exposure.
[02:37:52.560 --> 02:37:58.080] But you're still, you know, you're at four to eight percent of your annual allotment.
[02:38:00.400 --> 02:38:09.840] A CT angiogram 20 years ago was 20 millisieverts, 40% of your annual radiation allotment on one test.
[02:38:09.840 --> 02:38:18.080] The last patient I sent for a CTA last week, because when we get the report, it also shows the radiation, less than one millisievert.
[02:38:18.400 --> 02:38:21.360] So mammograms are even less than that.
[02:38:21.360 --> 02:38:22.000] Yeah, yeah, yeah, yeah.
[02:38:22.160 --> 02:38:22.720] They're a fraction.
[02:38:22.960 --> 02:38:37.040] So it really is, it makes zero sense for a woman who has a lifetime risk of one in eight, and perhaps even higher if she's obese and drinks alcohol-wide, to avoid doing mammograms.
[02:38:37.040 --> 02:38:37.440] Correct.
[02:38:37.440 --> 02:38:37.680] Okay.
[02:38:39.200 --> 02:38:42.240] But again, I would never rely on a mammogram exclusively.
[02:38:42.560 --> 02:38:44.960] I would combine it with an ultrasound or the MRI.
[02:38:45.440 --> 02:38:48.080] But they're not concerned about people aren't really scared of the ultrasounds.
[02:38:48.400 --> 02:38:49.280] They're scared of mammograms.
[02:38:49.440 --> 02:38:51.600] Yeah, and MRI, of course, has a radiation.
[02:38:52.720 --> 02:38:58.960] But again, everyone has to, you know, you just have to, unfortunately, there's a lot of fear-mongering that goes on, but you just have to look at the numbers.
[02:38:58.960 --> 02:39:08.400] I mean, it's crystal clear that a mammogram has a very, very, they might be confusing it with, there was another test, I'm blanking on what it's called now because it's never done anymore.
[02:39:09.760 --> 02:39:12.400] It's called, I think it was called Molecular Breast Imaging.
[02:39:12.400 --> 02:39:15.840] It was another high, high-intensity mammogram.
[02:39:15.840 --> 02:39:17.840] It's, again, I've never seen one done.
[02:39:17.840 --> 02:39:20.160] I don't think they've been done in years.
[02:39:20.160 --> 02:39:27.280] But pre-MRI, like pre-utility for other tests, it was done, it was also about a 20 to 30 millisievert.
[02:39:29.680 --> 02:39:37.640] I'm sure there's a complete misinformation and misunderstanding where people are confusing mammogram from what's called an MBI, is what the test was called.
[02:39:37.640 --> 02:39:39.240] Well, this is good to clear up.
[02:39:40.120 --> 02:39:42.280] Because I mean, I'm not just, I'm not kidding.
[02:39:42.280 --> 02:39:46.600] Like, I know people, I know women that have this fear.
[02:39:46.600 --> 02:39:53.720] So, you know, I think stepping, sort of stepping back, just one more thing I want to ask you about is like blood cancers.
[02:39:53.720 --> 02:39:55.080] Is there any, like, what is that?
[02:39:55.240 --> 02:39:59.880] Well, liquid biopsies are very good on blood cancers, actually, because you have the highest proportion of those cells.
[02:39:59.880 --> 02:40:04.360] Like, you're going to get a much higher concentration of cell-free DNA.
[02:40:04.360 --> 02:40:16.680] So, yeah, we actually, that's actually one of the areas where I'm most excited about the liquid biopsies is on leukemias and other sort of hematologic issues, such as myeloma and things like that.
[02:40:17.000 --> 02:40:23.800] And for people listening, wondering about the cost of it, it's typically, it's like 900, like about $1,000, right?
[02:40:23.800 --> 02:40:25.240] And I don't think it's D to C.
[02:40:25.240 --> 02:40:27.720] So, meaning I think you have to go through your doctor to do it.
[02:40:27.720 --> 02:40:30.280] I don't think you can just do the test willy-nilly.
[02:40:30.280 --> 02:40:32.040] I don't think you can, yeah.
[02:40:32.200 --> 02:40:33.400] But I don't know for sure.
[02:40:33.400 --> 02:40:35.400] Yeah, I'd be surprised if you could.
[02:40:35.400 --> 02:40:43.160] So, on the breast cancer topic, you know, kind of going into another area, just I know we gotta, we got, we're, we're doing okay.
[02:40:43.160 --> 02:40:50.200] Um, but I really want to get your thoughts on this, this topic, which is, you know, broader sense hormones.
[02:40:50.520 --> 02:40:59.880] Um, but also just like if you look at the way a woman ages before menopause, I mean, she's aging slower than a man, right?
[02:40:59.880 --> 02:41:01.960] Like by several striks.
[02:41:02.200 --> 02:41:02.840] Yeah.
[02:41:03.160 --> 02:41:08.080] When she hits menopause, I mean, it's like a, you hear this quote-unquote cliff.
[02:41:08.080 --> 02:41:08.600] They fall off.
[02:41:08.600 --> 02:41:14.680] Like a woman, in terms of their aging, they fall off this cliff, but like it's no longer, I mean, it's just, they go rapidly, you know, down.
[02:41:15.040 --> 02:41:22.560] So what are, what are, let's just talk about some of the risk factors that women face, you know, after menopause and why.
[02:41:22.880 --> 02:41:32.960] Yeah, so obviously what happens in menopause is three hormones that are really important to a woman during her reproductive years go away.
[02:41:33.280 --> 02:41:35.200] And they go away in very short order.
[02:41:35.360 --> 02:41:37.680] So it can be quite dramatic.
[02:41:37.920 --> 02:41:41.600] And obviously those hormones are estrogen, progesterone, and testosterone.
[02:41:41.600 --> 02:41:54.720] I always mention testosterone because it's easily forgotten, but it's important to not forget it because a woman's concentration of testosterone in her, and by the way, testosterone declines slower than estrogen and progesterone.
[02:41:54.720 --> 02:41:56.080] Estrogen and progesterone really go down.
[02:41:56.080 --> 02:41:57.920] Testosterone kind of gradually goes down.
[02:41:57.920 --> 02:42:09.680] But like right now, we're sitting here and you're, you know, you're 45, presumably, you know, you're still in the throes of your reproductive, you know, you're at the tail end of your reproductive capacity, but you haven't hit menopause yet.
[02:42:10.320 --> 02:42:15.760] Your testosterone right now is at least 10 times higher than your estrogen level.
[02:42:15.760 --> 02:42:16.240] Wow.
[02:42:16.240 --> 02:42:18.000] In absolute quantities.
[02:42:18.000 --> 02:42:19.840] And by the way, that's the highest.
[02:42:19.840 --> 02:42:21.040] That's if you're ovulating.
[02:42:21.040 --> 02:42:24.160] So your peak estrogen is around ovulation.
[02:42:25.120 --> 02:42:32.800] If I take you in the early follicular cycle or in the luteal cycle, your testosterone could be 100 times higher than your testosterone.
[02:42:32.800 --> 02:42:34.560] So it's very important to understand.
[02:42:34.560 --> 02:42:41.360] Don't get confused by the units on the lab test because they're reporting them in nanograms per deciliter versus picograms per milliliter.
[02:42:41.360 --> 02:42:51.360] And so the estrogen number looks bigger, but in terms of absolute amounts of it, testosterone is still by far the most dominant hormone for both men and women.
[02:42:51.360 --> 02:42:55.920] So these things go away and a whole bunch of things happen.
[02:42:55.920 --> 02:43:02.440] Now, in the short run, and the things that generally get the most attention of the medical community are these vasomotor symptoms.
[02:43:02.440 --> 02:43:04.200] So the hot flashes and the night sweats.
[02:43:04.200 --> 02:43:07.400] And these are kind of the first things that women tend to notice.
[02:43:07.400 --> 02:43:12.920] I mean, they might notice that their period is becoming irregular, their cycle is lengthening, and things of that nature.
[02:43:12.920 --> 02:43:17.640] But in terms of actual symptoms that are disruptive to their quality of life, it are these vasomotor symptoms.
[02:43:17.640 --> 02:43:20.040] So hot flashes and night sweats.
[02:43:20.360 --> 02:43:26.920] It's not clear why some women get these horribly and some women actually don't get them at all.
[02:43:26.920 --> 02:43:31.640] Most women do get them to varying degrees.
[02:43:31.640 --> 02:43:34.840] And again, there's a spectrum there.
[02:43:35.160 --> 02:43:40.200] Other women will talk about things like brain fog, sleep disturbances.
[02:43:40.200 --> 02:43:47.800] And again, the sleep disturbances could be related to what we just said, because I got to think, if you're having hot flashes and night sweats, that can't be good for your sleep.
[02:43:47.800 --> 02:43:54.280] So, you know, is that sufficiently driving the sleep disturbances, or is there something else that's driving them?
[02:43:55.160 --> 02:43:59.080] As time progresses into menopause, other things will occur.
[02:43:59.080 --> 02:44:00.760] There will be sexual changes.
[02:44:00.760 --> 02:44:05.720] So vaginal atrophy, dryness, and reduction in libido.
[02:44:05.720 --> 02:44:08.360] And again, those can be related, but they can be independent.
[02:44:08.360 --> 02:44:20.680] We know testosterone plays an important role in libido, and we know that estradiol plays an important role in vaginal absence of estrogen is driving the vaginal symptoms.
[02:44:20.680 --> 02:44:31.000] So, and of course, if, and then of course, you have pain with intercourse that's a result of all of those things as well, which then feeds forward on the decreased libido.
[02:44:31.320 --> 02:44:37.960] As you go a little bit further, you start to see another major consequence of this, which is the destruction of bone.
[02:44:38.280 --> 02:44:47.440] And I use that word, I'm being a little aggressive in my language there, but the truth of it is both men and women hit peak bone density in their early 20s.
[02:44:47.440 --> 02:44:55.200] And for men, if you look at the reduction in bone mineral density from their 20s on, it's a gradual decline.
[02:44:55.200 --> 02:45:00.880] For women, it's a gradual decline until menopause, then a very straight, harsh line decline.
[02:45:00.880 --> 02:45:23.840] And when you consider the risk of falling and the impact of a broken hip or femur later in life, both in terms of mortality and morbidity, you realize that that may be the single biggest risk of menopause on women, though not appreciated in their 50s and not only showing up until their 60s.
[02:45:23.840 --> 02:45:34.560] So, taken together, all of these symptoms, in my mind, completely justify the use of HRT in any woman who is willing to undergo it.
[02:45:34.560 --> 02:45:54.480] And unfortunately, and I've talked about this a lot on my podcast, I think there has been no greater disservice brought by the medical community onto anyone, but in particular in this case, women, than the abject failure of the interpretation of the Women's Health Initiative in 2001, 2002, whenever it was first published.
[02:45:54.720 --> 02:45:58.800] That's a study that was completely misinterpreted.
[02:45:58.800 --> 02:46:11.600] The press were, I mean, out to lunch in the way they interpreted the study, and the investigators were, in my mind, equally at fault for not clarifying it.
[02:46:11.600 --> 02:46:17.840] Now, at least one member of the team who was a part of that study, Joanne Manson, has been more vocal lately.
[02:46:17.840 --> 02:46:19.040] I had her on my podcast.
[02:46:19.040 --> 02:46:25.200] She's been more vocal in acknowledging the way in which that study was misinterpreted.
[02:46:25.200 --> 02:46:42.040] But unfortunately, the damage has largely been done, both in terms of the fact that there is an entire generation of women, by my estimate and by the estimate of my analysis, my analyst's analysis, over 20 million women have been deprived of hormones who would have otherwise received them.
[02:46:42.040 --> 02:46:48.520] And we've even come up with some calculations for how many lives have been unnecessarily lost as a result of that.
[02:46:48.520 --> 02:46:55.800] And then there's the ongoing damage, which is, you know, as Mark Twain is attributed for saying this, right?
[02:46:55.880 --> 02:46:59.880] Like a lie will travel halfway around the world before the truth is tied up its shoes.
[02:46:59.880 --> 02:47:07.640] So just as you said there are women out there who say, I can't get a mammography because, oh my God, of the radiation, they may in fact be thinking of an MBI.
[02:47:07.640 --> 02:47:08.600] There's just a misunderstanding.
[02:47:08.600 --> 02:47:17.960] Well, similarly, there are still women walking around today that thinking HRT increases the risk of dying of breast cancer when it never did, and it certainly doesn't today.
[02:47:18.600 --> 02:47:22.360] So let's talk a little bit about that.
[02:47:22.360 --> 02:47:24.920] Like, I know, like, I've looked into the Women's Health Initiative.
[02:47:24.920 --> 02:47:34.280] I've heard you speak about it, and some of the major, major flaws of that study were one, being.
[02:47:35.080 --> 02:47:38.440] Well, so I want to, let's talk about what the study did, right?
[02:47:38.440 --> 02:47:49.400] So the study took two groups of women, women who had a uterus and women who didn't have a uterus, and randomized each of those groups into two separate groups, treatment versus placebo.
[02:47:49.400 --> 02:47:50.280] Why was that done?
[02:47:50.280 --> 02:48:05.240] Well, it was well understood by then, as it still remains, that in women with a uterus, failure to give progesterone with estrogen increases endometrial hyperplasia.
[02:48:05.240 --> 02:48:13.560] So, if you take a woman with a uterus and you just give her estrogen, but there's no progesterone, her endometrial lining will thicken, will thicken, will thicken.
[02:48:13.560 --> 02:48:21.920] And as the endometrial lining gets thicker, so too goes the risk of hyperplasia and ultimately what's called dysplasia, which can lead to cancer.
