#129 - Tom Dayspring, M.D.: The latest insights into cardiovascular disease and lipidology

1. 0:00 – 3:45

   Intro

   1. PAPeter Attia0:01

      [upbeat music] Hey everyone, welcome to the Drive Podcast. I'm your host, Peter Attia. This podcast, my website, and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, full stop, and we've assembled a great team of analysts to make this happen. If you enjoy this podcast, we've created a membership program that brings you far more in-depth content if you want to take your knowledge of this space to the next level. At the end of this episode, I'll explain what those benefits are, or if you want to learn more now, head over to peterattiamd.com/subscribe. Now, without further delay, here's today's episode. My guest this week is Dr. Tom Dayspring. His name's probably familiar to some of you because back in October of two thousand eighteen, we released a five-part series with Tom, and that set of episodes, despite being quite technical, are some of the most popular episodes we've released, especially amongst people who really like to get serious about their understanding of cardiovascular disease. So we wanted to have Tom back basically to pick it up where we left off. And in this episode, we try to focus on things that have changed in the last couple of years, and that kind of loosely fell into three categories that we probe. The first is digging really deeper into the recognition of the importance of atherogenic lipoproteins. So kind of revisiting the idea of what ApoB is, why it matters, and both Tom and I discuss a little bit about how our views have changed with respect to the use of ApoB as a laboratory surrogate over LDL-P. And we get into all of the nuance around that with respect to VLDLs, triglycerides, Lp (a) , et cetera. We also get into why HDL cholesterol is a far less relevant metric, at least why we believe that to be the case. We then pivot a little bit and talk about risk assessment. Basically, how do you understand these metrics? How do you use these metrics? This is a lot of the clinician type stuff here around ApoB and triglyceride-rich lipoproteins. We, again, revisit the idea of Lp (a) and then finally, we bring it home with some discussion around therapies, and in particular, we talk about the continued evolution of the PCSK9s, the evolving data around omega-3 fatty acids, in particular, some of the controversy between EPA alone versus EPA and DHA. And obviously, we talk about the most recent addition to the lipid drug story, which is a, a drug called bempedoic acid, which has not been around very long, and probably many people are not going to be familiar with that, but Tom does a great job explaining that. Tom's a diplomat of both the American Board of Internal Medicine and the American Board of Clinical Lipidology. He practiced internal medicine in New Jersey for thirty-seven years, the last seventeen of which was devoted to consulting patients with lipid and cardiometabolic disorders. Between twenty twelve and twenty nineteen, he served as the chief scientific officer at two major cardiovascular biomarker laboratories. Since that time, he has been working with us in our practice, primarily on the research side of things, but also as a consultant advising on most of our cardiovascular cases. He's both a fellow of the American College of Physicians and the National Lipid Association, the NLA, and he's an associate editor at the Journal of Clinical Lipidology. He was also the recipient of the National Lipid Association two thousand eleven President's Service Award. He's authored and illustrated more manuscripts and book chapters related to lipids than I can count. And so without

2. 3:45 – 9:30

   The latest in the field of lipidology and cardiovascular disease

   1. PAPeter Attia3:45

      further delay, please enjoy my conversation with my mentor and friend, Tom Dayspring. [upbeat music] Hey, Tom. Thanks so much for, uh, for making time to sit down again and talk about lipids. It's been almost two years since we sat down for what still remains the longest podcast I've ever done, nearly eight hours, which I believe was divided into a five-part series that is still a very popular podcast series. And don't take this the wrong way, but I'm kind of surprised at the popularity of that episode, given that I thought it was really geared only towards people that were really, really diehard lipid fanatics. But it's had a broad enough appeal that I think we've agreed mutually that it makes sense to sit down again.

   2. TDDr. Tom Dayspring4:41

      That was amazing. First of all, it's always great to sit down with you, Peter, and, uh, chat about my little lipid world. But yeah, I'm shocked every time somebody tells me, "We've listened to the whole series, and I've done it three times." And I, I, I just can't imagine that, but, uh, I'm glad it came across pretty good.

   3. PAPeter Attia4:59

      You know, one of the things I wanted to do today, Tom, and I can promise you and all the listeners, we are not going to do this for another eight hours today.

   4. TDDr. Tom Dayspring5:05

      [laughs]

   5. PAPeter Attia5:06

      But what I want to do today is sort of, I think, kind of pick up the mantle from where we were a couple of years ago and talk about what's different since then. I think the last two years has seen a number of things that are actually pretty exciting in the, in the field of lipidology and the field of cardiovascular disease. Some of it's been at the really nuanced level scientifically. Others have been, frankly, at the broader level in terms of recognition of certain things that, you know, you've been talking about and many others, people like Alan Sniderman, have been talking about. A lot of this stuff is very clinically relevant. The way I pose this to you, and I think this, unless you're opposed to it, the way I'd love to kind of go through this is maybe use our time today to talk about things that are different today than perhaps they were a few years ago and dive into those things in enough depth that everybody from the, the layperson to the aficionado will have something to chew on.

   6. TDDr. Tom Dayspring6:08

      Yeah, that's a perfect strategy for today. Now, there's no doubt we'll reiterate some concepts that we went over in great depth back then, but we won't have that opportunity today. But... And you know me, Peter, I've always lived on the cutting edge of lipidology science, leading the charge, trying to understand new concepts that come down. But one of the great satisfactions of my career is much of what I've promulgated for the longest time has come to fruition. And, and that's what's really happened in the last two years. There are certainly some new concepts and some abandonment of s- some other issues, but it's just the... Y- you know my whole mantra for a long time, you know, we've known each other a decade probably, is that atherogenic lipoproteins are really the issue behind clinical atherosclerotic vascular disease. And although many of us have known it for a while, the data has just become so overwhelming that virtually all of the guidelines have signed on to that premise now that, uh, atherogenesis is certainly a sterol-mediated disease, but sterols are trafficked, uh, within ApoB-containing lipoproteins, which provides the vehicle that transports them into the artery wall, where they can in some start a pathological process. So it's the recognition of atherogenic lipoproteins that is now in the guidelines. And, you know, atherogenic lipoproteins are still diagnosed using various cholesterol metrics, but there are things beyond LDL cholesterol now that are in the guideline. And even ApoB is certainly within every of the contemporary guidelines in the last two years, and that's of course the Allen-Snyderman thing that he's been harping about for a long, long time. So it's atherogenic lipoproteins. Within that category, though, the things that are also emerging is what contributes to the atherogenicity of an ApoB particle? Triglycerides has really taken center stage, how they affect lipoprotein concentration and quality or functionality, whatever adjective you wanna ascribe to. It's the loss of the ability of at least the HDL cholesterol metric to be terribly informative to us, and it's the emerging, uh, significance for a lot of reasons of lipoprotein little a. So those are the big areas where change has really become important and is really useful at the bedside. Of course, pharmacology and intensity of pharmacology has also advanced, and we'll touch a little bit a- on that today, I'm sure.

   7. PAPeter Attia8:49

      To sort of summarize that, we're gonna talk about kind of double-clicking on ApoB/LDL particle, basically the atherogenic lipoproteins front and center in the pathogenesis of, of cardiovascular disease. We're gonna talk about the modification of our risk assessment, and I like that you brought up HDL 'cause I wanna have a pretty interesting discussion about that. And obviously, we're gonna talk about what's happened in therapies. There have been actually quite a number of things, including the continuation, more data around ezetimibe and PCSK9 inhibitors, much more data since we last spoke around omega-3 fatty acids. I spoke with Bill Harris about that, but I think we can go a little

3. 9:30 – 16:30

   Apolipoproteins—the key to understanding lipid biology

   1. PAPeter Attia9:30

      bit further, and there are a couple of other therapies. So let's start with maybe a little bit of a reminder for people as to what ApoB is. People like you and I sometimes use ApoB and LDL-P interchangeably as shorthand. That's not entirely correct. And when we last spoke, we probably disproportionately spoke about the number of LDL particles, and now we're gonna focus on ApoB. So do you mind explaining what the difference is both from a biology standpoint but also from a laboratory standpoint?

   2. TDDr. Tom Dayspring10:08

      And those are critical points, Peter, because it's one thing to talk about ApoB, but almost what you're saying about it depends how did you analyze it? What laboratory metric did you order that you think is telling you something about ApoB, whatever that encompasses? So to make a story very simple and short, you know, lipids go nowhere in aqueous plasma because they're hydrophobic. So for a lipid to be trafficked throughout plasma, it has to attach to a protein. Now, a few molecules of any lipid can attach to albumin, but that's not the primary way lipids get anywhere. Serious collections of lipids, hydrophobic substances, attach to fairly significant proteins which solubilize them, and these apoproteins, as they're called, proteins that wrap collections of lipids, provide structure and stability to this macromolecule that we're gonna call a lipoprotein. So the main structural protein that enwraps lipids in our body is apolipoprotein B. It's a five hundred kilodalton molecular weight protein, so it's pretty big, and it has a great ability to attract a lot of lipids to bind to it. But once the lipids are bound to it, this is a water-soluble lipid transportation vehicle. There's basically one other class of lipoproteins, and that is the HDL particles that you mentioned, and they have no ApoB on them. Their structural protein is apolipoprotein A-1, capital A dash either Arabic or Roman number one. So right away, we have a double classification of lipoproteins, the ApoB-containing, they're often called beta lipoproteins or the al- or the ApoA-1 are called the alpha lipoproteins. So now within that ApoB family, it always gets a little more complex in lipidology. The two tissues in your body that can make ApoB are the liver hepatocytes, and of course, the small intestine, which is absorbing a lot of lipids, so it has to put them in something if those lipids are gonna get into your plasma. So the apoB that's made in the liver is a big 500 kilodalton, uh, protein that I mentioned, and it's called apoB 100. Now, why do they add the 100 on it? 'Cause the intestine also produces apoB, but it produces a truncated version that has 48% of the molecular weight of the hepatic-produced apoB. So that's called apoB 48. So if the liver makes an apoB particle full of lipids, it's got one molecule of apoB 100 on it. If the intestine makes a big lipoprotein, and it does, they're called chylomicrons, that has one molecule of apoB 48. The, uh, intestine can put it in your lymphatics. It enters the systemic circulation. The liver just secretes it directly. So those are the two types of apoB. We're not gonna talk a lot about chylomicrons. They're in most people without a pathological, uh, genetic pathological issue. It's not your chylomicrons that are the, the major problem here. They're a postprandial lipoprotein. So the liver makes these apoB 100 particles, and they can go out. The liver can secrete them, but some of the particles that the liver secretes can be catabolized into smaller and smaller versions, even though they're still apoB proteins. So if we're gonna talk about the apoB 100 family, and I'm probably not gonna use the term 100 anymore, we're talking about very low density lipoproteins, intermediate density lipoproteins, and low density lipoproteins. And of course, part of the LDL family is lipoprotein little A, if you happen to produce that. Not everybody does to significant amounts. The names of those particles, as you know, they were originally discovered via ultracentrifugation, so the ones that floated on top of the tube were the very low density, the ones that sank to the bottom were the high density, and the in between were the IDLs and LDLs. Now, so the apoB family is VLDLs plus IDLs plus LDLs plus Lp little A if you have it. Well, that's true, but here's the reality. We have to look at plasma residence times. How long do these things float around? How long are they in your system? 'Cause that's important because these are the particles that have the potential to crash your artery wall and traffic sterols and whatever else into the artery wall. The chylomicrons I mentioned, their half-life is in minutes, their plasma residence time a few hours. The VLDL particles, their half-life is two to four to six hours, depending how rapidly they're catabolized. The IDL particles are a transient in between particle between a VLDL and an LDL. They're around for an hour or two. They're not, other than an unusual genetic condition, a player in this apoB game we're talking about. And finally, we have the LDL family. Now, LDLs have a plasma residence time of two to five days, and there are other attributes to the LDL that determines is it gonna just hang around for two days or five days. Clearly, the longer it hangs around, you're gonna have a lot more LDL particles than if you could rapidly clear them. So when we talk about whatever apoB metric you're doing, technically you are measuring VLDLs, their remnants, their smaller VLDLs, IDLs plus LDLs plus Lp little A. But because of the half-life, 90 to 95% of your apoB particles are LDL particles. So that's why many people say, "Hey, apoB is just another way of getting an LDL particle count." And that's true. Even in people who might have a lot of remnants, the remnant particle number is quite small. It is still way more LDL particles floating around in these people who might have these remnant VLDLs that cause issue. Not to say a VLDL remnant might not be a very injurious apoB-containing particle. It certainly is in some people. But if we're looking at the number, which is the primary driving force as to how an apoB particle enters the artery wall, LDL is king.

