#19 – Dave Feldman: stress testing the lipid energy model

1. 0:00 – 0:04

   Intro

   1. PAPeter Attia0:00

      [instrumental music]

2. 0:04 – 11:41

   Housekeeping and Peter's Post-Interview Verdict on Dave's Model

   1. PAPeter Attia0:04

      Hey everyone. Welcome to The Peter Attia Drive. I'm your host, Peter Attia. The Drive is a result of my hunger for optimizing performance, health, longevity, critical thinking, along with a few other obsessions along the way. I've spent the last several years working with some of the most successful top-performing individuals in the world, and this podcast is my attempt to synthesize what I've learned along the way to help you live a higher quality, more fulfilling life. If you enjoy this podcast, you can find more information on today's episode and other topics at peterattiamd.com. [instrumental music] Hey everyone. Before introducing today's guest, a couple of housekeeping issues. First, if you're enjoying the podcast and you'd like to wake up Sunday mornings to what I promise is a non-lame email on what I've been up to and the most interesting papers I've read or some other relevant insight, please sign up for my, uh, weekly email at peterattiamd.com. Secondly, if you have any questions on the papers, topics, or people, or anything that we discuss on the podcast, be sure to check out the show notes, which are at my website. My team puts a ton of work into doing this, and we've been getting great feedback on just how robust they are, so I just wanna make sure that people know it's out there if in fact you finish a podcast and you're like, "God, that was a little over my head in this area," or, "What were they talking about here?" Pretty much anything that's discussed on the podcast is going to be found in more detail there. So head on over there if that's something that interests you. Certainly today's podcast will provide an opportunity to test that. Third, if you're enjoying the podcast, it would be an honor if you would head over to Apple Podcast and leave a review. And if you don't like the podcast, I guess you can leave a review also, but I'm probably not gonna ask you to spend as much time [chuckles] doing so. All right, on to today's guest. Now, this is gonna be a slightly longer introduction than normal. Apologies in advance. If you positively, absolutely don't wanna hear it, just skip ahead, I don't know, five minutes or so. If you're a low carb enthusiast, you've undoubtedly heard about Dave Feldman and his cholesterol drop protocol and his take on what he calls lean mass hyper-responders, or people who go on ketogenic or low-carbohydrate diets see a very high LDL cholesterol and/or LDL particle number. You've probably also heard that Dave is somewhat skeptical of the LDL as causal paradigm or thinking in atherosclerosis, so you're probably, uh, gonna understand that out of the gate Dave and I don't really see eye to eye on the genesis of heart disease. We go right into the conversation assuming people know the background, and the reason for that is I knew that this was gonna be a long enough discussion anyway, and I'd already heard Dave on a number of other podcasts present his model and his observations. So I thought rather than recapitulate those things here, we would link to those previous shows, of which there are at least two or three, including a couple of presentations on YouTube, so that you can kinda watch those if you're not already familiar with Dave's hypotheses. I do recommend that you familiarize yourself with these because, as I said, I didn't really make the time in this episode for Dave to go into the depth that he would normally go into. And again, that wasn't out of any reason other than I knew that we were gonna have enough to talk about without that and I didn't wanna reproduce or recreate the wheel, so to speak. Now, I believe Dave is putting up a companion blog post for this episode, so if you head on over to his site, which is cholesterolcode.com, he will undoubtedly have his own links and show notes, and that will probably on some level overlap with what we do, but also probably provide some new information. Now, we've got a kind of a special treat on this as well, which is Tom Dayspring, who, if you don't know who Tom is, you certainly will by the next week or so because Tom is kinda my foremost lipid mentors, and I wanted him to make sure that anything that Dave and I said that wasn't accurate was sort of corrected. So he's actually taken a look at the transcript of this, which we usually pull together for our episodes, and he's kind of weighed in with some commentary, mostly clarifying and elaborating on some technical stuff, but even, as I said, correcting any mistakes that we've made. So hopefully Tom's clarifications to the transcript will be valuable to those who wanna kinda get on the next level of detail. The show notes will have lots of links to graphics that help conceptualize some of these topics we get into. I mean, a lot of the time that Dave and I were talking, we were looking at diagrams and pointing things out, and so we hope to reproduce that for you. Now, before jumping into this episode, I do wanna provide my summary and synthesis of where I've landed in my own mind when all was said and done. I think I came into this with a point of view, and I think I left with a slightly different point of view. And I think that it's actually kind of hard maybe to follow the logic in my mind as I go through the episode, so I thought in the days after we recorded this, which was in July this year, 2018, that I would sort of just put my thoughts down and sort of crystallize them. So again, kind of an unusual thing to do, but I do think that this is a complicated enough topic that it's helpful. Ultimately, I am not convinced by Dave's model. And again, truthfully, I came into this maybe 20% thinking that there was a chance I would find the, the argument convincing, but I left with that number being a lot less, and I'll explain why. There are basically three reasons. The first is Dave was unable to explain to me the mass balance, meaning how does one account for the greater amount of cholesterol in and the greater number of the LDL particles? Now, it's possible that at the time of this podcast being released, Dave has given more thought to the questions I posed and has an answer for that. But no one, including Dave, is disputing that the phenotype of interest has more LDL cholesterol and more LDL particles, so therefore there's only three ways this can happen, and these three ways are collectively exhaustive but not mutually exclusive. First, you can make more cholesterol. Second, you can clear less cholesterol. And third, you can transfer cholesterol from other pools that we didn't see previously, such as cell membranes, into pools that we now look at, such as the lipoprotein. I think the data makes the first of these cases by far the most likely, but Dave seemed unable to address why that would be the case, and therefore what could possibly account for this increase in the LDL-P and the LDL-C. So on first principles, my doubt of the model has gone up from where we started the discussion to where we are now because the person who developed the model wasn't able to really articulate to me one of the most fundamental tenets of any physical model, which is it must respect mass balance. Now, to be clear, even if this fundamental condition were met, it would not be sufficient to make the case that this phenotype is not at risk. It would be at best a necessary but not sufficient criteria. So in addition to not being able to really explain the mass balance of how these additional molecules of cholesterol show up in the LDL particles, the second thing that I found difficult to reconcile was that Dave argued that VLDL production was driving the LDL concentration. But the fact remains that in insulin-sensitive people, which presumably this phenotype that he's referring to are, it's actually the opposite that is true. There are fewer, not more triglycerides being exported from the liver, and there is less, not more ApoC3 on the VLDL particles. This would actually reduce, not increase, their residence time. In other words, these so-called lean mass hyper-responders would actually have less VL to LDL conversion than, say, someone with type 2 diabetes. And I even point out in this discussion that even the person with type 2 diabetes does not have nearly as much VLDL as we might think they do. So I really see no evidence whatsoever from this energy model, which is I believe the terminology Dave uses, that we could explain this phenotype on the balance of triglyceride export through VLDL to LDL. The third point that I still was not able to fully come to grips with was that basically even if you ignore the first two points I've made, which I would argue you can't, I'm still unconvinced at this notion that we should exclude the roughly 2,000 genetic mutations that are known to produce a phenotype of high LDL, high HDL, and low triglyceride. These are called natural experiments, and we have, as I said, about 2,000 of such these natural experiments. And surely at least some of these cases, for example, the PCSK9 gain of functions, are excellent proxies for the key features of these lean mass hyper-responders. And yet to ignore them for reasons that are not at all based in our understanding of the physiology of this disease, for example, the PCSK9 hyperfunctions somehow having toxic endothelium reactions in response to this inability or impaired ability to take up cholesterol, despite there being no evidence of that being true, because there's no evidence that PCSK9 hyperfunctioning patients use an LDL receptor to take up cholesterol into their endothelial cells, is to basically say that one doesn't want to know the answer to this question. Now, I, I believe Dave is about as intellectually honest as anybody is in this space, and I've made no secret of my general disdain for the groups of folks that claim that LDL is not causal in atherosclerosis. None of this is to suggest that I can be entirely certain that folks of this phenotype with very high LDL are absolutely at increased risk for atherosclerosis, or to state that more technically, that their risk for atherosclerosis is commensurate with their lipid profile. I don't know that, and ultimately, I don't think we'll ever really know that. Nothing that Dave or I discussed could ever definitively make that case for the reasons that, you know, make the study of lipids challenging. Science is based on skepticism, and certainty is forever elusive, so science gets better and gets sharper through this type of discussion. But that said, a body of evidence produces a probability of accuracy, and in the end, the probability of one idea here seems disproportionately higher than the other. And as I said coming into this discussion, I thought the probability that Dave's ideas were correct was quite low. But following this discussion, I feel, I would say, of a higher degree of confidence that his hypothesis is not correct. In other words, my confidence in the probability of his hypothesis being correct has gone down based on these three points I raise above. The idea of probability and, is the nuance that's sort of missing from this discussion, and that's what troubles me, I guess, is that people think that we're dealing with a disease that has one and only one risk factor, when in reality we know that atherosclerosis is incredibly complicated and is impacted by many things beyond the lipoproteins. But that doesn't diminish their role in the causality of atherosclerosis. In the end, I would ask you to make up your own mind, because ultimately anyone who's listening to this, whose LDL is through the roof as a result of going on a ketogenic or low-carbohydrate diet, has to make a decision for themselves. And so I hope that what Dave and I have discussed here allows you to make a slightly more informed decision than you could have made before. And some of the other guests that I have already had on this podcast, including Ron Krauss, or those that will be on the podcast, including next week's guest, Tom Dayspring, will allow you to further think through those issues. So without further delay, and with apologies for how long this intro took, welcome to this episode with Mr. Dave Feldman. [upbeat music]

3. 11:41 – 18:03

   Setting the Stage: Dave's Background and the Decision Problem

   1. PAPeter Attia11:41

      Hey, Dave. Welcome to San Diego.

   2. DFDave Feldman11:42

      Thanks for having me, Peter.

   3. PAPeter Attia11:44

      You're here for a conference, is that correct?

   4. DFDave Feldman11:47

      That's right, uh, Low Carb USA.

   5. PAPeter Attia11:49

      Got it. That would explain all of the low carb folks that seem to be in town this weekend.

   6. DFDave Feldman11:53

      [chuckles] How many are gonna end up showing up here?

   7. PAPeter Attia11:56

      None. I'm actually, uh, leaving very, uh, early tomorrow to, uh, go to New York.

   8. DFDave Feldman12:02

      Wow.

   9. PAPeter Attia12:02

      So I will, uh, be missing this.

   10. DFDave Feldman12:04

       I'm either deeply honored or very scared right now.

   11. PAPeter Attia12:07

       [laughs] No, I actually was gonna try to talk to one other person too, but they bailed on me and took a better offer. So this is going to be a bit of a different episode, Dave, in the sense that I think this will be, even by the standards of this podcast, perhaps a bit more technical at times, and I think this will probably be a podcast where you and I have already spoken offline. I suspect a lot of what we discuss will need to be included in show notes because there's just going to be so much visual stuff. There's so much data we're going to be talking about, and some of it's just quite graphical in nature, which is not to be confused with graphic. We will, uh, apologize in advance that this might be one of those shows when you're going to probably get the most out of it sitting in front of your computer. But nevertheless, hopefully we can certainly get some interesting stuff out of the way. I've been trying to think about how to set the stage for this because I think it's safe to say many people listening to this don't know who you are and don't know what we're going to be talking about or why we're even having this discussion. So I'm going to take a small liberty of trying to synthesize some of what I've heard you say in the past, but then turn it over to you to clarify it and kind of put it in context. From my standpoint, I think you're one of the more thoughtful people on what I would call the LDL is not necessarily causal in heart disease camp. And so certainly there's a, a number of people out there for various different reasons who have argued that the causality of, uh, low-density lipoprotein and atherosclerosis is not a foregone conclusion, and in fact, there may be a subset of people in whom it's not quite relevant. And what you and I have done over the years is had email exchanges and things like that, and you've been, uh, very curious. You've done a lot of self-experimentation, which you won't find a more sympathetic audience for self-experimentation than me. And I think in large part, we want to kind of explore some of the deep lipidology around these ideas. But ultimately, it comes back to a question, and this is, I think, the question that at least if I'm going to be selfish, is the question I care about, which is today I have to make a decision, and I mean that literally. So meaning at 5:00 this morning, I had a call with a patient. Luckily, he was in a different time zone, but we had to make a decision about his lipids. And I will have three more interactions with patients today, of which two will center around the same discussion. So ultimately, decisions have to be made about how to manage dyslipidemia, and most decisions have to be made with incomplete information. So I certainly don't have any expectation that we will emerge from this discussion knowing an answer, but nevertheless, hopefully we'll have clarified a few things. So before I go any further, Dave, if someone were asking you, what are you known for with respect to this? So you can probably juggle five tennis balls simultaneously or something else. But with respect to this discussion, how does the low-carb community kind of describe you?

