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

Foreign. 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@peterattiamd.com. Hey everyone. Before introducing today's guest, a couple of housekeeping issues. 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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 going to ask you to spend as much time doing so. All right, on to today's guest. Now, this is going to be a slightly longer introduction than normal. Apologies in advance if you positively, absolutely don't want to 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 is causal paradigm or thinking in atherosclerosis. So you're probably going to understand that out of the gate. Dave and I don't really see eye to eye on the genesis o 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 going to 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 kind of 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 going to have enough to talk about without that, and I didn't want to 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 undoubted 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 kind of 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 episode, 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 want to kind of 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 want to 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 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 seem unable to address why that would be the case and therefore what could possibly account for this increase in the LDLP and the LDL cd. 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 were fewer, not more triglycerides being exported from the liver and there was 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 hyper functioning 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 believe Dave is about as intellectually honest as anybody is in this space, and I 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 make this 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 that you could have made before. And some of the other guests that I have already had on this podcast, including Ron Krause, 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. Hey, Dave. Welcome to San Diego.

Thanks for having me. Peter.

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

That's right. Low carb usa Got it.

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

How many are going to end up showing up here?

None. I'm actually leaving very early tomorrow to go to New York, so I will be missing this.

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

No, I actually was going to try to talk to one other person too, but they bailed on me and took a better offer. 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 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 and heart disease campus. And so certainly there's a number of people out there for various different reasons who have argued that the causality of 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 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 o' clock 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?

Well, 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 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 straight dopant cholesterol. And if I can, by the way, interject just this one thing. Thank you for making that serious. 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 of a one scientist, definitely tackling just exactly how far I could take moving around my cholesterol. And I'm going to 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 have 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.

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 privilege of listening to several of them, which is what helped me get more up to speed on some of your arguments. And, 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 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.

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 point 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 were African American, but your trig to HDL ratio of about 2 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.

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.

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 Lipoholics series. I think it was in 2013, might have 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 request that people draw the advanced lipid panels before. The other thing that is essential is that they get a sterile panel. And that's not to be confused with sterol, like, you know, il. It's sterol Ol. 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 ldlp. 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 certainly go over that. I think you'll find it super interesting.

Yeah. And I think it's worth stratifying that just for a moment for the audience. What you're referring to 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 base. 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.

The blood test tells us nothing about the triglyceride burden within the lipoprotein directly. But. But we know that that's one of the cargoes. 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.

Yeah, it's 30.

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 resurfaced, circulated 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? It's sort of an idiotic discussion that I can't. 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 one 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 going to 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, colonstanol, 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 ldlp. 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, 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, because it's. This is really. They're neither better nor worse.

It's.

They just are what they are. Right?

Right.

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.

For what it's worth, what you just mentioned, I myself have not gotten a sterile test. 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. I do want to 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. 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.

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 Peak C1 like one transporter in the ATP binding cassette which is called, it's usually referred to as ABC G5 G8. 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 in my chol 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? 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.

Absolutely.

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 what year did all this start for you?

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.

And that was with a triglyceride of 80.

Yes, actually that's correct. That was the very last time that was that same test. 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, if I want to say like 103. And at the doctor's office they said, well, yes, this is the second year in the row, but we'll keep monitoring it. And I said, well, no thanks. I'm going to start trying to figure out what it is 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 forms. Diabetic forms. They were talking about this LCHF diet, which I would then find out as 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 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 it 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 is 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 five nines, something along those lines. And my sister's 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.

This is like late 2015.

Correct. So November 2015, I believe my total cholesterol was 329. My LDL C was 200 and I want to 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 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 Dahl. 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 when you say the pattern, just to be clear, the increase in LDL cholesterol on the presence of a low carbohydrate, high fat diet.

No, I actually mean it being a network.

Okay, so say more about that.

Lipoproteins are a boat. This is going to be one on one. But let's kind of do that for the listener for a second. There are 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 going to 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 want to 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 want to 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 apo lipoproteins. 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.

I think we're going to have to.

Yeah, we're probably going to 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 going to go and why and what excited me about. As I was learning about this, 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 from a payload perspective, is primarily an energy distribution network. It appears as if its primary job, more than any other job, particularly kylo microns 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 get the sense of it in many ways this has a lot of overlap with techniques that we use right now and how we build networks out of servers.

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 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 APOC2, 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 APOB48, as you know, that comes in and then the APOC2 interacting with the LPL is what's extracting that. Oh, yeah, great. Dave just whipped up a great picture. So we're going to link to all this stuff. Yeah. So, Dave, if you can make A note of this one, 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 going to 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 delipidate the hdl, 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 ctep, as you alluded to. And that goes the other way.

Right, like, you mean HDL actually taking the cholesterol and giving it to the LDL to take back to the liver?

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

I see what you're saying.

Yeah, through C type. 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 going to link to is not actually showing that, is that about 40% of LDL comes directly from the liver. It's de novo created.

Right. Tom? Dave Spring linked me to the study that I had since read on. This one. Really?

Which one is this? The Frank Sacks.

I don't remember. I don't remember the authors. They get into the different subspecies of Apo, C3s and Apoe, and how they counterbalance each other as far as degree of affinity for clearance and so forth.

Yeah, that's sort of un. I mean, I shouldn't say it's unrelated. This stuff's all related. So we'll park this topic because 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 APOB1 hundreds are carrying APOE, and when they do, they actually have much more rapid clearance, as.

In having APOE only and not having APOC3.

Well, that's actually a good question. APO C3 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 going to 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 APOC3, which increases their residence time. And the same is true on ldl.

I do want to follow up on that point though.

Yes, yes, yes, we absolutely will, because 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 Apoc3 and for LDL triglyceride concentration, which goes back to a point we had a few minutes ago.

And for anybody listening who's developing that assay, please reach out to me because for all 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.

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 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 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?

And that was actually one of the questions I had for you, was how, with a kinetic study, can you actually determine if an APOB100 lipoprotein that was secreted by the liver ever has, say, an APO C2 on it? I think you and I would probably be in agreement that we don't know.

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

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.

So I would argue that depends. 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.

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, and that's your job. And you know what? 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 going to 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.

Well, we sort of know. I mean, we know that if. I mean, what Frank Sachs paper showed is if you take patients with low triglycerides, and I believe he used a cutoff of 130 milligrams per deciliter. 38% were de novo secreted by the liver. 62% came from either IDL or VLDL, where you had de novo. I don't think the paper differentiated between which ones went IDL to LDL versus VLDL to IDL to ldl. So that's an important point. The second thing is the half life. I actually had to go back and look at these kinetics because I did a podcast with Ron Kraus, as you know, I mean, I don't remember when we recorded it. I think it came out kind of recently. But he mentioned that LDL half life was a day. And I was like, I always thought it was longer than that.

The literature says two to four days.

No, actually, if you go back and look at the kinetic study, people are confusing half life with residence time. The half life of an LDL particle is about a day. Now, it can be longer, but that's a pathologic state, which gets back to this APOC3 thing that's interesting. Yeah, you can have a pathologic state where LDLs will hang around longer. But if you look at the actual kinetic studies, and Brown and Goldstein did this work, and this is part of the work, I believe that they won a Nobel Prize for the kinetics of LDL are pretty well understood using very elegant tracers. And we'll link to that paper because I actually had to go back and look at it because I was surprised by Ron's answer when he said that the LDL particle half life is really only a day under non pathologic states. So, but you're right, if I look at your LDL particles and I see 3,000 nanomole per liter, I do not know with absolute certainty how many of those your liver made directly versus not. But again, assuming you're insulin sensitive, assuming you fit Sachs's model of patient, that would suggest that, you know, roughly 40% of those were just de novo created. And then of the remaining 60, some of those were from De Novo IDL and some came all the way through the VLDL pathway.

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 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 ldlp. 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 LDLP would be.

Higher, so let's use this as a moment because I want to 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 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.

Can I interrupt just for one second? Have the people at Virta Health released any of these data? Because they would probably, probably have the most rigorous database on this.

Here's a little bit of my qualification here. The problem that I have is at least with what we see@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 are seem to be metabolically flexible. Virta, of course its pool of participants, they had to start. I, I hope I don't get this wrong, but I believe that their BMI is at a much higher level when they start.

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.

Right.

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

I would prefer a broader base.

Okay, all right, sorry.

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, 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 called 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. You mean LDL cholesterol, 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 HDLC 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 three 4s and four 4s. And we have not been able to identify any other SNP or anything that's clearly associating this type, including the PPAR.

Alpha and PPAR gamma.

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.

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

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, etc. 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, a qualifying 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.

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 arteries. 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 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 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 LPs 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 OX LDL 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.

Right.

It's giving you probabilities of things that are largely stochastically governed that are going on in your artery. And the OX LDL 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.

Can I actually ask a little more on that one? So we already know that LDL particles, specifically APOB100 at the LDL stage, have alpha tocopherol. I think is how I'm saying. Basically it's vitamin E. Right. 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.

I don't know about that. And if it were solely true. So 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.

Because I've actually been wanting to get into this a lot more recently and correct me if I'm wrong, 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, that also can bring about the role of LP that can cleave off the oxidized phospholipids. That's ultimately what Lppla2 is. Right? Correct. The enzyme that's ultimately involved in 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 white 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.

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 there's sufficient evidence to suggest that part of the role of LDL is to combat the oxidative stress.

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

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

Interesting.

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

Okay, that's definitely something I would like to follow up because I'm genuinely curious about that myself as to whether or not they can be oxidized sufficiently that they'd get picked, because it also may be something 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.

Yeah. Meaning what you're basically asking is, how do we know they weren't oxidized? Never inside the subendothelial space. 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.

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.

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 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.

Interesting. But 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 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, the more likely it is that you would just live longer, period.

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 maybe 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, a trade off? Yes. So the question there is, 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.

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?

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

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.

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. 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. 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. 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 was 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 Snyderman's lifetime exposure model. So a lot of people are critical and say it didn't show a mortality benefit, it just reduced revascularations 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. That would be the ideal study.

That would. That would be. Okay, you actually. You talked about this in the street. Dope.

I know.

I remember going on.

That's right, the magic wand test. Yeah.

And I think it's worth plugging in something important here. You've already said this on a prior podcast, and I don't want anyone to misunderstand that you don't necessarily buy into the 0 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.

The way I would say it is this. So 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, because there's going to 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.

Extra points for the phosphorylated insert, by the way. That's for us. Lipid files.

Yeah, yeah. So necessary but not sufficient is the relationship between oxygen and fire. Oxygen is necessary but not sufficient for fire. Can you have oxygen and not fire? Yes. Can you have fire without oxygen? No. The lower the concentration of oxygen, the less likely you are to spontaneously get a fire. So. And again, that's a bit of an oversimplification because there are so many other factors. Endothelial health and oxidation and inflammation, of course, are so important here. But the problem I have with the zero LDL model, which, again, I think. I don't want to speak for people who. But I think what people are basically saying is there's a subset of people in the medical community who are saying we should just be driving LDL to zero because, you know, that's the best thing. Well, my view is, as you said, no, that's not necessarily the best thing. That might be the best thing for the heart. In other words, it might be the best thing to lower the risk of atherosclerosis, but it's irrelevant because it might come at other costs. And so it depends on your point of view, I do from time to time, get into arguments with other physicians who take care of my patients as well, because I'm not a primary care physician, so I have to share my responsibility with other physicians. And about twice or three times a year, I do have to sort of go to war with one of these docs, and it's usually over one extreme or the other. And the most recent example of this was a patient of mine who came to me on 80 milligrams of Lipitor, which is the maximum dose of Lipitor. He had a very high calcium score and a very bad cta, but he had not had an event that we knew of. But for all intents and purposes, this is a secondary prevention patient, meaning we define secondary as has he had an event or not? Well, he has had an event. His event is, look at his coronary arteries. Right. But nevertheless, he came on 80 milligrams of Lipitor, and his, you know, his LDL cholesterol was very low, but his particle number was not quite at goal. The goal for a patient like that would be 10th percentile or lower, given how you're aggressively, you're managing. He also had a slight elevation of lp, so I added Zetia, which, because he had very high levels of absorption, not uncommon given how much his cholesterol synthesis was being hit. And that brought him into goal. So now he was totally at goal. His cardiologist was happy. I was marginally happy. But what I didn't like was his Desmosterol level was now unmeasurable. Now, it turned out it was unmeasurable before, but I was so fixated on just trying to get him in the right zone. But now we had some breathing room, and I said, you know, now that I'm thinking about it, oh, and by the way, in the interim, Repatha and Pralulent had been approved. These are PCSK9 inhibitors. And I thought, this guy has no measurable cholesterol in terms of synthetic function, so it's very, very low. Now, a lot of people are right now going, aha, aha. That's the problem with those statins. They inhibit cholesterol synthesis. Well, careful. That's true, but every cell makes more than enough cholesterol for its own use, with maybe a couple of exceptions. Gonadal tissues, steroidal tissues, during periods of high stress, need to borrow cholesterol from other tissues. But for the most part, every cell can sufficiently produce its own cholesterol. Cholesterol.