4. 16:30 – 21:45

   ApoB as a preferred metric over LDL-P

   1. TDDr. Tom Dayspring16:30

      And that's why our metrics of apoB or LDL particle count are what are at the top of all the guidelines. And of course, the metric most people use are LDL cholesterol and non-HDL cholesterol.

   2. PAPeter Attia16:43

      I mean, Tom, on a personal level, the reason I have switched to apoB in our practice, which is obviously heavily influenced by the work that you've discussed, the work that people like Alan Sniderman have been doing for many years, frankly comes down to a consistency factor. So we had historically relied on LDL-P, LDL particle number, as a concentration count. But frankly, in the span of eight years, went through three technologies to do that, right? Two generations of NMR coupled with electrophoresis. And while in the end we felt the electrophoresis provided the most accurate measurement, you always have a problem when you don't know what you're comparing it to. So if we have gen one NMR, which is probably still being used by LabCorp and Quest today, that is probably quite inaccurate compared to gen two NMR, but the percentiles, meaning the populations of people that were measured, are still what we use to understand where someone lies, it puts you in a bit of a dilemma as a clinician or as a patient, you want to continually upgrade your technology. In other words- If you're talking about getting a new iPhone, you don't really care that your phone is so much better than two generations ago's phone because all your metrics are better and there's nothing to be gained by comparing yourself to how much better you are. But when you're talking about diagnostics, it does matter where your reference range is and if you're moving it. So do you agree with my logic for switching to ApoB a year ago as now being a much more homogeneous way to assess patients even across labs? So especially now in light of COVID, we can't always use the same lab to measure ApoB. So, you know, I might be sending a patient to one lab versus another lab, and I, I just feel like we're getting better results this way. Does that jive with you?

   3. TDDr. Tom Dayspring18:49

      No, that makes total sense. And a real important take-home point for listeners is pick your favorite metric, Peter's right now is ApoB, mine right now is ApoB, and stick with it. Don't do ApoB this time and an LDL particle count via NMR. Peter didn't even mention Quest has a particle number technique called ion mobility transfer that people... They're not comparable. All biomarkers you should ch- consistently try and use. Of course, the same lab, not always possible, but the same assay. And the ApoB immunoassay is pretty standard throughout the industry. It's not like everybody's got their own ApoB assay. The NMR can vary widely. The other big reason to do that, consistency of results over time, is sooner or later, yourself, you're going to read the guideline or maybe your patients are going to go, "All the guidelines talk about ApoB. There is no guideline telling you to do a NMR LDL-P or an ion mobility LDL-P." So it's another reason to just stick with the ApoB. And I think there are less false positives with the ApoB. It's just been my, my personal experience. I've been an NMR guy all my life, and as we g- got better and better, we just so often saw totally unexplainable discordance between LDL-P and ApoB, that that is overwhelming for ApoB. So I think that's where you should be in today's world as your marker of atherogenic lipoproteins.

   4. PAPeter Attia20:19

      Yeah, I think we saw that especially with the second generation NMR. It was almost like it had become too sensitive. We were seeing discordance that far exceeded what the Framingham or MESA data predicted the discordance should have been. And that's really actually what took us to the ion mobility assay. But again, I'm, I'm actually very... From a diagnostic and management standpoint, I'm actually quite comfortable with, with where we are. I think the th- final point I'd add to that, Tom, is just the economic one. You know, frankly, I think the cost of an ApoB is, y- you know, at least in Canada, and the only reason I know that is 'cause Alan Sniderman is at McGill and, you know, he's been pounding this for a while. I mean, we're talking about a three or four dollar test, so there is no excuse for any physician to say, "We're not going to order your fancy ApoB because it costs too much. I'm going to order the LDL cholesterol." I think that excuse has lost all of its water.

   5. TDDr. Tom Dayspring21:14

      It's so true, and Alan just published a beautiful paper where he's researched the cost of ApoB assays, 'cause, you know, even some of the people in the guidelines always, "Oh, we can't say ApoB, it's so expensive." That's an old excuse that is no longer applicable to 2020. So of all the technologies to quantitate atherogenic lipoproteins, ApoB is the most affordable. And even, y- you know, look, labs sometimes change crazy, but if you tell a lab you want to pay a cash price, it's really pretty

5. 21:45 – 34:15

   Therapeutic goals for apoB concentration

   1. TDDr. Tom Dayspring21:45

      cheap.

   2. PAPeter Attia21:45

      Yeah. Let's go back to kind of the macro point here around ApoB, which is a greater coalescing around the idea that, that ApoB concentration matters. So I think it's very well understood that two of the biggest risk factors for cardiovascular disease are smoking and hypertension. I don't think there is any ambiguity that cigarette smoking and high blood pressure increase the risk of cardiovascular disease, and they both appear to do so through a mechanism that weakens the endothelium or creates an injury to the endothelium. The question now becomes, as you put it, Tom, how ironclad is the story that it's the ApoB-bearing particle in the presence of injured endothelium that is the Trojan horse that begins this destructive trajectory of taking that cholesterol into the subendothelial space, becoming retained, undergoing this chemical oxidation process, which then kicks off an inflammatory response that paradoxically, as an attempt to repair the damage, results in what can be a fatal injury. There are other hypotheses. For example, there are people who note, and we have... I mean, look, I have a patient in our practice, Tom, you've weighed in on her case, walks around with a total cholesterol of 300 and something, an LDL cholesterol of 220 milligrams per deciliter, an ApoB of 170 milligrams per deciliter. She's in her late 60s and her coronary artery calcium score is zero. We have elected to not treat her with any lipid-lowering therapy. In other words, there are exceptions to this. How do we reconcile that?

   3. TDDr. Tom Dayspring23:40

      Well, it's [chuckles] the human body and medicine. As you know, not all smokers are going to come down with lung cancer or chronic obstructive lung disease. Why not, if that's such a horrible risk factor? I try to explain this a co- and I've certainly seen cases like you say where, oh my God, if I was just going to say, "Give me your ApoB or whatever cholesterol metric, you're going on three drugs right now. You got no choice." And maybe in the old days we, uh, approach people that way, but no more. I think you have to individualize your whatever risk factors you discover that might wind up causing atherogenesis and then figure it out. So particle number is certainly a major factor that might force it in, but not always. Endothelial function, although you can certainly, if you review the history of this and how do you really determine endothelial function, not everybody has serious endothelial dysfunction who winds up with atherosclerosis. So particle number itself in some people can just make the particles go in. I think if we take most adults, who's not gonna have a little bit of endothelial dysfunction? So I agree with you, it's a combination of something about atherogenic particles, be it their number, endothelial dysfunction. But I'm talking more and more now when I discuss any type of lipoprotein, I don't care which subgroup you want to talk about, I think we certainly have to know its particle concentration, but I like to talk about particle quality. So what are the other attributes of any d- a lipoprotein that might contribute to its atherogenicity or in, in some perhaps not understood mean re- make it relatively it's not going to generate atherosclerosis? And there certainly have to be things like that going on. So as we're getting smarter, we're looking at other components of the lipoproteins that could be other proteins that are on them, that could be their complex lipidome, and trying to see, aha, can that help us discern whether in you a given particle concentration is more worrisome than it is in the next, in the next person. So there's a lot going on. And also from the gist of this conversation, listeners will know atherosclerosis, atherogenesis is a multi-complex, multi-factorial disease. And that's why even when Peter and I, if we consult on a case and we realize in this person we have to beat up ApoB and get their particle numbers to a more physiologic range, we don't stop once we do that. We examine in great detail for other things that might be injuring the endothelium or the arterial wall and see are any of those treatable or so. So we're getting a little bit smarter on lipoproteins, but there certainly is more to it than just particle number.

   4. PAPeter Attia26:26

      Do we think that there's a limit to where the benefit of reduction becomes diminishing or even J curves in the other direction? So we discussed it in the first episode significantly. We did so again with Ron Krauss. It wouldn't be, you know, the worst idea in the world a couple of years from now to sit down and do it again and reexamine the data, but I- but again, I think the causal relationship between ApoB and atherosclerosis is as strong as virtually anything we see in medicine for which you can't do the perfect experiment, where you have to rely on natural experiments. Nevertheless, maybe it's not entirely clear what the dose response looks like. So if you have somebody whose ApoB is a hundred and sixty milligrams per deciliter, there's a risk reduction that comes to lowering it from one hundred and sixty to one hundred and lowering it from one hundred to eighty and lowering it from eighty to sixty. What do we know about the risk reduction in lowering it, say, from sixty to forty to twenty? And I ask both what we could infer pharmacologically and non-pharmacologically. In other words, from the Mendelian randomization versus the pharmacologic.

   5. TDDr. Tom Dayspring27:41

      Well, even using pharmacologic trials and Mendelian randomization, you're go- the concept you're gonna come across with is lower is better. And with the pharmacologic thing, we're modulating things that either have clinical trial proof that if you lower them it's good or the Mendelian, uh, randomization, looking at genes where that drug might be doing something, it works. Now, you do need a few ApoB-containing lipoproteins. They do traffic other lipids. They traffic fat-soluble lipoproteins. But we must never confuse abetalipoproteinemia where nobody or that person can't make them or hypobetalipoproteinemia where they make a few, enough to traffic those other things that a lipoprotein might have to traffic. But even the guidelines where they examine people base-- looking at their baseline ApoB or LDL cholesterol, the first thing they suggest, at least in the higher risk people, is try and get a fifty percent reduction, and that's where most of the bang for the buck is gonna be. Now, if you still have options that you can lower it further, yeah, the trials show, yeah, there is incremental reduction events, but it's a much smaller absolute risk reduction in dropping it the fifty percent or, or so. So I don't know if that answers your question. So most people don't have the type of levels where with modern therapeutics, with modern lifestyle, we can more often than not attain physiologic concentrations. And if I want to talk about ApoB, that's probably under fifty milligrams per deciliter if we can get there. That's what the newborns have. That's when you go in clinical trials, if you take it down that low, you see your most risk reduction. And so far, at least with pharmacologic lowering of ApoB with the currently FDA-approved drugs, there is no signal of harm.

   6. PAPeter Attia29:37

      Yeah, again, it's funny you-- because I was just about to say with the current crop of drugs, specifically the PCSK9 inhibitors, we are routinely seeing patients who easily can get an ApoB into the twenty to forty milligram per deciliter range. You and I actually sat down a couple of months ago and did a calculation to estimate how much cholesterol is actually contained in the circulating lipoproteins versus that which is in cell membranes. Do you remember doing this with me?

   7. TDDr. Tom Dayspring30:13

      Not per se, but, uh, and where we're developing equations, you're the master of that.

   8. PAPeter Attia30:19

      Well, it was one of these things, right? It was, it was sort of like, look, you know, when you look at a person's plasma glucose level, you realize pretty quickly it represents a tiny fraction of total body glucose. And similarly, there's such a concern about plasma cholesterol level, but, you know, given how essential cholesterol is, it's understandable why people would be concerned that low cholesterol could be problematic. But once you do the calculation and realize virtually all of the cholesterol in the body is contained within the cell membrane or within the steroidal producing tissue, the circulating amount is a very narrow window into the total amount of cholesterol, and therefore a reduction of, say, 60 milligrams per deciliter to 50 milligrams per deciliter of ApoB, or even something more extreme like a full 50% reduction of total cholesterol, 200 milligrams per deciliter to 100 milligrams per deciliter, does not represent a significant reduction in total body cholesterol. This is a very important point. All right, let me repeat it. You have a total body cholesterol that you measure in the plasma that says, "Oh, it's 200 milligrams per deciliter." That goes down to 100 milligrams per deciliter. Let's say the LDL fraction reduced from, you know, 150 to 75 or something. Someone might say, "God, you just cut cholesterol in half. That can't be good for you given the importance of cholesterol." But my point is, no, you simply cut the amount of cholesterol being carried by the lipoproteins in the plasma in half. That doesn't capture the majority of the cholesterol.