[02:48:14.920 --> 02:48:27.520] In other words, unopposed estrogen will increase the risk of endometrial cancer.
[02:48:27.520 --> 02:48:30.960] So, to this day, we know this and we do this.
[02:48:31.600 --> 02:48:40.000] So, if you had a uterus, you were put into a group where the treatment group was given conjugated equine estrogen and MPA.
[02:48:40.000 --> 02:48:45.840] So, that's estrogen taken from horse urine and a synthetic progestin.
[02:48:45.840 --> 02:48:48.640] And the treatment, and the placebo group was just given a placebo.
[02:48:48.640 --> 02:48:54.720] And then, in the other group, the no-uterus group, they were just given conjugated equine estrogen versus placebo.
[02:48:54.720 --> 02:48:58.240] They didn't have to be given the MPA, the synthetic estrogen.
[02:48:59.520 --> 02:49:03.760] These women were on average considerably older.
[02:49:03.760 --> 02:49:09.440] They were, I want to say, seven to ten years out of menopause at this point.
[02:49:10.640 --> 02:49:36.800] And the study was looking at a number of outcomes, but it was terminated early at about five and a half years when it was noted that the women in the CEE plus MPA group versus the placebo had a 0.1% higher risk of developing breast cancer.
[02:49:38.240 --> 02:49:46.640] Interestingly, the women in the CEE alone group had a lower risk of developing breast cancer.
[02:49:46.640 --> 02:49:56.640] So, the study was halted, and the headline read: Estrogen increases the risk of breast cancer by 25%.
[02:49:56.640 --> 02:49:59.040] Well, this wasn't correct.
[02:50:00.440 --> 02:50:13.320] It is true that in the CEE plus MPA group, that group had five cases of breast cancer per thousand women.
[02:50:13.320 --> 02:50:17.960] compared to four cases of breast cancer per thousand women in the placebo group.
[02:50:17.960 --> 02:50:22.520] And it is true that that's a 25% increase in the relative risk.
[02:50:22.520 --> 02:50:25.320] But of course, the absolute risk is 0.1%.
[02:50:25.320 --> 02:50:29.080] There was no difference in breast cancer mortality.
[02:50:29.080 --> 02:50:37.880] In other words, there was an extra one case of breast cancer, but there was no difference in breast cancer mortality.
[02:50:37.880 --> 02:50:48.520] Those data, by the way, have been updated every decade or so, and we now have like 19-year follow-up on that group, and that fact still remains true.
[02:50:48.520 --> 02:50:56.200] To this day, there is still no difference in the mortality of breast cancer in the CEE plus MPA group.
[02:50:56.520 --> 02:51:05.320] But you see, it would be impossible to make the case that estrogen is the cause there when in the other group you saw the exact opposite effect.
[02:51:05.320 --> 02:51:16.760] You saw that the CEE group alone had a lower incidence of breast cancer and eventually even a lower mortality due to breast cancer.
[02:51:17.080 --> 02:51:26.840] So I feel like, I don't know, maybe a 10th grade science student might come up with a different hypothesis than estrogen is the culprit.
[02:51:26.840 --> 02:51:29.560] In this group, you have A plus B.
[02:51:29.560 --> 02:51:31.320] In this group, you have A.
[02:51:31.320 --> 02:51:32.520] What could be the difference?
[02:51:32.520 --> 02:51:33.960] Might it be the B?
[02:51:33.960 --> 02:51:51.920] So I think most people who think about this problem today acknowledge that it's probably the MPA that was driving the very, very small, clinically insignificant, but statistically significant increase in breast cancer incidence that had no translation to a mortality difference.
[02:51:52.240 --> 02:51:54.800] And you might ask the question: well, is MPA in use today?
[02:51:54.800 --> 02:51:57.920] And the answer is pretty much by nobody.
[02:51:59.120 --> 02:52:01.360] I've never once prescribed MPA.
[02:52:01.360 --> 02:52:05.200] I've never seen a patient come to me who's taking MPA.
[02:52:05.200 --> 02:52:07.760] There probably are some patients on it, but I doubt it.
[02:52:07.760 --> 02:52:08.640] And what is MPA again?
[02:52:08.960 --> 02:52:10.160] It's a synthetic progestin.
[02:52:10.640 --> 02:52:19.280] Nowadays, women take bio-identical, micronized oral progesterone, or they use a progesterone-coated IUD.
[02:52:19.920 --> 02:52:25.280] If they don't benefit symptomatically from progesterone, progesterone is a funny hormone.
[02:52:25.280 --> 02:52:28.480] Some women really don't respond well to it.
[02:52:29.040 --> 02:52:32.000] It doesn't help their symptoms in any way, shape, or form.
[02:52:32.000 --> 02:52:33.920] And in those women, we don't even use it.
[02:52:33.920 --> 02:52:36.480] We just use a progesterone-coated IUD.
[02:52:36.480 --> 02:52:43.120] And that provides the local protection that prevents endometrial hyperplasia.
[02:52:43.840 --> 02:52:52.400] So in that sense, you know, I could dive deeper and deeper and go through the weeds on the whole study, but the punchline is very clear here, right?
[02:52:52.400 --> 02:53:00.800] Which is estrogen absolutely did not drive either the incidence of breast cancer or mortality associated with breast cancer.
[02:53:00.800 --> 02:53:03.360] And again, that was not true in 2002.
[02:53:03.360 --> 02:53:05.280] It was not true in 2006.
[02:53:05.280 --> 02:53:06.480] It is not true today.
[02:53:06.880 --> 02:53:20.560] That is one piece of the study that I didn't catch because, you know, when trying to sort of deconstruct it, it was like, okay, well, the synthetic, of course, versus bioidentical versus the age of initiation.
[02:53:20.560 --> 02:53:28.480] So, like you said, these women were like 10 years, I mean, like on average, like after menopause had hit, was another factor.
[02:53:28.480 --> 02:53:31.880] And then, you know, some of them were very, very unhealthy again.
[02:53:29.680 --> 02:53:35.720] Yeah, it was a very unhealthy population to begin with.
[02:53:36.360 --> 02:53:39.720] The other thing about it, by the way, is we don't use oral estrogen anymore.
[02:53:40.040 --> 02:53:41.480] Yeah, so that's another question.
[02:53:41.480 --> 02:53:45.800] What, so can you talk about a little bit of the differences?
[02:53:45.960 --> 02:53:56.120] Just, you know, sort of not so much into the deepness of it, but like the difference between, you know, oral estrogen, bioidentical estrogens, topical, like, you know, what?
[02:53:56.440 --> 02:54:09.080] So the only estrogens that are used today are bioidentical, which means they're estradiol and/or estriol, but there is no FDA-approved estriol product.
[02:54:09.080 --> 02:54:12.280] So there are three estrogens, E1, E2, E3.
[02:54:13.240 --> 02:54:16.680] There's some important nuance here that maybe justifies explaining.
[02:54:16.680 --> 02:54:35.640] So estradiol can be turned into estrone, which is E1, and it can be turned into E3 estriol, but E3 cannot be turned into E2 or E1.
[02:54:35.640 --> 02:54:37.640] So that's a one-way arrow.
[02:54:37.960 --> 02:54:43.640] E3 can be turned into, this is complicated.
[02:54:43.640 --> 02:54:44.280] Let me start.
[02:54:44.440 --> 02:54:50.040] E1 can be turned into a 2, 4, and 16-hydroxyestrone.
[02:54:50.040 --> 02:54:57.560] So you've got E3 that can go into an E, sorry, E1 can be turned into a 2-hydroxy, a 4-hydroxy, or a 16-hydroxy.
[02:54:57.560 --> 02:55:04.600] E3 can actually be turned into the 2-hydroxy, but not the 4-hydroxy or the 16-hydroxy.
[02:55:04.600 --> 02:55:11.080] Virtually all the breast cancer risk probably comes from the 4-hydroxyestrone.
[02:55:11.400 --> 02:55:18.080] So you can get that from estriol, pardon me, from estradiol, but you can't get it from estriol.
[02:55:13.800 --> 02:55:20.400] There is no FDA-approved product for estriol.
[02:55:21.040 --> 02:55:30.960] So if a woman is taking estriol, which she's probably taking in a topical fashion in combination with estradiol, they usually refer to that as a bi-est.
[02:55:30.960 --> 02:55:34.320] You'll hear that abbreviated bi-est, which just means biestrogen.
[02:55:34.320 --> 02:55:43.760] So they'll combine in some fraction, anywhere from 50-50 to 80-20, estradiol with estriol, and a woman will apply that topically.
[02:55:43.760 --> 02:55:45.920] But again, that's not FDA-approved.
[02:55:45.920 --> 02:55:49.600] That is something that compounding pharmacies would have to make for a physician.
[02:55:49.600 --> 02:55:55.120] In terms of FDA-approved products, you have oral estradiol, bio-identical.
[02:55:55.120 --> 02:56:01.520] We don't use it because, frankly, there's a small but non-zero increase in the risk of hypercoagulability.
[02:56:01.520 --> 02:56:03.440] It just doesn't seem like it's a risk worth taking.
[02:56:03.440 --> 02:56:16.400] Like, the only indication in my mind for oral estradiol is for women whose skin will not permit the absorption of any topical estradiol product.
[02:56:16.400 --> 02:56:20.240] Our preferred product is an estradiol patch.
[02:56:20.240 --> 02:56:22.000] We use the branded version.
[02:56:22.160 --> 02:56:27.040] Actually, when it comes to hormones, I really prefer using branded versions of an FDA-approved compound.
[02:56:27.040 --> 02:56:29.760] We prefer to use something called the Vivelle DOT.
[02:56:29.760 --> 02:56:33.120] So it's an FDA-approved estradiol patch.
[02:56:33.120 --> 02:56:34.800] A woman applies the patch.
[02:56:34.800 --> 02:56:42.480] You apply the, you know, the patch comes in different doses, and you can trim it if you want more or less estrogen, and she changes it like every three or four days.
[02:56:42.480 --> 02:56:46.720] So, you know, you'll put it on your lower back or your hip, butt, something like that, on your shoulder.
[02:56:46.960 --> 02:56:49.360] You just put it somewhere where it's not sort of intrusive.
[02:56:51.280 --> 02:56:54.640] By the way, we do notice variable absorption with sauna use.
[02:56:54.640 --> 02:57:00.440] So if the time ever comes for you to use it, we should discuss paying attention to different absorption rates.
[02:56:59.680 --> 02:57:04.440] But nevertheless, we don't have any issues with that.
[02:57:05.400 --> 02:57:12.280] There are ostroestrogen pellets that can be inserted in the sub-Q space or into the fat, really.
[02:57:12.280 --> 02:57:20.040] And they're also not FDA approved, but they're still used pretty liberally by physicians who know how to put them in.
[02:57:20.040 --> 02:57:22.120] I used to do this for my female patients.
[02:57:22.120 --> 02:57:23.480] I don't anymore.
[02:57:23.480 --> 02:57:30.280] I just tend to prefer the patch, truthfully, because it gives a more steady-state level dose of the estradiol.
[02:57:30.280 --> 02:57:32.280] And you can make adjustments easily.
[02:57:32.280 --> 02:57:33.640] With the pellets, you put it in there.
[02:57:33.640 --> 02:57:37.400] You got to wait five or six months before you figure it out again and decide what to do.
[02:57:37.400 --> 02:57:41.800] So those are basically the ways in which you would take estrogen in.
[02:57:41.800 --> 02:57:49.160] And as I said, progesterone, you would do either oral, micronized, bioidentical, or you would use a progesterone-coated IUD.
[02:57:49.160 --> 02:57:54.120] They also do make progesterone suppositories, but for most women, the compliance with that is low.
[02:57:54.120 --> 02:57:57.080] It's just messy and kind of inconvenient.
[02:57:57.560 --> 02:57:59.720] There's also topical estrogen products.
[02:57:59.720 --> 02:58:05.400] So you do have some women who say, look, I just do not want to take estrogen under any shape or form.
[02:58:05.400 --> 02:58:19.400] I don't want any, you know, I don't want any estrogen in my body, but these vasomotor, pardon me, these vaginal symptoms are problematic, then you can use vaginal estrogen cream or vaginal suppositories of estrogen.
[02:58:19.400 --> 02:58:24.680] Again, that won't give you any of the bone protection, that won't stop the night sweats or anything like that.
[02:58:24.680 --> 02:58:29.480] But using vaginal estrogen products alone will at least ameliorate the sexual side effects.
[02:58:29.800 --> 02:58:42.200] What about the difference between like multiphasic versus whatever the mono, like when you so like giving women estrogen in like more like their cycle versus like the same dose like all the time?
[02:58:43.440 --> 02:58:51.680] We we would we would kind of use we sometimes do multiphasic on progesterone in the transition of perimenopause.
[02:58:52.000 --> 02:58:54.400] We don't do it once women are fully in menopause.
[02:58:54.400 --> 02:58:57.440] When women are fully in menopause, we just sort of stay at the dose.
[02:58:57.440 --> 02:59:08.720] Again, the dose that a woman is on is a very low dose relative to her premenopausal levels as indicated by the FSH.
[02:59:08.720 --> 02:59:09.280] Do you go?
[02:59:09.280 --> 02:59:10.320] So that was another question.
[02:59:10.320 --> 02:59:12.560] Do you like let's in your mind?
[02:59:12.720 --> 02:59:33.200] Yeah, well like determined, let's say a woman is either premenopausal or perimenopausal, like I guess postmenopausal too, but determining like measuring your estrogen, measuring your progesterone, measuring your testosterone, when in this cycle to do it and what are the level, like what to you would say, okay, this woman's transitioning to perimenopause?