   12. DFDave Feldman15:04

       Well, and many of them right now would describe me as a lipid expert. The irony is that I actually push off that reputation to some degree. I'm not a formally trained biochemist. I'm not a medical professional. I regularly feel like I need to emphasize that. In fact, I, I think that your series, "Straight Dope on Cholesterol," was probably a way for a lot of people, myself included, to kind of short-circuit a lot of the formal education that typically one would have to go through through a university to get to really the general concepts of lipoproteins and how they work within the system. And so what got me to this place, going a little bit backward, is that I went on a low-carb diet, and now this story is fairly ubiquitous. You hear it a lot. A number of people, myself included, saw their cholesterol rise substantially. After that happened, yes, per what you just talked about, I started doing enormous amounts of self-experimentation, and I started elucidating a pattern, and part of what motivated me to do that was that even though I had very little training on the medical side, I did have a lot on the network side as a software engineer, and I saw a pattern that looked very familiar to me. And without getting into a lot of geeky terminology, if there happens to be any software engineers listening, you'll probably be familiar with this term. It's called dependency injection, and it's something that gets involved with networks of distributed objects. And I saw that with lipoproteins, which you talk about at length in the, uh, "Straight Dope on Cholesterol." And if I can, by the way, interject just this one thing. Thank you for making that series. I know I'm not the only person listening right now who would say that it really was kind of a light during a very dark time. And so from that, kind of this whole journey began, and weirdly, I went from being a fairly well-paid software engineer to kind of a poor n of 1 scientist, [chuckles] definitely tackling just exactly how far I could take moving around my cholesterol. And, um, I'm gonna make an outrageous claim. I couldn't do it this week because I have too many things going on, but I had always fantasized about the possibility of having a conversation with you and given where I'm at on the research now saying, "I would like you to write down a number between 100 and 350. And then once you do, in about a week's time, I'm going to move my LDL-C cholesterol to that number, plus or minus 20 milligrams per deciliter." And I think that would've been a lot of fun, and maybe we'll get a chance to do that in the future. But the bottom line is I feel as if I've come across enough with my own mapping of my own metabolism that I found how I can move LDL cholesterol and LDL particle count up and down without medication or supplements by finding what I believe to be the primary influencer, which is the energy metabolism, especially that of fatty acid utilization for energy.

4. 18:03 – 30:27

   What Moves LDL-P: Triglyceride, Synthesis, Absorption and Clearance

   1. PAPeter Attia18:03

      Okay. I think the other thing we'll want to make sure listeners have done by this point, if they want to get really deep on the understanding of this, is probably go back and listen to at least one, but potentially two or three of the other podcasts you've been on. You've Been interviewed a number of times. I've had the, uh, privilege of listening to several of them, which is what helped me get more up to speed on some of your arguments. And I think rather than just spend an hour going over those again here, I'd rather we sort of get to it more quickly, which we will, and then let the listener go back and get that way of background. So with that said, let's talk a little bit about your story. So before you went on a low carbohydrate diet, you probably had a standard lipid panel. It probably showed what?

   2. DFDave Feldman18:52

      I believe the very last one that I had was typical of what I'd usually had gotten, which is my total cholesterol, I believe, was 186. My LDL-C was 131. My HDL was 40, and my triglycerides were 80.

   3. PAPeter Attia19:10

      Obviously, people who have heard me talk about this before will know that that tells us virtually nothing. Your total cholesterol is of no interest. Your LDL cholesterol of 131 by the Framingham puts you a little over the 50th percentile. Your HDL cholesterol of 40 puts you quite a bit below that, actually. And your trigs of 80 in someone who's Caucasian doesn't give us a great insight, gives us even less insight if you're African American, but your trig to HDL ratio of about two would be considered acceptable by most. Most people would even consider up to three acceptable. So we would have no way of knowing from this what your LDL particle number would be or your ApoB, which would be better predictors of your risk than any of these numbers here. But nevertheless, this is what everybody gets, right? This is sort of the standard test.

   4. DFDave Feldman20:00

      Yes, and in fact, anybody who's ever considering going on a low-carb diet, it's one of the first things I jump on, is I say, "Do me a favor and take a particle count test before you start the diet." Because I think a lot of us would be very interested to know what particle counts are before people start the diets. It may actually hold keys to understanding what's going on with what... I'm not sure if it was you or Tom Dayspring. I think one of the two of you first started using the term hyper-responder to elucidate those people who, going on a low-carb diet, see their cholesterol go high, not just their LDL-C, but their particle count.

   5. PAPeter Attia20:33

      Yeah, I think Tom would deserve the credit for that. In fact, it'll probably come up many times throughout this discussion, and we'll certainly link to it. Tom wrote a really fantastic piece on this in his Lipaholics series. I think it was in 2013. Might've been 2014. But it was following a number of cases that he and I had shared back and forth about this phenomenon. I would add something else, Dave. If you're gonna make a, a request that people draw the advanced lipid panels before, the other thing that is essential is that they get a sterol panel, and that's not to be confused with sterile like, you know, I-L.

   6. DFDave Feldman21:13

      [chuckles]

   7. PAPeter Attia21:13

      It's sterol, O-L. And the reason for that is that there are basically four things that are moving LDL particle number. And when I sit down with patients and talk about this, we always start from this place, which is what moves the LDL-P? Well, three things that move it are generally cargo related, and one is generally clearance related. So the two things that move at the macro level, the cargo, is the amount of triglyceride it's carrying and the amount of cholesterol it's carrying, or to be more specific, cholesterol ester. So to get a sense of what its triglyceride burden is, you can get a crude sense from looking at the serum triglyceride level, though there are no commercially available tests to my knowledge that actually measure the triglyceride content of an LDL particle. At the research level, that's been done, and I have some data on a self-experiment I did in 2012 where we tracked the movement of cholesterol ester and triglyceride through all of my lipoproteins, including chylomicrons. And if it becomes relevant, we'll, we'll certainly go over that. I think you'll find it super interesting.

   8. DFDave Feldman22:17

      Yeah, and I think it's worth stratifying that just for a moment for the audience. What you're referring to is, is if we do a blood test for triglycerides, that's inventory of all lipoproteins. So we're not actually gathering it on a per lipoprotein basis. And this is what you're saying is this test will help, or at least what we're trying to elucidate is exactly what it is on total triglycerides.

   9. PAPeter Attia22:37

      The blood test tells us nothing about the triglyceride burden within the lipoprotein directly, but we know that that's one of the cargos. And as a general rule, the more we see the triglyceride go up, the more we know we need particles disproportionate to their cholesterol content to traffic them. The next two things we look at that are also, quote-unquote, "cargo related" is the synthesis of cholesterol. Turns out we can measure that quite well, and we measure that by using a number of molecules, but most commonly a molecule called desmosterol, which is the penultimate molecule in one of the cholesterol synthetic pathways. So cholesterol synthesis begins, as you know, with the creation of a molecule from two molecules of acetyl-CoA. And many, many steps later, I believe it's north of 30-

   10. DFDave Feldman23:24

       Yeah, it's 30

   11. PAPeter Attia23:24

       ... you'll have this pathway where you'll go from desmosterol into cholesterol. So when we measure the desmosterol level, especially when we measure changes in it, absent any other drugs, because there are some drugs that can interfere with the conversion of desmosterol to cholesterol, but we get a sense of what the synthetic function looks like. And so there are some people that are hypersynthesizers. There are some people that have normal degrees of synthesis, and there are some people that actually synthesize a relatively low amount. The third thing we look at are phytosterols. So these are plant-based sterols, which means we can't make them. But by measuring them, we get a clever insight into how cholesterol may be recirculated in the body. So again, I know you know all this stuff, Dave, but I think for the listener, it's important for them to get a little brush up on this stuff. Most of the cholesterol in our body is endogenous, meaning we made it And then we recirculate it. Maybe about 15% is exogenous, maybe less. It would depend on a number of other factors, but the majority of the cholesterol that you eat, and every once in a while you see a funny case study, and there was one this week about, you know, guy eats 30 eggs a day and has low cholesterol. How is this possible?

   12. DFDave Feldman24:36

       [laughs]

   13. PAPeter Attia24:36

       It's sort of an idiotic discussion that I can't believe we're still having. Even Ancel Keys noted this a million years ago. Dietary cholesterol plays a very trivial role in the circulating cholesterol pool because it has esterified side chains that can't be absorbed. Nevertheless, you make all this cholesterol. We'll talk about in detail, I'm sure, how it's trafficked. It comes back to the liver. A portion of that is secreted through biliary means, and now that biliary cholesterol, along with phytosterols, are brought in through this Niemann-Pick C1-like-1 transporter into the enterocyte, where the LXR gene basically tries to regulate how much of this stuff do you need. And if it's doing its job correctly, it jettisons out anything excess through this ATP binding cassette G5, G8. Of course, there are people that have deficiencies in all of these things that can lead to hypercholesterolemia. And in theory, the system should balance itself out. People who are very high synthesizers tend to compensate by being low absorbers and vice versa. So the long-winded soliloquy was for a reason. It's not only important to get the lipid and lipoprotein numbers, but it also helps to know those three things at baseline, one of which you get for free. You're gonna at least get a benchmark of your triglyceride, but to also know your levels of desmosterol, which would be your proxy for synthesis, your levels of sitosterol, cholestanol, sitosterol. These things are phytosterols, meaning we can't make them, so the higher they are, the more we know we're absorbing sterol. The fourth thing that regulates LDL-P, so again, it's triglyceride burden, cholesterol synthesis, cholesterol reabsorption, the fourth thing is LDL clearance. Now, that is not as static as people would like to believe. It's probably not even as static as I used to believe. I used to believe that it was sort of genetically determined what your LDL clearance would be, and obviously there's a great variability there. We see it all over. But it turns out that that is highly regulated at the level of the liver. So even though we can use a drug to demonstrate the variability of it, a statin being the most obvious example, statins are specifically designed to increase LDL clearance from the liver by decreasing liver synthesis of cholesterol. Other changes in cholesterol concentration throughout the body, probably the burden of reverse cholesterol transport and other things, will also impact that clearance, and the majority of LDL, of course, is cleared hepatically. So we don't have an assay for that. So this is the one where I always have to say to patients, "The only way I can really figure out if your LDL-P skyrocketed because of defective clearance," which would, by the way, have to be a new onset of defective clearance, "is if the other three things don't change or if they get better," meaning they all... I hate to use the term better or worse, actually, 'cause it's, this is really, they're neither better nor worse. It's, they just are what they are, right?

   14. DFDave Feldman27:31

       Right.

   15. PAPeter Attia27:31

       But if the synthesis goes down, the absorption goes down, the trigs are largely unchanged, and the LDL goes up, the LDL-P goes up, then you know clearance has gone down. So most of the time you can't actually measure that unless you get lucky, and by measure I mean sort of impute. So anyway, this is helpful and I suspect this will offer an alternative hypothesis to sort of what we're seeing. But anyway, I apologize. I'm talking more than I should be.

   16. DFDave Feldman27:57

       For what it's worth, what you just mentioned, I, I myself have not gotten a sterol test.

   17. PAPeter Attia28:01

       Mm.

   18. DFDave Feldman28:01

       I haven't actually broken down these, but I've been particularly interested in this. And for what it's worth, I've been looking forward to this because I think I may actually be just the stealth interviewer in the room because I think it's just as possible I may be asking you more questions than you're asking me. [laughs] I do wanna add one thing to what you were just talking about on a lot of people go on a low-carb diet and they know they're bringing up their total amount of dietary cholesterol, who then see a likewise increase in their serum cholesterol, the cholesterol in the blood, naturally, because it's intuitive, come to the conclusion, "That must be because I am a hyper-absorber. I must be absorbing more cholesterol."

   19. PAPeter Attia28:38

       Mm-hmm.

   20. DFDave Feldman28:39

       And I think in the course of this conversation, this will help illustrate another reason why that may be the case, because you may in fact be trafficking more fat as energy and therefore it may be ride-sharing with cholesterol in these lipoproteins.