I think you're right on the most Part, I'm not sure if I am convinced that every, I mean, your body's running a buffet. That's the bloodstream. The bloodstream is this buffet of things that the body anticipates, it wants to make available on demand to cells. And I believe, I mean, again, this is kind of just the engineering approach.

But we don't know that's true. That's a hypothesis with respect to the lipoproteins at least.

Absolutely true hypothesis. But it's not been proven to the other, other side as well. Right? We can see that the synthesis can happen within most cells to be able to make their own cholesterol. Do we have even in vitro studies where we can actually observe that every amount of cholesterol that they would need would ultimately be synthesized even under periods of stress, like, for example, muscle repair and growth?

Well, we have natural experiments, right? We can look at the A beta hypolipoproteinemia patients who can't traffic cholesterol. Therefore they would be entirely dependent on their own cellular endogenous production. And they seem completely fine. So that's not proof, because we don't have proof to your point, but it's certainly evidence to suggest, I mean, we also know when that's off, right? So, like one of the first things we used to see in the icu though at the time I didn't pay any attention to it was anytime a patient came in and they were septic or under great stress, so they had what's called systemic inflammatory response syndrome. So you could be in a car accident, you were shot, you have a horrible infection. Their HDL cholesterol would transiently take a huge bump. And I didn't think anything of it at the time other than it was neat. It was like, wow, 2x bump in HDL cholesterol overnight. I think I would now look back and interpret those data as huge reverse cholesterol transport. Now the HDL is going out of its way to deliver cholesterol to probably the adrenal glands first and foremost because the enormous uptick of glucocorticoid, even epinephrine, norepinephrine are needed. So clearly there are examples of when this is not in a homeostatic balance. So I'll take your point that because.

The A beta lipoproteinemia patients in theory should be the ones who are outliving us, all right? They can take out the whole component of heart disease, of atherosclerotic plaque, everything. They should have massive longevity, relatively speaking to everybody else.

So there's only about 12 genes that are well enough studied. We have enough patients that we think we know something. And the most important of the longevity genes in cardiac is the hypo functioning Apoc3s.

And that actually shows a net, a net longevity benefit.

So work out of. Albert Einstein has identified these roughly a dozen genes and the hypo functioning APOC3s. I mean, most of those genes are like GHR, IGF. APOE would be one. Right. So APOE2 would carry with it protective benefits in terms of longevity, both cardiac, but more of it is neurodegenerative. But it's those C3s. In fact, as we have kind of alluded to a couple of times, I believe there's an antisense oligonucleotide in clinical trials now trying to impair APOC 3. So now that's becoming a therapeutic target.

Dave Spring alluded to that one actually.

Yeah. And again, this is one of those drugs that might not have much of a benefit in an insulin sensitive person. They may have already captured that benefit by lowering insulin levels.

Well, and that's actually part of what this kind of energy model, and particularly that with hyper responders, specifically lean mass hyper responders, comes back to. I know you don't necessarily hang out on Twitter too much, but you know.

That I have had more than I would like.

I have this pinned tweet. I've been pinging lots of lipid lowering experts on this and I've said, look, I'm looking for any studies that show people with high LDL will have high cardiovascular disease if they likewise have high HDL and low triglycerides. But there's one qualification. It can't be a gene or drug study.

That's two qualifications.

Oh, fair enough, two qualifications.

But 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.

Great.

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 6ft 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 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 the question you're asking, right?

Yes, yes. Well, so we'll double back to that in a sec. But basically you're taking us back to genes. And this is why this is another hypothesis fully untested. I'm in the process of trying to collect on it, but I call this loosely cellular lipid malabsorption, or I just generally shorten it to lipid malabsorption. Basically here's the issue that I have with the existing Mendelian randomizations. 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? That's what we all secretly we want your wand 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 without touching any other parts of the process. The problem is that I believe of I'm keeping a list of my own S&Ps of those genes that are 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 ldlp. 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 to.

Wait, wait, sorry, explain that part again. The last part.

Endothelial cells being dysfunctional.

Yes.

Would that be potentially problematic for atherosclerosis?

Yes.

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?

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

Well, if you've got defective LDL receptors.

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

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

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

Okay, but what about that which is.

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 overexpression over expression of PCSK9.

Gotcha.

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

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

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 hyper functioning 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.

But this again introduces a dysfunction on the lipid metabolism that has nothing to.

Do with the endothelium. That has nothing to do where atherosclerosis occurs. All that's doing is giving you more LDL and serious circulation.

Let me put it this way. Why not take anything that results in a higher level of LDL C or ldlp that doesn't impact any lipid absorption from any tissue at all.

Right. But that might be a bit of an artificial constraint. Right. I mean, as you pointed out yourself, and I think anybody listening to this will appreciate this is a complicated dynamic system. So it is going to be difficult to have some perturbation in a system that will lower or raise ldl that won't have some other effect. The question is, how do we, with some reasonable degree of certainty, look at those other effects and ask whether or not they're germane to the question of atherosclerosis and the causality of LDL to atherosclerosis. So I think the PCSK9 example is not an unreasonable one because we have a pretty clear understanding of what that gene does. We have a very clear understanding of where that protein lives and what it's doing.

But if anything, that's resulting in the other direction where if you have lower LDL C or LDLP from an underexpression, a PCSK9 that actually results in a hyper absorption of lipids, for example, in the liver.

Yeah. They have enhanced hepatic clearance. So both ends of that though, Right. So if you have hyper functioning and hypo functioning PCSK9 patients out there, both of whom exist, I believe the hyper functionings were discovered first. But the hypo functionings are kind of the ones that gave the drug companies the desire to go and, or not the desire, the, I guess the idea to go and create a drug to mimic that phenotype. But these patients walk around with LDL cholesterol of 10 to 20 milligrams per deciliter. And as far as anybody can tell, there's no other side effect of that.

Well, and this is the thing I want to zero in on is let's say that we do that. Let's say that we go, okay, never mind this side part of the lipid hypothesis end of it, or I'm sorry, the lipid metabolism end of it. We should then be able to look back at these people with the more novel versions of S&PS and assuming that there's at least a large enough population, we should see that longevity. Your mentioning of the Apoc 3 from earlier is the first that I've been able to find of that one. I'm interested to see if we would see that across the board with these people have these S and P's.

Yeah, I mean, I suspect it will have to do with how many of them there are and how long they're being tracked.

I sympathize with your concern. Is it's absolutely the case. Nutrition medicine, there's certainly a lot of personalities that are out there, but I can understand, at least for me on my end. I like hard endpoints over soft endpoints. Maybe it's just the engineer in me. I like ones and zeros. Death is pretty easy to diagnose, whereas soft endpoints. The downside is there can be arbitrary decision making on the part of the patient and the doctor is to.

Yeah, I heard you mention that on one of the podcasts. I got to tell you, I disagree with that. Having seen more patients in an ER when I was in residency with mis, I can honestly tell you, Dave never once knew what their cholesterol levels were. When someone comes in the ER with chest pain, I care about the advanced cardiac life support algorithm, which involves oxygen, which involves an ekg, which involves troponin, which involves morphine, aspirin, and potentially a trip to the cath lab. But we are in nowhere in that algorithm are we asking what's their ldl and letting that help us think is this indigestion versus other things? So I do take issue with calling MI a soft outcome.

It's not so much whether it's a soft outcome, it's whether or not there are things like, say, revascularizations that can be determined based on a decision on the part of the doctor and the patient that may or may not have to do with their knowledge of the lipids. Right, agree.

I mean, these are all different things, but I also think we should be careful not to take mortality as the only outcome. I will say this, and I hate putting on the stupid doctor hat because it sounds ridiculous in this context, but unfortunately I feel like I have to go back into and out of that world here. I would say at least half the patients that come to me do not actually find themselves asking for an extension in lifespan. My interest is longevity, but longevity has two components. How do you increase lifespan, meaning how do you delay death and how do you improve healthspan? Won't go into what that means, but the bottom line is there are many people who say, I honestly have no interest in living one day longer than I might otherwise live, but I want that quality to be much higher. So if we're going to say. And again, I don't necessarily agree with that. I think the bigger issue is a statistical one with all cause mortality, but nevertheless.

But you're going to modality like if somebody has an MI and it actually impacts their quality of life afterwards. Yeah, Right.

What if your quality of life is decreasing as a result of a procedure necessary or otherwise, or an mi, or a decrease in ejection fraction. Because, remember, about half the people who first present with atherosclerotic coronary disease present with sudden death, but half the people don't. Right? Half the people go through mi, stroke, God knows what else that follows. So, again, I see it as my chief responsibility to delay the onset of death. If a patient decides that that comes at too great a cost, that's great. That's their decision. In the end, the patients decide everything. But going back to what got us here, I am convinced that if patients didn't have ldl, there would be little to no atherosclerosis. If you could give them no LDL over the duration of their life. If a patient comes to you and they've already got disease and you lower ldl, I don't think that that gets them out of the woods. I think that that's sort of just stochastically moving them in the right direction. What we have to be careful of, and kind of going back to that patient I was talking about, is we have to be able to identify the patients in whom the risk of LDL lowering is starting to cause a problem elsewhere, meaning they're incurring an unacceptable risk elsewhere. And in the case of this particular patient, whose desmosterol levels had now become unmeasurable, my concern was we have overdone it. With him on the lipid side, there's a safer, easier way we can lower his LDL without impairing his cholesterol synthesis because of the limited, but to me, quite convincing data on the plausibility of Alzheimer's disease in patients with overly suppressed cholesterol synthesis. So I want to be really clear when I repeat that I am not suggesting that statins cause Alzheimer's disease, which I know the blogosphere loves to talk about. If anything, statins slightly increase the risk of diabetes in susceptible people over a great period of time. But at the population level, there's actually no evidence that statins are causing Alzheimer's. However, I think there are a subset of patients who are susceptible, and you have to be able to identify those patients. And that's the problem with population data, as you know, is you can lose the nuance. The nuance is you, right? What matters to you, Dave, in the end, I don't really care what your LDL is. I care about you not getting atherosclerosis. And if there is indeed someone walking around out there with an LDL, cholesterol of 300, who's not getting atherosclerosis, and there are indeed examples of that, then that's great news. But we have to sort of use this heterogeneous population based data to then try to probabilistically figure out what do you want to do with somebody at the individual level. So with this patient, in the end, after a lot of fighting, the decision was we're going to put him on Repatha or we're going to start cutting down the Lipitor until we get that Desmosterol to bump. And so we're still in the process of doing that, actually. So that to me is like kind of a, an example of what I would think of as hopefully where precision medicine would be going, which is you're now well outside of a clinical trial. Right. There's never going to be a clinical trial that's going to ask the question, if you take a bunch of patients and statinize them ad nauseam and you drive their cholesterol synthesis very low and follow them for 30 years, do a subset of those people get it? No. I mean, you have to be able to look at retrospective data where those things were gathered, and we'll link to what I consider one of the best papers on this topic.