[02:59:33.840 --> 02:59:36.480] You know, is there a let like a threshold levels?
[02:59:36.480 --> 02:59:38.720] Yeah, we look at day five.
[02:59:38.720 --> 02:59:42.480] So if day one is the day the period starts, regardless, right?
[02:59:42.480 --> 02:59:45.920] Even if it's just a bit of spotting, whatever it is, like that's that's the starting point.
[02:59:45.920 --> 02:59:50.080] On day five, somewhere between day five and day seven, we just like to do it on day five.
[02:59:50.480 --> 02:59:53.440] You look at estradiol levels and FSH levels.
[02:59:53.440 --> 02:59:55.680] That is your canary in the coal mine.
[02:59:55.680 --> 03:00:05.120] As that FSH level on day five starts to climb and that estradiol will start to come down, but it's mostly the rise in FSH, that's how you know you're getting closer and closer to the cliff.
[03:00:05.120 --> 03:00:12.960] Now, there's actually some interesting data that's looking at AMH levels and anti-malarian hormone MRI.
[03:00:13.040 --> 03:00:16.880] So this is basically telling you how many eggs you have left, how many follicles you have left.
[03:00:16.880 --> 03:00:26.160] So, this is something that fertility docs are constantly looking at in women who are, you know, struggling with fertility or deciding if they can still do, you know, have kids or go through IVF.
[03:00:26.160 --> 03:00:36.280] So, there may be some also some insight that comes from AMH, but typically watching the rising FSH on day five is what's telling you this is coming.
[03:00:36.600 --> 03:00:38.360] And then, of course, you marry that to symptoms.
[03:00:38.360 --> 03:00:44.440] So, I typically do not treat women until they're symptomatic in perimenopause.
[03:00:44.440 --> 03:00:51.800] So, we'll look at their labs and I'll say, you know, Rhonda, look, you're getting closer to something.
[03:00:51.800 --> 03:00:53.320] Let's just be on guard for it.
[03:00:53.320 --> 03:00:58.840] And then, you know, maybe six months later, you'll say, all right, I'm having some hot flashes and night sweats.
[03:00:58.840 --> 03:01:00.040] Well, okay, good.
[03:01:00.440 --> 03:01:02.680] And you, by the way, you still may be ovulating.
[03:01:02.920 --> 03:01:05.560] You know, this can, this is what perimenopause looks like, right?
[03:01:05.560 --> 03:01:07.320] So to me, that's when you start treating.
[03:01:07.320 --> 03:01:09.800] And you can get away with much lower doses.
[03:01:10.760 --> 03:01:20.760] But the point I wanted to make is: once you're in full-fledged menopause, like we're only giving you enough estrogen to get your FSH down to about 25.
[03:01:21.080 --> 03:01:23.960] You now never have an FSH above 25.
[03:01:23.960 --> 03:01:28.680] So remember, FSH and estrogen work in opposition to each other.
[03:01:28.680 --> 03:01:32.520] So the lower your FSH, the higher your estradiol.
[03:01:32.840 --> 03:01:40.520] You right now, with your regular cycle, you've probably never seen an FSH above 12.
[03:01:40.520 --> 03:01:45.480] Just to give you a sense, at your lowest estrogen right now, your highest FSH is 12.
[03:01:45.480 --> 03:01:58.440] When you're in menopause, you're going to be managed to an FSH of about 25 to 35, which means your estradiol is going to be lower than it is at any point in your cycle today.
[03:01:58.440 --> 03:02:05.080] But that's sufficient to take care of all of your symptoms and preserve your bone density.
[03:02:05.720 --> 03:02:16.880] So, preserving bone, preserving bone density, obviously symptoms, but preserving bone density, also lowering cardiovascular risk, lowering Alzheimer's risk.
[03:02:14.760 --> 03:02:19.120] Alzheimer's is less clear, Rhonda.
[03:02:19.360 --> 03:02:31.040] The data right now suggests the following: late initiation of HRT may be counterproductive for AD risk, may actually increase AD risk.
[03:02:31.600 --> 03:02:38.960] Early initiation appears to potentially only be beneficial in E4 women, but not E3 women.
[03:02:38.960 --> 03:02:39.520] Okay.
[03:02:39.520 --> 03:02:46.480] So, for you, I would say doubly beneficial to initiate at the time of menopause because of your E4.
[03:02:46.480 --> 03:02:46.880] Got it.
[03:02:46.880 --> 03:02:47.920] That's really good to know.
[03:02:47.920 --> 03:02:54.880] And also, defining what is early and late, like, you know, so that, you know, there was a study, there's a couple of studies.
[03:02:54.880 --> 03:02:57.520] One was the elite study, and one was the DOPS.
[03:02:57.520 --> 03:03:02.400] So, like, I don't know, it was like early intervention for estradiol or something.
[03:03:03.200 --> 03:03:07.760] And then there was another one that was the Danish osteoporosis prevention study.
[03:03:07.760 --> 03:03:16.400] And both of those studies, in the DOPS one, the initiation of the, they did estradiol.
[03:03:16.400 --> 03:03:21.200] I think they did like triphasic or something, but also they did the progesterone.
[03:03:21.200 --> 03:03:22.720] So I had progesterone as well.
[03:03:23.200 --> 03:03:38.320] It was like the cardiovascular disease risk or mortality went down, the B venous thromboembulism, like the things that happen that can increase with menopause went down over the follow-up, which was 16 years or something.
[03:03:38.640 --> 03:03:48.080] But these women only took it for 11 years, and they started at age either between the age of 45 and 58.
[03:03:48.080 --> 03:03:51.800] So perimenopause is in there, and also just, you know, you know, a few years ago.
[03:03:52.160 --> 03:03:54.640] This is to me the biggest unknown question, Rhonda.
[03:03:54.640 --> 03:03:56.320] And we don't know the answer.
[03:03:56.320 --> 03:04:03.560] And what's what I find very frustrating is we're not going to know the answer because nobody's going to do the study.
[03:04:04.440 --> 03:04:17.560] I am as comfortable with anything in medicine as I am that initiating HRT at the time of menopause does not increase a woman's risk of heart disease, breast cancer, or anything else.
[03:04:17.560 --> 03:04:19.320] In fact, it reduces her risk.
[03:04:19.320 --> 03:04:23.240] It clearly reduces her risk of heart disease, dementia, and BMD.
[03:04:23.240 --> 03:04:26.840] And it's either protective or neutral on cancer.
[03:04:27.240 --> 03:04:28.040] It was neutral on cancer.
[03:04:28.440 --> 03:04:30.760] It's protective or neutral on cancer.
[03:04:30.760 --> 03:04:33.560] I am very confident of all of those things.
[03:04:33.560 --> 03:04:35.720] Here's the thing we don't know.
[03:04:36.040 --> 03:04:38.520] What do you do 10 years later?
[03:04:38.520 --> 03:04:40.440] What do you do when she's 60?
[03:04:40.440 --> 03:04:41.400] Right.
[03:04:41.720 --> 03:04:51.320] And again, if you look at the HRT data from the Women's Health Initiative with all of its flaws, the answer would be you should probably stop.
[03:04:51.640 --> 03:04:57.560] But again, that study is so flawed on so many levels that I'm not sure.
[03:04:57.560 --> 03:05:06.680] And here's where I would argue: there's one area where you absolutely know things will get worse when you stop the estrogen, and that's bone density.
[03:05:06.680 --> 03:05:09.720] So the other things are a little less clear to me.
[03:05:11.720 --> 03:05:25.160] There's some opacity around what will happen to cardiovascular disease risk, dementia disease risk, and cancer disease risk if you start appropriately initiated HRT after 10 or 15 years.
[03:05:25.160 --> 03:05:29.240] But what is unambiguously clear is her bones are going to get brittle again.
[03:05:29.240 --> 03:05:33.000] Because the moment you take the estrogen away, bone density goes down.
[03:05:33.000 --> 03:05:38.440] Estrogen is the most important hormone in men and women for the regulation of BMD.
[03:05:38.760 --> 03:05:46.080] It is the chemical transduction system that turns force into bone building.
[03:05:46.400 --> 03:06:00.000] So we have basically strain gauges in our bones that are sensing forces on the bones, and that force is being turned via estrogen into a chemical signal to osteoblast and osteoclast to promote bone building.
[03:06:00.000 --> 03:06:01.920] And once estrogen goes down, that goes away.
[03:06:01.920 --> 03:06:08.560] So if you take the estrogen off a woman 10 years post-menopause, she will once again go into a rapid state of decline.
[03:06:08.560 --> 03:06:14.800] Now, she's still better off because she'll still be further ahead than where she is if you put her in decline 10 years sooner.
[03:06:14.800 --> 03:06:24.480] So, you know, I've had arguments with people on the anti-HRT side, and they say, you should never use estrogen for treating BMD because we have bisphosphonates.
[03:06:24.480 --> 03:06:27.520] And I say, first of all, you only use bisphosphonates for three to five years.
[03:06:27.520 --> 03:06:31.120] Two, they suck, meaning they're not as good as estrogen.
[03:06:31.120 --> 03:06:34.960] And third, you can use estrogen for longer.
[03:06:34.960 --> 03:06:39.120] And they say, well, yeah, but once you take it off, it still goes down.
[03:06:39.120 --> 03:06:40.640] And it's like, yeah, but it's a new baseline.
[03:06:40.640 --> 03:06:41.120] And it's a high-tech.
[03:06:41.280 --> 03:06:42.240] It's like waiting to retire.
[03:06:42.240 --> 03:06:46.640] Like you're going to have more in your retirement fund if you retire at 70 versus 60.
[03:06:47.600 --> 03:06:48.880] This is the big question.
[03:06:48.880 --> 03:07:20.000] Because, I mean, and my, and again, we've done a back of the envelope calculation that would suggest even if the risk of Alzheimer's disease or heart disease or cancer, even if you lost any protection from HRT and maybe had a slight increase in risk, given how big their risk of falling is, you might still end up being neutral risk, carrying out HRT indefinitely.
[03:07:20.320 --> 03:07:22.400] So this is where, you know, the lifestyle factors.
[03:07:22.480 --> 03:07:23.680] Which is quality of life.
[03:07:23.680 --> 03:07:24.000] Right.
[03:07:24.240 --> 03:07:42.840] But this is probably where lifestyle factors do play somewhat of a role as well, because if you have, obviously, if you've been doing resistance training up until that point and continuing it, you're building not only bone, you've certainly built up a lot of bone density reserve earlier in life, but muscle mass helps, right?
[03:07:42.840 --> 03:07:51.400] And then let me throw this at you because I've thought a lot about the nuclear hormone, nuclear hormones, basically.
[03:07:51.800 --> 03:07:54.280] So vitamin D is the one that I've really focused on.
[03:07:54.280 --> 03:08:01.480] And when I was doing a lot of research on it, so nuclear hormones, you know, we have steroid hormones, nuclear steroid hormones, I should say, sorry.
[03:08:01.480 --> 03:08:04.120] So we have estrogen, testosterone, vitamin D is one.
[03:08:04.120 --> 03:08:09.720] So these are binding to a receptor that, you know, in some cases, the receptor complexes with other ones.
[03:08:09.720 --> 03:08:18.280] It goes into the nucleus of a cell, which is where all the DNA is, and it goes down to the level of genes and it recognizes a little sequence of genes.
[03:08:18.280 --> 03:08:21.800] So in the case of estrogen, it's called an estrogen response element, an ERE.
[03:08:21.800 --> 03:08:25.400] In the case of vitamin D, it's called a VDRE, vitamin D response element.
[03:08:25.720 --> 03:08:33.880] There's a lot of overlap between vitamin D and the estrogen in terms of the genes they're regulating.
[03:08:33.880 --> 03:08:48.360] And so I'm wondering if avoiding vitamin D deficiency also becomes one of those important lifestyle factors because in some cases, obviously vitamin D also plays a role in bone metabolism, right?
[03:08:48.680 --> 03:08:57.080] But independent of that, also just looking at the crosstalk of the genes that vitamin D and estrogen are regulate, and they're like, they're both.
[03:08:57.080 --> 03:09:05.560] And the response elements are, they're different, but they're somewhat, I'm looking at that and it's like, oh, I wonder if there's like, that seems like you might be able to compensate a little.
[03:09:05.560 --> 03:09:12.120] So it's kind of another interesting, in addition to being, you know, physically active, resistance training, one of the most important things, right?
[03:09:12.360 --> 03:09:14.120] But also, like, I did a lot of jump roping.
[03:09:14.120 --> 03:09:16.480] I was a star jump roper as a kid.
[03:09:14.840 --> 03:09:21.760] Lots and lots of jumping rope, which there is evidence that that also builds bone density.
[03:09:22.080 --> 03:09:23.440] So I want to ask you a question about this.
[03:09:23.440 --> 03:09:38.400] So, what do we know about the relationship between call it naturally acquired vitamin D through sunlight versus supplementation of vitamin D exogenously through a supplement?
[03:09:38.880 --> 03:09:44.000] Do we have any reason to believe that those are different at the same level of vitamin D?
[03:09:44.320 --> 03:09:47.840] In the same, like in terms of like how vitamin D is acting.
[03:09:47.840 --> 03:09:51.520] So the thing is, is that when you're in sunlight, like there's other things going on.
[03:09:51.760 --> 03:09:52.560] Right, that's my point.
[03:09:52.560 --> 03:09:55.120] Like if you're outsourcing sunlight, you're more active.