   21. PAPeter Attia28:52

       Yeah, I think the terminology is going to be confusing. So when we talk about hyper-absorbers, we're referring very specifically to this mechanism about the, this Niemann-Pick C1-like-1 transporter and the ATP binding cassette, the, which is called, it's usually referred to as ABC G5G8. But as you said, that person who says, "Hey, Dave, I just went on a low-carb diet and I'm, you know, I'm eating more eggs and more this and more that, and my cholesterol has gone up," well, the problem with that is it's, like, wrong on many levels, right? We should never be talking broadly or vaguely about cholesterol. What went up specifically?

   22. DFDave Feldman29:26

       Right.

   23. PAPeter Attia29:27

       Did LDL cholesterol go up? Did LDL particle number go up? Did total cholesterol go up? Et cetera. But it's quite likely that those two things are not causal, meaning the person who's increasing their consumption of dietary or exogenous cholesterol is also usually increasing their consumption of dietary fats.

   24. DFDave Feldman29:46

       Absolutely.

   25. PAPeter Attia29:46

       And as we'll talk about later, I'm sure, one of those subtypes of fats in a subset of susceptible individual seems to set off a hypersynthetic pathway for cholesterol, which when we get to it, I want to share with you my data set on hyper-responders, meaning these patients, which is what is the pattern of hyper-response? Because not everyone has this experience where they go on a ketogenic diet and their LDL skyrockets. I didn't have that experience, but I have the privilege of getting to see the blood of tens if not hundreds of people over the past few years, so I get to see, oh, sometimes this happens. Sometimes it doesn't. What else is going on here? So

5. 30:27 – 36:52

   Dave's Story: Prediabetes, Keto and the Lipid Spike

   1. PAPeter Attia30:27

      What year did all this start for you?

   2. DFDave Feldman30:28

      In April of 2015 was where I got my second A1c of 6.1, which is the hemoglobin test, which suggests that I'm pre-diabetic.

   3. PAPeter Attia30:37

      And that was with a triglyceride of 80?

   4. DFDave Feldman30:39

      Yes. Actually, that's correct. That was the very last time. That was that same test.

   5. PAPeter Attia30:42

      Okay.

   6. DFDave Feldman30:43

      So when I saw that, I then immediately felt compelled to go and learn everything I could on how to change my blood glucose levels, because also I had a fasting glucose of, I wanna say, like 103. And at the doctor's office, they said, "Well, yeah, this is the second year in a row, but we'll keep monitoring it." And I said, "Well, no, thanks. I'm gonna start trying to figure out what it is that I can do to dodge type 2 diabetes, because it's rampant on my dad's side of the family." And so I started to go to diabetic forums, diabetic forums. They were talking about this LCHF diet, which I would then find out is a low carb high fat diet. I would then look a little bit further. I found out about the ketogenic diet, and it all sounded very interesting. And I remember at that time asking on the forum, saying, "Okay, now wait a sec. How can I be sure my cholesterol won't go up?" And at the time, the, the common answer was, "Well, it only happens for a few people, and even then it's complicated, but it's really probably not a problem." And there wasn't really a very solid answer to it, but I felt at least confident enough that it was unlikely to happen to me, and therefore I would go ahead and take the shot because my cholesterol numbers were generally pretty good. I did like hearing that it typically raised HDL, and that was the one thing my doctor would occasionally ping me for. He'd say, "Like if your HDL was a little bit higher." So after I started, both my dad and my sister got enticed to do it as well. My dad's type 2 diabetic. His last A1c was like 8.3. My sister's not diabetic, but was hypertensive. They both get inspired. They end up going on the diet. To this day now, my dad's in the 5.9s, something along those lines, and my sister's, uh, no longer hypertensive when she's staying on the diet fairly well. The two of them get their cholesterol test before I do, after they start the diet around the same time, and both of them, I warn them in advance their LDL cholesterol might bump a little. And sure enough, that is what happened to both of them, but it wasn't that concerning. I get mine a little bit later, about seven and a half months later, and mine skyrockets.

   7. PAPeter Attia32:47

      So this is like late 2015?

   8. DFDave Feldman32:49

      Correct. So November 2015, I believe my total cholesterol was 329. My LDL-C was 200 and, I wanna say 250. I can't remember. Somewhere around there. And that was a very cathartic moment for me, at least as far as I'm looking at the lab work. I'm going, "What the heck happened? How did I get to this place?" And for two very miserable weeks, I found this guy, Peter Attia, who happened to already have a lot of data [chuckles] and a lot of a great series. I like engulfed your series, but I could hardly understand it at the time, and I started reading up on Thomas Dayspring. I found Tara Doll. I started looking at just anybody and everybody who could say anything about lipids. And in the course of doing it, that's when I started seeing this pattern, as I started, like, tweaking a little bit into Clinical Lipidology, the book, and-

   9. PAPeter Attia33:40

      When you say the pattern, just to be clear, the increase in LDL cholesterol in the presence of a low carbohydrate, high fat diet?

   10. DFDave Feldman33:47

       No, I actually mean it being a network.

   11. PAPeter Attia33:50

       Okay.

   12. DFDave Feldman33:50

       That-

   13. PAPeter Attia33:51

       So say more about that

   14. DFDave Feldman33:51

       ... lipoproteins are a boat. This is gonna be 101, but let's kind of do that for the listener for a second. They're lipid-carrying proteins, and so your body makes them, and they make them at numbers we can't even imagine. They're measured in quintillions, which is like a million trillions. And it's doing this both in the gut and in the liver, and when they make it, they're basically packing in lipids that these cells need. And in particular, they pack just about every kind of lipid, not just triglycerides, which your body uses for energy, but also cholesterol, which we're gonna be talking about a lot, but also fat-soluble vitamins like A, D, E, and K. And it packs all of these the same container, but what's neat about it is this boat, in order for it to get to the cells that wanna make use of it, need to have a complex system in place so that they can kind of special order what it is that they wanna take off of these lipoproteins. And that's where it gets interesting, because the lipoproteins have these kind of snaky bumps on the top of them that are proteins, that are the apolipoproteins. And hopefully we don't have to get too technical for the audience on that, but of course, I'll appreciate it if we can. [chuckles] Um-

   15. PAPeter Attia35:00

       I think we're gonna have to, but yeah.

   16. DFDave Feldman35:01

       Yeah, we're probably gonna have to, but it's those apolipoproteins that you could relate on a computer side to, like, metadata, to, like, headers, for example, as far as where it is that they're gonna go and why. And what excited me about as I was learning about this is I was like, "I don't know how much of this I'm projecting my own experience as a software developer, but this looks like a very complex series of distributed objects that clearly, if I'm looking at it from a payload perspective, is primarily an energy distribution network." It appears as if its primary job, more than any other job, particularly chylomicrons and VLDLs, are to deliver this fat-based energy to tissues. That's what they go out with, and that's what they come back typically not with, coming back to the liver. And because almost everything ends up coming back to the liver, this looks like it's a central regulator. And in that sense, this looks, I mean, in many respects, it has many attributes common to what we would call in software as a cloud network, something we use a lot. And it's very important to be able to do things at scale, but particularly with the level of interaction that goes on with the lipoproteins between each other. It's not like these boats go out autonomously and never have any interaction beyond just going to dock and dropping off their different cargo. They actually constantly connect with each other through things like cholesterol ester transfer protein, phospholipid transfer protein, and so forth. These are different ways in which they, in the process of moving through the bloodstream, actually have further interactions that move around the total pool that's being used by the entire system. And hopefully I didn't get too technical there, but you, you get the sense of it. In many ways, this has a lot of overlap with techniques that we use right now in how we build networks out of servers.

6. 36:52 – 47:19

   Lipoprotein Lineages, ApoC3 and LDL Origins

   1. PAPeter Attia36:52

      So I think we do need to get pretty technical on this because I suspect that you and I will draw different conclusions from the data, and in my experience, the easiest way to understand where those differences lie is to sort of start to get into some of the things that we would view differently. So I'll start with one thing that you said. So I like to be, I think, maybe clear on where I believe the chylomicron, the VLDL, the IDL, and the LDL are coming from, going, and what they're doing. Now, we can't actually know for certain any of these things. I've had some very interesting discussions with people about this over the years, and, I mean, I've had one of the most brilliant lipidologists I've ever spoke to said, "Why do we have LDL?" To which the answer is, it's just God's cruel trick on our species.

   2. DFDave Feldman37:39

      [laughs]

   3. PAPeter Attia37:39

      Because, you know, most other species don't have the LDL burden we have. I think a more thoughtful answer, though, is the overwhelming burden of evidence is that the purpose of LDL is to carry out reverse cholesterol transport. You alluded to this already. You basically have these three different lineages, this is a bit of an oversimplification, of lipoproteins. You have these chylomicrons, which as you said, are primarily getting fat from the gut and very rapidly undergoing a process of hydrolyzing themselves and releasing through an apolipoprotein called apoC-II all of their triglyceride through interaction with something called lipoprotein lipase. So we have this rapid chemical reaction that very quickly gets rid of these incoming dietary, and sometimes non-dietary, because I want to be clear that we can't really distinguish exogenous and endogenous fat in that pool because you're going through that same recirculating process. But at the risk of oversimplifying, fat comes in the body. If you're on a high-fat diet, you're eating fat, it's coming in the gut. The chylomicron, which is its own little lineage because it has a different apolipoprotein, so it has this thing called apoB 48, as you know. That comes in and, and then the apoC-II interacting with the LPL is what's extracting that. Oh, yeah, great. Dave just whipped up a great picture, so-

   4. DFDave Feldman38:56

      We'll have this in the show

   5. PAPeter Attia38:56

      ... we're gonna link to all this stuff. Yeah. So Dave, if you can make a note of this one, [chuckles] and then that way when we're making the show notes, we'll link all that stuff. Okay. Then you have another path we're not gonna talk about much today, which is the HDL path. Totally different. These particles last much longer. They are primarily responsible for reverse cholesterol transport, of which there are two types. Reverse cholesterol transport means taking cholesterol from the periphery back to the liver. That can occur directly, which is when the HDL brings cholesterol itself back from another tissue to the liver, and the most important place it does this is from the subendothelial space. So if you have oxidized sterols waiting to cause atherosclerosis, the HDL can actually go and through another one of those ATP binding cassettes, it can delipivate the HDL, uh, the sterol, take it right back to the liver. That's direct RCT. But there's also indirect RCT, which is the LDL can bring cholesterol back, can give cholesterol to the HDL through CETP, as you alluded to, and that goes-

   6. DFDave Feldman39:59

      The other way, right? Like, you mean HDL actually taking the cholesterol and giving it to the LDL to take back to the liver.

   7. PAPeter Attia40:04

      No, the... Well, actually both. So LDL gives to HDL to go back to the liver.

   8. DFDave Feldman40:08

      Oh, I see what you're saying.

   9. PAPeter Attia40:09

      Yeah, yeah. Through CETP.

   10. DFDave Feldman40:10

       Yeah.

   11. PAPeter Attia40:10

       So that's indirect RCT, but it's that VLDL to IDL to LDL path that is governed by these apoB. Like, their lineage is described by apoB 100, which differentiates them. Now, one of the things I didn't learn until recently, and I don't know if this is accounted for in the model because the figure that we're gonna link to is not actually showing that, is that about 40% of LDL comes directly from the liver. It's de novo created.

   12. DFDave Feldman40:39

       Right. Tom Dayspring linked me to the study that I'd since read on this one. Uh, really-

   13. PAPeter Attia40:44

       Which one? Is this the Frank Sacks?

   14. DFDave Feldman40:46

       I don't remember. I don't remember the authors. They get into the different subspecies of apoC-3s and apoE and how they counterbalance each other as far as degree of affinity for clearance and so forth.

   15. PAPeter Attia40:57

       Yeah. That's sort of un... I mean, I wouldn't say it's unrelated. This stuff's all related. So we'll park this topic 'cause it's super interesting, but when these lipoproteins have apoE on them, which is pretty unusual, it's about 2 to 5% if my memory serves me correctly. We'll fact-check that. It might be different. But a very small number of these apoB 100s are carrying apoE, and when they do, they actually have much more rapid clearance.

   16. DFDave Feldman41:21

       As in having apoE only and not having apoC-3.

   17. PAPeter Attia41:24

       Well, that's actually a good question. ApoC-3 is clearly the worst actor you could have here. There's nothing worse than having an apoC-3 sitting on your apoB 100 cell. In fact, some would argue that may be the single worst thing you could ever have happen because it increases the residence time of them. So we're gonna come to this, I know, because you've written about remnants. I'm going to argue that we have no way of knowing what a remnant is without being able to measure apoC-3. Because when we look at a VLDL cholesterol, and I apologize to the listener, I swear we'll get back to our main point here. Unless we actually know something more than just how much cholesterol is in VLDL, we have no way of knowing whether it's an appropriate remnant, what we call a physiologic remnant or a pathologic remnant, and the pathologic remnants disproportionately carry apoC-3, which increases their residence time. And the same is true on LDL.