   9. TDDr. Tom Dayspring32:00

      Yes, thanks for refreshing my memory what you're talking about now. It's, uh, really pools of cholesterol throughout the body, and I think that I'm so glad you brought this up because this is just not even understood even in the lipidology community. We have a total body cholesterol. There are basically three pools. There's your brain, and nothing we're talking about today has anything to do with brain cholesterol. It's a separate system. It doesn't interact with the other cells in your body or certainly with the cholesterol in your plasma. So if it's not in your brain, where is cholesterol in your body? Well, it's either in all your peripheral cells, perhaps some more than others, or it's circulating in your plasma. And if it's in the plasma, where is it? There's an itsy-weensy amount bound to albumin. There's more bound within all of the lipoproteins that are trafficking in your body, meaning your ApoB and your ApoA1 particles. But believe it or not, if I wanted to search down blood cholesterol for you, I would suck out your red blood cells and extract cholesterol from them. Red blood cells carry far, far more cholesterol than do all of your lipoproteins put together. And the other crucial point you made subtly, and I hope everybody understood you, the amount of cholesterol within your lipoproteins has no correlation with your cellular cholesterol or even your red blood cell cholesterol. So whatever, however you're modulating some LDL, total cholesterol, HDL cholesterol metric, that tells you nothing about what might you be doing to the cholesterol content of your cells. So don't have a panic attack if you're making LDL cholesterol 30, because I can assure you virtually every cell in your body, even if that's your plasma LDL cholesterol, has more than enough cholesterol because it can de novo synthesize it. It can put it in its cell membranes or other organelles that require cholesterol. If it's a storogenic, storagenic tissue, it can produce a little more or perhaps delipivate some le- So there's no cell that's being deprived of cholesterol in the periphery when you're modulating lipids through lifestyle or drugs.

6. 34:15 – 37:00

   Drivers of atherosclerosis

   1. PAPeter Attia34:15

      Tom, what's the best explanation for why it's not the red blood cell that is the primary driver of atherosclerosis, given the fact you just stated, which is red blood cells contain within them a lot of cholesterol within their membranes and red blood cells clearly traffic to and from past the endothelium? I certainly have my own answer for this question. I think the histology makes it abundantly clear, but is there any thought you would add to that?

   2. TDDr. Tom Dayspring34:46

      No, I think histologically we know it's foam cells, and where do foam cells get their sterol content? From ingesting oxidized lipoproteins carrying cholesterol. Is the vasa vasorum, which supplies the arterial intima with blood cells, dumping red blood cells in there that are contributing cholesterol? Maybe a few molecules, but I, I don't think we have any evidence it's, that's a driver of cholesterol that's resulting in arterial wall pathology.

   3. PAPeter Attia35:14

      Yeah, this is one of those moments where sometimes a picture just serves a thousand words, and maybe this will be one of the best. I mean, we're gonna obviously accompany this podcast with a, a lot of figures and diagrams of yours. But what we're basically talking about is you have to differentiate from the vasa vasorum side, which is the non-luminal side of the vessel, where of course you have to have blood vessels to keep the artery itself alive, versus the luminal side where the endothelial lining is damaged by everything, including just daily life, but certainly high blood pressure, smoking, uric acid, high glucose, high insulin, shear forces, you name it, and that's what's allowing these lipoproteins in. But you're right. It's really this histologic examination that makes a very clear, unmistakable case that it's not the cholesterol in the membrane that's doing this. It's this trafficked cholesterol that ultimately becomes a foam cell through the macrophage's ingestion of the lipoprotein that is the insult. That's a pretty good tour de force on this topic

   4. TDDr. Tom Dayspring36:25

      One more little caveat, Peter. With that vasa vasorum, as you know, as you have an evolving plaque, it gets bigger and bigger and it becomes prone to erosion or rupture and the coagulation system. So there's nothing to say that even in a minuscule histologic rupture of a plaque that the vasa vasorum can't be contributing some clotting factors or something else to that pathological process.

   5. PAPeter Attia36:48

      It almost assuredly does. At some point, once you have damage, I would fully expect coagulation factors to be coming from both sides.

   6. TDDr. Tom Dayspring36:56

      Yes.

   7. PAPeter Attia36:56

      The luminal side and the vasa vasorum side. It's an all hands

7. 37:00 – 55:00

   Overview and current thinking on high density lipoproteins (HDLs)—Is it a useful metric?

   1. PAPeter Attia37:00

      on deck war.

   2. TDDr. Tom Dayspring37:00

      And the uric acid too probably, you know, which can crystallize just like cholesterol.

   3. PAPeter Attia37:06

      You touched on it in the outset, which is what have the guidelines stated with respect to other lipoproteins? So if we take a step back and we went back to the early 1980s, right? In the early 1980s when we were just beginning to talk about the subfractionation of cholesterol. So little history lesson for people. It's 1959-ish, early 1960s, Ancel Keys is clearly onto something and he is identifying a relationship between serum cholesterol and coronary artery disease. He's correctly identifying a relationship. And at the time, they're doing very rudimentary assessments saying, "Hey, if you take the people who are in the top 10% of serum cholesterol and you compare them to the people in the bottom 10% of serum total cholesterol, there's a profound difference in atherosclerosis." Most people are familiar with how that history went and, and, you know, where it got taken off the rails a little bit by what might be the root cause of those things. But nevertheless, it was pretty clear into the 1960s and '70s that something about serum cholesterol mattered. Eventually people began to, as you pointed out, Tom, begin to fractionate those things, so it wasn't just about total cholesterol. It became about different densities of those cholesterols and these lipoproteins, some of them were lighter, some of them were heavier, and really light and heavy are the wrong words. They had different densities. But one that emerged pretty quickly as a contrast to the low density lipoprotein was the high density lipoprotein. And through all of the epidemiologic work that emerged in the late '70s and into the early '80s, and that also, by the way, continued into the '90s through the work of Gerry Reaven as he was in the early stages of identifying what would be called metabolic syndrome at the time, called Syndrome X. It became clear that higher levels of cholesterol in the HDL particle, which unfortunately is erroneously often referred to as high good cholesterol, had a positive association, the opposite of what we have just been describing, which is high levels of cholesterol in the LDL particle. There's a lot less talk of that today, at least amongst the people who know what they're talking about. Unfortunately, there's still a lot of people who talk about that on social media. But why is it that we aren't sitting here in the guidelines talking about HDL cholesterol, the so-called, quote unquote, I hate to use this word, good cholesterol?

   4. TDDr. Tom Dayspring39:47

      [laughs] And you know I'm in your corner on that one. Folks, there's one cholesterol molecule. I don't care whether it's in your cell, whether it's in any lipoprotein in your brain. If I drew you the structure of cholesterol, it's identical. So how dare we a- put an adjective on it like that's good and that's bad. How do you know? So you don't. So they're silly terms, but they, they sort of evolve for a good reason. And this is a wonderful historical journey that you really have to do to figure out why did HDL have, like, such importance and now it's an afterthought. Although it's an afterthought, I must say virtually all of the current risk algorithms that are used to classify you as are you at high, very high, moderate, or low risk still use the metric HDL cholesterol to determine that because the data is just 40, 50 years old. The problem with HDL cholesterol as a metric is all those studies that seem to suggest, say, higher is better or lower is worse, were never adjusted for anything else. So you know observational type data, "Aha, I found the answer. Here it is. You got blue eyes and everybody with blue eyes gets this, that, or whatever." And of course you never adjusted for, "Oh, wait a minute, everybody with the blue eyes has this lethal thing going on also." So in retrospect, it turns out that the overwhelming majority of people who might have low HDL cholesterol have a high ApoB level, and that's what drives their atherosclerosis. So all guidelines, even though they might do your baseline risk using an ApoB metric like total or LDL cholesterol, they'll use HDL cholesterol as trying to figure out the lipid component to your risk. They use smoking and blood pressure and other things Peter talked about also. When they get to goals of therapy though, only because we have multiple trials now where for decades people have been trying this, that, and everything to raise HDL cholesterol, because if high is better than low, raising it has to be fantastic, and not a single trial has ever panned out that what you do to HDL cholesterol results in cardiovascular benefit.

   5. PAPeter Attia42:02

      Let's pause there for one sec, Tom, and just make sure people understand that. There have been multiple trials using at least two, maybe more technical approaches to raise that number that is unambiguously associated with better outcomes. Is that correct?

   6. TDDr. Tom Dayspring42:21

      No, there are no clinical trials that would support raising HDL.

   7. PAPeter Attia42:24

      No, no, no, no. I'm sorry. There have been multiple clinical trials that have attempted to raise HDL cholesterol.

   8. TDDr. Tom Dayspring42:28

      That's true, yes. And it's more than two drugs. There are other drugs that-

   9. PAPeter Attia42:32

      Yeah, yeah. I was saying more than two mechanisms of action.

   10. TDDr. Tom Dayspring42:35

       Correct.

   11. PAPeter Attia42:35

       At least two that I can think of. There might be-

   12. TDDr. Tom Dayspring42:37

       Yeah

   13. PAPeter Attia42:37

       ... there's probably three mechanisms of action that have been, that would all raise HDL cholesterol. But the point that you made that is, should not be lost on anyone is at best, those trials have been neutral.

   14. TDDr. Tom Dayspring42:52

       As have the Mendelian randomization trials looking at genetic surrogates of HDL and cardiovascular outcomes, yes.

   15. PAPeter Attia42:59

       And at worst, those trials have been harmful.

   16. TDDr. Tom Dayspring43:03

       Yeah. There are plenty of people, and you know them, you've seen them in your practice, certainly I have when I was practicing, with high HDL cholesterol who are full of plaque, and we do see people with low HDL cholesterol who, just like you said, you see some people with high LDL or total cholesterol don't have plaque. There are plenty of people with low HDL cholesterol who, my God, you don't seem to have much cardiovascular risk. So there has to be, if HDLs are important to the cardiovascular system, and I maintain they are, the metric HDL cholesterol is useless.

   17. PAPeter Attia43:35

       Yeah. And this is really where I think I want to go with this and just, I mean, there's so much we could say on this, but I, I think it's worth maybe even just explaining this very important point, right? Which is HDL cholesterol, the number that everybody sees when they look at their lipid panel, that if it's below 40 milligrams per deciliter is probably flagged as being too low. If it's above 70, your doctor gives you a high five. That is measuring the concentration of cholesterol within an HDL particle. Now, it doesn't tell you anything about the functionality of that particle, and this is where I think, I don't remember if it was Ron Krauss that said this, but someone said this to me and I've never forgotten it. It might've been Alan, actually. They said, "This LDL biology stuff is trivial. All you gotta do is lower it. It's the HDL biology that is really complicated. That's what the 21st century's gonna be about. We don't have a clue what we're talking about with HDL. We've been using this idiotic crude metric of how much cholesterol it contains. It is now completely clear that that was the wrong metric, and any attempts to increase it were futile. We've count the number of particles. We can even measure the size of them. That also appears to be almost as crude as what the cholesterol concentration is. But to come up with an assay that truly measures functionality may be beyond the scope of laboratories. Whereas with the ApoB LDL side of the equation, it really appears to be a stochastic problem. The more of these things you have to the first order, the more problems you have. You've already alluded to other attachments to them that can add second and third order terms. But, I, I mean, do you agree with my assessment, Tom, that this HDL problem is way harder and we don't have a clue what we're talking about?

   18. TDDr. Tom Dayspring45:30

       Oh, I, it's just so perfect what you've just said in the last few minutes. It's, you know, we all use laboratory metrics to try and figure out what a given biomarker tells us and what we can do about it, and the only metric that's really available to the world, world now is HDL cholesterol, which Peter says that's a, the collective cholesterol mass within all the HDLs that exist in a deciliter of your plasma. If you are doing, uh, ion mobility or NMRs, you can get an HDL particle count, but that, although it might be a tad better than HDL cholesterol telling you something, there's so many exceptions to that rule that it's not a useful bedside metric either. But presuming, again, HDLs must perform some function in the human body, and part of that function might be either preventing or putting out arterial wall plaque fires that have many, uh, etiologies, how can we measure what Peter referred to as the functionality of the HDL particle? You know, being a fireman's son, if you listened to that last podcast, I look at HDLs as fire engines, but I know any fire department has about 10 different types of different fire trucks, and they all supply something different that firefighters can use to extinguish a fire. Some might carry chemicals, some might carry ladders, axes, water, some carry more firemen than others. So what type of fire truck do you need at a given scene? Well, it depends what the heck the scene is all about. So what do HDLs do? They certainly traffic some degree of cholesterol, which it turns out is probably just there for stoichiometric reasons, make it a spherical particle to which other things can attach. The other things that are in that HDL... Remember, HDLs are tiny, so they don't carry a lot of cholesterol. Here's a stat that will astound a lot of people. If I took the average HDL particle, the average size HDL particle out of your plasma, how many molecules of cholesterol would be inside of it? About 45. How many molecules are in the average size LDL particle? About 1,500, 2,000. So the volume of a sphere is the third power of the radius. What might influence even the cholesterol content of 45 cholesterol molecules within an HDL? Well, it's a sphere. There's only so much can go in there. What if that HDL was carrying extra triglycerides for whatever reason? Well, it couldn't carry very many cholesterol molecules, so that would be a cholesterol-depleted HDL. What if that HDL, if I had five groups of HDL particles, same size, same cholesterol content, but they all had different phospholipids on their surface lipidome, or they all were trafficking different proteins? They all have ApoA1, but what else are they carrying? And those proteins have a multitude of functions. Dan Rader years ago always told me, "Tom, HDLs are part of the innate immune system."