But getting back to the challenge, in a sense, you're saying by ignoring the genetic data, that the genetic data basically answers the question to your satisfaction to where you don't need to look at my own.

I think of it as the genetic data coupled with the pharmacologic data, coupled with the mechanistic data give me a high enough degree of certainty that I am willing to act in a certain direction. Remember, everybody, me, you, whoever's listening to this, they have to make a decision.

Sure.

Indecision is a decision. So when you showed up with a hemoglobin A1C of 6.1, did you have type 2 diabetes? Nope. Your doctor said, hey, I'm cool, just waiting. But you said, no, indecision is not a decision anymore. I'm going to do something about it. Because presumably you said, look, I have a family history of this. I think I have a sense of what the progression of it is, and quite frankly, I don't want to wait until I have this disease to do something about it. So you decided indecision was not a viable decision. Sometimes indecision is a reasonable decision. But the point is people have to understand they are making a decision, whatever they decide to do.

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 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?

I'd want to know more data. But yes, if I didn't know anything else other than, let's say all cardiovascular.

Risk markers, save LDL of 200 or higher, LDL P of typically 2000 or higher, everything else is just pristine, perfect. Like CRPs at the floor, their LPPLA maybe.

Let's look at this patient here. So 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, because 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 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 read off some of his numbers just for the folks, Dave, does he? He doesn't quite meet your lean mass because his trigs might be a bit higher. But talking about this guy's numbers.

So total cholesterol is 504 LDL is that high. I know what you're doing there.

No, I'm just kidding.

I get this all the time where somebody sends me just that number. 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 Friedwald equation. So when it's direct, that actually is a direct measurement. That matters for Remnant. Hope we'll get a chance to talk about Remnant.

We will talk remnants for sure.

So LDLC at 362. HDLC at 94, triglycerides at 125. The very first question I would ask if somebody was sending this to me is whether it was faster or not.

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

Oh, he does.

Okay.

So he would be typical for lean mass.

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

Do you want me to keep going on the particles?

Yeah, go. Hit the particles.

So APOB is 283. That actually is a little higher than I'm used to seeing. LDLP is above 3500. Small LDLP is at 1483. Small, dense LDL C is at 47.

All right, we'll stop there and come back to it. So I've told you that everything else on this guy looks pretty good. Is this guy at risk?

I'm actually looking ahead because I would have cared about these other markers that could indicate inflammation. So, for example, the fibrogen is. Is very high. LPPLA 2 is above 600. I don't know. In fact, I think I actually just tweeted about this recently. I don't know that I've seen an LPPLA2 above 300 or 400. I think of the labs that have been sent to me, and I don't get a chance to interpret oxidized LDL. But you have the LDL as above 135. So I would say by this lab, as it looks, I would be concerned about the triglycerides. I would ideally want the triglycerides to go down.

But is it your impression that if his trigs were normal, he would be okay?

I would be interested to see if the other inflammatory markers linked back to the reason as to why the trigs would be a bit higher. That would be something I would be very curious about. But, yes, if you were to say, I think where you're trying to drive to is if I had only the information of the lipid panel itself, and it did say not 125 on the triglycerides.

Let's make it even easier. Let's pretend that this patient had a zero calcium score.

Well, zero calcium score. I'm not entirely on calcium score, but I do care about calcium score. The thing is, is I would say if you were to give me the same numbers, Let me make this easier. I have Craig Moffitz, who's very close to this, except that his triglycerides are much lower. If it was the same one, then I would. I would wonder if there really was a risk. Yeah.

Okay. So again, that is a decision that every patient's going to have to make in that situation. In the case of this patient, I feel very strongly that he is at increased risk, though I think on many other metrics. I think his risk of cancer, he's actually an APOE 23 this patient, so his risk of dementia is going to be a bit lower. He's metabolically quite flexible.

But if his other inflammation markers were low, like the lppla, the ox, ldl, all the stuff that was below, would you feel he was at risk? If the only thing that was different.

Was I would still feel he is at risk because, again, this is one of the three legs of the stool. Right. It's the burden of lipoprotein. It's the endothelial function or health, and it's the inflammatory response to it. And I can't measure number two very well. Right. And even number three is pretty kludgy, meaning all of these things like fibrinogen and CRP are not very specific. So you have to sort of, at the individual level, be very careful. You don't draw too much of a. Of a false sense of confidence. But look, looking at him, he has among the lowest asymmetric and symmetric dimethyl arginine levels I've ever seen. These are staggeringly low. I would have expected those to be through the roof. So ADMA and SDMA are things that we use to look at endothelial health. They inhibit nitric oxide synthase. So when ADMA and STMA are elevated, you're inhibiting nitric oxide synthase. You have less nitric oxide produced in the endothelium. You're more prone, obviously, to constriction.

I've never taken that test. I'd be interested in trying it again.

Just because I'm cheap and I didn't want to print up a bunch of paper. I only printed two pages of this guy's labs because those are the two that are most relevant. But you can take my word for it, the others were exceptional. Right. Like, this is a guy who looked really good across the the board. The question is, should anything be done? Now, if this patient had a negative calcium score, which he did not, but if he did, I would have still recommended lipid lowering therapy and or modification of diet. Why modification of Diet Because I've now seen more of these patients than I can count. And there is a pattern that is emerging. I think I wrote about this in one of the cholesterol things. But the pattern that always occurs in these folks, and I say always with a relatively small n, maybe there's 30 of these cases I've seen is this exact pattern. This one he's like a perfect example of. So his desmosterol is very high. Remember what we talked about at the outset? Yes. When a patient's LDL particle number is through the roof, you go through the checklist. Are there triglycerides high? No. There's no way in hell A trig of 120 accounts for someone being above the 99.9 percentile of LDL particle. Does he have an LDL receptor defect? It turns out I don't think so because I've seen his. Even though I haven't seen his LDLP, I've seen his LDL C off a ketogenic diet and it was 125.

Right. Is he lean and or fit?

He is.

Okay.

Yep. So his cholesterol synthesis is through the roof and his cholesterol absorption is quite high as well.

Are these affordable tests? Because I would definitely want to turn these around to the existing group of lean mass hypertension.

I'm sure the cash cost on these is not onerous, but my point is I think that the explanation for this phenotype is the upregulation cholesterol synthesis from the saturated fat. I don't think this is an energy issue per se. I think this is a sterile regulated binding protein issue or some sort of regulatory path around what the body is doing with ketones and or saturated fat. Tom Dayspring told me this a long time ago and I totally forgot about it. And then the other day I went and looked up a case because I never paid attention to this. We used to see patients all the time with diabetic ketoacidosis. So these are usually patients with type 1 diabetes that come in the ER and usually it's precipitated by some acute illness. But basically what happens is their glucose level becomes very high. They don't have enough insulin, of course they get a bunch of electrolyte abnormalities, but they present with very high levels of ketones. This actually is an emergency. So all the talk about ketosis being dangerous, this is the example of where it is very dangerous. It's life threatening. So what I didn't realize is I went back and looked. It turns out A lot of these people have very elevated levels of LDL cholesterol, total cholesterol. Now they also have elevated levels of triglyceride. But of course it's hard to know exactly what's driving that. But once you correct this metabolic deficit, which is quite easy to correct, it's basically potassium, IV fluids, glucose and insulin, and you normalize their glucose levels and their fluid balance and their electrolytes, the cholesterol returns to normal. So it might be that the ketones themselves are a substrate to make more cholesterol. And again, we'll link to a great paper that Tom wrote on lipoholics several years ago where he goes through the biochemistry of how saturated fats specifically and ketones could in a susceptible individual produce this phenotype. And so bringing it back to this idea of genes, we might really be dealing with a subset of people, these hyper responders, whoever, whatever percentage of the population they are. Who are the people that are susceptible to this? Because you were not going to find a leaner person exercising harder than I was when I went on a ketogenic diet. But I never had this response.

But there is a distinction that I tend to find, and this is Occam's razor. Again, more theory. And I'm actually going to be testing this myself in the next series of experiments that I'm doing. There is a difference between those people who are doing things like say endurance running and weightlifting or resistance training in that I think that there's a greater overall gradient of receptor mediated endocytosis for muscle repair and growth. Now I could be wrong about that, but I'll be very curious to see if that turns out to be the case when I'm doing it myself.

Sorry. A greater amount of endocytosis of which lipoprotein, and for this product of LDLP in particular into muscles.

Yeah.

For what product?

For repair and growth.

So you're saying that in these people they're relying on their LDL for cholesterol delivery to the muscle.

Well, and phospholipids and just about anything else that would be inside of an LDL particle. There's existing studies that are out there as far as like those people who do like a lot of weight training will also see lower LDL C. And this is why I was saying it's completely theoretical. I'll actually be testing this myself over the next few weeks because I'm actually going to be eating to a very fixed diet, fixed sleep schedule, fixed everything, and then actually be introducing basically any way in Which I can get my muscles sore in a very fixed fashion that I can then turn around as data. And if the hypothesis is true, I would expect that my LDL C and my LDLP might change.

But I'm confused. Why is the runner's muscle more demanding than the weightlifter's muscle or vice versa?

The other way around that I doubt I would see the weightlifter actually seeing a difference because I think there's more use of the product of LDLP directly by the cells. I may be wrong about that.

But what's the evidence that that's happening?

The evidence as far as the keto gains groups, I'm sure you've heard of them.

No.

There's a ketogenic group that's ketogains. There's not as many lean mass hyper responders that come out of that group. They'll tend to see their LDL C go up, but not as pronounced as those people who are like say runner types or aerobic types or even people who are doing yoga. There seems to be actually a more pronounced difference of higher LDL C depending on how much you're doing resistance training or anaerobic training.

I'm not aware of any evidence to suggest that the muscle is relying on LDL for delivery of anything, including energy.

Well, and I'm not so sure about it on energy. What I'm thinking about is in terms of just raw material as far as damage that can happen to, for example, the membrane of a cell. And I realize this is kind of a key difference between us in that your sense is that effectively anything that the cell is going to need, it can basically synthesize on its own. Right?

No, I think my sense is that Occam's razor would at least have me start from a place of plausibility. And I'm not, I'm not aware of any data that suggests that LDL is functioning to do this.

What's the value of non hepatic receptor mediated endocytosis from your perspective?

So you're talking about very specifically the little bit of LDL that gets out of circulation either with or without a receptor to non hepatic tissue.

Yes.

Yeah. My sense is the most important value of that would be to tissues that need more cholesterol to synthesize hormones, but.

Specifically cholesterol and not like the phospholipids or anything else that's on.

You know, I think the phospholipids probably may be more delivered through others. I mean, certainly the VLDL delivers Far more phospholipid than ldl. But LDL is really a custom built package for cholesterol. Like if you look at how many cholesterol molecules fit inside an LDL particle versus even an HDL particle. Remember, the HDL is the general of RCT and yet it can still only carry about 50 molecules of cholesterol. The LDL particle can carry 1500 molecules of cholesterol. That's staggering when you again consider the size of these things. Right. Like it's tailor made for that and that is largely conserved. I don't want to get us too far in the weeds, but I did actually did a very interesting kinetic experiment many years ago. So I did three blood tests every day for three days, like the full NMR panel. But this is with kinetics, so this is not commercially available. So what you're looking at is my ability to track and you'll have to lay it down because I barely remember what I did here. But this is pre workout, immediately, post workout, four hours later, looking at my LDL particles, my VLDL particles, my HDL particles, both in terms of their cholesterol and triglyceride content.

You see them going down yourself.

I don't see any change in the cholesterol content. 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.

Right.

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 going to link to it so you'll see it. We're basically talking about this idea of how much movement of cholesterol is going to 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, was a crazy intense bike ride.