   18. DFDave Feldman42:13

       I do wanna follow up on that point, though.

   19. PAPeter Attia42:15

       Yes. Yes. Yes. We, we absolutely will, 'cause it's such an important point, and to me, it's one of the two most interesting clinical assays I'd like to see developed. I would love to see a clinical assay for apoC-3 and for LDL triglyceride concentration, which goes back to a point we had a few minutes ago.

   20. DFDave Feldman42:31

       And for anybody listening who's developing that assay, [chuckles] please reach out to me because for all of the self-experimentation I do, I mean, one of the things I didn't mention is that I literally just did my 100th blood draw last Tuesday. I've obviously done enormous amounts of self-testing to do this, and that's exactly one of the things I want to check is how dynamic or not dynamic the distribution of things like ApoC3 are based on, for example, existing illness or the energy distribution and so forth. So anyway, I realize we're kind of getting in the weeds here, but that's-

   21. PAPeter Attia43:02

       Yeah, I mean, you should have a low level of C3 because your insulin levels are quite low. So C3 tends to move with insulin. So this-

   22. DFDave Feldman43:12

       Right

   23. PAPeter Attia43:12

       ... may be one of the things that explains why someone with type 2 diabetes who is hyperinsulinemic will, on a particle for particle basis, maybe even have a greater burden of, of the lipoprotein because the actual residence time of each of their particles, both VLDL and LDL, is longer than someone with lower insulin. So you have this de novo creation of VLDLs and you have this de novo creation of LDLs and they form this circulating pool. But to my knowledge, we can't really differentiate those when we look at that snapshot. I can't tell is that an LDL that came from a VLDL or is that an LDL that came straight from the liver in that form?

   24. DFDave Feldman43:53

       And that was actually one of the questions I had for you was how, with a kinetic study, can you actually determine if an ApoB 100 lipoprotein that was secreted by the liver ever has, say, an ApoC2 on it? I think you and I would probably be in agreement that we don't know.

   25. PAPeter Attia44:12

       We don't have any clinical way to measure that.

   26. DFDave Feldman44:15

       Right. And in that sense, I fully concede that I can't be sure even with the energy model that the LDL particles that I'm seeing, the LDL-P, that I can say with any level of real confidence how many of the total proportion of those were truly for energy delivery.

   27. PAPeter Attia44:32

       So I would argue that depends. [chuckles] This is where we get into the semantics. I would argue none of them are for energy delivery because that's not what LDL does. But I think what you mean is how many of them came from VLDLs that were trying to deliver energy.

   28. DFDave Feldman44:46

       Right. Originated as VLDLs for the purpose of doing it. If the job of your... In the morning, let's say that your job is to deliver pizzas.

   29. PAPeter Attia44:55

       Right.

   30. DFDave Feldman44:55

       And that's your job and you know it only takes you about an hour to do. And then guess what? The rest of the next two to four days, you're actually gonna be patrolling the neighborhood. You're the neighborhood watch and you're going around, you're also, you know, helping to fix up people's houses or something along those lines. Somebody who comes into the neighborhood and sees a whole bunch of these cars patrolling, they don't know how many of those people actually delivered pizzas before they got started on that part of the shift, and that's basically what we're both coming to, right? We don't actually know how many people left the liver, how many VLDLs left the liver versus-
7. 47:19 – 52:42

   Defining Lean Mass Hyper-Responders

   1. DFDave Feldman47:19

      So with that in mind, here's what I would speculate, and this is purely hypothetical, but I would speculate if you were to grab a whole bunch of people who are, and we'll hopefully get into this model that I'm talking about that I call lean mass hyper-responders. People who are at the far end of the spectrum. They are athletic, they are thin, and they are very, very low carb, and therefore see very high levels of LDL-C and LDL-P, but they also have very high levels of HDL-C and low levels of triglycerides. I suspect that they would show a very high rate proportionally of VLDL secretion, that they actually are trafficking a lot more for their energy triglycerides in VLDL particles and therefore have succeeding LDL particles as to the explanation as to why their LDL-C and LDL-P would be higher.

   2. PAPeter Attia48:09

      So let's use this as a moment, 'cause I, I wanna get into that in greater detail, but let's take that step back and have you maybe just put a little bit more color on what you mean by your lean mass hyper-responder phenotype.

   3. DFDave Feldman48:22

      For those people who go on a low-carb diet, some subset, and nobody seems to agree on this because there's really not been any large study done on it. Some people will say it's 5%, some will say it's 30%, will, like me, see that their LDL, their total cholesterol, they will see both of those rise substantially.

   4. PAPeter Attia48:39

      Can I interrupt you for one sec?

   5. DFDave Feldman48:40

      Yeah.

   6. PAPeter Attia48:41

      Have the people at Virta Health released any of these data? Because they would probably have the most rigorous database on this.

   7. DFDave Feldman48:49

      Here's a little bit of my qualification here. The problem that I have is at least with what we see at cholesterolcode.com, the blog that I have, we have lots and lots of hyper-responders that send it in. There is seeming to be a higher proportionality of people who are lean and/or fit, who seem to be metabolically flexible. Virta, of course, its pool of participants, they had to start out, I hope I don't get this wrong, but I believe that their BMI is at a much higher level when they start.

   8. PAPeter Attia49:17

      Well, it's a company obviously that is dealing with patients with type 2 diabetes. So yes, they're not going to be disproportionately lean and fit to begin with.

   9. DFDave Feldman49:25

      Right.

   10. PAPeter Attia49:25

       So you're saying that that basically wouldn't be the ideal pool to observe this phenomenon?

   11. DFDave Feldman49:29

       I would prefer a broader base.

   12. PAPeter Attia49:30

       Okay. All right, sorry.

   13. DFDave Feldman49:31

       So with that said, it's absolutely true. They've got some of the most pristine data. They also have that data that I would be looking for where they get NMRs, for example, before the participants start. So that was nice too. They're going to have so much great data that comes out of that. But getting back to hyper-responders per what you were talking about before, this was what we call people, and this predates me, who would go on a low-carb diet, would see their LDL cholesterol, their LDL particle count climb. And then there seemed to be a subset, and I wrote about this about a year ago last month, of people who are on the furthest end of the spectrum actually tend to have the highest levels overall of LDL cholesterol, but also have other things in common. This pattern is very distinctive. They would have, say, an LDL of 200 or higher.

   14. PAPeter Attia50:22

       You mean LDL cholesterol?

   15. DFDave Feldman50:23

       Sorry, LDL cholesterol of 200 or higher, HDL-C cholesterol of 80 or higher, and triglycerides of 70 or lower. And this is so prominent to the extent to where I even did this kind of recently at another conference. I called out another speaker to where I said, "I'm very interested in your lipid numbers because I think you might be a lean mass hyper-responder." And she said, "Well, I hadn't actually taken it in years." And we tested it on the spot and it hit all of those points. Her LDL-C was 189, her HDL-C was 80, and her triglycerides were 70. And this seems to so far span across all sorts of, for example, ApoE types, ApoE 3-3s and 2-3s, as well as the 3-4s and 4-4s. And we have not been able to identify any other SNP or anything that's clearly associating this type.

   16. PAPeter Attia51:15

       Including the PPAR alpha and PPAR gamma?

   17. DFDave Feldman51:18

       That's one of the ones I wanted to follow up on, particularly since I heard your podcast with Rhonda. And I had a bunch of people on Twitter just send me full body pictures for me to use in this most recent speech I did on lean mass hyper-responders.

   18. PAPeter Attia51:29

       You have to be careful with that. You can get into trouble that way.

   19. DFDave Feldman51:32

       I did say be sure to respond this tweet where I'm specifying exactly what I'd be using them for. So anyway, generally speaking, they tend to be very fit. They tend to be very thin. And oftentimes, and you kind of had a story of your own from before I even got into this, they'll say, "I really don't want to stop. I really love this way of life. I feel better than I ever have in my life." And I give the same answer not too far different from yours. And then I say, "Okay, generally speaking, I feel like all of your markers look great, low inflammation across the board." Of course, I give the standard, "I'm not a medical doctor and this isn't medical advice," et cetera. But all that said, it's hard for me to come to the conclusion that you're in trouble unless we can likewise see further markers such as expanding CIMT and CAC and so forth that's going to show that you actually are developing higher rates of atherosclerosis. Now, I'll qualify in advance because I'm sure you'd want to say this as well. And I've mentioned this to several people. Things like atherosclerosis can develop without any sign for a fairly long period of time. For example, I think it's what, 60% before you even see occlusion in the lumina, for example.

8. 52:42 – 1:00:24

   How Atherosclerosis Develops: Retention, Oxidation and OxLDL

   1. PAPeter Attia52:42

      Well, let's back up a little bit. So I always want to be careful that when people are talking about CIMT and CAC that we're never using those in the same terms as we would think of biomarkers, right? So a biomarker, what you've described is let's look at your LDL cholesterol or better yet your LDL particle number. But remember something, a CAC, which is a calcium score, so it's a dry CT scan that very quickly scans over the heart and just picks up calcification, no anatomic detail, or a CIMT, which is a type of ultrasound that looks at the intimal thickness, so that's one of the walls of the artery's thickness in the carotid arteries in the neck. These are both tests that are used to try to gauge advanced disease. So the real way to think about this is to, and I think Ron and I talked about this at length in the podcast, is to look at a pathology textbook. When you look at the autopsies, you'll get a sense of what's going on. Long before you have luminal narrowing, which may or may not accompany a problem, you have a very clear documented path of what this disease does. So again, I think you know this, Dave, but I think for the listener it is worth repeating this if they don't want to go back and read some of the posts I've written on the progression of atherosclerosis. When we're born, we have these beautiful arteries. The arteries have this endothelial lining, so this very thin type of cell that coats the luminal, meaning the part that's closest to where the blood is flowing. So there are spaces between these and via diffusion, lipoproteins get in there and out of there all the time. This is relatively well understood to be a gradient phenomenon. So the more of the lipoproteins you have, the more of them that are going to go in. But as we talked about earlier, other things will influence it. The residence time, for example, which might be why this ApoC3 thing is such a pain in the butt, because if it allows these cells to stick around longer, bad things happen. Now, what most people don't know, I think, is that an LDL particle is more likely to come back out when it goes in there than it is to stay in there. That's good news. HDL particles always come out of there. There are other types of particles, Lp (a) and pathologic VLDL remnants can do the same thing as well. The problem occurs when proteoglycans bind to, and let's just make math easy and not get into the LP little a's and the VLDLs at the moment. Let's just talk about the LDL since that's the largest burden of this. But when these proteoglycans bind to the LDL and it gets retained, all of a sudden now you have something that's where it's not supposed to be. That's not where we want that thing. It's obviously in a high oxygen environment, so it's going to undergo a chemical reaction called oxidation because it's carrying a cargo, a sterol, that... And by the way, they can be carrying phytosterols and other things like that, but these things have ample opportunity to undergo an oxidative reaction. It's that oxidative reaction that then kicks off an inflammatory response in the endothelium. Now, the good news is today we at least have one laboratory test that can measure that burden of oxidation. It's called the OxLDL assay. Now, this has been around for a while, but clinically we've only been using it for a couple of years. Because it turns out some very small percentage of those LDLs, once they are oxidized, escape back into the circulation. So by sampling those, we can track indirectly, hey, what's the likelihood that oxidative damage is happening? So for me, this is one of the most important metrics I look at, because I want to spend some time later on going over some clinical cases. I want to see some of the data on yours. I want to show you some of the data that will explain maybe how I'm thinking about this. But this oxidized LDL, which is well documented and described in different quintiles, right, is giving you a small sample of what's going on. But for the listener, it's important to understand that when you get a blood test, that's not telling you what's happening in your artery.

   2. DFDave Feldman56:33

      Right.

   3. PAPeter Attia56:33

      It's giving you probabilities of things that are largely stochastically governed that are going on in your artery. And the OxLDL is no exception. Even though it's a beautiful marker, it's still dependent on the idea that a subset of those oxidized sterols are now escaping.

   4. DFDave Feldman56:52

      Can I actually ask a little more on that one? So we already know that LDL particles, specifically ApoB 100 at the LDL stage, have a alpha-tocopherol, I think is how I'm saying. Basically, it's vitamin E.