   19. PAPeter Attia48:29

       Wow.

   20. TDDr. Tom Dayspring48:29

       They're little fire engines. They're carrying God knows what that could go into wherever there's inflammation in your body, a swollen knee, any in-tissue injury or your arterial wall, and they could maybe help what's going on there because they're trafficking immunomodulatory functionality molecules, or they could go in because, oh my God, these are corrupt HDLs. They're carrying bad junk, which is further inflaming it. We have no way of measuring those now. Uh, I mean, researchers can do lipidome analysis of the phospholipids, the sphingolipids, the ceramides that are in HDLs. We can... You know, they've identified over 150 different proteins that might be on an HDL. Now, they're not all on one given HDL, but some HDLs may have two of this protein, none of that, and you have different groups of HDLs. In my analysis, they're different types of fire engines carrying different things. Peter, in our lifetime, there will never be an affordable, reproducible, uh, high throughput way of evaluating any of this. People are hanging their hats now on the ability of HDLs to efflux cholesterol from a cell, and hey, if an HDL can suck some sterols out of your foam cells, yeah, I'm kind of thinking that's pretty good, but it's probably a minuscule function of the hundred other functions that HDLs can do. So what if the HDL is pulling out some cholesterol, but it's dumping other crap in the process? So if we ever had an HDL function panel, it's going to be a dozen or more [chuckles] type tests, which we're not going to see because of nobody's going to pay for them. The research to be done to prove that these have relevance in a large clinical trial is just not going to be done. So that's the dilemma.

   21. PAPeter Attia50:14

       There are such panels, right? I mean, I think, I feel like I've seen a couple of commercial panels that attempt to subdivide the HDL particles even further. I, I've never personally been able to know what to do with such panels, and, and I... You know, these days, I don't even look at ApoA1 anymore. I'm, I'm really focusing most of my efforts on VLDL cholesterol as a poor man's proxy for remnant, triglyceride basically as a strategy for how to lower apoB, apoB, Lp (a) , and then focusing just frankly much more on the metabolic stuff that we've talked about, the obviously glucose, insulin, homocysteine, uric acid, much more aggressive stance on blood pressure. But i- in some ways, my, my lipid world has become a little bit easier in light of this discussion we're having.

   22. TDDr. Tom Dayspring51:02

       It is because you've got the ability based on analysis and understanding of things to not order these silly hocus-pocus HDL panels that are being offered by people as a way to generate revenue. Now, look, I've been associated with labs all my life. I'm not at the present time. I don't work for any lab that does or doesn't do any of these tests you're talking about. But mostly those panels that you look at, they're looking e- they're reporting HDL size. They're reporting ApoA1. Peter knows there can be from one to five molecules on ApoA1 on your various HDL species. So you have just a few HDLs carrying a lot of ApoA1, or do you have a ton of HDLs that carrying little ApoA1, and that could be a misleading metric. People are looking at some of these phospholipids now. Some labs are offering ceramide levels or sphingosine levels. But again, the tr- you can find something that might support that, but then you have to weigh it against the apoB and the things that are almost beyond discussion, and you would realize this is contributing nothing to me. Why am I even ordering this? Am I trying to impress some patient that I can use big words and this means anything? So they're silly. I'm in awe for doing research on HDL functionality and looking into it so we all get a better comprehension of it. I'd love to have a test that tells us what I talk about, the flux of HDL particles, h- how do little incy wincy HDLs mature, fill up, then what do they do with that cholesterol, and are they catabolized? Are they not catabolized? Are your HDLs pulling cholesterol out of an artery wall and then sharing it with an LDL that might take it right back into the artery wall? So there's just so many phenomenal issues, uh, to get into with HDL. But right now, don't waste your money. You're going to get an HDL cholesterol. Everybody's going to be doing a lipid panel. Do not waste your money, time, or your brain energy on trying to figure out these HDL metrics.

   23. PAPeter Attia53:03

       So let's, at that junction, pivot now to more of the risk assessment stuff We have talked probably on at least two podcasts about Lp (a) . You and I spoke about it during our marathon podcast. I think we had an AMA segment where Bob Kaplan asked me a lot of questions about Lp (a) . It's still on my list of things to do. I'd love to have Sam Tomecki on the podcast. For people who don't know, Sam is certainly among close to the world's experts on Lp (a) , and I think, frankly, a dedicated podcast on this topic is warranted given that directionally, one in 10 people listening to this podcast has an elevated Lp (a) , and it represents, unless you correct me, Tom, I believe it would represent the single greatest genetic driver of atherosclerosis. So here we have this thing called Lp (a) that tragically most people don't know they have. You know, I'll tell you a funny story. Have you ever heard of this reality TV show called "Alone"?

   24. TDDr. Tom Dayspring54:08

       No.

   25. PAPeter Attia54:09

       I don't think I've watched TV in 12 years, but it, it now shows up on Netflix, and I do watch Netflix from time to time. So a friend of mine mentioned to me the other day, he goes, "You gotta check out this, this show called 'Alone.' It's right up your alley. People, they take these people who have remarkable survival skills and they throw them out in the world's worst environment, 10 of them, separately of course, and, uh, basically the person who last calls uncle wins half a million bucks." So I'm into season six right now, which is... It's the first one I've watched, but it's, it's clearly into a, a really nasty part of the Arctic. So I'm watching this and I'm just humbled by the fact that these people can survive any length of time. Anyway, one of the guys in the show, you know, you learn their backstory and he's-- this guy looks as impressive as anybody I've ever seen, but somehow it comes up that part of his motivation

8. 55:00 – 1:13:15

   Lipoprotein(a)—the most dangerous particle you’ve never heard of

   1. PAPeter Attia55:00

      for doing this is he had a heart attack like the year before, and I think he's 39 on the show, implying that he had his heart attack at the age of 38 or thereabouts. Now, if you looked at this guy, Tom, you wouldn't think this is the kind of guy that could have a heart attack. I mean, he looks... He is a specimen. And of course, what's the first thing that comes to my mind? Well, I've seen this story play out 50,000 times, right? I mean, I, my, my wife's grandfather died at 40. He was a firefighter, fit as a fiddle, dropped dead of a heart attack at 47 in my mom's dad's arms when he was 16. So I know the story very well, and it's, to me, it's Lp (a) until proven otherwise. Anahad O'Connor wrote a great story about this in The New York Times several years ago, disclosing that he himself found he's a carrier of Lp (a) . So always want to make sure everybody stops, reevaluates, makes sure that they aren't a high Lp (a) carrier. What else is on our list of real risk assessment here? And, and by the way, feel free to just pile on to more Lp (a) stuff, 'cause this to me is... I mean, this, this is interesting stuff. And I do think, unlike my pessimism around HDL, where I don't think we're going to learn a whole heck of a lot about it, I think we're just scratching the surface of differentiating between really aggressive Lp (a) 's versus not as aggressive Lp (a) 's, and I'm optimistic there.

   2. TDDr. Tom Dayspring56:26

      Well, you're right, and of course, on the favor of Lp (a) being dangerous is the, a bunch of Mendelian randomization trials which don't exist for any HDL metric or so. So right away, it's a, a marker that requires more serious evaluation or so.

   3. PAPeter Attia56:43

      You want to remind people again what it is? I guess I glossed over that, you know.

   4. TDDr. Tom Dayspring56:47

      Sure. For those new to this, a low density lipoprotein is, uh, a collection of cholesterol, triglycerides, phospholipids wrapped by a single molecule of apolipoprotein B. Because of the size and density, it falls within a certain fraction of that centrifuge tube, and it's called low density. But all lipoprotein subclasses are heterogeneous. They consist of big particles, small particles, or maybe a particle carrying something else that doesn't really change its density that much, so it separates with the LDLs. An Lp (a) is basically, you have your LDL part of this macromolecule, but co-attached to the apoB structural protein is another protein that shouldn't be there, and it's called apoprotein little a, and by little a we mean small case, not a capital A. And that molecule that attaches apoA, you know, can vary in molecular weight, size, length, et cetera, but that's beyond this discussion. So it's an LDL that's carrying an extraneous passenger. And here's the problem. We know people with high Lp (a) that, God, they s- don't seem to be bothered. They're not coming down. There's no premature family history in them. And other people's, the example Peter just gave, my God, there are atherosclerotic wrecks at young ages. So I also just, as I've sort of iterated about other lipoproteins, I think when we're talking about Lp (a) in the year 2020, we are talking about, all right, let's, what's its mass? What's its Lp (a) particle number? But I also think we have to be smarter on understanding the quality or other attributes of this Lp (a) particle. What makes this apo (a) attachment maybe terrible for that guy who had his heart attack at age 38, but here are other people who they're coming in at age 80 and they got high Lp (a) and they're not full of plaque or so. And one of the things we're beginning to understand is, look, apoA has potentially some thrombogenic properties which perhaps get expressed in some people more than others. But more and more, one of the functions perhaps even of apoA, why it even evolved, is a little scavenger protein that attaches to oxidized lipid moieties, specifically oxidized phospholipids, oxidized sterols. They bind to it with great affinity, and maybe that little- garbage truck full of oxidized particles, if it could bring it back to the liver or some other tissue that could catabolize it, those oxidized lipid moieties, which tend to be destructive to cells, are not getting to cells. So, um, we are beginning to have metrics that are starting to appear and available in the real world that we can measure the oxidation, the oxidized lipid moieties that are on apoA. They're actually... It's called oxidized PL phospholipids on apoB. And if you say, "Well, these oxidized phospholipids are on all the apoB particles," to a minuscule degree for, because of the affinity of oxidized lipid moieties to apoA, the overwhelm- if you have a positive oxidized phospholipid apoB, the overwhelming majority of apoB particles trafficking those oxidized lipids are Lp (a) particles. So if two people came to consult me tomorrow, they both have an elevated Lp (a) metric, one has a normal oxidized phospholipids on apoB, but the other one is elevated, based on Sam Tsimikas and others wor- uh, work, I'm gonna be a little more worried about that person who's, my God, not only do they have this undesirable particle, but this particle is loaded down with injurious other lipids that are potentially very harmful. So that's one aspect of it. We're nowhere near being able to test for the thrombogenicity, if that's a big factor of apoA and everything. So there are other ways of doing this. I mean, I, all the time when I get my weekly email from Peter Attia, "Here's the podcast this week," I'm waiting for Sam Tsimikas who... But for those of you still waiting for Peter to nab him, he's pretty active on Twitter, and he, he really tweets a lot of good information on the cutting edge of what's coming down with Lp. I think it's Lp little a dash underscore doc something like... But go on Twitter and Sam Tsimikas, T-S-I-M-I-K-A-S, and you'll be happy you followed him. So there's just a lot to understand, Peter. So it's who has it, and by the way, the new guidelines are, the European guidelines suggest that everybody ought to have it once in their life as they approach adulthood, and you never need repeat it unless somehow you're trying to modulate it or maybe you go through menopause where it can go up a little bit. But it's a genetically determined marker. You have it or you don't have it. If you don't have it at age 18, you're not gonna have it at age 68. So it's a one-time test, and it helps us... Before we talk, let's do thorough cardiovascular risk assessments, no matter what your apoB is, and this would be one of the tests that at least the Europeans have signed on to now. The National Lipid Association, other people have issued guidelines to it, and they're still telling you, "Well, do it for unexplained heart attacks or strong family history of heart disease." To me it's, again, it's not a very expensive test. Get it once and for all. But there's so much to talk about this, uh, Peter. And in the future, I mean, there are ways, what would you do for somebody with high Lp (a) ? We have strategies, which is mostly attacking apoB right now and any other cardiovascular risk factor. But there are drugs in the pipeline that may give us better alternatives to perhaps stop your liver from making apoA.