[03:09:55.120 --> 03:09:56.240] And you're nitric oxide.
[03:09:56.240 --> 03:09:59.760] Like there's like other things that you're getting from the sunlight.
[03:09:59.760 --> 03:10:01.840] So there's a confounder there.
[03:10:02.000 --> 03:10:16.960] But I mean, like with respect to, let's say, forget every, like, let's say you finally, you, you convert the vitamin D3 into the 25-hydroxy vitamin D into the 125, you know, at that level, it's, it is the same, like, you know, to some degree.
[03:10:16.960 --> 03:10:28.000] I mean, that's not, when it's, when it's binding to the vitamin D receptor, like the actual 125 hydroxy vitamin D, which is the active steroid hormone, it's the same.
[03:10:28.800 --> 03:10:39.600] Now, with respect to like, you know, your body regulates how much vitamin D3 is converted or is released in the bloodstream and converted into 25 hydroxy vitamin D at the level of sun exposure.
[03:10:39.600 --> 03:10:44.000] So at a certain level, you're not making the vitamin D3 when you've gotten so much of it.
[03:10:44.000 --> 03:10:45.760] That's how you avoid toxicity, right?
[03:10:45.760 --> 03:10:47.440] Like you're not, you're not going to keep.
[03:10:47.600 --> 03:10:51.440] Yeah, what's the highest level of vitamin D a person can ever get to naturally?
[03:10:51.440 --> 03:11:00.680] Meaning, if you just like took an individual and put them in the sun, put, you know, shorts only, no shirt, go out there and work in the sun for all summer.
[03:11:00.840 --> 03:11:01.480] Like, how high?
[03:11:01.480 --> 03:11:05.560] Like, how high were my vitamin D levels when I was in high school working construction?
[03:11:05.560 --> 03:11:22.440] I know, I, I, I know there's like data out there where people have looked at like, you know, you know, people that are that are like out in the they're out they're outside all the time, but they're all they're honestly often looking at people like in the tropics and stuff that have more melanin.
[03:11:22.680 --> 03:11:23.160] Yeah, yeah.
[03:11:23.160 --> 03:11:26.840] Yeah, which again, so it might depend also on that.
[03:11:27.000 --> 03:11:36.200] But that would be an interesting at least way to say, like, if the body has a built-in mechanism to say, I'm not going to let you make more vitamin D than this, supplementing above that would be a bad idea.
[03:11:36.200 --> 03:11:36.920] And it is, yeah.
[03:11:36.920 --> 03:11:40.680] Like, and so that's why looking at measuring that threshold is.
[03:11:41.720 --> 03:11:46.440] I think going above 60 nanograms per milliliter is probably still okay.
[03:11:46.440 --> 03:11:54.600] Like going to 80, you know, like there's studies looking at 80 and it's still associated with lower all-cause mortality.
[03:11:55.400 --> 03:12:04.680] And in fact, I mean, honestly, if you start to look at some of the literature, you have to take a really high dose daily for like a decade to start getting like the high calcium.
[03:12:04.680 --> 03:12:16.280] But like the problem is that when you absorb, when you have a lot of vitamin D, you absorb more dietary calcium and you also absorb more phosphorus and calcium plus phosphorus can precipitate, right?
[03:12:16.280 --> 03:12:22.040] And so like there's so many factors involved, but I think most people are not supplementing.
[03:12:22.040 --> 03:12:29.560] Like there's some people that are crazily supplementing and it's like they just think more of everything is good, but I don't think most people are doing that.
[03:12:29.560 --> 03:12:33.200] Like I don't think taking 5,000, 7,000 IEs, for most people.
[03:12:33.200 --> 03:12:35.640] Some people have to take more than that because they have SNPs, right?
[03:12:35.640 --> 03:12:40.520] And you've probably seen it in your patients where it's like, they got to take a high level just to get up to 30 or 40.
[03:12:41.000 --> 03:12:52.720] This, by the way, is why I think all these vitamin D trials, the mega trials, are so flawed: they're always doing it on the basis of A, they're taking too low a dose and they're doing it based on dose, not level.
[03:12:52.880 --> 03:13:06.320] Like to me, the dispositive study on this would be: take a whole bunch of people whose vitamin D is 30, give half of them a placebo, give half of them whatever vitamin D is necessary to get them to 60 or 80.
[03:13:06.320 --> 03:13:07.520] 80, yeah, get something higher.
[03:13:07.520 --> 03:13:08.960] Yeah, create separation.
[03:13:10.160 --> 03:13:12.560] But be like, do it the way we do blood pressure trials.
[03:13:12.560 --> 03:13:16.160] When we do a blood pressure trial, we don't say you're going to take a fixed dose of a med.
[03:13:16.160 --> 03:13:19.920] We give you whatever dose of the med is necessary to change the blood pressure.
[03:13:19.920 --> 03:13:28.240] So we're comparing two blood pressure levels, not placebo versus 10 milligrams of a drug that for one guy is too much and for one guy is too little.
[03:13:28.240 --> 03:13:39.040] And yet this isn't done in vitamin D, and I find it infuriating that we have no really good, reliable RCT data on what seems like a juggular question.
[03:13:39.040 --> 03:13:43.920] Are you better off with a vitamin D level of 80 than you are of 30?
[03:13:43.920 --> 03:13:55.840] I mean, again, we think the answer is yes, but the evidence-based medicine crowd will tell you no, because this trial that gave people 2,000 IU for 10 minutes found no difference.
[03:13:55.840 --> 03:13:56.160] Right.
[03:13:56.160 --> 03:14:02.000] Or they measured maybe, if they measured anyone's level, they measured like 10% of the population.
[03:14:02.000 --> 03:14:02.400] Yes, exactly.
[03:14:02.480 --> 03:14:03.680] Like the most recent study.
[03:14:03.680 --> 03:14:05.600] We only got a level on 10% of people.
[03:14:06.080 --> 03:14:09.840] With like, you know, the fact of the matter is so many people do have these SNPs too.
[03:14:10.160 --> 03:14:12.720] And I remember having an email dialogue with Joanne Manson.
[03:14:12.720 --> 03:14:14.400] This was years ago when I was postdoc.
[03:14:14.400 --> 03:14:17.200] And she was, I think at the time, she was doing the vital study.
[03:14:17.200 --> 03:14:18.240] It hadn't been published yet.
[03:14:18.240 --> 03:14:22.880] And it was like, please, please, can you get the SNP data in there?
[03:14:22.880 --> 03:14:24.320] Can you measure the levels?
[03:14:24.320 --> 03:14:28.000] Like, do everything, you know, like, it's so important.
[03:14:28.160 --> 03:14:29.120] But I'm with you on that.
[03:14:29.440 --> 03:14:31.800] I think what is clear is avoiding deficiency.
[03:14:31.800 --> 03:14:32.760] And I do say that a lot.
[03:14:33.160 --> 03:14:34.040] And where are you drawing the line?
[03:14:34.280 --> 03:14:35.640] Is 30 or 40 where you?
[03:14:29.840 --> 03:14:36.360] I say 30.
[03:14:36.600 --> 03:14:43.560] I mean, it does depend on: are you looking at what the Endocrine Society says is more of an adequate level or inadequate?
[03:14:43.640 --> 03:14:50.680] Are you looking at deficiency where you're like literally your bone health isn't good?
[03:14:51.960 --> 03:14:54.600] But for me, I want to know the same thing.
[03:14:54.760 --> 03:14:58.920] I'm always kind of like hovering around 50, 60, but I'm like, should I be at 80?
[03:14:58.920 --> 03:14:59.320] Yeah.
[03:14:59.800 --> 03:15:01.480] And I don't know.
[03:15:01.640 --> 03:15:04.040] So it's always like, okay, well, I'll err on the side of caution.
[03:15:04.360 --> 03:15:05.320] Err on the side of caution.
[03:15:05.320 --> 03:15:06.760] Certainly avoiding deficiency.
[03:15:07.640 --> 03:15:25.320] But even with respect to all these genes I'm talking about, what if there's some crosstalk with there is crosstalk, but what if there's some way that having a level of vitamin D, 50 or 60 nanograms per milliliter, does help alleviate some of the effects of having no estrogen?
[03:15:25.800 --> 03:15:26.520] We don't really know.
[03:15:26.520 --> 03:15:27.320] That's interesting.
[03:15:27.400 --> 03:15:29.320] It is, especially when you look at the mechanism.
[03:15:29.320 --> 03:15:41.000] And like I said, I spent a lot of time looking at these response elements and looking at the fact that estrogen can actually compensate for vitamin D deficiency in some cases with certain genes too.
[03:15:41.000 --> 03:15:42.120] And it goes both ways.
[03:15:42.120 --> 03:15:48.040] So I'm like, well, I feel like that should be an important component in the equation, right?
[03:15:48.840 --> 03:15:50.120] But I'm with you on the 10.
[03:15:50.120 --> 03:16:05.800] Like, even the studies I was talking about where there was protective effects against, you know, in the cardiovascular health, in cancer prevention with hormone replacement therapy, when initiated, like, you know, within a close range, like not greater than six years.
[03:16:05.800 --> 03:16:06.760] So it's six years or less.
[03:16:06.760 --> 03:16:10.120] So if you're doing it seven years, that's not part of the study.
[03:16:10.440 --> 03:16:12.840] They only did it for like 10 or 11 years and they stopped.
[03:16:13.400 --> 03:16:17.040] And it's like, well, what happens then when you're 65?
[03:16:17.040 --> 03:16:23.600] And if you started at 55, you know, like, so we don't know the question to that, I mean, the answer to that either.
[03:16:24.240 --> 03:16:25.680] But I'm happy that you're thinking about it.
[03:16:25.920 --> 03:16:26.080] So.
[03:16:26.320 --> 03:16:33.120] Oh, you know, one thing maybe even before we go to male hormones that I didn't mention on the female side was testosterone.
[03:16:33.600 --> 03:16:39.360] And this is, you know, I mentioned earlier, of course, the abundance of testosterone in a woman prior to menopause.
[03:16:39.360 --> 03:16:47.680] But what's far less studied is the impact of testosterone replacement in women post-menopause.
[03:16:47.680 --> 03:16:50.000] And this is something that is being studied.
[03:16:50.960 --> 03:17:00.240] So by the time this podcast comes out, there'll be a couple of podcasts I've released on the topic of sexual health, but through the lens of both male and female.
[03:17:00.400 --> 03:17:05.040] So Sharon Parrish and Mo Cara will be the two folks that I've discussed with on that.
[03:17:05.040 --> 03:17:08.080] And Mo's actually involved, he's at Baylor in Texas.
[03:17:08.080 --> 03:17:15.600] He's involved in a study that is looking at the use of testosterone replacement in women for sexual function.
[03:17:15.600 --> 03:17:27.040] So both Mo and Sharon talk extensively about the importance of testosterone in sexual function, specifically around libido and orgasmic function, along with arousal.
[03:17:27.040 --> 03:17:33.520] So this is like, I mean, I've said this before, you know, I said it, I think, to them on the podcast.
[03:17:33.520 --> 03:17:38.240] It's rare that I go into a podcast with so little information on a topic.
[03:17:38.240 --> 03:17:43.200] Usually I like, you know, like you, like, you know all the answers to the questions you're asking me because you've prepared for it, right?
[03:17:43.200 --> 03:17:48.240] But, you know, usually when I'm going into a podcast, I kind of know what's going on.
[03:17:48.240 --> 03:17:53.680] But I was blown away in my discussions with Mo and Sharon on these topics.
[03:17:53.680 --> 03:18:03.800] So the long and short of it is we have become much more liberal in our use of testosterone in women for any sort of sexual side effects.
[03:18:04.120 --> 03:18:12.200] Also, keep in mind, we've talked about it, but the importance of maintaining muscle mass as you age is imperative, just as imperative for women as it is for men.
[03:18:12.200 --> 03:18:14.520] And testosterone is the dominant hormone there.
[03:18:14.520 --> 03:18:19.240] So again, when people hear this, they kind of think, what are we talking about, like anabolic steroids?
[03:18:19.240 --> 03:18:21.880] And it's like, well, yeah, testosterone is an anabolic steroid.
[03:18:21.880 --> 03:18:26.440] What we're talking about is replacing women to the levels that they were at in their 30s and 40s.
[03:18:26.440 --> 03:18:37.000] These are very, very low levels of testosterone, typically about one-tenth the dose that men take to also have a physiologic replacement.
[03:18:37.000 --> 03:18:41.080] And that's about 1/10th the level that bodybuilders would take.
[03:18:41.080 --> 03:18:48.680] So we're not talking about huge amounts of testosterone, but just restoring someone to physiologic levels can have profound impacts.
[03:18:48.680 --> 03:18:54.120] But is that in combination with also giving these women the estrogen progesterone?
[03:18:54.360 --> 03:18:58.600] Because what would happen if you just were doing the testosterone?
[03:18:58.600 --> 03:19:07.000] And let's say a woman was 10 years out, missed the whole window.
[03:19:09.240 --> 03:19:13.560] And this is something that people have asked me: what do I do?
[03:19:13.560 --> 03:19:20.680] Like, how do I, you know, get some benefits, you know, without actually taking, you know, estrogen and progesterone?
[03:19:20.920 --> 03:19:22.280] Would you also give that person?
[03:19:22.520 --> 03:19:23.800] So there's two questions here.
[03:19:23.800 --> 03:19:24.760] There are, yeah.
[03:19:25.560 --> 03:19:26.360] Great question.
[03:19:28.040 --> 03:19:29.560] We handle each of those.