   5. PAPeter Attia57:06

      Right.

   6. DFDave Feldman57:07

      As part of the antioxidant defense system. Part of the purpose of an LDL particle is to actually provide that as a means to battle reactive oxygen species, right?

   7. PAPeter Attia57:18

      Uh, I don't know about that, and if it were solely true, it would make me wonder why people with LDL deficiencies wouldn't have deficiencies of those processes as well, whereas to the best of our knowledge, they don't.

   8. DFDave Feldman57:31

      Because I've actually been wanting to get into this a lot more recently, and correct me if I'm wrong, but basically there's a certain degree with which you've got vitamin E on board. On top of that, you've got the potential of the phospholipid shell to become oxidized. If you get oxidized phospholipids-

   9. PAPeter Attia57:45

      Mm-hmm

   10. DFDave Feldman57:45

       ... that also can bring about the role of Lp (a) that can cleave off the oxidized phospholipids. That's ultimately what Lp-PLA2 is, right?

   11. PAPeter Attia57:55

       Correct.

   12. DFDave Feldman57:55

       It's the enzyme that's ultimately involved in-

   13. PAPeter Attia57:57

       Yes

   14. DFDave Feldman57:57

       ... helping to... And this is also, I don't know how much of this is actually demonstrated, but is ultimately where a lot of the concept behind why it is you would have a higher detection of small lipoproteins, particularly small LDLs, can come around to, is if you're getting them constantly oxidized and having to constantly cleave them down to much smaller amounts, and then they constantly remodel.

   15. PAPeter Attia58:18

       Yeah, but we're getting off into two different things here. So let's come back to this. It's not clear to me that, that there's sufficient evidence to suggest that part of the role of LDL is to combat the oxidative stress.

   16. DFDave Feldman58:29

       Okay. Let's put that as homework that we'll-

   17. PAPeter Attia58:31

       Yeah. Yeah

   18. DFDave Feldman58:31

       ... catch up on after this. But this is relevant for whether or not we're detecting oxidized LDLs that had never entered the intima, right?

   19. PAPeter Attia58:39

       No. The oxidized LDLs that we're detecting have escaped the intima.

   20. DFDave Feldman58:44

       Interesting.

   21. PAPeter Attia58:44

       There's a very small subset that are getting out.

   22. DFDave Feldman58:47

       Okay. That's definitely something I would like to follow up because I'm genuinely curious about that myself-

   23. PAPeter Attia58:50

       Yeah, yeah

   24. DFDave Feldman58:50

       ... as to whether or not they can be oxidized sufficiently that they'd get picked. Because it also may be something, uh, that is part of the test or isn't a part of the test. But I'd be curious as to how we can actually determine that.

   25. PAPeter Attia59:01

       Yeah. Meaning what you're basically asking is how do we know they weren't oxidized never inside-

   26. DFDave Feldman59:06

       Correct

   27. PAPeter Attia59:07

       ... the subendothelial space? And that's a fair question. I don't know the answer. I know very little about this assay. I mean, I know the technical stuff of how the assay works, like it's an ELISA assay. I know what enzymes it's looking at. But the broader question is, without a tracer, do we know if that LDL has actually been in the subendothelial space where it was bound, oxidized, and then escaped or liberated? So fair question.

   28. DFDave Feldman59:30

       It's certainly relevant to this larger question of the value of LDL particles as to whether they play an important part of the immunological role.

   29. PAPeter Attia59:38

       Well, they do. Probably nowhere near as important as the HDL particle, which is probably why the HDL particle has such a long residence time. And the HDL particle, as important as it is for reverse cholesterol transport, both direct, where it's taking the lipid back to the liver directly, or indirect, which we talked about, and you corrected me, thank you, where it takes it to the LDL and the LDL takes it back to the liver. Certainly, some have argued that an even more important property of the HDL is the proteins that it carries, the immunoglobulins, all of the other things that it carries that play this important role in, in immune function. So it really seems that the overwhelming body of evidence is that the purpose of the LDL particle is to carry the cholesterol back to the liver.

9. 1:00:24 – 1:13:49

   All-Cause Mortality, Lifetime Exposure and the Zero-LDL Question

   1. DFDave Feldman1:00:24

      Interesting. But, hey, this gets back to the multipurpose value of a vehicle. Is it doing things other than that that also turn out to be relevant? And I think this kind of gets to the larger and more important question overall. Like the question that I started with going back to my November 2015 days was I thought very naively that in a few days I would learn all I would need to about cholesterol and lipoproteins, find the landmark study that had a gajillion people, and they would just show that if you had lower LDL cholesterol, you just died less. Like that was it, end of story. And at first I thought that I had found that because of I had found plenty that pointed to events and pointed to lower cardiovascular risk, but then wouldn't necessarily talk as much about all-cause mortality. I then had to learn about all-cause mortality. And then more and more, I felt like I couldn't get to something that really emphasized... I thought for sure at least I would see, for example, an elderly population, generally speaking, the lower your natural LDL, we can get into SNPs for example on this-

   2. PAPeter Attia1:01:27

      Mm-hmm

   3. DFDave Feldman1:01:27

      ... the more likely it is that you would just live longer, period. Uh-

   4. PAPeter Attia1:01:30

      But you have to remember how these studies are powered. So the challenge with ACM is I don't think any study in the history of civilization is going to be powered to detect that. It's hard enough to detect cardiac mortality in a study. I think we need to be more clear in what our concern is. If the concern is if you are less likely to die of heart disease, you are more likely to die of something else, then we should state that explicitly and say, "Hey, low LDL, while may be protective of cardiovascular disease," I will argue that is unambiguously clear and we can discuss that. But the bigger question is are you concerned that, well, it's increasing the risk of cancer or neurodegenerative disease?

   5. DFDave Feldman1:02:08

      A trade-off.

   6. PAPeter Attia1:02:09

      Yes. So the question there, that's a question of power. And so it's not uncommon in cardiovascular studies to see a reduction in coronary mortality with no change in all-cause mortality or a non-statistical change. You know, most of the time you just don't see a change or it's a change that's very slight, and then you have to ask yourself the question, even if it looks, you know, like, hey, death went up or down of other causes, you have to go back and ask yourself, was the study actually able to detect that? That's a very hard thing to detect.

   7. DFDave Feldman1:02:38

      Absolutely. And in fact, there's even a paper that I pointed to recently that says, is this even worth chasing after? Because it takes so much expense and time in order to get to a level in which it would be powered to detect for all-cause mortality, should we even make that part of the criteria that's required?

   8. PAPeter Attia1:02:53

      Well, there's a broader issue here, which is the lifetime exposure problem.

   9. DFDave Feldman1:02:57

      Exactly, and this is of course just the problem with atherosclerosis in general, is you do a drug study that's two, three years, but atherosclerosis doesn't take two to three years from zero to-

   10. PAPeter Attia1:03:07

       Yeah. I try to not get into any wars on Twitter, but once in a while I'm just, I don't know, I've had one too few Topo Chicos and I'll let it rip.

   11. DFDave Feldman1:03:15

       [laughs]

   12. PAPeter Attia1:03:15

       But if I have to see one more person try to tell me why FOURIER and ODYSSEY aren't interesting trials because they didn't show a big enough benefit, I might scream.

   13. DFDave Feldman1:03:24

       [laughs]

   14. PAPeter Attia1:03:25

       So just for the listener, FOURIER and ODYSSEY were trials that looked at two PCSK9 inhibitors. I want to also be clear before I get into my rant, I am never having an economic discussion about this.

   15. DFDave Feldman1:03:36

       [laughs]

   16. PAPeter Attia1:03:37

       I'm saying that because people often confuse efficacy and effectiveness and cost and value and benefit, and I am not for a moment suggesting those things don't matter. I am not going to argue one way or the other that the cost of a PCSK9 inhibitor is worth it. That's an individual decision. Unfortunately, that decision is for most people made by their insurance company, and that's totally reasonable. I'm only interested in this as a conceptual tool, which is does inhibiting PCSK9 make a difference? And if you had told me, I remember knowing this, that FOURIER and ODYSSEY had such short time horizons, I thought there's no way they'd find a benefit. In particular, FOURIER. So FOURIER took patients with an average LDL cholesterol of something like 90 or 92 milligrams per deciliter. These patients were already on the maximum tolerated dose of a statin. Okay, so they're at the 10th percentile in terms of their LDL-C, and in 2.2 years showed a reduction in events? The null hypothesis should be it should have never worked. You should have needed 20 years to show any benefit when you understand Alan Sniderman's lifetime exposure model. So a lot of people are critical and say it didn't show a mortality benefit, it just reduced revascularizations and events in 2.2 years, to which I say you're looking at that incorrectly. The fact that it showed anything, to your point, Dave, lifetime exposure, is staggering. Also, on patients who are already maximally statinized. So coming back to this thing about lifetime exposure, this is where the Mendelian randomization becomes a very important tool in understanding LDL's causality. What you alluded to at the outset, you are correct in noting is deficient. There is no lifetime study where without a drug you can prospectively manipulate LDL and follow people for 100 years and determine outcomes.

   17. DFDave Feldman1:05:40

       Yeah.

   18. PAPeter Attia1:05:40

       That would be the ideal study, right?

   19. DFDave Feldman1:05:41

       Yeah, that would, that would be.

   20. PAPeter Attia1:05:42

       Okay.

   21. DFDave Feldman1:05:42

       You, you actually, you talked about this in The Straight Dope, uh-

   22. PAPeter Attia1:05:45

       I know, I remember sort of going on-

   23. DFDave Feldman1:05:46

       ... with the wand

   24. PAPeter Attia1:05:46

       That's right, the magic wand test.

   25. DFDave Feldman1:05:48

       Right.

   26. PAPeter Attia1:05:48

       Yeah.

   27. DFDave Feldman1:05:48

       And I think it's worth plugging in something, uh, important here. You've already said this on a, on a prior podcast, and I don't want anyone to misunderstand that you don't necessarily buy into the zero LDL hypothesis. You don't know that you would have LDL at zero. So you do believe there's some kind of trade-off, and you mentioned a few, for example, commonly known diseases for when your LDL actually gets to such a low level, like cognitive diseases and so forth.

   28. PAPeter Attia1:06:10

       The way I would say it is this. So I'm, I'm glad you brought this up because it is a very important distinction. I absolutely believe that the lower the LDL, the lower the risk of cardiovascular disease, all other things equal. Why? Because LDL is necessary but not sufficient for atherosclerosis, and I say that full stop. Now, it's important to understand what necessary but not sufficient means, 'cause there's gonna be some people listening to this who are getting all phosphorylated now and they're just getting super pissed off, and my advice is sit down, shut up for a minute, and pay attention. Okay.

   29. DFDave Feldman1:06:44

       Extra points for the phosphorylated insert, by the way.

   30. PAPeter Attia1:06:47

       [laughs]
10. 1:13:49 – 1:27:37

    The Genetics Debate: Mendelian Randomization, FH and PCSK9

    1. PAPeter Attia1:13:49

       I've seen that. Here's my concern with that, Dave. I have no doubt in my mind that you are a truth seeker. I don't think that's true of necessarily some of your peers. I do think a number of your peers are deluded and so filled with their own confirmation bias and so unwilling to acknowledge that their precious low-carbohydrate diets could be hurting them, that not with malicious intent, but with blind carelessness, they are absolutely ambivalent to anything. I don't put you in that category, so I will challenge you in the following way.

    2. DFDave Feldman1:14:20

       Great.

    3. PAPeter Attia1:14:21

       When you say, "Show me an example of something that is not a genetic study that can point to that phenotype," the reason I would call issue with that is why would you limit yourself from genetic studies? It's sort of like me saying, "Show me... Like, I want to know if there are people who are six feet tall. I think they might be, but I've never seen one, so if you can go into a kindergarten class and find me one, I'll believe it, but y- you must limit yourself to the kindergarten class." I mean, that's an obscure example. What I'm basically saying is you're excluding so much potential data by excluding all of the genetics because when people talk about genetic studies, we have to remember something. Most of the genes, most of the SNPs that lead to alterations in lipids and lipid metabolism are completely unidentified. I mean, FH, for example, familial hypercholesterolemia, which would be the most obvious example to counter that point, you're excluding because it's a genetic condition. But what the listener might not know is that FH is a phenotypic diagnosis, not a genotypic diagnosis. FH is arguably the most heterogeneous collection of genes you can imagine. So why would we exclude looking at those people when that's, in many ways, one of the richest bodies of evidence for a natural experiment in, to answer the question, can you have high LDL-C, high HDL-C, low triglyceride, and still get atherosclerosis? That's what the question you're asking, right?