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

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

Fantastic.

Again, it's not commercially. These are not assays that can Be reproduced. 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 is 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 ldlp. So we'll link to a graph that shows LDLP versus LDL C. These are nine points across three days.

I wish I could go back in time, find the you. It was this, like 2012, 2013, something like that.

Yeah, probably 2011 or 2012.

I'd be Peter. This is Dave from the future. I need you to eat exactly the same thing you do on all these days.

Yeah, I pretty much did.

Oh, you did?

Yeah. Yeah, I can hold for that.

Yeah. Okay, good.

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

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

Yeah, but you're not going to 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.

Maybe I'm getting a little confused here. How do you know about the cholesterol moving out of the ldl P. 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. Okay, so it's sort of a flux.

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 know, we're talking about the pool. Correct. Not the individual particles. In that sense, yeah.

It's basically saying if you took four snapshots in a room and how many people had blue shirts on and how many people had red shirts on, and you saw the deltas, you could not infer the actual numbers that went in and out, but just the net delta. So there is either a net influx or efflux of people in blue shirts or red shirts.

Right.

That's the best we can do. Now, there may be some kinetic studies that could do even one better, but that's, to me, pretty interesting stuff.

Let's circle back to remnants real quick. Okay, so this is why I kind of paused a little bit on the case study that you showed me where you had the triglycerides a bit higher. Now, as you know, it's. What is the poor man's version of remnants is you basically can just take your triglycerides divided by you probably.

Actually, no, no, no, no. We got to be very clear on this stuff. We're going to confuse the hell out of people. Okay, that's the poor man's version for VLDL cholesterol.

Correct.

Very important distinction. So the poor man's version, which should never be done because it is such an abomination, is to take the triglyceride level, divide it by five, and that number would be an estimate of your VLDL cholesterol.

What would you, Peter Attia, recommend as the most effective means by which somebody could determine their remnant cholesterol?

We can't. It's impossible. We have no way of knowing remnant cholesterol. Well, let me be clear. I think I know what you mean by remnant, which is why I'm asking that question. You're asking pathologic remnant. You're asking VLDLs that have shed their triglyceride and are now basically pathologic small started out as big triglyceride rich and now have shed that through their APOC2 to LPL pathway and now have the potential for atherosclerosis. Is that what you're meaning about remnant?

No. I now think we may think of it differently. So straight up, Wikipedia right now would define remnant cholesterol as basically all cholesterol that's not in either an LDL particle or in a HDL particle. So if you were to just subtract HDL cholesterol.

Yeah. So if you directly measure total cholesterol, which you can. And you can directly measure LDL cholesterol, and you can directly measure HDL cholesterol, you subtract those two and you have the amount of cholesterol that is virtually all in a vldl and presumably some.

Idl, if it's some idl, possibly chylomicron remnants. If you ate recently, but you shouldn't have any chylomicron remnants.

Yeah, that would. Yeah, that's very easy to exclude.

Right. But effectively, if you've had a fasted cholesterol test, pretty much all your remnant cholesterol pretty much will be in vldl. It has the longest residence time relative to the ideals.

That's correct. But that's sort of telling me, outside of very few pathologic states like Friedrichson type 3B's, that's as interesting to me.

As your eye color, the remnant cholesterol. Yeah. Really?

Yeah. I mean, it's generally going to be very low. It tracks quite well with triglycerides, though. There are lots of examples where it's been. Actually, I think I brought a copy of one of my other goofy experiments. I don't know if I probably won't find it anytime soon, but. But there was an example of how mine was so far off, it was like a 700% delta between actual versus predicted in one of these studies. But no, the point is, directionally speaking, I'd love to see a vldl cholesterol below 15 milligrams per deciliter, as calculated by taking non HDL cholesterol, subtracting the LDL cholesterol, which, if you have a direct LDL cholesterol is your best measurement of that. But whether it's 10 milligrams per deciliter, 15 milligrams per deciliter, 20 milligrams per deciliter. That just tells me the sum of cholesterol in all of my VLDL remnants. It tells me nothing about the pathology of them. It tells me nothing about what they've done or where they're going.

But that said, the question then becomes, even for as much as what you just qualified, does that become a more powerful predictor relative to something like, say, LDL cholesterol?

Maybe. But that's sort of like saying, is rubbing two stones together better than rubbing like two logs together to start a fire? It's like, why not just use a Zippo lighter? Right. It's sort of like we could split hairs on whether non HDL cholesterol or remnant cholesterol is a better predictor of cardiovascular disease than LDL cholesterol. But again, given that, you know, LDL cholesterol is such a crappy predictor of cardiovascular disease, I prefer not to really even think about that. That's again it's.

But we do have now a situation where this particular phenotype where lean mass hyper responders will have very low levels of VLDL cholesterol, have very high levels of LDL cholesterol, will have very low levels of remnant lipoproteins.

Well, but we don't know that. There's no way you've measured that. I've never measured that. That's not measurable in a commercial assay. That's worth its salt. I think VAP does a vague ass version of that, but it's sort of bunk. But look at this, look at Garvey's study. So we'll link to this as well. So this is actually measuring the number of particles. Right. So this is an insulin sensitive person. Their total FLDLP is about 1200. Their VLDLP is about 80. You go to someone who's insulin resistant but not diabetic, their LDLP goes up to 1435 on average, their VLDL goes to 84. Their IDL is counted. It's a rounding error though. And then you take the population with type 2 diabetes, their LDL cholesterol is up to 1600 nanomole per liter and their VLDL goes up to 100. So you're right, the VLDL is going up as you get more insulin resistant. But it doesn't appear to be very clinically relevant. Right. Because remember, it's all the burden of disease is from these apob bearing particles. And so, so the increase in VLDL particle number is not what's driving the risk of the disease. You actually had a really nice graph in one of your figures that showed you titled it as remnant that was going up. You know the figure I'm talking about. Yeah, we'll link to that as well. But you had a graph that showed, I think as people were becoming more insulin sensitive, their pool of remnants was growing.

Well, and actually I want to qualify something real quick if I think it's the graph you're talking about. It was the one downside to that is it was non fasted. Remember remnants which I've been trying to find more fasted remnants, which I have a problem.

It was in one of your talks.

It was in one of my talks.

But anyway, my point is what's missing from that analysis is APOB or ldlp. In other words, the expansion of that. See this study, which is, I mean the most elegant study of this ever done, shows that if you only saw the top line this to this, to this, everyone would be like, wow, the more insulin resistant you get, the more your total burden of APOB goes up. But what this is showing is where is that burden coming from? The VLDL only increased by 20 nanomole per liter, but the LDLP increased by 400 nanomole per liter.

Right. And the point I'm coming to is this is where we're in uncharted territory, is I don't believe this will apply to people who are ketogenic fat adapt. I don't believe this will apply to people who are very ketogenic fat adapted and particularly who have this phenotype. So let me see if I can come at it this way right now. If I were to be able to get the data set for Framingham offspring, because that is one of the studies that I was showing at from before, and I could basically just do this basic calculation of remnant cholesterol the way that we were talking about. And conceding the point that you said earlier that there's no way to truly know, would I still come up with a more valuable metric for subtracting HDLC and LDL C, particularly when associating it to all cause mortality relative to, like, say, ldlc?

Let me make sure I understand what you're saying. You're saying if you could develop an assay to distinguish between the pathologic remnants of VLDL versus the physiologic remnants.

I'm not even developing that. Let's say I'm not even developing. I'm just taking the existing HDLC and LDL C metrics as they're recorded right now. Like, I'm not even.

Oh, I see.

Okay. I'm just grabbing the data set as it is right now.

Yeah.

Will the remnant cholesterol that I get from that subtraction, will that actually be more relevant to all cause mortality than, say, LDL C?

I don't know, but it would certainly rival it. Again, the data are probably more clear on non HDL cholesterol versus LDL cholesterol. That's typically what the literature talks about. But as you can tell that non HDL cholesterol and LDL cholesterol are two of the three variables you would need. So there's a strong correlation between non HDL cholesterol and remnant cholesterol. And yes, I believe non HDL cholesterol is more predictive than LDL cholesterol.

But there's one problem with non HDL cholesterol that I definitely want to bring up for people who are on a low carb diet. If you're going to be powered much more by triglycerides directly, literally, triglycerides being brought to you in VLDLs, then that is going to be relevant. Now, again, conceding per what we talked about before, I can't know if I can stake my flag on it just yet. But I'd be willing to bet if I'm right on the energy model that in fact you are being powered more by triglycerides found in VLDLs, then you could have a higher resulting LDL particles. Effectively. The bigger question is, are particularly lean mass hyper responders showcasing directly that they are being powered much more by triglycerides brought on these VLDL boats, if you will, and therefore having more subsequent LDL particles.

Okay, so my hypothesis is that that.

Is not the case, that it's the higher degree of synthesis.

Right.

Going on with the cholesterol.

That's correct. That it is a higher degree of synthesis, which may or may not also be matched by a higher degree of absorption.

If you're wanting to suggest a way that we could test this, how would you suggest that?

Before I do that, let me unpack where I think energy is moving from. Right. So I think we all agree that someone who is very insulin sensitive on a low carbohydrate, high fat diet is utilizing a lot of triglyceride. We agree on that.

Yes.

Okay. Let's take an artificial construct and separate endogenous from exogenous triglyceride. Meaning someone on a low carbohydrate diet is eating themselves and they're eating triglycerides from the outside world.

Right.

Assuming they're in the phase of getting leaner. Right. So they're, they're losing weight, or even someone who's weight static. They're utilizing their own internal stores of triglyceride that they're replenishing if they're staying weight stable.

100.

Okay. So the exogenous triglycerides enter the body through chylomicrons. That's a pure lymphatic play through ctep. That's rapid hydrolysis. I think we all get that. I think it's this other endogenous pool that's interesting.

And if I could just interject this one thing, because this is one thing we're dancing around that we both know, that probably somebody who's not familiar with my work should be aware of. Chylomicrons. They drop off these triglycerides and they're just gone. Almost like Depending on who you're reading, within minutes to hours at the most. So if you're taking a fasted cholesterol test, per what we were talking about earlier, you shouldn't see any chylomicrons or chylomicron remnants. They should be gone. And the cholesterol payload on those chyloid microns should be gone. So with that in mind, go back to the endogenous triglycerides.

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 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. 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 going to 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 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 is 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, because remember, there's still de novo ILDL production in the liver 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 is 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?

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

Usually measure them by the way, as one.

Yeah, it's a little frustrating because a lot of this terminology gets interchanged, but the free fatty acids that are ultimately making it back to its liver 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.

But this depends on his energy requirement. I mean, of course, while he's running. And I wrote a blog post on this a long time ago, which I guess we ought to 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, 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 straight up mass balance. Yeah. 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.

Right.

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

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 adipose.

And they might be though. And that's my point is we don't know. What we know is that in which gets back to their 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 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 an ergostat of the body. I borrowed 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 N ergostat. So as an engineer, you'll appreciate the nomenclature. Right. It looks kludgy to someone who's not an engineer to say why would he call it an N ergostat. 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. 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 extra corporeal support for the liver. It is too complicated.

Anybody who follows me knows just how much I'm loving this. Because you're the. You're the preacher's 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. Whatever you're giving it, it's having to parse out and figure out and balance the ledgers and get everything.

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 ignore the water weight and stuff like. Like I'm talking about legitimate weight loss.

Metabolism exceeds.

Right, 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.

Yes.

So we agree on that completely. I look at his remnant cholesterol of 13 milligrams per deciliter and say, okay, it doesn't tell me anything. So I apologize because I've sort of lost your question. Was looking at that, what could we infer?

And this probably gets to just the larger problem that I feel like remnant cholesterol is helping us to Address is why is it that anybody would have high triglycerides at all? Why aren't all triglycerides making their way to either the tissue that's using it immediately, the skeletal muscle or the cardiac tissue or to the adipocytes if the body means to not have it sitting inside of lipoproteins parked in your bloodstream.