   5. PAPeter Attia1:02:36

      Let's talk about that a little bit. So up until, I would say, a few years ago, the only strategy for patients... Le- let's assume that we've confirmed that a patient's Lp (a) is elevated, and furthermore, let's confirm that we have reason to believe that in that patient, the Lp (a) is also problematic. And, and again, this usually shows up in family history. It's not a subtle thing. A lot of times I'm taking the family history from a patient before I've got the blood test. Th- that'll be, there, those could be offset by weeks. And it's because we give our patients the template to work on this, they come in with a very thorough family history. They really know what happened to, you know, the mother's older sister and the grandfather and all of these other things. And, you know, you usually just see this history of heart at- lots of heart attacks before the age of 60. Obviously, it can be confounded by people who are heavy smokers and things like that, but-

   6. TDDr. Tom Dayspring1:03:32

      Yeah, let me just interrupt you for one second, it'll be a minute, because published yesterday in the Journal of the American College of Cardiology is a study and a fantastic editorial, and they looked at people with terrible family histories of heart disease and people who had Lp (a) issues or they didn't, and the conclusion was simple: don't have high Lp (a) if somehow you can avoid that, which you can't. Don't have as terrible family history of coronary artery disease, and I don't know how you avoid that. But if you want the worst scenario, don't have both Lp (a) and phy- So Peter, what Peter is just saying is now backed up by a nice study.

   7. PAPeter Attia1:04:10

      Yeah. I love the, uh, best advice is choose healthier parents. So let's assume we're in that situation, which is we have high Lp (a) and we have the n- the family history that is not favorable, or something else that's even more germane to the patient, which is a positive calcium score, something to that effect. Well, again, historically, our best bet would be remove all other risk to the extent that it is possible. So we lower all other apoB maximally pharmacologically. We optimize completely all of the metabolic parameters that we've discussed briefly here but touched on in greater detail elsewhere, and that includes everything from modulating blood pressure as aggressively as it needs to be to controlling all of these other factors that don't get enough attention in my book, the uric acids, the homocystines, things like that. But then, as you pointed out, there's a strategy now that says, "Wait a minute, what if we knock out the liver's ability to make apoA?" And all of a sudden you wouldn't have an Lp (a) . So what does that strategy look like and, and where is that strategy in the pharmacologic pipeline?

   8. TDDr. Tom Dayspring1:05:21

      In pretty early trials, and of course, any cell, and we're talking about the liver here, if the liver is the primary site of production of apoA, and it is, if we could mess with the genes through, uh, ASO therapy, we could probably stop a cell from making a given protein. If we can stop the liver from making apoprotein little a, if you don't have that, you certainly, the liver can't secrete it, so it can attach to LDL particles, transforming them into LP little a particles. So that's almost like a no-brainer. The Mendelian randomization trials says don't have high apoA or LP little a, so let's just inhibit its synthesis, as we've done with other things that contribute to coronary artery disease, and that has to work. Yes, provided that protein doesn't screw-- or that ASO treatment doesn't screw up something else or, uh, cause a downside to it, and that's why you ultimately have to do large clinical trials looking at not only event reduction, but safety. But those drugs are in early... You know, and like anything else, the first generation of those antisense oligosaccharide drugs that came around, they've perfected them, so there's a second generation of them now that they've made even more hepatoselective so they can dose less of it, and it goes right into the liver. But they're phase one, phase one-two trials. And Novartis, I believe, has now acquired the product that, uh, they're gonna put it in a major, which has just started enrollment, a phase three trial on let's not. But here's the problem. Peter knows the billions that probably have to be invested when you're developing a drug of that type of magnitude to reduce something. You're not gonna do it on every Tom, Dick, and Harry who has a trivial LP little a. You want that first trial to work, because if it doesn't, that's it. The drug, the drug is dead. It'll never be tested in lesser risk people. So the only way you can get into this current apo little a synthesis modulator, uh, drug is you have to have had an atherosclerotic clinical event, a myocardial infarction, a stroke, blah, blah, blah, stents, and you have to have an astronomical, like upper quintile concentration of LP little a. Because Mendelian trial suggests if you're going to get benefit by lowering apo little a or LP little a, it has to be a pretty significant drop in it. So you're not going to take somebody with a trivial LP little a elevation and, you know, if you tested fifty thousand of them, maybe it would work, but. So if they go through this first trial, and it'll probably take three, four, five years to show efficacy and safety, then they're going to have to maybe do some s-sub, uh, trial analysis, and then is anybody even going to fund the primary prevention trial with this drug, with the cost that that takes? I don't know. So even if you're somebody who's had a heart attack because of LP little a and you're waiting for this drug, you got five, ten years to wait. And for primary prevention, go on to other ways that clinicians are attacking this problem right now, because you're not going to have anything.

   9. PAPeter Attia1:08:37

      Why is it that statins, which are probably the most potent drug until five years ago to lower LDL, and by definition then lower ApoB concentration, have virtually no effect on LP little a, but this new class of drug that's been around for five years called PCSK9 inhibitors, while even more potent in lowering LDL, seem to also be able to lower LP little a?

   10. TDDr. Tom Dayspring1:09:10

       I think there's two reasons there, and one, we've gotten enough trials now that seem to show, depending on your ApoA makeup, do you produce the large high molecular weight ApoA or the smaller low molecular weight ApoA, which in epidemiologic trials seems to be way more associated with atherosclerosis, that if you're one who does produce the low molecular weight short ApoA, which means because it's such a small protein to make, the liver can make a ton of it, secrete it. So they actually, even though their molecular weight of apo little a is lower, they have much higher LP little a particle counts. If you have that isoform of the LP little a, statins can induce the synthesis of that. Statins do not affect the synthesis of the larger apoA moiety. So in some people, Peter says statins do not much to LP little a concentrations, but there is a small component where statins will actually raise it a little bit. And people get scared. They go, "Well, I'm lowering LDL cholesterol, LDL particle counts a tad, but I'm raising LP little a." Even Sam Sumikas will tell you, "Don't worry about it." LP little a, if you learn nothing else about our LP little a discussion, is a minority LDL particle. So even though if you have the small isoform, a statin may be raising LP little a a tad, it's so blowing away the LDLs that don't have apoA attached to it, that at the end of the day, you have less cardiovascular risk, and that little excursion in LP little a concentration is probably meaningless. Now to go on to the second part of the questions, the PCSK9 inhibitors don't have an effect on the synthesis of apoA in the body, so at least they're not aggravating it in some people. But we're still in our infancy trying to understand how LP little a particles are either catabolized or cleared, and it's probably due to multiple receptors. The LDL receptor is part of it, and a PCSK9 can give you more LDL receptors than a statin probably can, putting aside the synthetic interference with it. But PCSK9, they're finding, has effects now on apoE receptors and three or four other Lipoprotein clearing receptors that are expressed in liver and other cells or so. So, I mean, that's... There's got to be better clearance of the particles with the PCSK9 inhibitors than there is with LDL receptor expression with statins or statins plus whatever other ApoB-lowering drug you're going to add to it or so. So I, I think that's where we're at right now. Most of the time, these people are going to wind up on statins plus PCSK9 unless they can't tolerate a statin or there's, or there's another reason not to use a statin. So that's my explanation right now, Peter. That, that-- I think we touched on that a little bit in the last podcast, and we still don't have a lot of info on clearance of Lp little A particles.

   11. PAPeter Attia1:12:15

       And as you said, it's, it's quite variable. I mean, we've seen patients where they're on a PCSK9 inhibitor for other reasons, and every time I put somebody on one, I recheck their Lp little A just for another reason than to gather our own data on how much of an effect the, the drug, either Praluent or Repatha, is having on Lp little A. And there's-- the range is zero to 60, 70% reduction. I mean, that's literally how broad it is, with probably a median reduction of a third.

   12. TDDr. Tom Dayspring1:12:46

       Yeah, so two important points here. One, Lp little A is not an acceptable goal of therapy because there wouldn't be trial data in support, even though we all think that's probably going to be good. But I think most people like Peter when he prescribes it sort of likes to at least see what happens to get his own information or so. But realize that's not what you're making a therapeutic decision on per se is the Lp little A concentration. So, uh, uh, just keep that in mind when you, when you're following up on these people.

9. 1:13:15 – 1:17:45

   Are low density lipoprotein triglycerides (LDL-TGs) a useful metric?

   1. PAPeter Attia1:13:15

      One last thing I want to circle in on you with that you and I spoke about a couple of years ago. It was an experimental metric that was being bandied about. In fact, I remember you guys ran it at THD on some of my serum, but I, I don't know that it ever saw the commercial light of day, which was... I think it was like LDL triglyceride concentration. Have those tests ever seen the light of day?

   2. TDDr. Tom Dayspring1:13:45

      I think if you look around enough, you might find a lab. It's a very easy, uh, assay. Danka makes it, where you could get a, an LDL triglyceride level. And by the way, just a f- another thought jumped into my brain on that Lp little A. As I told you, there are other things that attach to even LDLs and HDLs that make them less clearable or more atherogenic. And a very recent study show, believe it or not, there are Lp little A particles that carry ApoC3. [chuckles] You're not going to clear that particle if you make it, so maybe that's-

   3. PAPeter Attia1:14:18

      The double whammy.

   4. TDDr. Tom Dayspring1:14:19

      Yeah. Oh my God. But anyway, back to LDL triglycerides. People, uh, I often tease them if you said, "You know what? We're really cost-effective. We're only going to allow you to have one lipid concentration on this person, nothing else," I would tell them, "Give me an LDL triglyceride level, certainly not an LDL cholesterol level." And remember, ApoB is a lipoprotein metric, not a lipid metric, so that's what I would really take. But the triglyceride part of the core of any lipoprotein has a lot to do with plasma residence time of that, uh, particle, what else might be attached to that particle. Even I, I, I alluded to it a little bit in my brief HDL discussion before. Dan Rader calls them fat HDLs. What if your HDL particle is not carrying very many cholesterol molecules, it's carrying triglycerides? Well, he's shown, God, that was a decade ago, that those fat HDLs, meaning triglyceride-enriched, are dysfunctional. They're carrying some of the bad stuff that HDLs carry, that don't allow them to do their cardioprotective functions. So if triglycerides gets into an LDL, number one, what happens to an LDL that's floating around? And it might still be a big LDL because it's full of triglycerides and not cholesterol, but it's a, has a very great affinity for lipase enzymes that line our arteries or the surface of the liver. So hepatic lipase is a very potent triglyceride, this phospholipase, that is just like a fly trap looking for flies. It's looking for triglyceride-enriched HDLs, and if it binds to it, it will extract, hydrolyze the triglycerides. So if I had a LDL full of triglycerides and I pulled the trigs out, what am I left with? Well, that's an LDL particle that's lost a lot of surface phospholipids as well as a lot of core triglycerides. I have the so-called small LDL or dense LDL. I try not to use both adjectives together because they're redundant. And we have plenty of evidence that, yeah, it's no good to have a increased total LDL particle count, but ch- if-- try not to have too many small LDL particles because the evidence has certainly emerged that particle for particle, they're probably more atherogenic than the more buoyant, larger LDL particles for a variety of reasons, and the bigger non-triglyceride-rich LDL it might, might be a better fit for an LDL receptor that's going to clear it. So LDL triglycerides, basically, if you told me it was high, I know you probably got a high LDL particle count, ApoB. I know you have the small LDL particles. I know where those triglycerides probably came from, your VLDL triglyceride-rich particles, your chylomicron particles, and when they traffic, transfer their triglycerides to LDLs, they become remnant lipoproteins, which Peter has alluded to. And you can bet those same triglycerides are invading the HDL particles contributing to HDL functionality. And last but not least, in the studies where they've looked at LDL triglyceride, many of the inflammatory markers are high because those particles set off the inflammasome in various endothelial cells and elsewhere. So it, it's a really simple, easy-to-do metric that could tell us so much,

10. 1:17:45 – 1:21:30

    Tom’s preferred lab measurements

    1. TDDr. Tom Dayspring1:17:45

       and I think If I saw it was up, the first thing I'm saying, "Oh, I'm dealing with an insulin-resistant person," 'cause that would be the most common cause, not some genetic triglyceride problem.