    4. DFDave Feldman1:15:47

       Yes. Yes. Well, so, so we'll double back to that in a sec, but basically you're taking us back to genes, and this is why, uh, like, this is another hypothesis, fully untested. I'm in the process of trying to collect on it, but I, I call this loosely lipid, cellular lipid malabsorption, or I just generally shorten it to lipid malabsorption. Basically, here's, here's the issue that I have with the existing Mendelian randomizations, and for that matter, almost all of the gene-based studies, is what we're trying to get is, as much as we can, the isolation of just a higher gradient of LDL particle count, right?

    5. PAPeter Attia1:16:19

       Mm-hmm.

    6. DFDave Feldman1:16:19

       That's what we all secretly... We want your wand-

    7. PAPeter Attia1:16:21

       Right

    8. DFDave Feldman1:16:21

       ... that you're talking about where we could wave it and then there's just magically more LDL particles in some people, or for that matter, less LDL particles-

    9. PAPeter Attia1:16:30

       Right

    10. DFDave Feldman1:16:30

        ... without touching any other parts of the process. The problem is that I believe of... I'm keeping a list of my own SNPs of those genes that are, uh, either resulting in higher or lower LDL-C, and unfortunately of the ones that I find in the Mendelian randomizations, they don't just result in the higher LDL-C and LDL-P. They also come to be that way because there's a lack of lipids or lipoprotein uptake by the cells. Therefore, particularly with endothelial cells, you've got to be concerned that that could cause dysfunction and therefore could be a reason for why you would have higher levels of atherosclerosis. And this is why, like, I'm trying-

    11. PAPeter Attia1:17:12

        Wait, wait. So explain that part again, the last part.

    12. DFDave Feldman1:17:14

        Endothelial cells being dysfunctional.

    13. PAPeter Attia1:17:16

        Yes.

    14. DFDave Feldman1:17:16

        Would that be potentially problematic for atherosclerosis?

    15. PAPeter Attia1:17:20

        Yes.

    16. DFDave Feldman1:17:20

        Okay. Then why would we want to look at any SNP that would in any way impair or inhibit them relative to a normal person's endothelial cell?

    17. PAPeter Attia1:17:30

        Why do we believe patients w- or a subset of patients with FH as a result of their FH have defective endothelial cells?

    18. DFDave Feldman1:17:37

        Well, if you've got defective LDL receptors-

    19. PAPeter Attia1:17:39

        There's no receptors on the endothelial cell. It's diffusion mediated.

    20. DFDave Feldman1:17:43

        Yes, but you've got the receptors with the adipocytes, right?

    21. PAPeter Attia1:17:45

        Yes, but at least 20, if not 40% of LDL uptake is not even receptor bound in the body.

    22. DFDave Feldman1:17:53

        Okay. But what about that which is-

    23. PAPeter Attia1:17:54

        And not all cases of FH have receptor deficiencies. So there are at least 2,000 vaguely identified genetic causes of familial hypercholesterolemia. They have fewer receptors, so the PCSK9s are a subset of FH, right? About 3 to 5% of patients with FH have-

    24. DFDave Feldman1:18:12

        Overexpression of PCSK9

    25. PAPeter Attia1:18:14

        ... overexpression of PCSK9.

    26. DFDave Feldman1:18:15

        Gotcha.

    27. PAPeter Attia1:18:15

        In fact, that's how PCSK9 was first discovered.

    28. DFDave Feldman1:18:17

        Okay, but in that case, you're impacting a cell's capability of uptake for lipids or for lipoproteins, right?

    29. PAPeter Attia1:18:24

        Yes, you are in that situation. Those patients' livers will take up less LDL because they... PCSK9 is a protein that does, among other things, degrades the LDL receptors. Because they have hyperfunctioning PCSK9, they are more rapidly degrading their LDL receptors on the livers, so they're taking up less LDL particles, which explains why they have higher LDL.

    30. DFDave Feldman1:18:48

        But this, again, introduces a dysfunction on the lipid metabolism itself.
11. 1:27:37 – 1:41:39

    Case Study: A Hyper-Responder Patient and Peter's Synthesis Hypothesis

    1. DFDave Feldman1:27:37

       Absolutely. Well, and for what it's worth, as I say outside of here, and as I'll say on this podcast, as I actually just said at, uh, the speech, I don't know if you saw the one that I did from last month, I told people I prefer they not be echo chambering. I prefer they find everything that challenges from every side. So with that said, going back to the lean mass hyper-responder, you would say, given what you know right now, given everything we've just talked about, that they are at high risk of cardiovascular disease. Would that be correct?

    2. PAPeter Attia1:28:04

       I'd wanna know more data, but yes. If I didn't know anything else other than-

    3. DFDave Feldman1:28:09

       Let's say all-

    4. PAPeter Attia1:28:09

       Yeah, yeah

    5. DFDave Feldman1:28:09

       ... cardiovascular risk markers save LDL of 200 or higher, LDL-P of typically 2,000 or higher.

    6. PAPeter Attia1:28:16

       Mm-hmm.

    7. DFDave Feldman1:28:17

       Everything else is just pristine perfect, like CRP is in, at the floor. Their, their LP-PLA may be-

    8. PAPeter Attia1:28:23

       Let's look at this patient here. So we're gonna... We'll link to these labs. I asked this patient... This is a patient I saw last week, so that's the only reason I printed this up, 'cause I see this so often, but I'm like, "Let's just get the last one." So this is a gentleman who's been on a low-carb diet for a couple of years, is achieving amazing success with it. He's a new patient to me, but he's been around the block on this stuff before, and he's got an amazing history of his labs going back many years. So I've seen what he looks like on and off all of these therapies, on and off drugs, et cetera. But he's one of these guys where, uh, across the board looks fantastic, right? His glucose disposal is remarkable. His insulin levels are very low. His C-reactive protein is 0.3, so everything looks good. So r- read off some of his numbers just for the folks, Dave. Does he... He doesn't quite meet your lean mass 'cause his trigs might be a bit higher, but talk to me about-

    9. DFDave Feldman1:29:16

       Sure

    10. PAPeter Attia1:29:16

        ... this guy's numbers.

    11. DFDave Feldman1:29:17

        So total cholesterol is 504 L-

    12. PAPeter Attia1:29:19

        Is that high?

    13. DFDave Feldman1:29:20

        Uh, [laughs] this is... I, I know what you're doing there. [laughs]

    14. PAPeter Attia1:29:24

        No, I'm just kidding.

    15. DFDave Feldman1:29:25

        I, I get this all the time where somebody sends me just that number, and they go-

    16. PAPeter Attia1:29:28

        No, no, no. Okay. G- go ahead.

    17. DFDave Feldman1:29:28

        But anyway, total cholesterol 504, LDL-C Direct... And it's worth emphasizing just real quick for the listener when they say direct, it's very important to notice that because usually LDL-C on a typical lab is actually calculated through the Friedewald equation. Uh, so when it's direct, that actually is a direct measurement, and that matters for remnant. Hope we'll get a chance to talk about remnant.

    18. PAPeter Attia1:29:47

        We will talk remnants for sure.

    19. DFDave Feldman1:29:48

        So, uh, LDL-C at 362, HDL-C at 94, triglycerides at 125. The very first question I would ask if somebody was sending this to me is whether it was fasted or not.

    20. PAPeter Attia1:29:59

        Yeah. This was, but I've gone back and looked at all of his other trigs, and he actually normally does reside below about 70.

    21. DFDave Feldman1:30:06

        Oh, he does?

    22. PAPeter Attia1:30:06

        Yeah, yeah.

    23. DFDave Feldman1:30:06

        Okay. So he would be typical for a lean mass-

    24. PAPeter Attia1:30:08

        Yeah

    25. DFDave Feldman1:30:08

        ... hyper-responder.

    26. PAPeter Attia1:30:08

        He might have just eaten dinner a little too late or some... You know, I'm not, I'm not sure what was going on.

    27. DFDave Feldman1:30:12

        Do you want me to keep going on the particles?

    28. PAPeter Attia1:30:13

        Yeah.

    29. DFDave Feldman1:30:13

        Okay.

    30. PAPeter Attia1:30:14

        Go, go hit the particles.
12. 1:41:39 – 1:55:44

    Peter's Exercise Kinetics Experiment and Remnant Cholesterol

    1. PAPeter Attia1:41:39

       I don't see any change in the cholesterol content. I mean, it's minimal change in cholesterol content, right? What I think you see here is, yeah, wow, under really periods of super high intense exercise, I actually did take some triglycerides out of this.

    2. DFDave Feldman1:41:52

       Right.

    3. PAPeter Attia1:41:53

       Minimal out of here. By the way, this backs up Garvey's data, which is there's virtually no way to distinguish what's going on at the VLDL level. I mean, we can't tell what's a remnant here or what's not a remnant. I apologize for the listener. We're looking at the chart, but we're gonna link to it so you'll see it. We're basically talking about this idea of how much movement of cholesterol is going into and out of the LDL particle under these extreme conditions. So I just did different types of workouts. So on this day, I did a crazy high-intensity interval training. On this day, I did a crazy intense swim, and I think on this day was the hardest workout of them all. It was a crazy intense bike ride.

    4. DFDave Feldman1:42:27

       And the listener can't see this, but I'm smiling ear to ear. It's almost as if you knew I was [laughs]

    5. PAPeter Attia1:42:31

       I forgot I did this. I did this, uh, six, seven years ago.

    6. DFDave Feldman1:42:35

       Ah.

    7. PAPeter Attia1:42:35

       And, um-

    8. DFDave Feldman1:42:35

       This is fantastic

    9. PAPeter Attia1:42:36

       ... again, it's not commercially... You know, these are not assays that can be reproduced.

    10. DFDave Feldman1:42:39

        Right.

    11. PAPeter Attia1:42:40

        And again, I suspect you and I will look at these differently, right? I'm looking at these to say the VLDL is definitely moving its triglyceride. The LDL a little bit. The cholesterol's barely moving. Now, this is different from a broader issue, which is how much did my cholesterol actually change in those nine blood draws? Well, that was the variability of my LDL-P, so we'll link to a graph that shows LDL-P versus LDL-C. These are nine points across three days.

    12. DFDave Feldman1:43:10

        I wish I could go back in time, find the year. What is this, like 2012, 2013, something like that?

    13. PAPeter Attia1:43:17

        Yeah, probably 2011 or 2012.

    14. DFDave Feldman1:43:19

        I'd be, "Peter, this is Dave from the future."

    15. PAPeter Attia1:43:21

        [laughs]

    16. DFDave Feldman1:43:21

        "I need you to eat exactly the same thing you do on all these days."

    17. PAPeter Attia1:43:24

        Yeah, I pretty much did.

    18. DFDave Feldman1:43:25

        Oh, you did?

    19. PAPeter Attia1:43:26

        Yeah, yeah, yeah.

    20. DFDave Feldman1:43:26

        Okay.

    21. PAPeter Attia1:43:26

        I controlled for that. Yeah.

    22. DFDave Feldman1:43:27

        Okay, good.

    23. PAPeter Attia1:43:28

        And I was timing exactly when I would eat it. This is back when I was very strictly in ketosis.

    24. DFDave Feldman1:43:32

        Fantastic. That's effectively what I'll be doing. So I'll actually have... I'll add a two to your N, but I'm super excited to be seeing this now.

    25. PAPeter Attia1:43:40

        Yeah, but you're not gonna have, unfortunately, this. I mean, this to me is the interesting part, is This is the part that surprised me the most, was how little the cholesterol was actually moving out of the LDL even when the particle was going down. And remember, the height of this bar is artificial. It doesn't mean anything. This is not the LDL-P, right? This is milligrams per deciliter, milligrams per deciliter of cholesterol, of triglyceride.

    26. DFDave Feldman1:44:04

        Maybe I'm getting a little confused here. How do you know about the cholesterol moving out of the LDL-P?

    27. PAPeter Attia1:44:09

        Because, well, what I can say is before the workout, there was 116 milligrams per deciliter of cholesterol in the LDL, and after the workout, that's what was there. This is how much triglyceride was in the LDL. That's what was there.

    28. DFDave Feldman1:44:22

        Okay.

    29. PAPeter Attia1:44:22

        So it's sort of a flux.