So that's a totally separate question. I want to come back to this remnant cholesterol question though.

But that's where look, this is why like the original graph that we talked to. This is why I draw that dotted line. I draw a lot of people's attention attention to it. This is kind of the core emphasis.

So this is the energy delivery support diagram for the person who's going to be looking at this later.

Right. We see that the chylomicron. I mean if I'm going to way oversimplify it, but not by too much chylon. Micron's job deliver fat based energy.

Yeah. But is so far gone that it's not really entering the discussion. We're talking about outside of very, very rare diseases.

Hdl not to deliver energy. We'll just say things not related to delivering energy. But I just call it supposed to support generally speaking operations not related to delivering energy.

I agree with that.

Okay, last line. Liver, this being the APOB100 containing lipoprotein is the one lipoprotein that clearly is pulling double duty.

No, no, but hang on. Remember now we're. This is where your diagram which you acknowledge is oversimplified. The oversimplification is hurting you. Right. So the liver has three purple arrows coming out of it. Vldl, idl, ldl.

Agreed. Which is why earlier I was emphasizing that I believe there's a higher secretion of VLDLs overall for those people with lean mass hyper responders. Which is very relevant to our discussion. And how do we know that it's a theory? I'm not saying that. What I'm saying is if this arrow is fatter, if the VLDL secretion is at a greater degree, it would make sense why there would be more remodeled final LDL particles remaining and why we would see the inversion pattern in the first place. Because it originated in order to deliver more of those triglycerides which was brought about.

So why the excess cholesterol if that were the case? Dave, wouldn't you hypothesize that the LDL particle would be very high because you have more VLDL particles but they're shedding all of their triglyceride in an effort to deliver their energy payload. But you shouldn't have an increase LDL cholesterol. You should actually have a reverse discordance from what we see in the insulin resistant patient where we typically see the LDL particle number being disproportionately higher than the LDL cholesterol by percentiles. Of course, in absolute numbers that's always the case. In other words, if I was buying your hypothesis, I would say the LDL cholesterol should be very low. You should have very cholesterol depleted skeleton particles that were mostly used to shed triglyceride as vldl.

Instead we see the concordance, we see the LDL C and the LDLP very concordant in people who don't appear to have other types of diseases.

Well, at that point they're so high it's hard to know, but they're clearly not discordant in the direction that would make sense given your hypothesis. In other words, what I'm getting at is why is there so much cholesterol in those LDLs?

Correct me if I'm wrong, but as far as the actual drop off rate, the LDL C is still going to be relatively standard on a per particle basis in a healthy subject. How much variability is there typically in LDL C per LDL particle? Because, and again, correct me if I'm wrong, I thought that the secretion level tends to be fairly standard. Kind of like a spare tire is standard per car.

Yeah, it's, it's.

The triglyceride levels can be very variable.

Yeah, but so can the cholesterol levels. I mean they have capacity to carry a lot. But think about it like you have large and small particles that even for the same amount of cholesterol, for the same amount of triglyceride, have different amounts of cholesterol. But the bigger point is where is the cholesterol coming from? So if we go back and look at my guy or look at Moffitt. So Moffitt's LDL cholesterol was 335 milligrams per deciliter.

Right. But that's what's in circulation in the blood at that time. So the larger question.

So hang on, just to be clear, Dave, is there any point during his 24 hour day when that number is like 30 milligrams per deciliter of LDL cholesterol in his bloodstream?

I don't believe so.

So in other words, if you take the area under the curve, if we could get real time LDL cholesterol number on Moffitt and integrate him over 24 hours. We could argue, for argument's sake, he's going to be always over 300mg per deciliter. His AUC would be very high.

Yes, for the LDL particle. I mean, basically what we're talking about is what's. I almost want to say it in terms of like birds in the air. Right. Like you have so many ships that have left the dock that are continuing in circulation. I guess here's a different question that I'll pose back to you. How much of cholesterol?

Wait, cholesterol? I'm actually asking this because I'm trying to understand it.

How much of this cholesterol has already made a lap? Are you thinking of this in terms of it's all getting synthesized and then reabsorbed and then recreated again?

Let's go back and make sure we're agreeing on the same conditions here, notwithstanding the experiment where they eat a ton of fat and they go from having incredibly high LDL to very high ldl. But let's just take a moffitt over the course of a week. Assume you could do real time LDL.

Cholesterol sampling on him and specifically LDL cholesterol.

Yes.

Okay.

Or everything. Everything that's on your page. You could sample his total cholesterol, his HDL cholesterol, his LDL cholesterol, his VLDL cholesterol and his LDL particle number. You could sample all of these things in every second for a week. I think we're agreeing that he will always have a very high LDLP and a very high LDL C and a low vldlc. Correct.

Unless he eats a lot of fat.

We'll come back to that after. But yes, sure. Okay. So given that the half life of his LDL is a day, where is that extra LDL cholesterol coming from?

I believe it's being recycled.

Well, it's always being recycled. How is his being recycled? So where is he deficient in cholesterol that a person who has an LDL Cholesterol of 100 is not?

I guess I don't understand the question. Where is he deficient in cholesterol?

Yeah, if he's got 335 milligrams per deciliter of cholesterol in his LDL particles, are you telling me that he has less cholesterol in his cell membranes or less of it somewhere else? So he has more cholesterol in his body?

Correct.

Why?

For the Same reason that we would have, say, life rafts on a boat. And once we have more boats, we have more life rafts. If we had a harbor just outside this window. Right. And you had 100 boats. And on those hundred boats, their main job is to deliver something unrelated to life rafts. They're delivering cargo to. To the other island. Right. And they deliver. And 100 of them go out, 100 of them come back, and then demand on that island has changed. Now they need to deliver five times as many things as they were delivering before.

The problem with that analogy is it assumes a completely fixed number of life rafts per boat.

It definitely does.

But that's not how lipids work.

How does it work?

There's much more flux in the system. And furthermore, you could ask the question in reverse. Why isn't it higher?

Why would an LDL C be higher on a per boat?

Yeah. Why wouldn't LDL C be higher in that patient? In other words, what's regulating it? What's regulating how much LDL cholesterol he.

Has the demand for the boats themselves for LDL particles.

What's driving that demand? This is, I think, where we differ. Right.

The demand is for the cargo, the originating cargo that is clearly getting used.

Right. But we agree that the VLDL vanishes very quickly.

The VLDL remodels to LDL very quickly.

Yes, but if you go through the kinetics of this, I can't follow why he should still have that much LDL cholesterol unless he is making more cholesterol. In other words, I've tried to think of this 10 Ways to Sunday. The only way on a mass balance that I can explain this hypothesis is if he's making more cholesterol and not.

If he's recycling the same cholesterol. Like, certainly he's making more relative only.

If he were depleting it in some other store. So in other words, I'm making this up. But like, if you could say, well, all of us, I mean, you probably know this. Everyone loves to quote this fact, Right? Like, red blood cells have more cholesterol in them than LDL particles. Right?

Right, right.

So the LDL denier loves to say, well, we don't think red blood cells are causing atherosclerosis, and yet they have more ldl, you know, blah, blah, blah, blah, blah, whatever. But my point is, unless you've depleted a pool of cholesterol elsewhere in his body, just on mass balance, you had to make more of it.

As far as I understand, the liver can recycle cholesterol as many times as it wants.

Again, that's true. And the liver and the gut have a very clear pathway, which is.

So correct me if I'm wrong, the liver is the only organ that can actually degrade cholesterol. Right? Non hepatic tissues can't degrade cholesterol.

Well, again, it depends what you mean by degrade. You mean, remember, cholesterol has no caloric value. It's something that we metabolize. Right.

If you were synthesizing more, you're saying it's going to go somewhere if it needs to be synthesized more.

Right. If you're synthesizing more, presumably you have a higher growth of the organism, you have more cells, you need more cells. Because obviously probably the highest demand for cholesterol is for cell membranes. So that's what I'm trying to figure out. It's like where, where is all this extra cholesterol coming from if it's not being synthesized de novo?

And that's my larger point, the inversion pattern is part of what should bring this to light is why then when I have an enormous amount of fat over 3 days I would see my LDL C drop by 73. Why would I see my LDLP drop by 1,115 in 3 days from eating huge amounts of dietary fat? Why would that happen?

I mean, it's an interesting question, I'm just not sure. All it's basically saying is you have a way to perturb those levels. I mean, I'll give you another just anecdote here. You know, I did a one week fast. I went keto for a week and then ate nothing for a week. And now I'm actually back on keto for a week for a week and I'm checking my blood every seven days. So that was my LDLP before I, that's my normal LDLP. So I'm walking around at 920 nanomole per liter. This is after, you know, months and months of time restricted feeding with virtually no carbohydrate restriction other than just I don't eat crappy carbohydrates.

Right?

So then I went keto for a week and look, my LDLP actually went up. Now I don't think I would meet criteria for being quote unquote, a hyper responder because it went up to 1380, which is not that high. But you know, that's still a significant jump for me. Right. Okay, what should it have done when I fasted for a week? Shouldn't it have gone up according to this model.

Well, here's the catch. The catch is I only know the three day window. I don't have a lot of data from people who fasted for a week. As in just water fasting.

I do.

Okay. You do?

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

Okay. Who are fully ketogenic. And you're saying it typically goes down, not always ketogenic?

No, sometimes they're, 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 want to 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.

Wow, fantastic.

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 counterexamples to anything and everything. But the general principle seems to be under caloric deprivation, LDL goes down and under fat deprivation, LDL goes down.

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. And I'm very curious about this.

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

It does seem to matter in this case. And you'll like this, at least in our own data with Apoe 4S, seems more likely. If you're an Apoe 4, you will see a drop somewhat in saturated fats.

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 young guy who went on a ketogenic diet. Was crushing it, meaning, like, everything was going well. I mean, he'd, 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 LDLP.

Right. It maxes out at 35.

Yeah. I was like, oh, I didn't actually realize the assay stopped at 3500. 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 OX LDL assay was commercially available, so I didn't have that. But, you know, his CRP and his LPPLA 2 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 going to do about it? And he was young. I mean, the guy was 30, so it wasn't like we had to do something tomorrow. This is not a guy who's going to have a heart attack in a week.

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

Well, what he pushed back on was because 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 want to 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 going to die of a heart attack tomorrow, but he's like, look, I'd rather live to 60 and feel this way than lived 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 lipoholics 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, because that was the other thing. This guy didn't want to leave ketosis because 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 going to basically have to become a non stop 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 it for this purpose. And sure enough, I think he came back at like 1300, 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.

Have you been keeping track of their PUFA levels too? Because it's hard to add a lot of MUFAs.

Their PFA is going up.

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?

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 Apoe 4 carrier.

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

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.

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 level.

Did notice you're pushing up and down on LDL C within supraphysiologic levels? Meaning if I recall seeing your data. Do you mind showing me that again?

Unfortunately, the computer died.

Oh.

That's why I've had it closed. But yes, what you'd see is an inversion graph.

No, and I'm very familiar with it and we'll obviously link to it. But it's.

It was.

As I describe it, you're showing that you can move your LDL between the ranges of very high and stupidly high.

No, like I've.

I've moved what's the lowest you've ever got.

Your LDL 98. And I suspect. I see, okay, I suspect I could get my LDL down to 70 if I was willing to go through with it. There's another part of this conversation we haven't had a chance to touch on, but that you might find very interesting since we talked about the liver. And again, more theory. So about 80% of what I've talked about is an explanation that I'm trying to fit onto what I know. And this is definitely one of those. But I suspect, given the data that I have for the whole second phase of my research, that actually part of how I'm reducing my triglycerides in the blood through a certain series of experiments I call carb swap experiments, is that I'm just trying to get a certain threshold of glycogen stores up in my liver, which seem to be at a certain point, meaning that there will be less VLDL secreted and therefore less ldl. That's the theory.