    2. PAPeter Attia1:17:55

       Right. And again, I think perhaps the reason why people aren't leaping up and down to, to bring this to market is, you know, frankly, if you're looking at VLDL cholesterol and you're looking at all of the markers of insulin resistance, along with the lipoprotein markers we've discussed, I, I think you get the story. And look, I mean, taking a step back, let's play devil's advocate for a moment. I think that it's worth doing ApoB over non-HDL cholesterol. There are some people who are so opposed to advanced lipid testing that they will argue as long as you have non-HDL cholesterol, you don't even need to measure ApoB because, of course, the non-HDL cholesterol is measuring the LDL cholesterol, but somewhat correcting for the additional VLDL by adding the VLDL cholesterol, cholesterol. What is your take on the idea of non-HDL cholesterol versus ApoB as they are somewhat proxies for the same problem?

    3. TDDr. Tom Dayspring1:18:58

       Well, I'm in the Sniderman school and he's published on this extensively. I find it, all right, it's probably gives you a little bit more information for the reasons you just described-

    4. PAPeter Attia1:19:07

       Versus LDL cholesterol, yeah

    5. TDDr. Tom Dayspring1:19:09

       ... beyond LDL cholesterol. But as Sniderman has clearly shown in several studies, even though non-HDL cholesterol correlates with ApoB a little bit better than does LDL cholesterol, there's still 20, 30% of the population in our diabetic sensor resistance where they're discordant, and where there is discordance even with non-HDL cholesterol and ApoB, risk follows ApoB. So why am I wasting my time with it? Uh, you know, look, it's all useful. It might help you pick what therapy you want to use, but at the end of the day, I see no need to follow your non-HDL cholesterol. I'm following ApoB because I'd be a fool if I told you I normalized your non-HDL cholesterol and I've eliminated your lipoprotein-mediated risk. Until you measure the quantitate of these particles and [chuckles] if we ever get a quality test, that, that's a silly thing to say to a patient.

    6. PAPeter Attia1:20:05

       Mm-hmm. Yeah, exactly. We saved $3.

    7. TDDr. Tom Dayspring1:20:07

       [laughs] Yeah. And, uh, we might spend a little time or you're very good at explaining it. How do you determine VLDL cholesterol in your patients, Peter? You're not dividing triglycerides by five, the old Friedewald formula.

    8. PAPeter Attia1:20:22

       No. So we use a lab that, that is actually giving a VLDL cholesterol, and even if they didn't do that, we would still take total cholesterol and subtract from it LDL cholesterol and HDL cholesterol. Not perfect either because in that situation sometimes the LDL is calculated, but I always do a back of the envelope trig divided by five. It's not close enough.

    9. TDDr. Tom Dayspring1:20:46

       No, that's true. And listen, you made a key point here, which maybe went over people's heads. You cannot do that calculation if you have a calculated LDL cholesterol. You must have a directly measured LDL cholesterol, 'cause total cholesterol is LDL cholesterol, VLDL cholesterol, and HDL cholesterol. So if you subtract a directly measured HDL cholesterol, a directly measured HDL cholesterol, in effect, you have a directly measured VLDL cholesterol, which in our current world is about as close as you're going to get to an evaluation of remnants. I think in our last podcast we talked why there are exceptions to that rule, and that's a, a more complex discussion. But please, you can't

11. 1:21:30 – 1:30:45

    The latest in lipid-lowering therapies

    1. TDDr. Tom Dayspring1:21:30

       get VLDL cholesterol using the Friedewald calculated LDL cholesterol.

    2. PAPeter Attia1:21:36

       All right. Let's talk a little bit about therapies. Statins have been around forever. They still take up most of the air in the room. They are the workhorse of lipid-lowering therapy. Is there anything new and exciting to talk about? I would say that there's no new statin on the market today that wasn't there two years ago. Is the most recently introduced statin, uh, Livolo?

    3. TDDr. Tom Dayspring1:22:01

       Yeah, and that's probably y- 10 years ago [laughs] introduced now, so-

    4. PAPeter Attia1:22:05

       Yeah

    5. TDDr. Tom Dayspring1:22:05

       ... yeah, there's nothing new.

    6. PAPeter Attia1:22:05

       What, what, what do you make of that, Tom? Why, why are we not seeing more statin innovation?

    7. TDDr. Tom Dayspring1:22:10

       Two things. I think third-party payers would never pay for a new branded, uh, statin. They're gonna always insist you use the cheapest generic that's appropriate to the degree of LDL lowering that you need. So to... And there are seven of them on the market now, so I don't think a bean counter at some pharma is looking for, "Let's get a new statin." We're well aware of potential downsides to statin things. We have to look for who tolerates them, who doesn't. I don't know that they're somehow gonna invent a new statin that brings none of the potential downside of a statin to the equation. So they're looking at other, uh, therapies that will... Now that we understand it's atherogenic lipoproteins, that will reduce that, and if your investment pays off, you'll have a branded product for X number of years, and you might get a little return on your investment. So I don't think we're gonna see another, uh, statin right now. The biggest thing that's happened with s- statins and in a guideline, you know, in the old days when we had nothing else to do and we didn't know a lot about all this lipoprotein stuff is, "Hey, you got the s- most trivial elevation of some LDL metric, mostly LDL chole- You're going on a statin. I want them in the drinking water." In the old days, "Oh, Tom, I just took a statin because they just reduce heart attacks." You and I know there is an, an event reduction, but there's plenty of residual risk even if you're aggressively using a statin, so there always is more to the story. But I think the newer guidelines give you a lot more ability to ascertain in a given individual After you do your thorough cardiovascular risk assessment, you and I do our own risk assessment, which is a little different than what the guidelines might offer. But then once a person crosses a certain threshold of atherosclerotic risk, then it becomes plausible to consider a statin. And there's more to it than per se the LDL cholesterol level. There, there's all those other factors that go into risk assessment, and there are other adjunctive diagnostics now. You-- Earlier we briefly alluded to coronary calcium scoring, Lp (a) . They would be things that current guidelines says, "Geez, if you're hemming or hawing, should I give a statin? Should I not?" Or the patient, "I don't wanna take it." At least do a CAC, at least do an Lp (a) , look at the family history, as you mentioned, look at the blood pressure, other concomitant risk factors, and factor that into, "Do I wanna use a statin or other ApoB-lowering therapy?" So that's the biggest change with statins. They-- Nobody's saying, "Hey, they belong in the drinking water." You should carefully choose who you're advocating statin therapy to.

    8. PAPeter Attia1:24:51

       Any sort of rules of thumb just in terms of the alchemy of this? Uh, you mentioned that there are seven out there. You know, in our practice, we really only pick from four of them: Livalo, Crestor, Lipitor, and Pravastatin. Uh, I mean, most of these are generic now, and if you listen to the podcast with Catherine Eban, which I know you did, we are actually still pushing for branded whenever we can get it, and if we're not getting a branded version of those, we cross-check with who the generic supplier is, and we've seen differences, right? We've seen that a two versions of Rosuvastatin can produce different outcomes. So our default position is that all generics are crap until proven otherwise, and that's why we use a tightly controlled list of, of meds. But I don't think I've ever prescribed Simvastatin, for example. What, what's your take on some of the older statins versus the four-- I mean, the reason I think we look at Prava and Livalo is mostly for the sensitive patient, and then Crestor and Lipitor, Rosuvastatin and Atorvastatin being kind of the workhorse.

    9. TDDr. Tom Dayspring1:25:57

       Yeah, well, you're just too young, Peter, and old fogies like myself, uh, uh, Lovastatin or Mevacor was the first statin that came around. Simvastatin was next, and then Pravastatin, Pravachol came. So, uh, we have a lot of experience with those drugs. But as time went on, and pretty early on, there was a pretty, uh, rational thing that whatever the reason, Pravastatin is a safer statin to use than Simvastatin or Lo- uh, Lovastatin, and it turns out that was mostly related to drug-drug interactions, where Pravastatin is pretty clean. Subsequent to that, the only statin that is even cleaner than Pravastatin on drug-drug interactions is the Livalo, so Pitavastatin would be its generic name. So that's t- in, in today's polypharmacy world where i- and we're not only even talking about prescription products, but the multitude of supplements or God knows what people wind up taking, we have no way to check on drug-drug interactions, so you're probably gonna get into less trouble with Pitavastatin or Pravastatin. Of course, along came Rosuvastatin many years later after Pravastatin, and it shared some at least pharmacokinetic attributes with the Pita- uh, Pravastatin in that it was a hydrophilic statin, kinda hepatoselective, but it was way more potent on a milligram, uh, uh, basis than Pravastatin. So it became a... A- and over that evolution of all those early statins, y- you know, every three years, we had lower and lower and lower LDL metric goals which weren't there when we first started, so what used to be acceptable is no longer acceptable, so it's very easy to transform from the hydrophilic Pravastatin to the way more potent hydrophilic Rosuvastatin, and that pretty much was my statin of choice thereafter, unless you had to putz around because of statin intolerance, where y- you would try some of those other things. Personally, once all this was known and once Rosuvastatin hit the market, I don't think I ever prescribed another Lipitor dose again, unless, you know, third-party payers are influencers here. They sometimes tell people, "You either take this one or here's what you're gonna have to pay if you don't go on our formulae." So that can factor into its use. Now, Lipitor is a potent statin. Milligram for milligram, it's not as potent as Rosuvastatin, but you can get whatever LDL reduction if you use a higher dose of Lipitor as you can with a somewhat lesser dose of Rosuvastatin. So unless a third-party payer is telling me to use it, I'm probably not gonna advocate Lipitor. Just there are more drug-drug interactions, and it is lipophilic. There's perhaps other issues at play. You and I have talked about statin's ability to get into the brain and everything, where lipophilic statins might be have a little more bit propensity to do that than hydrophilic statins. So there are other issues at play that would influence where you're going. The other thing that... And I'm gonna disagree, and I think it's the way you practice too. All of the guidelines right now say, "Okay, you've made a decision to use a statin. Pick the two most statin, the most potent statins." That means you're on Lipitor or Crestor, and prescribe it at the maximum dose. Uh, because the way these trials were designed, [chuckles] you know, lower is better. They all stu- you know, they... Very few trials where they took people with minuscule LDL cholesterol levels and threw statins at them. So they want you to get, "Hey, the clinical trial shows this statin at that dose works. Maybe there's pleiotropic effects that that statin is doing too." So how do you know? You have to be evidence-based. I don't buy it. I think virtually all of the statin's contribution to atherosclerosis reduction is ApoB reduction, and I think you've known me long enough That rather than maximizing a statin using the gorilla dose day one, I would prefer to start with a smaller dose, again, dependent on your risk and your metrics. I mean, if you're coming off an acute coronary syndrome and your LDL metric is off the chart, okay, I'll start with a big one. But I'd rather take that baby statin, meaning a lower dose of a statin, and perhaps optimizing it with a second ApoB-lowering drug. And for the longest time, we had ezetimibe, which has since been proven in clinical trials to further reduce benefit, and also in Mendelian randomization trials, looking at the Niemann-Pick protein. And now we have the new guy on the street, this bempedoic acid, which is a weaker cholesterol synthesis inhibitor affecting an early on cholesterol synthesis step. Also, that has Mendelian randomization support. And if you can't use a statin or if you can use a statin, if you add this to the statin or even the triple therapy statin ezetimibe bempedoic acid, maybe you

12. 1:30:45 – 1:38:15

    The different pathways among various lipid-lowering drugs

    1. TDDr. Tom Dayspring1:30:45

       can avoid the expensive PCSK9 inhibitor. So we have a lot more therapeutic options nowaday, Peter.

    2. PAPeter Attia1:30:51

       And then talk about the differences in the synthetic pathways between these two drugs, or where are they targeting the synthetic pathways and what makes them different? Is one more hepatic selective, or is it really a question of potency with respect to where they're blocking the chain?