[03:19:29.560 --> 03:19:31.960] I hate to say this because it sounds like such an obvious cliche.
[03:19:31.960 --> 03:19:34.440] We handle each of those on a case-by-case basis.
[03:19:34.760 --> 03:19:37.240] So I won't sugarcoat it.
[03:19:37.240 --> 03:19:42.920] Like, we're not very comfortable doing, initiating HRT in women who are 10 years out.
[03:19:42.920 --> 03:19:52.800] But at the same time, we realize there are a lot of women who are 60 today who went through menopause at the height of the stupidity around the WHI.
[03:19:52.800 --> 03:19:58.720] And as a result of that, like they're worse off today than they would have been had they been on the appropriate hormones 10 years ago.
[03:19:58.720 --> 03:20:03.360] And we have to make a very difficult decision about whether it's worth additional risk.
[03:20:03.360 --> 03:20:06.720] And I say that because we don't know what the risk is.
[03:20:07.360 --> 03:20:19.120] And so the way we handle that is we basically try to figure out what is your risk of AD, ASCBD, and cancer, specifically breast cancer, as it stands now.
[03:20:19.440 --> 03:20:36.880] And, you know, for example, if a woman is especially high risk for one of those things, particularly AD, if she's a 3-3 or even a 3-4-4-4, and/or if she's very high risk of breast cancer, we might be a little bit more reluctant to do so.
[03:20:37.200 --> 03:20:44.000] Or if we do it, we do it at an even lower dose than we normally would, and we have to increase our surveillance around those things.
[03:20:44.320 --> 03:20:46.400] So not an easy question.
[03:20:46.400 --> 03:20:54.000] To your other question, would we be comfortable using testosterone in isolation without opposition?
[03:20:54.640 --> 03:21:00.720] I would say at this point, I'm not, I'm not, I don't think I know the answer to that question yet.
[03:21:01.360 --> 03:21:07.280] And I think that that's something that would need further study before we could sort of make a clear recommendation.
[03:21:07.920 --> 03:21:14.720] In the cases of the, in your clinical practice, you're handling the hormone replacement therapy.
[03:21:14.880 --> 03:21:16.480] Is testosterone part of that equation?
[03:21:16.480 --> 03:21:19.080] Or do you ask, is it like a more of a symptom thing?
[03:21:19.080 --> 03:21:24.920] Like my libido is down, even though I'm also on estrogen with it's not a standard.
[03:21:25.120 --> 03:21:27.120] Yeah, it's not, nothing is standard, right?
[03:21:27.120 --> 03:21:28.320] Everything is bespoke.
[03:21:28.320 --> 03:21:31.560] And I think that that's just really important for anybody listening to this, right?
[03:21:31.560 --> 03:21:35.560] It's like you don't want to go to somebody who's does paint by numbers.
[03:21:29.840 --> 03:21:37.240] You know, paint by numbers is a bad approach.
[03:21:37.400 --> 03:21:38.760] Everybody's on this, everybody's on that.
[03:21:38.760 --> 03:21:39.400] No, no, no.
[03:21:39.400 --> 03:21:43.480] It's like, you know, some women do not absorb testosterone very well.
[03:21:43.480 --> 03:21:47.320] Pardon me, do not absorb estrogen very well from a cream.
[03:21:47.320 --> 03:21:50.680] Some, you know, might end up requiring to take it orally.
[03:21:50.680 --> 03:21:54.200] Some much prefer a cream, some prefer a patch.
[03:21:54.200 --> 03:21:57.960] Some can tolerate, some only need this dose, some need that dose.
[03:21:57.960 --> 03:22:00.360] Some need a very small amount of oral progesterone.
[03:22:00.360 --> 03:22:05.800] You do need at least 100 milligrams to oppose the estrogen at the endometrial level.
[03:22:05.800 --> 03:22:09.000] So somewhere between 100 and 200 is probably necessary.
[03:22:09.000 --> 03:22:11.800] Some can't tolerate it at all, and you have to use the IUD.
[03:22:11.800 --> 03:22:14.680] When it comes to testosterone, there's lots of ways to deliver it, right?
[03:22:14.680 --> 03:22:20.200] So one of the most interesting ways that's being studied now is using an FDA-approved product.
[03:22:20.200 --> 03:22:31.480] It's not approved for this use, so it's called Natesto, and it's an intranasal testosterone spray that is FDA-approved for male use for testosterone replacement therapy.
[03:22:32.440 --> 03:22:34.120] But it's being used off-label.
[03:22:34.120 --> 03:22:38.120] It's also being tested in a clinical trial for libido in women.
[03:22:38.120 --> 03:22:39.800] It has a higher acting.
[03:22:39.800 --> 03:22:46.360] So another point to think about here is where the testosterone, where the androgen receptors are, factors into it.
[03:22:46.360 --> 03:22:59.480] So the intranasal testosterone probably is more rapid acting in terms of sex drive and libido, whereas the intravaginal testosterone for women increases orgasmic function.
[03:22:59.480 --> 03:23:06.120] So even the way in which you use testosterone can impact function and what your indication is.
[03:23:07.400 --> 03:23:14.840] And a question I have is, well, one of the questions I had regarding men had to do with the types of testosterone you're administering.
[03:23:15.040 --> 03:23:25.120] But taking a step back, you hear a lot about low T, low T, and there's this controversy around it.
[03:23:25.120 --> 03:23:26.720] Like, what defines low T?
[03:23:26.720 --> 03:23:27.840] Is it a level?
[03:23:27.840 --> 03:23:30.480] Is it a combination of levels and symptoms?
[03:23:31.200 --> 03:23:37.600] So, how are, like, we're looking at menopause in women, we're talking about an average age of about 51 or something like that, right?
[03:23:38.240 --> 03:23:43.360] Men, let's take the same period of life from men, okay, 50s.
[03:23:43.680 --> 03:23:46.960] Do they start to experience like a decrease in testosterone?
[03:23:47.440 --> 03:23:51.680] Yeah, but it's more gradual, and it starts, frankly, in your 20s and 30s.
[03:23:52.320 --> 03:23:58.720] So, male testosterone probably peaks in the 20s, and it's just a slow, steady decline.
[03:23:59.760 --> 03:24:08.800] It's not like in the case of women where they, you know, they go through puberty, they have these hormones that are cyclical, and then fall off a cliff.
[03:24:08.800 --> 03:24:14.320] With men, it's sort of you go through puberty, you kind of peak, and then you're on a slow decline down.
[03:24:14.640 --> 03:24:16.480] So, you're right.
[03:24:16.480 --> 03:24:29.360] Low T is really a combination of levels and symptoms, and it's really important to remember that symptoms matter because levels are really, well, how can I put it delicately?
[03:24:29.360 --> 03:24:33.520] I mean, just not as helpful as we'd like to believe they are.
[03:24:33.840 --> 03:24:36.720] And it actually comes back to something you talked about a minute ago, right?
[03:24:36.720 --> 03:24:39.760] Which is how do these hormones work?
[03:24:39.760 --> 03:24:51.680] These hormones work by binding to androgen receptors, and the testosterone-androgen receptor complex has to make its way into the nucleus where it impacts transcription factors.
[03:24:51.680 --> 03:25:01.640] Now, we know that not all men have the same density of androgen receptors, and we know that not all androgen receptors function in the exact same way.
[03:25:01.640 --> 03:25:09.960] So, we have this problem, which is we sit here and we measure testosterone levels in men, and maybe we measure bioavailable or free testosterone, but those are just estimates.
[03:25:09.960 --> 03:25:13.640] They aren't actually telling you free testosterone level.
[03:25:13.880 --> 03:25:18.600] You're measuring total testosterone, you're measuring sex hormone binding globulin, you're measuring albumin.
[03:25:18.600 --> 03:25:28.760] You use those to estimate the free amount of testosterone, but that's still an estimate, kind of like LDLC calculated by the Friedwald formula is an estimate.
[03:25:28.760 --> 03:25:36.440] And then you sort of have to guess: well, maybe their androgen receptors are saturated, maybe they're not.
[03:25:36.440 --> 03:25:54.600] But if you're giving a guy testosterone in the presence of mild to low T, you're assuming his androgen receptors are not saturated, and therefore giving him more testosterone will lead to an increased saturation of the AR and will lead to more nuclear transcription.
[03:25:54.600 --> 03:25:57.160] But we have no way of measuring that.
[03:25:57.160 --> 03:26:07.960] And so, what I always say to patients is: I got to see a certain set of symptoms in combination with a biochemical set of labs that makes sense.
[03:26:07.960 --> 03:26:13.320] And then we have to test it out, but it's not going to be a placebo test, so we're going to have a placebo effect.
[03:26:13.320 --> 03:26:22.360] And then, if the response we see isn't a hell yes, I think we should pull it all off and see if we notice a response in the deficit.
[03:26:22.360 --> 03:26:24.520] And I'm looking for symptoms as follows, right?
[03:26:24.520 --> 03:26:27.080] So, I'm looking for some signs and some symptoms.
[03:26:27.080 --> 03:26:28.440] Most of it is symptoms.
[03:26:28.440 --> 03:26:33.160] So, it's reduction in libido, reduction in energy, mood.
[03:26:33.480 --> 03:26:43.400] And then, on the signs, we're kind of looking for insulin resistance, difficulty putting on muscle mass, and difficulty recovering from exercise.
[03:26:43.400 --> 03:26:45.760] Those are kind of your big ones.
[03:26:44.760 --> 03:26:51.920] And some combination of those signs and symptoms, coupled with a biochemical story that's plausible.
[03:26:52.240 --> 03:27:03.280] So, you know, your total testosterone might be below the 30th percentile or even 40th percentile, and your free is commensurate with that, even though, again, that's an estimate.
[03:27:03.280 --> 03:27:06.320] There's probably reason in my book to initiate.
[03:27:07.600 --> 03:27:12.080] And is there a level that you decide to go to?
[03:27:12.080 --> 03:27:15.920] Like, so, I mean, is there like a threshold where it's like, this is too much testosterone?
[03:27:16.080 --> 03:27:19.040] Yeah, it's actually kind of like what we were talking about on the vitamin D front.
[03:27:19.040 --> 03:27:21.360] Like, don't be too incremental.
[03:27:21.360 --> 03:27:22.640] You're not going to get the answer.
[03:27:22.640 --> 03:27:32.080] So, if, and again, each lab is going to have different scales, but in the lab, we use the fifth percentile of total testosterone.
[03:27:32.080 --> 03:27:36.240] Well, let's do free testosterone because we actually, even though free is an estimate, we kind of look more closely at free.
[03:27:36.240 --> 03:27:45.520] So, approximately the fifth percentile is five nanograms per deciliter, and the 95th percentile is about 24 nanograms per deciliter.
[03:27:45.520 --> 03:27:48.160] So, call it five to 25, basically.
[03:27:48.480 --> 03:27:58.640] So, if a guy is at eight and we have the case to make that he's going to, we should try TRT, I'm not going to take him to 12.
[03:27:58.640 --> 03:27:59.760] It's incremental.
[03:27:59.760 --> 03:28:04.240] Like, I'm going to take him from eight to 20 and see if something matters.
[03:28:04.320 --> 03:28:21.440] And if he says to me at 20, I don't feel any different, and we take it away and he says, I don't feel any different, unless we were only treating this for insulin resistance and muscle mass, those were the only things, in which case I would say we still say the course and see if those things get better.
[03:28:21.440 --> 03:28:36.360] But if he, you know, if we were doing this because there was, you know, some of the other actual symptoms, then I would say that, look, this guy might have been already saturated at eight nanograms per deciliter where he started, and all that additional testosterone may have done him no good.
[03:28:36.680 --> 03:28:45.640] Whereas somebody else might have been woefully under saturated, and when you increased him by 150%, you actually got benefit from it.
[03:28:45.960 --> 03:28:50.040] Does the like injection versus like a gel, does that matter?
[03:28:50.760 --> 03:28:53.480] We're very biased towards injections.
[03:28:53.720 --> 03:28:56.040] I think they're far more consistent.
[03:28:56.840 --> 03:29:02.680] I think you have variable absorption, and it doesn't just vary by individual, it varies by time of day.
[03:29:02.680 --> 03:29:12.360] So, you know, for example, like if you're if you just finished a workout and you're sweating and you even if you go and have a shower, you're still kind of in a less absorptive state than maybe if you're cold.
[03:29:13.320 --> 03:29:15.720] You know, what part of your body do you put it on?
[03:29:15.720 --> 03:29:17.640] Do you have to exfoliate the skin first?
[03:29:17.640 --> 03:29:19.000] Do you have hair on the skin?
[03:29:19.000 --> 03:29:21.800] You know, you want to put it on an area that doesn't have hair.
[03:29:21.800 --> 03:29:23.400] There's just more issues with it.
[03:29:23.960 --> 03:29:26.760] So we recommend an injection.
[03:29:26.760 --> 03:29:33.400] We also recommend instead of doing it every two weeks, which is standard, doing it twice a week at obviously a much lower dose.
[03:29:33.400 --> 03:29:38.600] So typical dose would be somewhere between 80 and 100 milligrams of testosterone a week.
[03:29:38.600 --> 03:29:42.040] So it would be 40 to 50 milligrams twice a week.
[03:29:42.040 --> 03:29:47.720] And that produces just a much more steady level because you're really trying to get the steadiest level possible.
[03:29:47.720 --> 03:30:00.520] And the problem with doing it every two weeks, which was usually done in the days when people would go to their doctor to get the injection and you wanted to minimize the inconvenience of that, you're just supra physiologic for four or five days.