I'm sorry, say again? By moving glycogen, you're doing what again?

I'm trying to think about it more like as an engineer, whether right or wrong, I think, okay, if I were trying to engineer this body and I were caring a lot about the long term tank of storage, which is your adipocytes, but I was also to care about the short term tank, what is the reason why it would make sense from a mechanistic standpoint as to why the body would want to be so adamant about mobilizing these triglycerides for fuel in a low carb, high fat athlete, especially somebody who's very lean. And the short Occam's razor, from my perspective is it comes down to, well, there's very low glycogen stores relative to somebody who's on a high carb diet. This isn't to say that they have bottomed out glycogen stores, but relatively speaking, there's less play. And because of that, it makes sense as to why the body would activate more lipolysis, have more of the free fatty acids moving through, keep making it more available, et cetera. Okay, so then how could I tweak that?

But wouldn't that also just as easily be explained by the fact that when someone's walking around with 60% of the glycogen in their muscle, there's by definition, assuming they don't have a sort of pathologic condition, there's not much circulating glucose and therefore it's probably they're Also in a low insulin environment, which is fostering lipolysis.

Right. But it's gradiated. There's threshold points which are part of what I'm trying to isolate out. And there seems to be a threshold point with me, for example, if I have around 90, it seems to be at the last time I tested this, if I had around 90 carbs per day, Net carbs per day. Carbs per day. That seems to be the magic threshold that if I do that for about three days, my LDL C will just drop like substantially. Now, let's say I did 70 net carbs for three days. I've already done that. Doesn't do it. I have to get up to a certain threshold. And once I get up to that certain threshold, which seems to be somewhere around 90, all other things being equal, like I have to structure my life around this, where I, like, sleep the same amount and so forth. That seems to be the point at which there's an actual drop. And I actually wrapped that around. One of my presentations is I actually had a fat shake, a ketogenic shake for, I want to say three days, for a washout period. And then for just two days, I added what I thought would be the calculation to demonstrate what I was looking to do. So I swapped out the fat for carbs, kept it isochloric for two days. I had one that was a lower amount and one that was a higher amount. I can't remember the numbers right off hand. But then to further emphasize this, I switched back to the high fat diet for the next five days. And we saw my LDL C drop almost immediately and continue to remain low for the next five days. And in fact, it got to the lowest point at the end.

So it seems to be at least as sensitive on your carbohydrate intake as your fat intake. Right?

Correct. And this is very relevant because again, I'm still thinking about this from the energy model.

But hang on, I'm not just saying this isn't interesting, but for this to be relevant, it has to be reproducing something that's going to last over much longer than five days. How do we know if these effects aren't transient? And also how do we know they're relevant if they require an extreme condition such as, you know, one of them. I know you talked about how you just have to force feed yourself a ton of fat.

Yeah, that was the very first presentation of my data where I was having just a very high protocol.

But that also dropped your LDL C. Paradoxically, Correct, Correct. 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 LDLP 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?

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 T. Are right, that this, regardless of how we got here, if you have a high LDLP 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 going to be quite a skeptic. But all of that said, if I come to a point in which I can feel convinced that LDLP is in fact atherogenic absent remnant lipoproteins, absent having high hdl, low triglycerides, 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 LDLP alone here. So I think one thing that sort of.

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 would be very careful. Again, very interesting.

We have to be very careful what we mean by remnant it. 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 LDLP 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.

So, look, just generally speaking, I think dismissiveness in general, but we do have to care about the quality of evidence.

Oh, we sure do. Let me offer 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.

I think that's a fair point.

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 away to, like. I just don't buy that. I think there were strong personalities and lousy science. Those are very different things.

And let me go on the record with saying I basically agree. I feel like they're really the easy.

Part to agree with. Yeah, this is the hard part that's coming up.

Okay, good.

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 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 going to 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.

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't 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 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, but.

You'Re also, as we talked about, when you inject LPS in somebody, you're going to 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 for sure. Of course it's going to want all of the energy substrate it can muster and all of the hormonal precursors it can muster.

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.

Yeah, I mean, 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?

No. Okay, so if I could take all the LDL particles out of your body right now, I could feel totally confident that you will not die of atherosclerosis.

Okay, so does that not imply that LDL is necessary but not sufficient for atherosclerosis?

I don't disagree with that. Without question, LDL particles are important.

It's important for some people to understand that because I do think, put it this way, I've certainly heard people in this community argue the following, that the burden of proof should be on the lipidology community to demonstrate that LDL is causal rather than the reverse. And I find that comical. If it weren't for tragic.

Let's go back to the analogy for a second. Are ambulances causal for ambulance related deaths? Absolutely. They're a part of the problem. If I took life saving the same thing.

Because what you're basically saying is, look.

I'm emphasizing an association over a causation. We both realize that. Right? So, okay, it could be in this town you actually are in worse shape if an ambulance picks you up. There's very incompetent EMTs and their life saving measures are poorly done. And therefore, if you could ban all ambulances in this town, you'd find that.

Actually all men were a Mendelian randomization of ambulances would ferret that out.

I would agree. If there wasn't anything associated in the ambulance in the Mendelian randomizations with response by ambulances in the first place.

The only way I think you can discount the Mendelian random minimization is if you believe that the mutations that you're measuring, because. So you're looking at a series of mutations that are affecting a phenotype, in this case cholesterol level. You'd have to convince yourself that each and every one of those is also affecting something else that's driving the underlying cardiovascular process. Yes, yes, but we've already went through this. Right. It can't be the LDL receptor because that's not even ubiquitous and there aren't LDL receptors on any of the humans.

I want this tested on a healthy vascular system. However that's occurring, I want every cell to.

Hang on a minute. Why does a person with FH not have a healthy vascular system when they're born?

When they're born, yeah.

Meaning they inherit a clean slate. Right. Someone who's born with FH has a normal, beautiful vascular system that over time, in most of them becomes destroyed.

Just answer this question. Is there any cell in somebody who has FH that would function like a normal cell in somebody who doesn't have FH in order to be able to acquire the lipids or lipoproteins it wants to take?

Yes. There are plenty of patients with FH who do not have defective, completely defective LDL receptors and therefore are not impeded.

Put it this way, lipid metabolism is not impeded, is what you're saying.

Not all of them. Again, we have to be very careful when we talk about FH because there are least 2000 known versions of that disease. It's very cumbersome. So that's why I think it gets. FH gets talked about like it's one disease. It's a phenotype that has all of these things that can cause it. So the broader question is, is everyone with FH struggling to make steroid hormones?

I don't know the answer to that question.

No. In fact, FH may be slightly protective in the case of an infection and in the case of diabetes. And one argument for that, the diabetes one's a little hard to explain. The infection 1. FH has stuck around for a long time. So there may have been a time when having the ability to mount an incredible immune response would have proved to have a survival advantage.

Right.

And if you have four times the cholesterol of somebody else, that's one moment in when that could come at a huge advantage.

Right. Which gets back to the immunological response.

Sure.

But to get back to the larger point, I wouldn't blame somebody who has a poor digestive system for being malnourished. As long as we can count on everybody's tissues to be properly nourished.

And you mean by blaming them, like help me understand what you mean by that.

What I mean by that is if there was a problem with absorption of lipids or lipoproteins unrelated to total quantity of LDL particles, that's what I'm going to care about and I hopefully will have an answer on this soon. I'm actually working with a couple researchers who I'm trying to get an SMP list together that doesn't include lipid metabolism issues. So Ronald Krause who you had on from earlier, he was talking about this that he. They are looking right now on for example lots of the genetic studies and he was explaining the receptor issues associated with. And this is how you end up with higher levels of LDL C or ldlp, right? Is that you end up having less absorption, particularly on the liver side. But I'm especially interested in non hepatic.

Tissues that there are. There are people with Niemann Pixi 1 like 1 transplant deficiencies. There are people with ATP binding cassette deficiencies who have a huge increase in cholesterol. It has nothing to do with an LDL receptor. It's a transporter.

I'm not pointing just to the LDL receptor. I'm pointing to just the health of the cell. If the health of the cell is not compromised, then I'm interested if the lipid metabolism difference.

But why would someone whose ATP binding cassette in their enterocyte that is not appropriately excreting cholesterol, they're therefore driving up the recirculated cholesterol pool. Why does that mean that their endothelium is somehow defective?

I would have to follow what the path is that we're talking about. I don't know that I could give an answer to that until I can actually see the study that's associated. If you can take a biopsy of anybody who's going to have this issue and you can basically effectively see that the cells for which there would be targeted there is not going to be any problems. I wouldn't have any problem with using it. I mean basically what we really want, what we really want is just the means of just an overproduction on the part of the liver without it touching any other part of the lipid system. And your point? I'll make your point for you. It's hard to get an S and P that doesn't in some way touch other parts of the lipid system. But that's also the point against it. You see what I'm saying?

So let me ask you this. You're saying, look, I want more evidence. And I mean, I think science is based on skepticism. I completely respect that. But I think we also have to temper that with some modicum of understanding probability theory and saying, look, at some point, the probability looks disproportionately one way versus the other. So right now, what would your confidence be in the idea that LDL is playing a causal role in atherosclerosis just as endothelial dysfunction and inflammation play a causal role in atherosclerosis?

Let's make a distinction. The distinction is, if you're saying, is it part of the development of an atherosclerotic plaque, it's nearly 100%. If you're saying, is it the total quantity of LDL particles absent any inflammation or anything else along those.

Nobody's saying that. Nobody reasonable is saying that. So again, listen to what I said, right? So you've got three things that we can sort of use a metaphor and say they form the three legs of the stool. Three things have to happen for someone to get atherosclerosis. Each of them is necessary, none of them alone are sufficient. That's just the nature of complicated biology.

Let me help you with the question. I think this would be a better way of asking it. If given the same quantity of oxidative stress, whether it's low or high, would you rather have 1000 nanomoles of LDL particles or would you rather have 2000 nanomoles of LDL particles?

Yeah, we don't need to ask me that question. I think the question is, what would you rather have?

I used to think that I would say the first that I would rather have 1,000. I would say last year was probably more like. Could be about the same difference. Learning what I've learned, especially with the antioxidant defense system and so forth, and particularly given my own data, especially with the CIMT data that I presented recently, I don't know if, I don't know if you've seen that one as well. I was, I was getting crowded into media thickness test every six months. And during those six months, in the beginning of this diet and through the experimentation, I was running at LDLC levels of 200 or higher, LDLP levels of 2000 or higher for four tests in a row. You can actually see the regression that's happening on both the left and right side of the carotid arteries.

Yeah. I mean, again, I don't want to get started on cimt, which is hopefully it's the same tech doing it the exact same way. I mean. I mean, I'm guessing your CIMT initially was pretty good, and it may have gotten a little bit better, but I don't know. CIMT is even worse than calcium scoring, frankly.

Fair enough.

But again, Dave, we're putting a couple of n of how manys we're saying, look, these three little interesting anecdotes are basically calling us to suggest that the null hypothesis around this topic should be what you're discussing, rather than what I think is a remarkable body of scientific literature that is not without its problems and that is not absolute in its inference.

But it's not what I'm saying. What I'm saying is.

It might not be what you're saying, but it's certainly what a lot of people are using your words to say.

I have an energy model that a lot of people are utilizing probably overly simplistically, but if my energy model is right, it would suggest as to why. The answer of why, David, you haven't.

Even described it correctly to me today. Right. I mean, I guess it depends how liberal we want to be with the term model. Right. But there is no evidence that the LDL is there to carry cholesterol. You have yet to explain to me where Moffatt got his cholesterol.

You're talking about to the quantity that he has it at.

Yes. The guy's got three times the amount of LDL cholesterol.

I think it typically tracks with the total particle count.

You have to give me the mass balance. You're an engineer. You know this stuff just as well as I do.

If you are a hyper responder coming to cholesterol code right now and you turn over your lab, I can look at your LDL C and before you.