    3. TDDr. Tom Dayspring1:31:05

       Yes. The cholesterol synthesis pathway is something like thirty-seven steps. Each step has its own different enzyme catalyzing, catalyzing the transformation of these precursor products into the next down the stage. Statins happen to inhibit what's called the rate-limiting enzyme. It's the third step in the cholesterol synthesis pathway. And of course, that's modulated by the enzyme HMG CoA reductase. Statins, uh, pretty significantly in a dose-dependent fashion inhibit that enzyme, so you can seriously slow down cholesterol synthesis in various cells. The one cell we really want to do it in is the liver, because that's the cell that has the greatest propensity to upregulate LDL receptors that can clear our ApoB-containing particles. So statins do that. Now, if you can deplete cholesterol pools beyond what a statin can do in the liver, you will express more LDL receptors. So when we use ezetimibe, we block intestinal absorption of cholesterol or backflux of bile cholesterol into the liver, further depleting hepatic cholesterol pools, you will get more expression of LDL receptors. So now we have this new bempedoic acid. It's called an ATP citrate lyase inhibitor. Well, the first step in cholesterol synthesis is citrate, made in mitochondria coming out of the Krebs cycle, is transformed to acetyl-CoA, which boom, then goes down and becomes after, uh, it becomes HMG and then the subsequent things. So this bempedoic acid is called an ACL, ATP citrate lyase inhibitor, but it's a pro drug. You swallow it, it's only uptaken by the liver, and it inhibits an enzyme in the liver that you can't make acetyl-CoA. So hey, the less acetyl-CoA you make, you're gonna make less HMG, and then therefore, that's gonna-- you'll have less substrate for the statin to add onto. So collectively, you get additional ApoB lowering. The cool thing is, 'cause one of our biggest downsides to statin is people get these myopathic symptoms, be they weakness, muscle aches, or whatever. You know that. It's a big problem with statin therapy, probably more prevalent than what clinical trials would show us. But this bempedoic acid does not have any uptake in the muscle cells. There's a specific receptor that pulls it into the liver. So it is hepatoselective. Look, rosuvastatin is somewhat hepa- hepatoselective 'cause there is a special cellular receptor that pulls in rosuvastatin, but other cells can pull rosuvastatin. Rosuvastatin can give you muscle aches, so it's not quite as hepatoselective as bempedoic acid.

    4. PAPeter Attia1:33:55

       Do you know what they saw, Tom, in the trial versus placebo for muscle soreness? Because even PCSK9 inhibitors still had some noise with respect to muscle soreness, even though mechanistically it's not entirely clear why. Whereas at least the statin, there's some explanation as to why someone could experience muscle soreness. I'm just kind of curious as to what the head-to-head-

    5. TDDr. Tom Dayspring1:34:17

       Yeah, no, they did look at that, and it's not zero. So there are still people who... But they've also shown studies that you can give-

    6. PAPeter Attia1:34:25

       You give a placebo and you'll have-

    7. TDDr. Tom Dayspring1:34:26

       A placebo and people get muscle aches still. So, but it's, you know, and they did c-comparative trials versus a statin versus a placebo, and there is definitely less with it or so, but it's not gonna be zero. So it's worth a trial if you're really hung up. So I think right now it's use, and it, rem- the FDA approved it. The FDA says, "Look, you gotta go do a big outcome trial," which the company is doing. But Mendelian randomization suggests it would work. Before we ever had outcome trial with ezetimibe, Mendelian randomization data suggested that reducing cholesterol intestinal absorption would reduce cardiovascular events, and that turned out to be so. So and, uh, they only had to do was a certain amount of, of phase three safety trial, and the FDA let it come on the market. And its use was, you can add it to a statin in people with familial hypercholesterolemia, who the statin probably is not gonna get you to goal by itself, and you can combine it to that. Or even very high-risk people, where you didn't blow your LDL-C down to seventy or fifty, whatever you're trying to do it, you need adjunctive LDL cholesterol ApoB lowering. You can co-prescribe the bempedoic acid. And they also allow you to co-prescribe ezetimibe with it. In fact, the company that manufactures this, and the brand name is called Nexletol, they also have been given FDA approval because there are a lot of statin-intolerant people out there or people who need triple LDL-lowering therapy, that we're gonna give you a combo product, which is bempedoic acid plus ezetimibe. I guess it's priced a little cheaper. So rather than swallowing two pills, you could just take that combo pill. You could add it to a statin or not. And look, I think for the nightmares of the world, you could ultimately, if you had to, add PCSK9 inhibitor. The end of the day, if you're good at individualizing your therapy, I think we have four apoB options nowaday, and you're gonna go down a, a fairly standard path because not everybody can afford a PCSK9 inhibitor, not everybody might be at the type of high level risk that the FDA wants you to be at to or the third-party payer wants you to be at. But it's a fun time to be in the apoB world. We have a lot of therapies, and we're not even talking about addressing triglycerides, which there are therapies that do that that might contribute to apoB lowering also.

    8. PAPeter Attia1:36:46

       The statin works a lot by the hepatic upregulation of the LDL receptor. Do we think that's the case here as well, or do we think that this is more about the actual reduction of cholesterol synthesis?

    9. TDDr. Tom Dayspring1:37:01

       But remember, if you inhibit cholesterol synthesis, you're gonna deplete-

    10. PAPeter Attia1:37:05

        You increase the L-

    11. TDDr. Tom Dayspring1:37:05

        ... hepatic pools of cholesterol, which will-

    12. PAPeter Attia1:37:06

        Yeah

    13. TDDr. Tom Dayspring1:37:07

        ... through the sterol regulatory element binding protein, upregulate LDL receptor expression, perhaps some VLDL receptors or other things like, like that, a- apoE receptor. So who-- at the end of the day, probably depleting hepatic cholesterol pools is what you have to do.

    14. PAPeter Attia1:37:22

        Is still its primary driver. So, so really, at least on some level, bempedoic acid is attractive because it's more hepatic selective, even if it's less potent. And remind me again, what do we think is the relative potency compared to a statin?

    15. TDDr. Tom Dayspring1:37:36

        If you look at its monotherapy trials, y- it's like ezetimibe. You're gonna get anywhere from a ten to eighteen percent lowering of LDL cholesterol by itself, a tad less apoB, ten to twelve percent, if you use it as a monotherapy. As you know with ezetimibe, with statins, there's a wide range of responses. I think with all these drugs, there are hyperresponders, middle-of-the-road responders, and hyporesponders. And I think, uh, that probably has a lot to do with how much synthesis of cholesterol, how much absorption of cholesterol, what type of LDL receptors do you make or express.

13. 1:38:15 – 1:49:45

    The latest on EPA and DHA

    1. TDDr. Tom Dayspring1:38:15

       So there's a lot of factors at play, but if you want a generalization, that's what it is.

    2. PAPeter Attia1:38:20

       And now you alluded to it, but what do we think about in terms of what's changed in the last couple of years in terms of our thinking about EPA and DHA specifically?

    3. TDDr. Tom Dayspring1:38:29

       Well, two things, and it's been a long time, and I-- nobody has respected triglycerides more than I have been lecturing about triglyceride-rich lipoproteins forever. And I knew despite all the nonsense that it doesn't matter what you do to triges, you don't reduce events like you do with LDL cholesterol 'cause of improperly designed trials and enrollment of people who basically didn't have triglyceride issues and giving them triglyceride-lowering drugs. But anyway, we're far enough down the road that not only does m- the Mendelian randomization trial certainly suggest, look, there are certain genes that are involved with triglycerides that are seriously involved with atherosclerosis. So it's very plausible if at least through those mechanisms we improve triglycerides, you're gonna reduce disease. So for the longest time, what was our-- other than lifestyle, what was our way to lower triglycerides? We had niacin around forever. We had the emerging fibric acid story, which progress, progress, progress until the terribly improvised trials that were done to let's see if fibrates work. They didn't give them to anybody who had high triglycerides, so of course the fibrate didn't work. But there's always been this, "Hey, omega-3s, uh, really, uh, are a potentially triglyceride-lowering drug, and maybe we should use them." Anybody who's known Bill Harris for the longest time as I have, you have, know, yes, omega-3s, if you really wanna get triglyceride lowering from an omega-3, you better be using serious, serious doses of the... You don't give a gram. You don't give two grams if you wanna get rid of triglycerides or, better yet, triglyceride-rich lipoproteins. If there are other attributes to omega-3s, we have no way of measuring that. Now, I know there almost certainly are because, you know, omega-3s are a crucial part of cell membranes and cell signaling. But if we're just gonna deal in our lipid world and you wanna have an omega-3 on board to help you combat triglyceride-rich lipoproteins, you wanna have a maximum dose, which looks to be four thousand milligrams a day. So this was the belief Bill used to always-- "Listen, don't tell me that you gave somebody a thousand milligrams of omega-3 and you didn't reduce heart attacks." [chuckles] The odds are strong you could never reduce heart attacks with that drug, you know? So now we got confused because as we started to realize this, they started to do trials with, okay, let's give four grams of omega-3s, and let's really not make the fibrate mistake, put them in the drinking water. Let's enroll people into these trial who have high triglycerides. Many of those people also have concomitant low HDL cholesterol, but that necessarily doesn't have to be an entry criteria. But you better have a triglyceride level above a certain degree, or we're not gonna waste our money giving omega-3s to people with triglycerides of forty-two. And lo and behold, the first trial that started to come down the pike was done in Japan sev-- God, probably almost a decade ago, the Japan EPA trial. You know, and Japanese people eat a lot of omega-3s, so they have higher baseline levels anyway. So they just gave them, for whatever reason, EPA only on top of a statin. And they didn't necessarily have to have high triglycerides, but many of the people did. And lo and behold, although it was not a blinded trial, the evidence was pretty good that, wow, this is really plausible that EPA at a high dose, four grams a day, reduces macrovascular outcomes when given with a statin that, of course, is working on, uh, the LDL metric you're looking at. So, you know, of course, people say, "Aha, that's proving omega-3s work." Nobody was given a lot of credence, perhaps other than the people who produce it, that, oh, this is unique to EPA. Most people are taking omega-3s, are taking some combination of EPA and DHA. But as long as you're gonna take four grams of that, why wouldn't it do exactly? So here's what happened. [chuckles] So after that EPA trial, the company that makes the branded EPA medication, which is Vascepa, Amarin is the company, did a major clinical trial called REDUCE-IT, where they enrolled people with... who were taking whatever statin they had to take to get their LDL cholesterol below 70. And in general, these were high-risk people. They had some degree of coronary disease or they were full-blown diabetics or had a lot of cardiovascular. So it wasn't a low-risk primary prevention type of study. You h- had to have a triglyceride above 137 to get into that trial. Most people, it was 150, but, you know, the triglyceride assay always varies plus or minus 15 points. So they would let you come in if you had a 137 because they thought in a week you're gonna have 150. [chuckles] So they enrolled people. That was the cutoff. You had to have that. And lo and behold... And you were maximized on whatever statin it took to get your LDL-C under 100 at the time. Pretty good. And lo and behold-- And we haven't come up with much in the world so far. At, at least it has a big trial saying we lower residual risk with a statin. Ezetimibe did it in acute coronary syndrome survivors to a certain degree. But this high-dose EPA, two grams twice a day with food, because it is an ethyl ester, theoretically it needs to be de-esterified before it's absorbed. There was almost a 30% residual risk reduction. That's mind-boggling, to be hon- after taking a statin. But they would still say, "Oh, that's fantastic. We all have to start using omega-3s at the appropriate dose way more than we ever did." But a lot of believers, and I think probably Bill Harris and myself said, "Yeah, but we could also just give four grams of EPA plus DHA," because deep down many of us believe DHA is a pretty important omega-3 fatty acid too, if for no other reason than your brain needs it. But I believe all cell membranes need it to a certain extent. And not everybody can convert EPA to DHA, although most people probably can. So AstraZeneca had acquired a free omega-3 fatty acid, meaning it's not an ethyl ester, which means it has, uh, better absorption, better pharmacokinetics, more bioavailability, and it was called Epanova. But it was EPA and DHA, but free EPA and free DHA. And they enrolled basically the same type of people, high triglycerides, maybe the HDL cholesterol is low, at-risk people. And two years into the study, the company just stopped the study. It's never been published, so we don't know, but the reason was its futility. We're not seeing a signal at two years that it's gonna work, so we're not wasting any more money on this.

    4. PAPeter Attia1:45:31

       Yeah. This, this was last November, right, Tom?

    5. TDDr. Tom Dayspring1:45:34

       Yeah.

    6. PAPeter Attia1:45:35

       I gotta tell you, this caught everybody off guard, didn't it? 'Cause-

    7. TDDr. Tom Dayspring1:45:38

       It surely caught me

    8. PAPeter Attia1:45:39

       ... it was certainly announced that the study was being stopped, and I would say most observers, myself included, felt, "Oh, wow, they're stopping it because the signal is so big."