[03:30:00.520 --> 03:30:05.240] Then you're kind of physiologic, and then you're actually backed down to being very sub-physiologic before the dose.
[03:30:05.240 --> 03:30:06.360] So we'd like to avoid that.
[03:30:06.760 --> 03:30:12.600] Is there any, like, what's the relationship between testosterone replacement therapy and like the prostate?
[03:30:13.320 --> 03:30:14.480] Yeah, very well studied.
[03:30:14.720 --> 03:30:16.960] So a couple things we know as clear as day, right?
[03:30:14.280 --> 03:30:21.520] So we know that the lower the testosterone, the higher the risk of high-grade prostate cancer.
[03:30:14.680 --> 03:30:27.600] So again, contrary to popular belief, testosterone replacement therapy does not increase the risk of prostate cancer.
[03:30:28.880 --> 03:30:33.600] But what it does do is potentially increase BPH, benign prostatic hypertrophy.
[03:30:33.600 --> 03:30:36.560] So it does increase the size of the prostate potentially.
[03:30:36.880 --> 03:30:39.280] So one needs to be mindful of that.
[03:30:39.280 --> 03:30:41.520] And also, there are side effects of testosterone, right?
[03:30:41.520 --> 03:30:50.160] It will drive hair loss in an individual who's susceptible to hair loss through the sort of androgen pathways there.
[03:30:50.480 --> 03:30:53.120] It can increase acne in a susceptible individual.
[03:30:53.120 --> 03:31:02.160] Again, these things are typically more the type of side effects that people talk about when testosterone is being used in supraphysiologic levels.
[03:31:02.160 --> 03:31:11.040] So I'm just trying to think the last time we saw a patient who had acne, I'll probably see it once a year.
[03:31:11.600 --> 03:31:14.320] So these are really infrequent side effects.
[03:31:14.480 --> 03:31:18.000] But we do have a lot of patients who are concerned about hair loss.
[03:31:18.000 --> 03:31:23.040] And so we say, look, I mean, there are strategies around that.
[03:31:23.040 --> 03:31:26.400] Of course, you can take a 5-alpha reductase inhibitor.
[03:31:26.560 --> 03:31:32.320] So those are drugs that block the conversion of testosterone to dihydrotestosterone, which is a more potent androgen.
[03:31:32.320 --> 03:31:36.480] And that's the androgen that's driving androgen-specific hair loss.
[03:31:38.400 --> 03:31:40.720] Or they might say, you know, like I've had patients say, oh, you know what?
[03:31:40.720 --> 03:31:45.120] Like my hair matters more to me than my testosterone, and I don't want to testosterone.
[03:31:45.840 --> 03:31:48.560] So, those are the things that we just kind of want to point out.
[03:31:49.200 --> 03:32:04.760] The only other thing that's worth noting is I do believe that in a susceptible individual, in the short run, there's probably a slight increase in their risk of cardiovascular events with testosterone, and it's probably borne through an increase in blood pressure.
[03:32:05.080 --> 03:32:12.760] So, there was a very large study that looked at kind of high-risk men, and they were given testosterone.
[03:32:12.760 --> 03:32:22.440] And at one year post-initiation of TRT, there was a slight increase in the risk of major adverse cardiac events in the testosterone group compared to the placebo group.
[03:32:22.440 --> 03:32:33.560] That vanished at two and three years, almost suggesting that the highest-risk men, probably those that were closest to having an event, were actually pushed over the edge a little bit.
[03:32:33.560 --> 03:32:39.480] Again, I would probably attribute that to an increase in blood pressure as the thing that was potentially driving it.
[03:32:39.480 --> 03:32:46.920] So, you know, we're not keen to put guys on testosterone until we have the house in order with respect to everything else.
[03:32:47.480 --> 03:32:50.840] What sort of blood pressure do you, like, levels do you like to?
[03:32:51.080 --> 03:32:52.280] We're very aggressive, right?
[03:32:52.280 --> 03:33:01.560] I mean, if you look at the sprint trial, I think it's very clear that 120 over 80 or better is the place to be, and that's better than 130 over 85, which used to be the standard.
[03:33:01.560 --> 03:33:02.600] For hypertension, right?
[03:33:02.600 --> 03:33:03.160] That's right.
[03:33:03.480 --> 03:33:03.960] Okay.
[03:33:03.960 --> 03:33:05.880] So, we're very aggressive.
[03:33:06.360 --> 03:33:17.800] The good news with blood pressure, unlike the lipid, you know, we spent a lot of time talking about lipids, and a listener may come away from that thinking, okay, there's some dietary stuff, but you guys didn't talk about exercise, and you're right.
[03:33:17.800 --> 03:33:19.560] Exercise doesn't move lipids that much.
[03:33:19.560 --> 03:33:24.040] Like, you're going to be, you're heading down the path of pharmacology much sooner on the lipid front.
[03:33:24.040 --> 03:33:32.120] But blood pressure is just as big a risk factor for cardiovascular disease as lipids, and it's way more amenable to, I hate the word, but lifestyle intervention.
[03:33:32.120 --> 03:33:36.600] You know, losing weight and exercising will fix a lot of people's blood pressure.
[03:33:36.600 --> 03:33:37.480] Not everybody.
[03:33:37.480 --> 03:33:44.440] We have some very lean, fit, healthy people in our practice who still have essential hypertension, and it has to be lowered pharmacologically.
[03:33:44.440 --> 03:33:54.560] But for many people, losing 20 pounds and exercising, especially cardio, is going to do amazing things on their blood pressure.
[03:33:54.560 --> 03:34:00.960] Have you looked at, so I have a relative who exercises, good diet.
[03:34:00.960 --> 03:34:06.320] Like the only thing that lowers her blood pressure is hot tubs.
[03:34:06.560 --> 03:34:07.200] Interesting.
[03:34:07.200 --> 03:34:08.400] In addition to the exercise.
[03:34:08.400 --> 03:34:08.880] Interesting.
[03:34:08.880 --> 03:34:13.200] And it's like very, she's also a very high stress, like so she's, which is obviously.
[03:34:13.520 --> 03:34:14.800] I wonder if, it's funny.
[03:34:14.800 --> 03:34:24.800] I wonder if it's the impact of, you know, whether it be sauna or hot tub on hypercortisolemia that might be having the indirect effect on blood pressure.
[03:34:24.800 --> 03:34:27.120] Because she is absolutely prone to high cortisol.
[03:34:27.360 --> 03:34:28.800] She's like, it's a very high stress.
[03:34:28.800 --> 03:34:34.560] And the other thing is, you know, so Dan, he also, I mean, he exercises a lot.
[03:34:34.880 --> 03:34:36.480] Like we have the same diet.
[03:34:37.040 --> 03:34:42.560] My blood pressure, I mean, like, I've got phenomenal blood pressure, like always, always, I mean, like, really low.
[03:34:42.560 --> 03:34:46.640] Like, I'm actually on the side of like, I need to make sure I'm not like too low.
[03:34:46.640 --> 03:34:46.800] Yeah.
[03:34:47.760 --> 03:34:54.320] But he, at times, like, when measuring it at home, by the way, people at home should just get an automated cuff, right?
[03:34:54.320 --> 03:34:55.440] I mean, like, absolutely.
[03:34:55.440 --> 03:34:56.240] I mean, it's just yeah.
[03:34:56.240 --> 03:35:01.040] And then when you finish this story, I'll walk through to make sure everybody's measuring correctly because it's very important.
[03:35:01.280 --> 03:35:02.240] Yes, please do.
[03:35:03.280 --> 03:35:06.080] He has hemochromatosis.
[03:35:06.080 --> 03:35:06.480] Okay.
[03:35:06.800 --> 03:35:11.840] And there's some other relatives that had it and noticed that their blood pressure was high.
[03:35:12.000 --> 03:35:17.440] Like we're talking people that are like very physically doing lots of these are like running marathons.
[03:35:17.440 --> 03:35:20.000] They're doing, you know, like they're very, super healthy.
[03:35:20.000 --> 03:35:25.120] And donating blood seemed to help normalize the blood pressure for whatever reason.
[03:35:25.120 --> 03:35:25.520] I don't know.
[03:35:26.080 --> 03:35:28.880] Which is important for obviously getting rid of the iron and hemochromatosis.
[03:35:28.880 --> 03:35:29.400] Right.
[03:35:29.120 --> 03:35:32.760] But the other thing that's really helped, so Dan is doing that now.
[03:35:33.080 --> 03:35:42.680] But the other thing that seems to really help him, I mean, he does sauna, hot tubs, exercise, you know, and there'll be times when he's in his office working and he's like 135 systolic.
[03:35:42.680 --> 03:35:44.040] And it's like, what in the world?
[03:35:44.040 --> 03:35:45.800] That's crazy, right?
[03:35:46.760 --> 03:35:48.680] Green shakes help him.
[03:35:48.680 --> 03:35:51.560] So like tons of like nitrates.
[03:35:51.560 --> 03:35:54.040] So a bunch of like green vegetables.
[03:35:54.040 --> 03:35:56.200] And these are like nasty tasting shakes.
[03:35:56.200 --> 03:35:57.720] These aren't like good tasting ones.
[03:35:57.960 --> 03:35:58.760] Not AG.
[03:35:58.760 --> 03:35:59.400] No.
[03:36:00.840 --> 03:36:03.480] And that will help him as well.
[03:36:03.480 --> 03:36:07.640] So yeah, exercise is very important, but like there's also like.
[03:36:07.880 --> 03:36:10.120] Has he tried like cocaflavonoids, things like that?
[03:36:10.120 --> 03:36:12.120] You know, we, I was, I give that to him.
[03:36:12.120 --> 03:36:13.080] So another story.
[03:36:13.080 --> 03:36:14.280] No, I wasn't doing that.
[03:36:14.520 --> 03:36:17.480] We haven't been doing that because we take a lot of our vitamins at night.
[03:36:17.480 --> 03:36:19.160] We do take some fish oil in the morning.
[03:36:19.160 --> 03:36:27.640] I did mention that to him because another story, my mother, who is sedentary, she's lost a lot of weight, but she's still overweight.
[03:36:28.200 --> 03:36:31.880] She, you know, she, she, she's losing the weight was great.
[03:36:31.880 --> 03:36:33.800] I mean, she's lost like 75 pounds.
[03:36:33.800 --> 03:36:35.240] Like, she's lost a lot of weight.
[03:36:35.320 --> 03:36:40.520] You look at the pictures, it's like years to her life have been extended just by that alone.
[03:36:40.920 --> 03:36:48.680] But I can't, like, I can get her in the sauna sometimes, but it's still, it's still like a little bit more of an effort.
[03:36:49.000 --> 03:36:52.920] But one thing about her is she will take the vitamins I give her.
[03:36:52.920 --> 03:36:57.000] And she's got, she's homozygous for MTHFR.
[03:36:57.000 --> 03:37:08.360] If she's not taking a high-dose like B supplement along with like methyl folate, like her homocysteine will go high and her blood pressure goes up.
[03:37:08.360 --> 03:37:13.880] And she had stopped taking all those because she wasn't over my house all the time when I was giving it to her every day.
[03:37:13.880 --> 03:37:27.280] And so I got her, you know, this like sort of like battery of supplements that I was giving her, including all the methyl folate and lowering her, things that were lowering her homocysteine, along with magnesium and cocoflavanol.
[03:37:27.280 --> 03:37:28.880] So I was giving her Cocovia.
[03:37:29.360 --> 03:37:31.120] She was getting four of those pills.
[03:37:31.120 --> 03:37:32.960] She gets four and she still takes them.
[03:37:32.960 --> 03:37:37.360] Her blood pressure went from like 155 to like 125.
[03:37:37.360 --> 03:37:42.400] Okay, her doctors are like, they wanted to get her on anti-hypertension treatment before she came to me.
[03:37:42.400 --> 03:37:44.720] And it's like, and this has been like months now.
[03:37:45.840 --> 03:37:47.680] It's happy, you know, she measures it at home.
[03:37:47.680 --> 03:37:48.960] She takes, she does logs.
[03:37:48.960 --> 03:37:54.480] I mean, so I'm very happy about that, you know, the fact that she's been able to do that.
[03:37:55.280 --> 03:37:59.920] But again, it just, it shows that there are, they definitely are lifestyle factors.
[03:37:59.920 --> 03:38:09.440] I know you hate that word, but, you know, exercise being one of the main ones, but there are people also that in addition to being very physically active, like they still get high blood pressure, you know?
[03:38:09.680 --> 03:38:09.920] Yeah.
[03:38:09.920 --> 03:38:22.880] And there, and, and, you know, I don't think we have the outcome data to look at the direct impact of cocoflavonoids or all the suite of B vitamins that are necessary to lower homocysteine and their impact on blood pressure.
[03:38:22.880 --> 03:38:23.920] But here's what we do know.
[03:38:23.920 --> 03:38:29.520] And again, this is mechanistic, and it's very strong mechanistic, but that doesn't necessarily equate to outcomes.
[03:38:29.520 --> 03:38:40.240] But we know that as homocysteine is elevated, it impairs the clearance of something called asymmetric and symmetric dimethylarginine.
[03:38:40.240 --> 03:38:42.800] I don't know if you've talked about ADMA and SDMA.
[03:38:42.800 --> 03:38:48.960] And ADMA and SDMA directly and indirectly inhibit nitric oxide synthase.
[03:38:49.280 --> 03:38:56.000] So we know that homocysteine is associated with poor outcomes in cardiovascular disease.
[03:38:56.400 --> 03:39:11.080] And I think that this mechanism of homocysteine impairing the clearance of ADMA and SDMA is the mechanistic link because when you directly inhibit nitric oxide synthase in the endothelium, you are preventing the creation of nitric oxide.