That's fine. That's fine. Look, that. That's just pattern recognition. That's not the interesting thing to me, I'm asking a very important physiologic question which you have yet to provide an answer to, and it seems to be the central tenet of your belief system. Where did Moffitt get his cholesterol? Why does he have three times more than he had before?

And the short answer to that is he synthesized it and he's recycling it. Now there's some degree with which he's synthesizing.

So this is a totally different answer than before. He has now increased his synthesis of cholesterol. He doesn't have the same circulating pool. This is not a shell Game with boats, right?

No, I was talking about circulating before.

No, but what I certainly didn't hear you say before was that he has actually increased his own endogenous production of cholesterol.

There's some amount where you're increasing it in order to meet that existing demand. I don't know how much that is.

But this is different than what I understood you to say earlier. Which is the reason he has more cholesterol is. It's just. It's along for the ride with the boats and he has to have more boats, which defies.

No, that is correct.

But that defies the principle of mass balance. You can't create matter out of nothing.

I'm not saying he's creating matter.

Okay, so he had to make more cholesterol. I don't see a way around that.

I'm not disagreeing with him making more cholesterol. I think where we're disagreeing is I think you're saying in total he's making three times more every day. Am I wrong on that?

On average, he is making three times more or reabsorbing three times more. But just based on what I'm seeing.

Reabsorbing at the liver or reabsorbing in non hepatic tissues, probably in the gut.

That'S where the majority of the reabsorption is taking place.

Okay, in other words, he's sending it back out the other side.

Well, again, this is what we look at these sterol numbers for. When the desmosterol goes through the roof, plus or minus the phytosterols. That tells you these patients are. Are making more cholesterol. Okay, but here's the question. If this were purely about energy, he shouldn't be making any more cholesterol. He should have more particles, perhaps, but they should be cholesterol depleted.

You answer this question for me. When does somebody make more cholesterol depleted? Because everything that I've read in clinical lipidology and so forth is it's like a standard quantity on the non triglyceride side of the ledger. If you're making cholesterol on a per particle basis, it can vary on a per particle level, but generally speaking, it tends to hit averages that are fairly consistent.

But this is an unusual circumstance you're describing, right? This is the whole purpose of this experiment, is you're describing people who, it's not unusual, you're saying is so great for triglycerides that they're doing that you make more boats.

But the boats, if they already have a standard Composition. Why would they change that standard composition per boat?

So are you telling me that you're saying that the large LDL particle and the small LDL particle in the insulin resistant versus the insulin sensitive patients have the same cholesterol composition?

No, that's my point. My point is getting back to remnant cholesterol, why it is that I think there would be something that would happen on that dotted line, something before and after. Right. Why would there be a problem with somebody who's metabolically deranged with their cholesterol relative to one of these people that are theoretically metabolically flexible? Why would there be a difference? And the short answer to that short answer is I don't know fully all of the aspects to it. I do know though, there seems to be a longer residence time with VLDLs and we see that because that's the fastest blood test.

Yeah, no, we know that. That's explained very clearly by Apoc3, the residence time on VLDL for that matter as well in pathologic states.

So if I became more insulin resistant and therefore ended up with higher VLDLs, I couldn't say 2 years later have healed that and then have less VLDLs?

No. Look back to the Garvey study. There's a reason I printed this up because I knew we'd be talking about this over and over again. There's very little difference. To try to impute or infer something about remnant cholesterol from VLDL is as complicated as trying to assess LP by looking at LDL cholesterol. Think about that for a moment. When you look at LDL cholesterol, if it's directly measured, do you agree that it's the sum total of LDL cholesterol plus LP cholesterol? Yes, I believe that's how it excludes vLDL cholesterol and IDL cholesterol because they contain APOE, whereas the LPA and the LDLP do not. So if you have a direct cholesterol measurement, the LDL C is technically LDL C plus lp, but there is no way on God's green earth you can look at that and infer what the LP is is Right.

Without testing directly.

Yeah. And similarly, we don't know what's going on with these VLDLs, but meaning in Moffitt, because we haven't measured it, but we've measured this in patients that span the spectrum of insulin sensitive to diabetic. And that doesn't appear to be the answer. The difference in the atherogenicity, the difference in the residence time and the difference in the total apob load appears all driven through the LDL particle, not the VLDL particle particle. So something else explains why they have more ldl.

That's what I want to find out. Again, I am very upfront about what it is that's theoretical and what isn't.

But we kind of already know the answer to that question. It's the triglyceride content.

But until we can actually test it on people who are fat adapted or ketogenic, we can't say that we do. When we can do a kinetic study on VLDL secretion with people who are particularly like lean mass hyper responders, then we'll have some idea.

But Dave, that will only offer you an explanation. It will not change the question of risk. Yes, let's say you can do the kinetic study and hopefully somebody wants to fund this because it is an interesting question. Again, I've done the kinetic study on myself. You've seen my data. I lose triglyceride, not cholesterol, which I would expect, right? I am seeing cholesterol basically stay the same in those cells during the periods of extensive exercise and fasting. We're seeing triglyceride movement within the cell. But the point is, even if this theory turns out to be correct, it's an explanation, not a reason. It's an explanation for something, but it's not a reason to ignore it, is it?

This is where I think we're getting circular. It's an explanation as to why it could be benign or even beneficial. And that's where we're disagreeing ultimately, which I figured we would be. Right? Why would you have high ldl? For a good reason. And your answer would be there wouldn't be one, right?

No, no, that's not true. There wouldn't be a good reason. With respect to cardiovascular disease, there are plenty of good reasons to have high ldl. We just talked about them. The FH patients obviously get some benefit from their high ldl. But from a cardiovascular standpoint, I don't think there is a single good reason to have high ldl. And I am not aware of a single card carrying lipidologist or member of the community that spends a lot of time in this literature that could come up with one. And I've been asking, I mean, it's something I've been very interested in. Give me a teleologic reason to have high LDL from a cardio protection standpoint. I mean, I was asking this question seven or eight years ago. I mean, There is no answer. So again, doesn't mean that having high LDL is always bad. But it's really important to understand this distinction. The other thing to keep in mind is lots of things in biology are not linear. So look at Gilbert syndrome. Gilbert syndrome is a very common condition. 2 or 3% of people listening to this have it, probably don't even know it, but they have elevated unconjugated bilirubin, but very slightly elevated. So if you've had a blood test done, you probably know down at the bottom it says alt ast bilirubin and normal bilirubin would be less than 1. But these patients with Gilbert typically get to about 2, well in half a dozen studies, these patients have an enormous risk reduction in cardiovascular disease. Why, why would having a slight doubling of bilirubin, which by the way, at high levels is toxic. So if you walk around with a bilirubin of 10, you're not going to be around very long. And those patients present, they get sick, they have obvious symptoms, they're jaundiced, and they usually have some pathology that's leading to it. But these patients can walk around with a bilirubin of 1.6 to to 2 and they seem to be getting a benefit from it. And they also seem to have lower ldl. And even if they don't have lower ldl, because the literature is mixed on this, they always have lower OX ldl. And it may be that the best explanation is that bilirubin has antioxidative properties, so they get this protection from cardiovascular disease, but it's a U shaped curve, or an inverted U shaped curve rather. Meaning as that bilirubin gets higher and higher, they start to lose any of that benefit.

Right.

Meaning whatever oxidative benefit they get, it's more than being outweighed by the damage that comes from that elevated bilirubin. So I guess my point here is even if there's an explanation for why this is happening from an energy trafficking standpoint, which again, I really want to be clear, I do not think there is. I do not think that energy trafficking is, explains this phenotype, I think that is not the Occam's razor answer. I think the Occam's razor answer is they're making a boatload more cholesterol. Because I think we have pretty good data to suggest that.

Which I'm dying to test, by the way.

Yeah, yeah. No, I mean we should make sure that you can and that other people can do this. But of course, the point here is it still won't actually answer the question what should you do about it? Just because there's a reason for something doesn't mean that it's a benign condition or that it should be ignored.

I agree. And not only that, separate subjects. I'll even go a step further and say it could be a used shape curve on this end as well. It could be that you could have an LDLP of say, 1800. And it turns out that's actually the bottom of the curve. And people at 1800 don't turn out to be as high risk as people that are like the one you just showed me above 3500. I not only grant that, I also further tell lean mass hyper responders I may turn out to be right on my cautious optimism as far as the risk in cardiovascular disease, but it could turn out that there's something, something else we haven't yet determined that's a problem with this phenotype, which is another reason why we should be sharing all the symptoms that may be coming along with it as well. But all of that said, all of that said, the larger question is why then would I be able to identify a certain set of parameters that when studied, seem to suggest that high levels of LDL C. I want some with high LDL P. Doesn't prove to be problematic. And that's why I want to get a hold of something. I want to get a hold of really large data by stratifying. Stratifying for hdl, high hdl, stratifying for low triglycerides.

No, no.

And stratifying for high ldl.

You know, if they're not at increased risk for cardiovascular disease. How long will you need to follow them to know that?

Well, that depends on the data set I can get a hold of. I. Not in your space. So I have to work with other people who are researching.

You're saying you want to do this with retrospective data.

Correct.

Okay. So meaning this is your challenge to say don't give me genetic data, don't give me drug data.

I'd like just normal, non drug, non genetic stratified people, preferably. And I'd like to stratify just on those three. Just on hdl, ldl.

Even though your patients probably have some genetic snips that are explaining their phenotype.

Oh, I would definitely want to know that as well. That's why I'm trying to actively get the 23 in me. I would love to send it away.

And the point is, you're excluding anybody who has anything that could be called the genetic alteration, even though the patient population you're trying to understand this in almost assuredly has a genetic alteration that's rendering them susceptible.

I'm not trained to exclude that.

But you just said you don't want to consider any of the genetic drivers of fh.

Let me emphasize, if you're making a study that is gene specific, then it's the gene that drives the detection, the discovery of those people, right? I don't want to do that. I want to actually see if I can get a broad based study of people who happen to already have high hdl, low triglycerides and high LDL and see if they have high rates of not only cardiovascular disease, but all cause.

But again, I come back to the FH patients. You can't find a more broader demographic of people in terms of variable genetic inputs that produce a phenotype similar to what you're looking at.

I think we're just going to end up in one of these got to agree to disagree moments until I can.

Which is fine, I totally respect that. But I just want you to understand what it sounds like from over here is you're looking, looking for six footer and you're not going to be happy till you see a six footer. And gosh, doggone it, you're not going to leave the kindergarten classroom until you find one.

I would argue the opposite. I would say, look, if I could right now just grab a million people in the United States, just absolutely randomly determine, why would that not be significant data? If I found that people there was the stratification for which high LDL did not result in high levels of cardiovascular disease or all cause mortality.

Well, because if you're going to do that honestly, you're going to say, well, they can't have a single genetic mutation, they can't be taking a single drug, and they can't be on any funky diet.

Let's say all of that turned out to be true.

What if they don't exist?

If I found that out, that would be definitely something I think would be very interesting to my followers. I would turn that back around.

But you'll never know if you found that out or not, Dave.

Well, I've already found two studies that do stratify for those three and of the two that do, high LDL does not result in high rates of cardiovascular disease.

Wait, wait, you're talking about these glycogen storage disease cases?

No, no. Framingham offspring has one study where they stratified by 3 and I. Unfortunately, my computer is dead or I'd show you the other one. There's another one that stratified discretely between below 170 LDLC and above 170 LDLC. And the high HDL low triglyceride group when compared to above and below were nearly identical both on the high side and on the low side.

Yeah, but this study didn't stratify by apob.

Right. I would love to have apob.

Okay, but that's the Quebec Heart study for you right there.

The Quebec Hard study has the stratification by all three of those metrics.

The Quebec Hard Study. Here, I've got it. Printed it up here.

Oh, fantastic.

Basically is showing it has nothing to do with the ldlc once you know, the apob. Look at the risk.