    30. DFDave Feldman1:44:24

        Right. Because here's the thing. I mean, in a sense, we're sort of, I know you can acknowledge this as well, we don't exactly know what the true circulatory level of recycling is. You're just saying on a per particle basis for testing it afterwards, like for example, you don't... We're talking about the pool.
13. 1:55:44 – 2:14:27

    Energy Flux and the Mass Balance Standoff

    1. PAPeter Attia1:55:44

       So endogenous means we're dealing with the pool of triglycerides that are coming out of you as the person. So you have adipocytes. Adipocytes store triglycerides, and those triglycerides are Hydrolyzed such that you have free fatty acids that will be transported. So where do they go? So they, when they come out of the adipocyte, who picks them up? Albumin. So albumin then does two things. It can take it directly to the muscle so that the muscle can use it in the highly fat adapted athlete, or it can take it back to the liver and it can be repackaged in VLDL or it could be turned into a ketone if we're getting into an extreme state of someone who's ketotic. So let's talk about Craig Moffitt, who looks like a super fit dude who's running around, has a total cholesterol of 457 milligrams per deciliter. His LDL cholesterol is 335, his HDL cholesterol 109, and his trig is 67. So you have, I'm assuming you did the math correctly. I'm not gonna check it, but if that's presumably the LDL is direct. His remnant cholesterol is 13 milligrams per deciliter and by the way, that's not terribly far off from what you would get by the, uh, trig by five formula. He's not that far off. Okay, fine. So where is he getting his energy? So let's say he's out for a run, right? So he's not eating anything and he's fat adapted, so he's, and he'll say he's fasted. Let's make it even easier. He's fasted going out for a run. So his adipocytes are releasing free fatty acids to albumin. The albumin is taking some fraction of that to the muscle directly and they're undergoing beta oxidation there. The albumin's also going back to the liver and some amount of that is being converted into beta hydroxybutyrate, which goes down its own metabolic pathway and some amount of that is being packaged in either a VLDL or an IDL. 'Cause remember, there's still de novo ILDL production in the liver.

    2. DFDave Feldman1:57:43

       Right.

    3. PAPeter Attia1:57:43

       Just as there's de novo LDL production. Those VLDLs and IDLs are leaving the liver and dropping off their payload of lipid to that tissue. So the tissue's basically getting ketones from the liver, triglyceride from albumin directly to the muscle and triglyceride through the VLDL and IDL directly to the muscle. Do we agree on that?

    4. DFDave Feldman1:58:06

       We do. I'm just gonna expand a little bit on what you just said. So yes, it's full body lipolysis in that you're, he's releasing the free fatty acids. In the literature, they're usually calling them NEFAs, non-esterified fatty acids, but we'll just keep it to free fatty acids. It's getting released from all over.

    5. PAPeter Attia1:58:20

       And we usually measure them, by the way, as one.

    6. DFDave Feldman1:58:22

       Yeah. It's a little frustrating 'cause a lot of this terminology gets interchanged, but the free fatty acids that are ultimately making it back to its liver are getting packaged into the VLDLs. While we're talking about the target sites of the muscles for which are making use of triglycerides, I should emphasize that I believe that the primary purpose of the creation of those is to replete everything. So it's not just to fuel the muscles, it's also to put it back into the adipocytes that just now released it as well. In other words, Craig Moffitt, like many people who are lean mass hyper-responders, if we could install a little turnstile into their adipocytes, we would see that turnstile just spinning like crazy. They barely park the triglycerides there before it's heading right back out and that's because there's less total adipose mass overall on Craig Moffitt compared to somebody who's a lot heavier and therefore there needs to be more global supply of VLDLs relative to somebody else who has a lot more fat mass.

    7. PAPeter Attia1:59:21

       But this depends on his energy requirement. I mean, of course-

    8. DFDave Feldman1:59:23

       Absolutely

    9. PAPeter Attia1:59:24

       ... while he's running, and I wrote a blog post on this a long time ago, which I guess we ought a link to called, it's something about fat flux. I don't remember the name of it exactly, but the gist of it was oversimplifying a fat cell as having two input doors and one output door. The two input doors being the de novo lipogenesis door, which is still an esterified entry door, but I separate it as a different storage f- meaning it's coming from a carbohydrate, not from a fat. And then you have the re-esterification door, which is the turnstile that allows fat to go right back in and then you have the lipolysis door which allows the fat to exit. So a person who is in fat balance has a situation where L, lipolysis, equals the sum of the esterified de novo lipogenesis plus the re-esterified fatty acids. Agreed? That's just ma- straight up mass balance.

    10. DFDave Feldman2:00:11

        Yes. Yeah.

    11. PAPeter Attia2:00:12

        So when Craig's running, he's in negative fat flux. Make no mistake about it. His de novo lipogenesis is zero at that moment. His esterification is something and his lipolysis has to be something bigger.

    12. DFDave Feldman2:00:24

        Right.

    13. PAPeter Attia2:00:25

        If he's not depleting glycogen, which if he's highly fat adapted, he's not.

    14. DFDave Feldman2:00:28

        And maybe it's worth putting out a distinction. I'm not talking about whether they were successfully, at the moment that he's running, successfully re-esterifying these fatty acids back into the adipocytes.

    15. PAPeter Attia2:00:38

        And they might be though. And that's my point, is we don't know.

    16. DFDave Feldman2:00:40

        Right.

    17. PAPeter Attia2:00:40

        What we know is that in, which gets back to the question of-

    18. DFDave Feldman2:00:42

        But, but do we know that it's the job of the liver to keep maintaining that buffet, to keep putting that energy back out there? And generally speaking, we do know that. It's just to what degree.

    19. PAPeter Attia2:00:51

        My hypothesis is yes. My hypothesis is, which is not, by the way, I don't think this is a commonly held view. I think a lot of people would disagree with me, but my view is that the liver is the energo stat of the body. I borrow that term from Mark Friedman who wrote an amazing chapter on this in 2008 that has been one of the most influential things in my thinking on appetite. But he described the liver as the energo stat. So as an engineer, you'll appreciate the nomenclature, right? It's looks kludgy to someone who's not an engineer to say, "Why would he call it an energo stat?"

    20. DFDave Feldman2:01:23

        [laughs]

    21. PAPeter Attia2:01:24

        But in engineering speak, that makes perfect sense. But that the liver is probably most susceptible to detecting some currency of circulating energy and circulating metabolites. ATP would be the most logical thing for it to be sensing. So probably ratio of ATP to ADP or ATP to AMP or ADP to AMP, something like that. But yeah, I think the liver, I mean, I think most people don't appreciate how impressive the liver is in general.

    22. DFDave Feldman2:01:50

        Just-

    23. PAPeter Attia2:01:50

        Like, I was just talking to a patient this morning and I said, "Look man, here's the deal. Anything that goes wrong with you can be supported extracorporeally, right? You get into a coma, no problem." You need to go on a left ventricular assist device. Okay, it sucks, but, like, it's there. You need dialysis, you need a ventilator, all that stuff. We do not have extracorporeal support for the liver. It is too complicated

    24. DFDave Feldman2:02:11

        Anybody who follows me knows just how much I'm loving this because you're the, you're the preachers preaching to the choir by far. I've often referred to the liver as, like, the straight-laced partner who always puts up with your crap.

    25. PAPeter Attia2:02:23

        [laughs]

    26. DFDave Feldman2:02:24

        Says whatever you're giving it, it's having to parse out and figure out and, and balance the ledgers and get everything in and-

    27. PAPeter Attia2:02:29

        No, no, that's, that's a great point, and that was part of the other point I made to this patient who was not in any way opposing that view. He was just asking if the elevation we'd seen in his liver function tests, which was mild, could explain a synthetic issue to which the answer was not a chance in hell under normal circumstances because the liver has an enormous capacity to do its job under even the most ridiculous stress. So going back to Craig, at the moment that he is running, which is the same as saying if someone's losing weight while they're on a low-carb diet, they are in negative energy balance, they are in negative fat flux. And again, when I say losing weight, let's ex- ignore the water weight and stuff. Like, like, I'm talking about legitimate weight loss where shedding of-

    28. DFDave Feldman2:03:09

        Metabolism exceeds... Right.

    29. PAPeter Attia2:03:11

        Yeah. But that's what it means, right? Like, on a practical level, it means lipolysis. The amount of fat that is leaving the fat cell has to exceed that which is reentering it. And again, I don't know that this is entirely relevant, but you've alluded to it, so it's worth reiterating. Not all of that is oxidized, right? Like, some of that free fatty acid leaves, doesn't get oxidized, and guess what? Gets mopped back up, provided the hormonal milieu still permits it.

    30. DFDave Feldman2:03:34

        Yes.
14. 2:14:27 – 2:26:24

    Fasting, Fat Manipulation and the MUFA Experiment

    1. PAPeter Attia2:14:27

       I've done this on multiple patients who have done three, five, and seven-day fasts.

    2. DFDave Feldman2:14:31

       Okay. Who are fully ketogenic, and you're saying it typically goes down?

    3. PAPeter Attia2:14:34

       Not always ketogenic, no. Sometimes they're just, you know, fat adapted, sometimes they're not. Sometimes they're actually insulin resistant, and we use the fast to kick them into a state of ketosis to make it easier. And again, I wanna be very careful. This is simply just anecdote because I've only done this on maybe 30 people, but this is not uncommon. I mean, look, my LDL cholesterol went from 64 to 37 after the fast. I mean, it went way down.

    4. DFDave Feldman2:14:58

       Wow, fantastic.

    5. PAPeter Attia2:14:59

       And that's consistent with what I see. Now, that's not the reason I'm fasting, to be clear. I don't -- I'm not using a fast to manipulate lipoproteins. I'm doing it for a completely unrelated reason. But my point is, I always see, and again, I can say always because it's a relatively small N. Obviously at a large enough N, you're going to see counter examples to anything and everything, but the general principle seems to be under caloric deprivation, LDL goes down, and under fat deprivation, LDL goes down.

    6. DFDave Feldman2:15:25

       I've got to put in the one footnote, and it's an annoying footnote that I keep putting in. I really need to, and this is why I'm dying to get these parts of the exercise, I need to look at a population that also is not getting any particularly weight training or resistance training and so forth. Whether it's my theory or not, that seems to impact overall lowering LDL-C numbers.

    7. PAPeter Attia2:15:43

       But and I've got-

    8. DFDave Feldman2:15:43

       And I'm very curious about this in fasting in particular

    9. PAPeter Attia2:15:44

       ... I mean, I've, I mean, I've got that in my patients. Not every one of my patients lifts weights despite my best efforts.

    10. DFDave Feldman2:15:48

        [laughs]

    11. PAPeter Attia2:15:50

        So I think the more common thing that we see is that when you put people on a high-fat diet, the ones that go on to have this hyper response, as you note, their trigs usually go down. Their cholesterol goes through the roof, and it's driven by a doubling, tripling, or even greater output of synthetic biomarkers like desmosterol. Now, for reasons I don't understand, you also tend to see at least two other three phytosterols go up. Now, one thing we didn't talk about, though I wrote about it, so I'm sure you know about this, is this seems reversible if you eliminate the saturated fat.

    12. DFDave Feldman2:16:27

        It does seem to matter in this case, and you'll like this, at least in our own data with ApoE4s. Seems more likely if you're an ApoE4, you will see a drop somewhat in saturated fats.

    13. PAPeter Attia2:16:39

        So I don't think I have a large enough sample size because I've only put seven patients through that protocol, and I wrote about the very, very first one, so that's probably the only one that you've seen that I've talked about. But this was a, a young guy who went on a ketogenic diet, was crushing it, meaning like everything was going well. I mean, he'd ne- you know, he got through the adaption period. I mean, his performance was exceptional. All, you know, mentally never felt better. He was not an overweight or metabolically ill guy to begin with. He was just kind of a normal software guy who just decided he wanted to take it to the next level. But then he showed up with labs not unlike these. He was the first guy I ever saw where there was a greater than sign on the LDL-P.

    14. DFDave Feldman2:17:18

        Right. It maxes out at 3,500.

    15. PAPeter Attia2:17:20

        Yeah. I was like, "Oh, I didn't actually realize the assay stopped at 3,500. This guy's my guy." He looked better on some of the other metrics. He didn't actually have a lot of the inflammatory stuff. This was before the OxLDL assay was commercially available, so I didn't have that. But, you know, his CRP and his Lp-PLA2 were okay. But we had the discussion, right? Which is the discussion that at the end of the day, I'm accountable for having, which is what are we gonna do about it? And he was young. I mean, the guy was 30, so it wasn't like we had to do something tomorrow, right? This is not a guy who's gonna have a heart attack in a week.