[03:39:11.080 --> 03:39:16.200] And of course, that's what cocoflavanols actually do the opposite of that.
[03:39:16.200 --> 03:39:27.400] So I think the one-two punch of lowering homocysteine and raising nitric oxide synthase activity via cocoflavanol could certainly explain a reduction in blood pressure.
[03:39:27.400 --> 03:39:28.200] That's really interesting.
[03:39:28.360 --> 03:39:35.240] I was giving her the cocoflavanol just because I had seen the studies on increased blood flow, and I'm like, okay, we need that, you know, like we need that.
[03:39:35.480 --> 03:39:36.600] Measuring blood pressure.
[03:39:36.840 --> 03:39:44.920] Yeah, so this was established really clearly through the sprint trial, and this has basically been now kind of the gold standard for how we use an automated cuff.
[03:39:44.920 --> 03:40:00.360] So that trial was done by having individuals sit for five minutes, check a blood pressure, no stimulation during that time, so not talking, not looking at a phone, not doing anything, and then repeat that two more times.
[03:40:00.360 --> 03:40:12.840] So it's a 15, I'm not suggesting this is what Dan does or what anybody does, but just so you understand at the level of how the trials are done, you're sitting for 15 minutes, having a check at 5, 10, and 15 minutes.
[03:40:12.840 --> 03:40:23.560] You're sitting like this, the cuff is two inches above the elbow, and the cuff is right at the level of the right atrium.
[03:40:23.560 --> 03:40:28.680] So, you know, you're, and by the way, if anybody wants to do this experiment at home, it's really interesting to do.
[03:40:29.080 --> 03:40:36.840] Put an automated cuff on your arm and put your arm here, put your arm above your head, and put your arm in the right spot, and look at how big a difference you get.
[03:40:36.840 --> 03:40:39.640] So, measurement errors are a huge problem.
[03:40:39.640 --> 03:40:41.880] Being overstimulated is a huge problem.
[03:40:41.880 --> 03:40:45.000] So, you really want to make sure you're getting an accurate reading of that blood pressure.
[03:40:45.760 --> 03:40:53.200] And we have our patients do that twice a day, you know, an early in the day and a late in the day check.
[03:40:53.200 --> 03:40:56.560] And then, you know, we just have everybody do that for two weeks to start.
[03:40:56.560 --> 03:40:58.880] And that's what's considered your blood pressure.
[03:40:58.880 --> 03:41:04.320] So, you know, the idea that you're going to walk into the doctor's office and get a blood pressure is not valuable for most people.
[03:41:04.320 --> 03:41:07.360] So, when someone says, what's your blood pressure?
[03:41:07.360 --> 03:41:15.040] It should be, what's the average of those two weeks of twice-daily checks done where you take the five-minute protocol and test perfectly?
[03:41:15.040 --> 03:41:18.480] And I think everybody listening to this should know that number.
[03:41:18.480 --> 03:41:19.440] Yeah, that's great.
[03:41:19.440 --> 03:41:22.480] I'm going to like, I'm going to do it.
[03:41:23.920 --> 03:41:27.280] Peter, so this has been amazing.
[03:41:27.280 --> 03:41:30.160] I mean, so much information, actionable information.
[03:41:30.160 --> 03:41:35.440] A lot of people listening here, they want medicine 3.0.
[03:41:35.440 --> 03:41:37.840] They want aggressive prevention.
[03:41:39.360 --> 03:41:49.200] Do you have some tool, like some pointers, maybe some strategies that people can work within the existing healthcare system to kind of like help them?
[03:41:49.200 --> 03:42:01.120] Like, how can they, you know, get some of these tests that we've talked about, whether it's through Boston Heart or, you know, doing the Grail, working with their physicians to like being able to order them?
[03:42:01.120 --> 03:42:06.960] You know, like, how can people try to get as close as they can to medicine 3.0?
[03:42:07.600 --> 03:42:10.960] I mean, we've, I hate to sound like a shameless plug.
[03:42:10.960 --> 03:42:15.840] We've created something to help do this because, you know, I've talked here about our practice.
[03:42:15.840 --> 03:42:17.440] Our practice is super small.
[03:42:18.880 --> 03:42:34.600] It's just never, there's no desire to scale this practice, and we will never be able to meet the demand of the, you know, the people that want to come in and the amount of room that we can make because it's just not, the model doesn't make sense, right?
[03:42:29.600 --> 03:42:36.920] It's, it's too labor-intensive the way we're doing it.
[03:42:37.240 --> 03:42:43.160] But the good news is, like, I really don't think you need to be my patient to get the benefits of what we do.
[03:42:43.160 --> 03:42:52.760] I really think you can get most of these benefits if, first and foremost, you are a really thoughtful consumer of your own healthcare information.
[03:42:52.760 --> 03:42:56.040] So, to that end, we've created this product called Early.
[03:42:56.440 --> 03:43:03.400] It is, I mean, it's going to be fully released next year, but it's having a limited release this year.
[03:43:03.400 --> 03:43:08.200] So, we released it for four days in the spring just to our subscribers.
[03:43:10.120 --> 03:43:12.040] The reception to that has been very positive.
[03:43:12.040 --> 03:43:15.800] It's going to be released again once more this year just to people on a wait list.
[03:43:15.800 --> 03:43:19.560] So, anybody who goes to, I'm ashamed to say I don't know the website.
[03:43:19.560 --> 03:43:22.680] I think it's early.com, but maybe it's earlymedical.com.
[03:43:22.840 --> 03:43:23.640] Yeah, I don't know.
[03:43:23.640 --> 03:43:24.440] Google Early Medical.
[03:43:24.600 --> 03:43:25.560] Yeah, yeah, something like that.
[03:43:25.720 --> 03:43:30.200] And there's a waitlist, and those who sign up on the waitlist will be offered the next window.
[03:43:30.200 --> 03:43:32.360] It'll be a very short window in the fall.
[03:43:32.360 --> 03:43:35.480] And basically, that program does everything, right?
[03:43:35.480 --> 03:43:42.440] It walks you through everything, how to operationalize everything that I've written about in the book or that we're talking about here today.
[03:43:42.440 --> 03:43:47.320] It also allows you to directly go to any lab you want.
[03:43:47.320 --> 03:43:53.240] And we've, and we have no affiliation with any of these people, so we don't want to make any money on how these labs are done.
[03:43:53.240 --> 03:43:58.280] But you can run our panel at Boston Heart and get all these results.
[03:43:58.280 --> 03:44:02.360] And then we sort of, you know, give you our dashboard on how to walk through these.
[03:44:02.360 --> 03:44:04.840] We give you the, these are the ranges.
[03:44:05.080 --> 03:44:12.360] And what I hope to be able to do, because so far, a lot of people who are buying this product from us are physicians.
[03:44:12.360 --> 03:44:25.600] What I really hope will eventually happen is we'll have a critical enough mass of both people who are buying this who want this kind of medicine and physicians who are buying this who want to practice this kind of medicine that there could be sort of a match made here.
[03:44:25.920 --> 03:44:32.080] And, you know, the good news is I think a lot of physicians really want to practice this way.
[03:44:32.720 --> 03:44:37.280] And the challenge of practicing this way is you just have to get re-educated.
[03:44:37.280 --> 03:44:38.720] And that takes a little bit of time.
[03:44:38.720 --> 03:44:40.480] And that's why we've put this together, right?
[03:44:40.720 --> 03:44:44.640] We've sort of taken two and a half years to build this program, this curriculum.
[03:44:44.640 --> 03:44:46.080] And it's an investment.
[03:44:46.080 --> 03:45:00.960] I make no, you know, it's probably 30 hours of video plus tons of downloadable material that are, you know, lead you through a bunch of exercises you have to do, like how to take a correct family history, like what to really look for in your family history.
[03:45:01.600 --> 03:45:05.920] Stuff like we're talking about, the blood pressure stuff, how to check the labs and all those things.
[03:45:05.920 --> 03:45:21.760] So, you know, I think that that's, I think that's the way to, maybe not at the societal level, you know, I don't have the policy solution for how to fix medicine, but I think at the individual 11, at the individual level, just sort of taking control over it and saying, okay, I'm done with medicine 2.0.
[03:45:21.760 --> 03:45:23.440] It's time to go to medicine 3.0.
[03:45:23.440 --> 03:45:30.960] And medicine 3.0 is really about highly preventive, super early, personalized care.
[03:45:31.600 --> 03:45:39.440] There are a couple of personal questions that I'm going to ask you just at the very end of this that I know people are also very interested in.
[03:45:39.440 --> 03:45:54.440] One being your ideal, your ideal diet and exercise routine and other factors that you're doing for longevity, or maybe for the day or for the week, whichever way you kind of bunch them in.
[03:45:54.320 --> 03:45:59.680] Like, like what's ideal for you for you to, you know, improve your longevity.
[03:45:59.680 --> 03:46:00.760] I know that's a very general way.
[03:46:01.000 --> 03:46:02.440] With respect to nutrition and exercise?
[03:45:59.760 --> 03:46:07.320] Nutrition, exercise, and anything else, sleep, like, you know, sauna, whatever, whatever's your ideal like program.
[03:46:07.640 --> 03:46:08.680] Full suite, yeah.
[03:46:09.320 --> 03:46:10.600] Well, I will say this.
[03:46:11.000 --> 03:46:17.160] I'm sure that everything I'm about to say is going to make me sound really rigid, and people are going to be like, that guy's a psycho.
[03:46:17.160 --> 03:46:21.080] So I'm always a little hesitant when in talking about what I do.
[03:46:21.480 --> 03:46:23.400] Well, people want to know what you do.
[03:46:23.720 --> 03:46:24.200] Okay.
[03:46:24.760 --> 03:46:30.200] So look, probably compared to most people, I am considered quite regimented.
[03:46:31.080 --> 03:46:34.040] I'm way less regimented than I used to be.
[03:46:34.920 --> 03:46:37.400] But nevertheless, here's sort of how I think about things.
[03:46:37.400 --> 03:46:39.640] So let's start with sleep.
[03:46:40.440 --> 03:46:50.920] I really take my sleep seriously and I'm, you know, someone who believes, who functions best with a consistent bedtime and wake-up time.
[03:46:50.920 --> 03:46:57.960] So I am in bed usually for eight hours a night, and that's typically 10 to 6.
[03:46:58.280 --> 03:47:02.440] And that usually results in probably seven and a half hours of sleep.
[03:47:03.400 --> 03:47:06.920] I'm going to just rattle off the names of things I use because I don't have any affiliation with these things.
[03:47:06.920 --> 03:47:09.320] So I use 8 Sleep as my mattress cover.
[03:47:09.320 --> 03:47:11.160] I love what these guys have done.
[03:47:11.400 --> 03:47:16.680] It's a fantastic cooling product, and it's made an enormous difference for me.
[03:47:16.680 --> 03:47:18.440] I've been using it for the last three years.
[03:47:18.440 --> 03:47:20.440] Most of our patients are using it.
[03:47:20.440 --> 03:47:23.080] There are other products out there, and I've tried them, and they're good.
[03:47:23.080 --> 03:47:25.320] This one, I just happen to fancy the most.
[03:47:25.320 --> 03:47:26.040] Agreed.
[03:47:28.040 --> 03:47:33.400] I'm also very particular about what I'm doing before bed and what I'm not doing before bed.
[03:47:33.400 --> 03:47:36.280] So I really, and I'm not perfect with this.
[03:47:36.280 --> 03:47:44.680] I'm not perfect with any of these things, Rhonda, but I really go out of my way to not look at anything that's going to activate me.
[03:47:44.680 --> 03:47:48.160] So I try not to look at email for a couple hours before bed.
[03:47:44.840 --> 03:47:49.520] In fact, I have two separate phones.
[03:47:49.840 --> 03:47:54.080] I have like my regular phone that has email and social media and junk on it.
[03:47:54.080 --> 03:47:57.120] And then I have what I call my bat phone that literally has nothing.
[03:47:57.120 --> 03:48:08.560] It's just, it has like the remote to the TV, you know, and it has like a phone and email, but like, oh, sorry, a phone and text, but only like two people know the number, my wife and my daughter.
[03:48:08.560 --> 03:48:10.720] And that's about it.
[03:48:10.720 --> 03:48:11.280] And the camera.
[03:48:11.280 --> 03:48:15.840] So it's basically an excuse to have a camera and a phone if I'm going someplace and I don't want my phone with me.
[03:48:16.160 --> 03:48:19.680] So that's kind of the phone that's with me if I'm watching TV downstairs or something like that.
[03:48:19.680 --> 03:48:23.600] But I can't even be tempted to look at social media or look at email.
[03:48:23.600 --> 03:48:29.600] So it's all in this spirit of like turning the system down before bed.
[03:48:30.480 --> 03:48:35.920] Even little things like I'll brush and floss my teeth before I go in the sauna because I sauna before bed as well.
[03:48:35.920 --> 03:48:41.360] So that once I'm done with that sauna and shower, like I'm just going straight into bed.
[03:48:42.000 --> 03:48:45.680] So for me, that's also a very productive sleep trick.
[03:48:45.680 --> 03:48:47.680] There's certain supplements that I use to sleep as well.
[03:48:47.680 --> 03:48:59.600] So I'm a fan of glycine, ashwagandha, magnesium L3N8, and just straight mag oxide as well.
[03:48:59.600 --> 03:49:03.200] I don't use melatonin or phosphatidylserine unless I'm jet lagging.
[03:49:03.200 --> 03:49:06.320] If I'm time zone hopping, I'll use those as well.