Okay. I'm trying to get those three in conjunction. I want to specifically stratify those three. And in software, this is where I get a bit frustrated because I feel like there's such a cultural difference between medicine and software. We're used to having just loads and loads of free data, just like we're awash in free data. Google can't wait to give me everything that I want to see. I requested. I've actually applied.

I know, I've heard you talk about it. That's. And are you being denied that or do they not have the data?

They just don't return my emails. There's even people that I would think would be sympathetic inside the low carb community and I'm not going to try to call them out, who I've also tried to get this information from and I just can't get it. And I want just a nice clean regression on three axes. That's all I want. That's nice and fat. So triglycerides, HDL and preferably ldlp. Now, there is an important distinction we've got to make with apob because APOB can in theory also include remnant lipoproteins.

Yeah, LDLP is more accurate than apob.

Right. And LDLP would be extremely fantastic if you could help me get in touch with that data set. I would be very interested. Not with any major adjustments. I mean, you know, whatever comes proportional, something like that might be fine. But just generally speaking, if I could get a big fat data set and stratify on those three axes, I think that would say a lot as to whether there's any validity to the energy model overall.

So when you look at the MESA data, which stratify on a Kaplan Meier curve, the difference between LDLC and ldlp. You're saying that that's not relevant because it.

The thing we're dancing around here is obviously when you have high HDLC and you have low triglycerides, it suggests a number of different things. But more broadly, it's suggesting a properly functioning lipid energy system. And probably not being in a state.

Of a challenge of HDL C tells us absolutely nothing. If we've seen enough from Mendelian randomizations. And another, how many more CTEP failures do we need to see? HDL cholesterol tells us nothing about HDL function. In fact, anytime you increase HDL cholesterol, pharmacologically, you seem to make patients worse.

I know, but these are modifications to the existing lipid system, if you.

I get that, Dave, but boy, if you're going to hang your hat on, it's all about HDL C triglyceride. I mean, wow, we are so far beyond that in the lipid world at this point. Like, if you're going to go through this brain damage, make it for something worthwhile.

But wouldn't you predict right now that if I did hang my hat on those two things, on those two markers against LDL C or APOB or ldlp, that it would fail? That if I were to say, hey, I want to get a stratification just of high HDL C and low triglycerides, that you'd say, sure, Dave. I'll bet you $10,000, I'll give you 100 to 1 odds those people with high LDL, even if you stratify for those two, will still have high rates of cardiovascular disease.

Again, I'd have to completely see the patient population before I could even hazard a guess.

But right now you would assume that, right?

I am going to assume that LDLP is going to be a stronger marker of prediction than HDL C. And that's.

Not what I'm making the case on. What I'm making the case on is whether or not there's a properly functioning lipid metabolism, which would be indicated by all three of these.

No, you have absolutely no understanding of the lipid metabolism by looking at HDL C and triglyceride. I think not even close. No, no, no. This isn't like we can disagree on things that are nebulous. This is not nebulous, Dave. This is. I mean, again, I hate that I'm saying this because I sound like a jerk and I don't to spend more time with lipid people. You really do. You are not dealing with your Peers at this. You have to go and figure out, like, HDLC is just categorically not a useful metric. It is like a first order term on a. Like. No, no, it's not even that. Like in engineer speak, it's the fourth order term on a fifth order polynomial.

That hurts, Peter. That hurts.

No, I mean, come on. It's just not that interesting.

I'm just kidding.

Look, it's super crude and don't confuse the ubiquity of it with its utility. Right? The ubiquity of it is. Yeah, it's cheap, it's easy, everybody's got it. But like, let's not let people listen to this and get lulled into a false sense of, hey, if my HDL is high and my trigs are low, who cares what my LDL is? And unfortunately, I want to prove that right or wrong. Well, first of all, you'll never prove anything in science, so let's be really clear on our lingo, okay? No, no, no, it's very important. No, no, it's important. Important for your listeners to understand that.

Fair enough, fair enough.

Nothing is proved. It's like probability.

Sure, but likewise, would you say the lipid hypothesis is proofed?

Absolutely not. I just said there's nothing outside of mathematics that exists in a proof.

Right?

Nothing. And I have the basis of the luxury of having been a mathematician once, so I get it. There's a luxury of being able to write QED at the bottom. We will never do this here. And if people are sitting there saying, well, I'm going to keep eating my bacon and eggs like it's mainlining and ignoring my LDL C because my HDLC is high and my trigs are low because, you know, I'm on a low carb diet. And somehow that makes me special because no one's proved that this is wrong. Wow, that's not the legacy I want.

So what if I continue to find more data sets that actually support that? What do I do?

I don't know. I don't know what that means. What do you mean by more data sets, meaning more anecdotes?

No, I'm talking like, let's say I do actually get a hold of Framingham offspring. Let's say I get a hold of. I forget what some of these larger data sets are and what you have to go.

Mesa.

Mesa. Sure. Let's say I can get MESA and I can stratify for those three and it's showing the same thing without doing a lot of adjustments or anything along those lines. What Would I tell my followers? I would say no. It looks as if still there's further evidence that's showing high LDLC in this case is not problematic. Or MESA did actually stratify for ldlp, didn't it?

Yes.

Yeah, so that'd be a great example. MESA would be fantastic data to get ahold of. Is that something you think I would ever actually be able to see or be able to run regressions against?

I've never thought of it, but I agree with you. That would be great. I don't know who gets the data.

But would that be compelling to you if it turned out that we could run regressions? Let's say that it was in the next room right now and we worked it up on the computer and sure enough, I went by these stratifications I was looking for that are like identical to somebody who would be, and they were typical to somebody who was already a lean mass hyper responder and it would show that they didn't have high rates of cardiovascular disease. Would that be compelling data to you?

I think compelling is the wrong word. The question is how would it add to the existing body of literature that informs a decision we have to make every day with a patient? And the answer is I'd have to see the strength of it and decide how does this fit into the existing body of literature? I mean, that's the only way I can imagine thinking about this. But everybody listening to this and you and I all have to put our heads on a pillow at night with a null hypothesis against which we have to challenge existing data. And I'm not convinced that the null hypothesis here should be anything other than the lipid hypothesis. Now the lipid hypothesis gets bastardized all the time. It gets misstated all the time. It gets based on LDL C&A whole bunch of other stuff. But I'm talking about the real, honest to goodness, no bullshit LDL hypothesis, which again, I've written about eloquently and people have written about it far more eloquently, I should say. I've written about it in a kludgy way. Others have written about it eloquently. The lipoprotein, the endothelial damage, the inflammatory changes, all of these things cascading. That's my null hypothesis. And in the end, if there's data to counter that, I'm all for it. For example, even when you look at the IL1IL6 agonists, the low dose mesitrexate studies that showed you could delay or reduce cardiac events without Changing lipoproteins. I don't think I'm being delusional when I say that doesn't change the model. It actually feeds into the model. The model is there are three things that are driving this pathology. If you reduce one of them, things get better. All things equal. If blood pressure goes down, do outcomes get better?

I believe they do.

Absolutely they do.

Yeah.

Very potent. Why? Endothelial function. All things equal. If you stop smoking, do outcomes get better? Absolutely. So when you start to look at all of these things and again with those.

But by outcomes get better, you're specifying cardiac outcomes, Right? Cardiac outcomes.

The all cause outcome is a much more complicated question that probably is a podcast in and of itself to your question. Yeah, Dave, of course. Like, I'd be incredibly curious to see this. Who wouldn't be? But don't think that, like one regression analysis on MESA is going to turn over 50 years of data regardless of what it shows. The question is, how does it alter our understanding and thinking of the problem?

Look, the whole reason I'm even pursuing this particular strata is because of the model in the first place. I had to have something that I could conceive of that would inform the decision by which I would be looking for what the data is that would disprove it. That's why I'm in pursuit of disproving it. At the end of the day, Peter, I can't emphasize this enough. I'm not looking to talk to the echo chamber or looking to just maneuver around inside of a number of people that are going to congratulate me. I specifically.

But I think you're better off going to an NLA meeting than a low carb meeting.

Sure, but they're freaking expensive. I've looked at all of them.

I got the low carb community to fund you if they want to know the answer, because I don't think they do. If I'm going to be brutally honest, I think the worst of that crowd just want their confirmation bias. They have seen these incredible benefits of low carbohydrate diets and their belief is nothing can be wrong with this. Like we somehow live in a mono dimensional, monochromatic world where like, it's that black and white and if the diet is good for this, it can't be bad for anything. And they are so wed to that that they construct these crazy arguments. But if they share your passion for truth, then they should happily fund you to go to an NLA meeting and spend a week there and actually start hanging with these guys. Who are way smarter than me. Like, I'm a knucklehead. I mean, I know a lot about lipids for a knucklehead, but I'm talking about, like, the smartest people in the world are the ones you need to be talking to on this topic. And they're not at low carb conferences, I promise you that. They're not on Twitter and they're not playing patty cakes on their, like, high carb or whatever low carb blogs like. It's just not about that stuff, man. And again, I mean, I think what you're doing is really interesting. I don't agree with the model, but I'm glad that you're pursuing it. I wish you the best in pursuing it with the right people.

Absolutely. Well, and perhaps you'll be able to help me set up with the right people. I would definitely be more interested in finding those voices that can help tear at this model.

I would be more than happy to help in any way I can.

Great. I can't emphasize enough. As I anticipated, I was going to ask you more questions than you asked me. I'm really appreciative that you took the time to chat with me about this.

No, my pleasure, Dave. Thank you very much. I apologize if this just took longer than we thought it might have. And I know we went off on tangents all over the place. I guess this will be one where the show notes are probably quite helpful. But nevertheless, it was great meeting you in person. I didn't realize it's only been three years since you've been at this. It feels like a lot longer, actually.

It certainly does for me. And my wife was say it's felt twice as long for her. I mean, you have to realize something. Almost nobody knew about me a year and a half ago, and I knew almost nothing about cholesterol three years before that. This has absolutely been a fresh journey. And that's why I have to oftentimes emphasize that I'm not a formally trained biochemist and I really have a lot of gaps, I'm sure, in my knowledge that I'm looking to fill and find as fast as I can.

All right, well, it was great to meet you. Enjoy your time in San Diego. Oh, by the way, for the listener, this is being recorded on July 26th. It will be a long time before this goes up, Dave. So hopefully the listeners understand that whatever's transpired since then is just. We pre record these things many months in advance. We may have to bump it up a little bit, depending on maybe we can reshuffle it and get it out before the end of the year, which is probably right now where it sits in the pipeline.

But you're going to subject me to quite a hell because I'm guarantee every single follower I have is going to be knocking on my door until this thing is opened up.

We'll do what we can anyway man. All right, thanks so much. Absolutely awesome to finally meet you. You can find all of this information and more@peterattiamd.com podcast there you'll find the show notes, readings and links related to this episode. You can also find my blog and the Nerd safari@peterattiamd.com what's a nerd Safari, you ask? Just click on the link at the top of the site to learn more. Maybe the simplest thing to do is to sign up for my subjectively non lame once a week email where I'll update you on what I've been up to, the most interesting papers I've read, and all things related to longevity, science, performance, sleep, et cetera. On social you can find me on Twitter, Instagram and Facebook, all with the id PeterAttiyamd. But usually Twitter is the best way to reach me to share your questions and comments. Now for the obligatory disclaimer. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing or other professional health care services, including the giving of medical advice and note no doctor patient relationship is formed. The use of this information and the materials linked to the podcast is at the user's own risk. The content of this podcast is not intended to to be a substitute for professional medical advice, diagnoses or treatment. Users should not disregard or delay in obtaining medical advice for any medical condition they have, and should seek the assistance of their healthcare professionals for any such conditions. Lastly, and perhaps most importantly, I take conflicts of interest very seriously. For all of my disclosures, the companies I invest in and or Advise, please visit peterattiamd.com about.