    16. DFDave Feldman2:17:53

        'Cause I think when you were originally writing about it, he actually pushed back a little bit, like he wanted to come up with a-

    17. PAPeter Attia2:17:57

        Well, what he pushed back on was... 'Cause I basically said, "Look, man, I don't think the ketogenic diet's right for you. Like, these numbers are crazy." And he was like, "Yeah, I don't ever wanna go back to what I was doing before." I mean, he basically said in not so many words, like, "I'd rather die of a heart attack and feel this good than..." You know, and he's not saying like, "I'm gonna die of a heart attack tomorrow," but he's like, "Look, I'd rather live to 60 and feel this way than live to 70 and not." To which I say, totally fair, by the way. Like, that's a very reasonable trade-off to make, but let's also think about this a little more logically. So that was actually probably the first case I ever discussed with Tom, and this was I think back in 2011, and it was actually this discussion I think that led Tom to go on to write the lipoholic's case, even though it wasn't the patient that he used in that case, because he then went out and found others like them. And what we just decided was on sort of biochemistry first principles, we, our hypothesis was it's the saturated fat more than the ketones, 'cause that was the other thing. This guy didn't wanna leave ketosis. 'Cause my thought was let's just dial this back, get you out of ketosis. But so our hypothesis was both ketones and saturated fat can be readily converted into cholesterol, but if he's adamant on staying in ketosis, let's at least get his SFA down to 25 grams per day, which was hard. This is a guy that was eating about 100 grams of SFA a day, maybe 80 grams. I mean, it was a lot. And we basically just made most of it MUFA. So I said to the patient, I said, "Look, the way we could do this just for no other reason as the purpose of a thought experiment is you're gonna basically have to become a nonstop olive oil macadamia nut eater. Even the avocado you can't go hog wild on because eventually you'll get too much carbohydrate out of it for this purpose."

    18. DFDave Feldman2:19:40

        Right.

    19. PAPeter Attia2:19:40

        And sure enough, I think he came back at like 1,300, you know, after eight weeks or something like that. So six more patients have been so adamant about staying in ketosis and not taking any medication, but wanting to go through this experiment, and all of them have had the same response, which is if you can get them to mainline MUFA, you fix the whole problem without reducing or increasing to any measurable effect how much fat they're consuming.

    20. DFDave Feldman2:20:08

        Have you been keeping track of their PUFA levels too? Because it's hard to add a lot of MUFAs when you don't-

    21. PAPeter Attia2:20:12

        Their PUFA's going up

    22. DFDave Feldman2:20:13

        ... and you know the issue with that, with adding more PUFAs. The downside is, is There's the potential that you're actually adding more peroxidation on the particle basis.

    23. PAPeter Attia2:20:22

        Yeah. I mean, I think it depends. This is one of those areas where I'm trying to get a lot smarter and I want to make sure I'm not sitting in the echo chamber. I've historically measured RBC levels of arachidonic acid and all of those things and tried to keep track of the ratio of that to the EPA and the DHA and... But ultimately, I don't, I don't, I don't really think I know the answer to this yet, and I also don't think... My guess is PUFAs are not as bad as I've historically thought them to be, but they're probably not as good as MUFA. So notwithstanding that, I just want to talk about this from the level of the thought experiment, so to speak. My sample size of those people is too small to know if there's a relationship to their APOE gene. To your point, what I'm hearing you say is maybe that's more-- that's something that you're more likely to do in someone who's an APOE4 carrier.

    24. DFDave Feldman2:21:05

        It's been a proportional kind of thing that we've sort of noticed.

    25. PAPeter Attia2:21:08

        I don't know. But what I do know is it seems to point back to this idea that the hyper-responders, that the Occam's razor here is that they're making more cholesterol because that makes sense from a mass balance standpoint. Again, I'm still-

    26. DFDave Feldman2:21:20

        And I would have agreed with you were it not for this energy inversion that I see. If it were not the very thing that I said from earlier, that I could move my LDL-C to where I want to move it, that would be based on me basically arranging for a few days to eat to a certain level, and I'd be pushing down my LDL-C by eating up to a certain amount of saturated fat.

    27. PAPeter Attia2:21:39

        But notice you're pushing up and down on LDL-C within supraphysiologic levels, uh, meaning if I recall seeing your data, do you mind showing me that again?

    28. DFDave Feldman2:21:47

        Unfortunately, the computer died.

    29. PAPeter Attia2:21:48

        Oh, I'm sorry.

    30. DFDave Feldman2:21:48

        That's, that's why I've had it closed. But yes, y- what you'd see is an inversion graph and what, what does that-
15. 2:26:24 – 2:55:00

    Evidence, Skepticism and the Low-Carb Community

    1. PAPeter Attia2:26:24

       But the point is, we have to back up for a moment. Why does any of this stuff matter? In the end, if you're listening to this podcast or if you're sitting in front of me as a patient, you have a very important question you have to ask yourself if your LDL-P is through the roof as a result of what seems to be your diet. Does it matter and do you want to do anything about it?

    2. DFDave Feldman2:26:42

       Right. And this is why this is the most relevant question, is if you're right, and I'm not saying that I know for sure either way, but let's say that you're right. You, Peter Attia, are right that this, regardless of how we got here, if you have a high LDL-P because of being on a ketogenic diet, then there's a lot of people who need to know that if they're at higher risk. And I definitely want to be one of the people that brings that to their attention. I have emphasized this several times before, and I'll say it once more. I am on a journey of science, not of advocacy. I'm gonna be quite a skeptic. But all of that said, if I come to a point at which I can feel convinced that LDL-P is in fact atherogenic, absent remnant lipoproteins, absent having high HDL, low triglycerides-

    3. PAPeter Attia2:27:24

       But we already know it's absent remnant lipoproteins. I mean, there's a thousand studies including this to demonstrate that the atherogenicity between these people and these people, I'm pointing to the Garvey study, has nothing to do with what may or may not be remnants. The LDL-P alone here... So I think one thing that sort of-

    4. DFDave Feldman2:27:43

       I've not seen a study yet where remnant lipoprotein... I mean, I'll send you the ones I have. If you have some where LDL particle is more relevant than remnant lipoprotein, I, I would be very curious. It'd be very interesting to see.

    5. PAPeter Attia2:27:56

       Well, again, we have to be very careful what we mean by remnant. So there are clearly going to be a subset of remnants that are potentially the most pathologic on a per particle basis, but I think the body of evidence implicating the causal role of ApoB and LDL-P is so overwhelming. Is it perfect? Of course not. But I think what concerns me with this culture, when I say this culture, I mean this sort of low carb culture of LDL doesn't matter, is if I had a dollar for every time I had to see some low carb enthusiast basically dismissing the idea that LDL is relevant and touting the idea that statins are a big conspiracy theory, that's a really dangerous problem.

    6. DFDave Feldman2:28:38

       So look, just generally speaking, I think dismissiveness in general.

    7. PAPeter Attia2:28:41

       Okay.

    8. DFDave Feldman2:28:41

       But we do have to care about the quality of evidence regardless.

    9. PAPeter Attia2:28:43

       Oh, we sure do. Let me offer a, a, a very controversial viewpoint that I can't believe I'm about to voice publicly. I think one of the challenges in the low carb community is you have a group of people who have become very used to rejecting mainstream information because they did so with nutrition, right? If you are on a low carbohydrate diet, on some level you have decided that the ADA, the AHA, the USDA, the NIH, and the CDC are full of shit.

    10. DFDave Feldman2:29:12

        I think that's a fair point.

    11. PAPeter Attia2:29:13

        Okay. Do you know what? I think that when it comes to nutrition, that's largely true. Now, I think they're coming around, but I think it's largely true, and I think the body of evidence, the body of literature that pointed towards the food pyramid was quite shoddy. I don't think it was nefarious. I don't think this was as much of a conspiracy as people want to make it out to be. I don't think Ancel Keys was some evil dude who was, like, scheming a way to, like... I just don't buy that. I think there were strong personalities and lousy science. Those are very different things.

    12. DFDave Feldman2:29:43

        And let me go on the record with saying I basically agree. I feel like there really is-

    13. PAPeter Attia2:29:45

        Well, this is the easy part to agree with.

    14. DFDave Feldman2:29:47

        Yeah. [laughs]

    15. PAPeter Attia2:29:47

        This is the hard part that's coming up.

    16. DFDave Feldman2:29:48

        Okay, go ahead.

    17. PAPeter Attia2:29:49

        Okay? So what happens is a lot of people get into this mindset of, "Well, look, over here I saw an entire body of evidence that I was very easy to dismiss. And by the way, look at the results. Like, you don't have to be a rocket scientist. If you're sitting there following the food pyramid, getting fatter and sicker, and you abandon it and get better, there's the proof." The real problem, and a- again, I apologize for getting on a soapbox, the real problem is when people try to look at the last 50 years of lipid literature through that same lens. Nobel Prizes have been won in this field. Now, I know that somebody's gonna start screaming, "Oh, that's an appeal to authority. That's a logical fallacy." I got it. To you, whoever said that, I acknowledge it, but unless you're willing to go back and read every one of those papers, something even I have not done, though I've probably read more of them than most, we're talking about apples and oranges with respect to a body of literature here. The body of literature implicating LDL as having a causal role, a necessary but not sufficient role in the pathogenesis of atherosclerosis, is on a different level from the body of literature that gave us the food pyramid. And the real challenge, I think, in this low carb community, this LDL denying community, is they're throwing the baby out with the bathwater. Now, part of that is because I think there are too many doctors who are too lazy at the other end of the spectrum. They just assume, "Well, statins are what we give everybody. Anybody whose LDL-C is above 100 gets to be on a statin." And these doctors are equally guilty in my mind of being ignorant and not thoughtful and not understanding the pathophysiology of the disease. But somewhere between these is a measured space that requires a very careful consideration of the literature. So-

    18. DFDave Feldman2:31:34

        So with that in mind, to kind of broad base this pretty well, this whole energy model that we've been talking about, that I've been kind of walking you through and the audience to some degree, it's the lens by which I came up with the challenge. I didn't come up with the challenge because I was just like, "Today I just want to tweet out something that I think will get a lot of people annoyed." I believed that I looked at those two sides of the dotted line and I said, "It looks as if, if you are insulin resistant, we tend to see that there are high levels of triglycerides. We tend to see there are high levels of VLDL." Forget even remnant. We can detect VLDL to a certain extent. We can see that people who are down the range of metabolic derangement, they've got that, and that tends to be highly associated with cardiovascular disease. This is all on the energy delivery side. On the other side of the LDL, we tend to see on the support side that there can be further problems in the immunological role, and oftentimes that can be induced by, likewise, lipolysis You'll see on the, uh, the vitamin E studies, for example, this gets brought up quite a bit. For example, if you inject lipopolysaccharides into a body, you'll actually have higher fatty acid synthesis that's going on in the liver along with lipolysis in order to induce that higher response. So again, we see on that side, we see higher levels of triglycerides. And I kept coming back to it. I kept kind of, you know-

    19. PAPeter Attia2:32:51

        But you're also, as we talked about, when you inject LPS in somebody, you're gonna see a higher HDL cholesterol too. I mean, everything at that moment, LPS is a terrible toxin. Like, it's going to kick the body into a four-alarm fire.

    20. DFDave Feldman2:33:01

        For sure.

    21. PAPeter Attia2:33:01

        Of course it's going to want all of the energy substrate it can muster and all of the hormonal precursors it can muster.

    22. DFDave Feldman2:33:08

        Agreed. Agreed. So when we're looking at an association between LDL particles and a bad outcome, we want to absolutely confirm it was the cause and not the association, right? For the same reason that if we were to say, "I want to confirm ambulances aren't the cause of death for people who are dying inside of ambulances."

    23. PAPeter Attia2:33:28

        Yeah. I, I mean, the, we have to be a little careful with that analogy, so let's be clear. Can you get atherosclerosis without having an oxidized sterol taken up by a macrophage?

    24. DFDave Feldman2:33:38

        No.

    25. PAPeter Attia2:33:38

        Okay. So-

    26. DFDave Feldman2:33:40

        If, if I could take all the LDL particles out of your body right now, I can feel totally confident that you will not die of atherosclerosis.

    27. PAPeter Attia2:33:46

        Okay. So does that not imply that LDL is necessary but not sufficient for atherosclerosis?

Episode duration: 3:10:32