    9. TDDr. Tom Dayspring1:45:53

       [laughs]

    10. PAPeter Attia1:45:54

        And then they announced at the cardiology meeting actually it stopped because there's no signal.

    11. TDDr. Tom Dayspring1:45:59

        Yeah.

    12. PAPeter Attia1:45:59

        I'm a little surprised it hasn't been published yet. Are you?

    13. TDDr. Tom Dayspring1:46:03

        And annoyed, to be honest with you. Is there something they're hiding that didn't come out in that press release or the early discussion about it or so? So are there subgroups in there where maybe... You know, and I understand these trials are super expensive, and where they say, "Hey, we're cutting our losses. We'll have to take this out to five or six years before we ever see a signal." And I wish they had done that, but it's not my money.

    14. PAPeter Attia1:46:26

        But then they wouldn't have made the announcement. I mean, I guess to me the thing I'm trying to understand and-

    15. TDDr. Tom Dayspring1:46:30

        Well, they would have announced it if they're stopping it.

    16. PAPeter Attia1:46:32

        Yes, yes, yes.

    17. TDDr. Tom Dayspring1:46:33

        Yeah. Yeah.

    18. PAPeter Attia1:46:33

        Yeah, that's what I'm saying. But the, but if they were gonna keep running it, they probably wouldn't have made that announcement.

    19. TDDr. Tom Dayspring1:46:37

        Oh, no.

    20. PAPeter Attia1:46:38

        And, and so the thing that I'm trying to wrestle with, which I shouldn't spend any time on it, I'll just wait till it comes out, is how much of this is the vehicle versus the EPA/DHA split?

    21. TDDr. Tom Dayspring1:46:48

        You know, [pants] you gotta bring Bill Harris back on. Look, technically that should... If what we want to do is achieve a certain level of omega-3s in our blood, be it in a red blood cell or a cell membrane where we would measure the omega-3 index, which they did not measure in the REDUCE-IT trial, or whether you just want to reduce plasma free fatty acid levels. And by the way, that they did do in the REDUCE-IT trial, and though it's not been published yet, it has been presented that the efficacy of the EPA-only product highly depends on the level you did achieve with a serum. So again, to me, that supports going with four grams a day. Don't think you can get away with two grams a day, perhaps unless you're really checking the levels, but even that would be guesswork. So, uh, to take home points right now, people ask me, "Tom, EPA or EPA/DHA?" If I want to be evidence-based and you're in that type of risk category, I think you gotta go with EPA four grams a day.

    22. PAPeter Attia1:47:47

        What if triglycerides are below 150? What about the person with trigs 100 who still has residual ApoB risk?

    23. TDDr. Tom Dayspring1:47:54

        Yeah. It's an unanswerable question right now. I'm not afraid to keep using EPA, DHA. Whatever the magical mystery effects of A- EPA are, which is, y- you know, are all theoretical at the given moment, and they're checking a lot of biomarkers to try and explain this, and it's all winding up in this massive inflammatory world that's maybe it's do something or self- self-signaling world. Yes, but your brain needs some self-signaling from DHA too. So if I'm gonna throw four grams of EPA at you, I, as you know, am a big advocate of doing the omega-3 index. So if I'm giving you four grams of EPA only, but your omega-3 index shows me you have adequate DHA in your system, I know some of that EPA is being converted, so I'm kind of happy, and I don't perhaps necessarily have to co-prescribe some degree of DHA with you. My worry would be, what about somebody who's taken the four grams of EPA and the omega-3 index shows you you're still deficient in DHA? Then I think you gotta scratch your brain and do what you want to do, and, uh, might be, "Hey, let's start giving a little DHA."

    24. PAPeter Attia1:49:03

        Yeah.

    25. TDDr. Tom Dayspring1:49:03

        You know, but I can't buy into the concept that a little bit of DHA is negating EPA. Maybe that's true, and that's what the EPA purists will tell you.

    26. PAPeter Attia1:49:14

        Well, hopefully we have some published data in the next six months that can at least give us a hint. I don't think this study had enough in common with REDUCE-IT to answer that question, but I think it could potentially give us a clue.

    27. TDDr. Tom Dayspring1:49:28

        Yeah, and we're getting more and more data. They're doing additional trials with EPA and they're doing more sub-trial analysis. They've even shown some angiographic data with... Despite that great reduction in residual risk, if you actually look at plaque, it looks a lot better when you're taking four

14. 1:49:45 – 2:00:03

    Fibrates—an underappreciated treatment for hypercholesterolemia

    1. TDDr. Tom Dayspring1:49:45

       grams of EPA. So that's pretty encouraging s- of that type of study anyway. You know about predicting what a plaque image shows in event reduction, but it's good nonetheless.

    2. PAPeter Attia1:49:58

       Anything else on the pharmacology side, Tom, that's really interesting to you, especially in the last couple of years? 'Cause I, I like the way we've sort of at least tried to bring people up to speed on what the big changes have been.

    3. TDDr. Tom Dayspring1:50:12

       Listen, I still think fibrates are widely underused drug. I think for the right person where you've, through whatever method you use, have identified triglyceride-rich lipoproteins, perhaps those where you clearly see insulin resistance, they're diabetics and their insulin levels are high, that's where the fibrate sub-trial analysis shows miraculous things, not only with macrovascular endpoints, but with microvascular endpoints, retina, peripheral nervous system, renal function. So even though you might screw up creatinine a little bit, you're actually improving eGFR because of overproduction of creatinine, which in that case is not reflective of eGFR. So I, I think there still is a group of patients right now where fibric acids, the purest fibric acid, which isn't a pro drug, is that fenofibric acid, still sold as TriLipix. So I think if you have to use a fibric acid, if at all possible, that's the one to use. And the good news is there is a new fibrate, per- permfibrate, pemafibrate, that's being invested in clinical trials. It's called a SPARM, a selective PPAR alpha receptor modulator, that they're really high on, and there's big outcome trials going on with that yet. But, y- you know, nobody's gonna be using that or thinking about it until th- [chuckles] those trials are stopped for good reasons, bad reasons, or published, of course, and get FDA approval. So I think there's still hope with the fibrates. Niacin is a dead drug. I know there's gonna be a lot of people listening to this who, "Oh no, it's not." It's out of every guideline. There's not a single guideline in the world that recommends. You can use anything you want if you're stuck between a rock and a hard place, and I, I certainly know there are Lp (a) advocates. If you bring Sam on, he will still selectively use niacin in certain cases. But, uh, f- few in the lipidology world still agree with that.

    4. PAPeter Attia1:52:10

       Yeah. And back to your point on TriLipix, we, we probably have three or four patients on it, and man, it's a world beater. I had one patient who was probably... I mean, he looked like he had FH, and he looked like he also had, of course, a familial hypertriglyceridemia. I mean, you couldn't distinguish them. And even though you knew he was gonna end up on both a statin and a fibrate at some point, I just out of curiosity wanted to see what ApoB reduction we'd get starting with just the TriLipix. So his trigs were about four hundred to begin with. ApoB was over two hundred. The TriLipix took him from a triglyceride of four hundred milligrams per deciliter to about a hundred, if my memory serves me correctly, and that, that took the ApoB from wherever it was, high one hundreds, two hundred, down to, you know, somewhere between eighty and a hundred. So that's monotherapy of TriLipix, which was not the intention, but just in a stepwise progression showed you the potency.

    5. TDDr. Tom Dayspring1:53:11

       A- and unless you're dealing with a super humongous high risk and acute cornice, I don't think it's irrational to go down that route. There are plenty of people who y- you have to bat them over the head with whatever to convince them to use a statin, and maybe they'll say, "Well, I believe in triglycerides. You're giving me a triglyceride. I'll work with you. Well, let's see what the parameter..." Clearly, you picked the right person there where triglycerides were generating the ApoB particles and the multi mechanisms on how fibrates reduce triglyceride had a beneficial effect. I've actually, with Peter Jones, published data using NMRs on rosuvastatin and fenofibric acid, and y- you... In some people, there were pretty nice reductions in LDL particle counts using fenofibrate. Always more. But when you looked at the particle analysis, when you were even combining fenofibric acid with the fibrate, or excuse me, with the statin You got way more dramatic remnant reductions with the fibrate than you ever did with the statin. So another reason, and almost certainly that person with a trig of 400, there was some contribution from remnants in that person, you would think. So, uh, just don't forget fibrates. A tragedy to me are young lipidologists are not being taught about it. Few of them can give you a dissertation on fibrates and how they work and wh-what is their trial history. God, there's 40 years of trial history that you can always garner a little bit from any trial. So I find that sad that it's n-not even being taught anymore, and people badmouth or condemn it without knowing what they're talking about.

    6. PAPeter Attia1:54:45

       I always feel lucky to have been trained by dinosaurs.

    7. TDDr. Tom Dayspring1:54:47

       [laughs] Well, some of us have been around the block for a few times or so. But you know us old dinosaurs, when we meet you young, brilliant guys, you keep us... If I want to still talk to this guy, I got to keep up with this stuff because I know things I said 10, 15 years ago are silly now, because you got to keep learning. You know that. Guys like you are really good for me that I, I just can't rest on my laurels.

    8. PAPeter Attia1:55:14

       Tom, this has been, this has been a lot of fun. We were supposed to do this last week and we had some technical difficulties, so we postponed till this week, and I'm glad we did because it was, it was worth being able to do it and actually be able to look at each other through a screen as opposed to just have to do it by, by phone. And so I want to thank you obviously for your continued insight. You, you make a great difference in our practice. I guess I should fully disclose to people you are now basically full-time inside Attia Medical as a practice. You're on the backside of things doing mostly research, but we drag you into at least a third of our patient calls, and we always consult with you on all of our cardiovascular cases. So I hope you're also enjoying being back to clinical medicine somewhat, even though it's at a much lower volume. We certainly enjoy having you.

    9. TDDr. Tom Dayspring1:56:00

       Uh, it's been such a wonderful part of, if this is the finish of my career, still being able to do this. And you know, although I know a lot of this lipid stuff, the basic science, I've always been what I, I and Mike Davis calls a clinical lipidologist. None of this lipid stuff is meaningful if you can't use it at the bedside and make individualized, uh, things. So I'm just thrilled to be able to contribute to you. And I think one day, as you know, I'm trying to write and generate and put more and more of this into writing, and that will become available to your followers and subscribers. And so folks, stay tuned for that. And I will say, and maybe it's another podcast and there are probably better people than me to talk to, but the one thing we didn't get into today is the emerging genetic world, genetic analysis of lipoproteins, and specifically the genetic lipidosis, FH, who needs that type of testing, who doesn't, whatever you discover, what can you do for it? It's another whole serious podcast. So other than that, thank you for everything, Peter. Uh, meeting you a long time ago in Reno, Nevada was a big day in my life.

    10. PAPeter Attia1:57:11

        Oh, mine too, Tom. Thanks so much. Thank you for listening to this week's episode of The Drive. If you're interested in diving deeper into any topics we discuss, we've created a membership program that allows us to bring you more in-depth exclusive content without relying on paid ads. It's our goal to ensure members get back much more than the price of the subscription. To that end, membership benefits include a bunch of things. One, totally kickass comprehensive podcast show notes that detail every topic, paper, person, thing we discuss on each episode. The word on the street is nobody's show notes rival these. Monthly AMA episodes or Ask Me Anything episodes, hearing these episodes completely. Access to our private podcast feed that allows you to hear everything without having to listen to spiels like this. The Qualies, which are a super short podcast that we release every Tuesday through Friday, highlighting the best questions, topics, and tactics discussed on previous episodes of The Drive. This is a great way to catch up on previous episodes without having to go back and necessarily listen to every one. Steep discounts on products that I believe in, but for which I'm not getting paid to endorse, and a whole bunch of other benefits that we continue to trickle in as time goes on. If you want to learn more and access these member-only benefits, you can head over to peterattiamd.com/subscribe. You can find me on Twitter, Instagram, and Facebook, all with the ID PeterAttiaMD. You can also leave us a review on Apple Podcasts or whatever podcast player you listen on. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. No doctor-patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard or delay in obtaining medical advice from any medical condition they have, and they should seek the assistance of their healthcare professionals for any such conditions. Finally, I take conflicts of interest very seriously. For all of my disclosures and the companies I invest in or advise, please visit peterattiamd.com/about where I keep an up-to-date and active list of such companies. [outro music]

Episode duration: 2:00:03