[03:49:07.200 --> 03:49:08.400] So that's sleep.
[03:49:09.360 --> 03:49:13.360] On the nutrition side, I don't follow any particular diet.
[03:49:13.680 --> 03:49:16.560] I guess you could say I eat what would be called a balanced diet.
[03:49:16.560 --> 03:49:28.320] So, I'm an omnivore who will probably always struggle with food in the sense that, like, if left to my own devices, I would eat everything and too much of it.
[03:49:28.320 --> 03:49:30.760] So, I do need to be mindful about what I eat.
[03:49:30.760 --> 03:49:32.200] So, what do I pay attention to?
[03:49:29.680 --> 03:49:34.760] So, I just generally pay attention to not eating junk.
[03:49:34.920 --> 03:49:38.360] That's that's like the most important credo of my diet, I would say.
[03:49:38.360 --> 03:49:40.360] And I say this as someone who's done everything, right?
[03:49:40.360 --> 03:49:50.360] Like, I've been vegan, I've been keto, I've been like the most, you know, you know, hardcore fasting, intermittent fasting, time-restricted eating.
[03:49:50.360 --> 03:49:58.120] Like, I've done, there's no diet I don't think I've done for long periods of time, and I have found benefit in one form or another from various different aspects of these things.
[03:49:58.120 --> 03:50:07.880] But, you know, right now I'm mostly optimized around energy balance, which, you know, stay in energy balance, and protein intake.
[03:50:07.880 --> 03:50:15.960] And so, most of my conscious effort around my diet goes into making sure I'm getting 40 to 50 grams of protein four times a day.
[03:50:16.920 --> 03:50:30.280] And a lot of times, at least two of those are in meals that are just like just venison or just eggs or something where it's just a protein and there's not a lot of other stuff in it.
[03:50:31.160 --> 03:50:35.720] I do make sure I stop eating at least three hours before bed.
[03:50:35.720 --> 03:50:40.200] It really makes a difference going back to sleep that I go to bed a little hungry.
[03:50:40.520 --> 03:50:46.600] If I ever go to bed with my belly too, too full, it feels nice, but I don't sleep as well.
[03:50:46.600 --> 03:50:49.640] So, I really try to err on the side of going to bed a little hungry.
[03:50:49.640 --> 03:50:52.760] And that's, you know, I'm really lucky because we have young kids, so we eat early.
[03:50:52.760 --> 03:50:53.960] So, we're eating at six.
[03:50:53.960 --> 03:51:01.560] So, I'm going to bed typically with four hours between when I last ate and when I go to sleep.
[03:51:01.560 --> 03:51:03.080] We can talk about alcohol.
[03:51:04.600 --> 03:51:12.760] I'm in the camp that believes there is absolutely no benefit to alcohol at any dose from a purely, you know, biochemical standpoint.
[03:51:13.320 --> 03:51:18.880] However, I acknowledge that there are probably some pro-social benefits to it, and I happen to really, really like alcohol.
[03:51:19.200 --> 03:51:24.640] So I probably have, well, I don't know, it depends.
[03:51:24.640 --> 03:51:30.560] I mean, anywhere from zero to seven or eight drinks in a week.
[03:51:31.680 --> 03:51:38.240] Probably, I don't think there's a time that I can recall in the last five, six years where I've had more than two drinks in a day.
[03:51:38.240 --> 03:51:40.240] And I also try to do my drinking early.
[03:51:40.240 --> 03:51:43.760] Now, by that, I don't mean two in the afternoon, but I mean with dinner.
[03:51:43.760 --> 03:51:49.440] So that again, alcohol is completely, functionally, the alcohol doesn't factor into my sleep.
[03:51:49.440 --> 03:51:54.640] And I know this because I track all these things and I know exactly how alcohol negatively impacts sleep in me.
[03:51:54.640 --> 03:52:04.400] And I know that as long as I have that drinking done by six or seven, it doesn't show up anywhere on any metric that I'm tracking with respect to sleep.
[03:52:04.400 --> 03:52:09.760] Okay, exercise, most important thing from a physiologic standpoint for me.
[03:52:09.760 --> 03:52:15.840] I exercise every day and it's an, you know, it's much of what I do revolves around it.
[03:52:15.840 --> 03:52:45.680] So even here being in San Diego this week, I mean, it's like I have a membership at a great gym every time I'm here and I just know that I'm going to get up first thing in the morning and I'm going to go and I'm going to do my workouts and they're going to be completely, you know, they're not going to be the exact same workouts I'd be doing at home, but I'm still generally doing, you know, four hours of zone two a week with one sort of higher intensity workout that's geared towards VO2 max a week and then four strength training sessions a week.
[03:52:45.680 --> 03:52:48.720] So that's kind of the foundational pillar of everything I do.
[03:52:48.720 --> 03:52:56.080] And then there's other things that get layered on top of that, like rucking and recreational activities that are also physical as well.
[03:52:56.800 --> 03:53:03.800] So, and then the last thing I guess I would say on that, which we didn't talk about, but it's an equally important part of this, is mental health.
[03:53:03.800 --> 03:53:06.760] So, everything that we've talked about factors into.
[03:53:07.000 --> 03:53:15.640] So, the right sleep, the right nutrition, exercise, all of that factors into creating, you know, what I kind of describe as a wider buffer zone around distress tolerance.
[03:53:15.640 --> 03:53:27.720] And then, you know, therapy, which I do at least one session a week, sometimes two, plus journaling and, you know, doing something called dialectical behavioral therapy.
[03:53:27.720 --> 03:53:33.960] These things have been, you know, enormously important at increasing kind of the quality of my life in the past five years.
[03:53:34.600 --> 03:53:35.560] That's amazing.
[03:53:35.560 --> 03:53:37.800] I mean, thank you so much, Peter.
[03:53:37.800 --> 03:53:44.360] So if people want to, I mean, people definitely are going to want to hear more from you.
[03:53:44.360 --> 03:53:47.480] You've got a podcast, The Drive I mentioned, it's everywhere.
[03:53:47.480 --> 03:53:49.560] It's on YouTube, Spotify, iTunes.
[03:53:49.560 --> 03:53:51.960] You've got a book that is a must-read.
[03:53:51.960 --> 03:53:52.440] I read it.
[03:53:52.440 --> 03:53:53.720] It took me about seven hours.
[03:53:53.720 --> 03:53:54.680] I did a flight.
[03:53:54.680 --> 03:53:57.480] I mean, it was, but there were parts where I was like, I know this is a good idea.
[03:53:57.720 --> 03:54:04.120] I know what Peter has, his thoughts on this, and I was 2xing it, you know, whatever you want to call it.
[03:54:04.120 --> 03:54:07.000] But yeah, I was like, oh, you audio read it, you mean?
[03:54:07.000 --> 03:54:07.640] No, no.
[03:54:08.280 --> 03:54:09.160] I read it, read it.
[03:54:09.160 --> 03:54:10.520] And you read it in seven hours.
[03:54:10.680 --> 03:54:11.880] I did, but like I said, there.
[03:54:11.960 --> 03:54:13.000] You're a fast reader.
[03:54:13.000 --> 03:54:20.680] Well, I think the more important factor was I'm very familiar with your thoughts and lots of things.
[03:54:20.680 --> 03:54:24.280] There were things where I was like, I know, because I know, and I'm just skimming this part.
[03:54:24.920 --> 03:54:26.600] And then there were things that were a little bit more.
[03:54:26.600 --> 03:54:28.200] So phenomenal book.
[03:54:28.200 --> 03:54:33.960] I mean, lots of important, lots of things we talked about today, but even more and lots of applications there.
[03:54:33.960 --> 03:54:35.560] So it's called Outlive.
[03:54:35.720 --> 03:54:39.720] I went to a spa the other day and I saw it right there and I was like, awesome.
[03:54:40.400 --> 03:54:43.400] But you've got a website, I mean, peteratia.com.
[03:54:43.400 --> 03:54:46.000] Yeah, I think PeterArtea MD.com is the website.
[03:54:46.000 --> 03:54:49.040] That's where people can sign up for our newsletter, which comes out every Sunday.
[03:54:44.920 --> 03:54:55.280] And then I think earlymedical.com is a separate website where that other thing exists.
[03:54:55.760 --> 03:54:58.080] So question for you: when are you going to write a book?
[03:54:58.480 --> 03:55:01.520] Has this ever, is this ever something you've thought about?
[03:55:01.520 --> 03:55:02.720] I've thought about it.
[03:55:02.720 --> 03:55:05.840] I'm not sure that I want to go there.
[03:55:05.920 --> 03:55:24.080] I mean, I can't imagine the work, like, because your book was, I mean, it was impressive, you know, and to write a book in the scientific world like that that people are excited about, can understand, I mean, it's, it's really challenging.
[03:55:24.080 --> 03:55:30.320] So yeah, I mean, I guess all of those things are true.
[03:55:30.320 --> 03:55:35.040] And yet, I think as I stand here on this side of it, I can say I think there are benefits to it.
[03:55:35.280 --> 03:55:44.560] I don't want to talk you into doing something that's really hard because it is, but, you know, like Andrew Huberman is working on a book and, you know, it's hard.
[03:55:44.560 --> 03:55:45.040] He knows it.
[03:55:45.760 --> 03:55:50.640] But books do communicate in a way that podcasts don't.
[03:55:51.040 --> 03:55:53.680] And they reach different audiences too.
[03:55:53.680 --> 03:56:02.720] So there was a part of me throughout the process that was kind of like, because I started the book two years before I started podcasting.
[03:56:02.720 --> 03:56:07.840] And then as I'm into the book and podcasting, there was a lot of time when I thought, why am I doing this?
[03:56:07.840 --> 03:56:09.920] Like, this is such a waste of time.
[03:56:09.920 --> 03:56:12.640] Like, this is taking so much time.
[03:56:12.640 --> 03:56:16.400] And I could cover all of this material in 10 podcasts.
[03:56:16.400 --> 03:56:21.840] Like, the book could be summarized into 10 really well thought out podcasts.
[03:56:22.960 --> 03:56:25.360] But now that it's all said and done, I realize a couple things.
[03:56:25.360 --> 03:56:28.480] One, writing sharpens your thinking so much.
[03:56:29.200 --> 03:56:34.280] And I'm not saying that your thinking isn't sharp or that my thinking wasn't sharp, but there's just no two ways about it.
[03:56:34.440 --> 03:56:42.280] Like as I sit here talking, I'm sort of blabbering, but like when you have to write it down, you really have to get clear on what you're saying.
[03:56:43.560 --> 03:56:56.520] And as I said, there's, you know, there's probably somebody out there, more than somebody, there's probably a lot of people out there who would get to know who you are and what your message is going to be that wouldn't figure it out from a podcast.
[03:56:56.520 --> 03:57:01.560] So, you know, maybe there's a bunch of listeners who are saying, yeah, Peter, tell her, tell her, tell her.
[03:57:01.560 --> 03:57:05.720] So, but I think there'd be a lot of people who would love it if you wrote a book if you decided to make that commitment.
[03:57:06.040 --> 03:57:07.800] It's good to hear that from you for sure.
[03:57:08.120 --> 03:57:12.280] Especially being on the other side of it, you know, because you often wonder, was it worth it?
[03:57:12.280 --> 03:57:18.120] You know, like, Peter, there are other things that we didn't get to discuss, believe it or not.
[03:57:18.760 --> 03:57:21.240] So let's please do this again.
[03:57:21.560 --> 03:57:31.880] My podcast, your podcast, I want to do both because, you know, there's just, there's so much to dive into and we have so much overlap in our interests that it's always a pleasure to talk with you.
[03:57:31.880 --> 03:57:33.960] And so thank you again.
[03:57:33.960 --> 03:57:36.600] Really, really enjoyed this conversation.
[03:57:36.600 --> 03:57:43.160] Well, thank you for having me and thank you for pouring through the book and coming up with so many awesome topics to get through.
[03:57:43.160 --> 03:57:45.720] And it's funny that we barely go through half of them.
[03:57:46.680 --> 03:57:47.800] Thank you so much to Dr.
[03:57:47.800 --> 03:57:52.200] Peter Attia for his relentless pursuit of strategies to extend health span.
[03:57:52.200 --> 03:57:57.640] As a companion to today's episode, I've created a free evidence-based blueprint that you can download.
[03:57:57.640 --> 03:58:05.720] In this guide, which you can find at bdnfprotocols.com, you will find protocols designed to improve cognitive function and delay brain aging.
[03:58:05.720 --> 03:58:24.400] This guide explores modifiable lifestyle factors, the tactics, strategies, and things you can do, particularly when it comes to exercise, nutrition, and even supplementation, to improve cognition and enhance neuroprotection, many of which are at least partially mediated through increases in brain-derived neurotrophic factor levels.
[03:58:24.400 --> 03:58:28.400] In this guide, you will also find a section entitled Rhonda's Protocols.
[03:58:28.400 --> 03:58:40.000] These protocols are either practices I actively engage in or strategies I'm currently exploring, curated specifically for their promising potential for beneficial cognitive and neuroprotective impact.
[03:58:40.000 --> 03:58:44.640] These protocols are detailed and specific, everything you'd look for in a blueprint.
[03:58:44.640 --> 03:58:52.080] So, if you're looking to dive deeper into these insights and start applying them, head over to bdnfprotocols.com to get your free guide.
[03:58:52.080 --> 03:58:57.440] It's a valuable tool for anyone committed to optimizing their brain health and longevity.
[03:58:57.440 --> 03:59:00.800] Once again, that's bdnfprotocols.com.