Hey everyone, welcome to the Peter Atia Drive. I'm your host, Peter Atia. The drive is a result of my hunger for optimizing performance, health, longevity, critical thinking, along with a few other obsessions I've gathered along the way. I've spent the last several years working with some of the most successful top-performing individuals in the world, and this podcast is my attempt to synthesize what I've learned along the way to help you live a higher quality, more fulfilling life. If you enjoy this podcast, you can find more information on today's episode and other topics at PeterAtiaMD.com. In this podcast, I'm speaking with Dr. Ron Kraus. First and foremost, Ron is a very close friend and an amazing mentor. I was introduced to Ron probably five years ago and have worked with him closely in a number of capacities, and he's always served as one of the three or four lipidologists that when I get stumped on a really difficult clinical case, he's the person that I'm reaching out to, along with a couple of these other folks that hopefully will also have on the podcast at some point. He has certainly recognized globally for his research in lipidology. He wears a ton of hats. He's a clinician, obviously a lipidologist. His interest in nutrition, genetics, drug research is quite profound. He obtained, I believe both his college degrees and medical degrees from Harvard. He's board-certified in internal medicine, endocrinology, and metabolism. Currently, he's a senior scientist and the director of atherosclerosis research at the Children's Hospital in Oakland. When this episode would be talked about a lot of stuff, but obviously we're really focusing on atherosclerosis and cardiovascular disease. I was really excited to have this discussion with him because a lot of these topics I've certainly covered in writing. As some of you may know, I have that sort of nine-part straight dope on cholesterol series on the blog that I probably wrote about four or five years ago. Obviously, some of that's a little bit outdated and I also was quite deliberate when I wrote that not to be prescriptive, meaning I don't really get into this is the drug treatment you would do for this and I largely avoided a lot of that stuff. Whereas in this podcast, Ron and I get a little bit into this. This podcast was pretty technical at times, so my hope is that both the curious patient will get a lot out of that and hopefully the physician will get a lot out of this or the person that is also kind of on the front lines of having to make decisions about how to treat dyslipidemia and reduce the risk of atherosclerotic disease. I think there are a couple of really interesting things in this. I actually for the first time learned about Ron's motivation for this, both his family history and the five legendary articles that he read in the England Journal of Medicine that largely shaped his career. This is the stuff we talk about with Friedrichson Levy and Lee's who I've written about in the cholesterol series because these guys are sort of the fathers of this space. We certainly get into one of the age-old debates about LDL particle size versus particle number, lots of controversy here and I don't represent that we've necessarily resolved it but I think that's the beauty of talking with really smart, sophisticated, nuanced people is they have the humility to say we don't know the answer sometimes. We really dive deep into the whole statin discussion. For reasons that aren't entirely clear to me, this has become an increasingly controversial area and somehow it's turned into a binary discussion. Statins are good or statins are bad and very few things in life tend to be that binary, so I'm sort of surprised that it's turned into that. I don't remember if I even say this on the podcast but certainly have people have probably heard me say this before and I say it to patients all the time. Statins are tools and the most important thing when you have a tool is knowing how to use it and knowing when to use it. If you have a Phillips screwdriver, it's really important to know that it's very good at putting Phillips screws into things, it's not good at putting nails into things, it's not good at cleaning windows. I hope we can shed some light on that. We talk a little bit about the really interesting and recent stuff around chronic inflammation and the role that that plays in atherosclerosis, even independent of cholesterol levels. Perhaps for me personally, one of the most interesting things we discussed was another very controversial topic, which is around Niacin and Niacin, which is a branded version of that, which those of you who follow this world will know that Niacin was basically kicked to the curb a couple of years ago. I think that Ron's insights into that are incredibly interesting and actually have even made me re-question or re-evaluate, I guess, my willingness to ever consider using it again. Ron does a great job explaining the HDL paradox, meaning why is it that all the pharmacologic efforts to raise HDL seem to also raise heart disease or at best make it no better. Finally, we end with a discussion of PCSK9 inhibitors, which I suspect we'll have a completely dedicated podcast to this topic at some point. We touch on LP Little A, though later on in the release of this podcast, we're going to have a dedicated discussion on LP Little A. With all that said, you can find a ton more information, including a lot of links to the papers that Ron has mentioned, more information about Ron in the show notes, which are at
[email protected]/podcast. So without further ado, here is my conversation with Dr. Ron Kraus. Well, I'm here with Dr. Ron Kraus today, and this is a really exciting topic for me. People know I've written about this a lot. I talk about this a lot clinically, but the genesis of this discussion today is that about a month ago, I called Ron to have a discussion with him about one of my patients in particular. He was a patient who had a pretty elevated calcium score, if I recall, pretty significant LED calcifications. That's the artery on the left side of the heart. But he was very hesitant to do any treatment, and he wanted to second opinion, so I thought we should involve Ron. I remember I was sitting in my kitchen. We spoke for probably half an hour. At the end of the conversation, I said, you know, Ron, I wish we recorded that conversation because this is exactly the kind of stuff that I think a lot of physicians and patients would benefit from. And so I said, you know, why don't we do this again more formally and that brings us here today? Let's start with a big question, but an important one for where we're going. And that's basically the pathophysiology of atherosclerosis. A very recent review article I read described it quite eloquently as a smoldering inflammatory condition fueled by lipids. What does that mean? Well, first of all, thank you, Peter, for asking me to talk with you today and address this topic, which is, you know, I have a deep and longstanding interest in. Hopefully I can address the issues that you're also interested in. And we'll have a good conversation. Well, atherosclerosis, of course, is the underlying process that leads ultimately to vascular disease, particularly clinically offense, heart attack and stroke. It starts in childhood, as well known that there is early on, the buildup of cholesterol in the artery wall that forms what's called fatty streaks. And that's a process that's actually a fairly normal condition, even in young people. And if it doesn't progress any further than that, it's really not hazardous. It's a way that arterial tissue can put cholesterol in its cells. And some of that cholesterol is actually used for various purposes. So that's not necessarily a pathologic process, but it can progress. And when it progresses, there is a combination of factors that conspire to make that fatty streak into a much more toxic process. And it is fueled by lipids, the same lipids that lead to the fatty streak. But under conditions that many of us live under, there are changes in the lipoproteins that are taken up by the artery, and we'll talk about those in more detail in a minute. In particular, susceptibility to oxidation. And the change in the properties that allows them to stick more tightly to the artery wall. And when that happens, particularly the oxidative changes, it does trigger inflammation as a very early part of this next phase of the disease process. And inflammation is defined in one way as the accumulation of a cells in the artery wall that deliver various inflammatory molecules, that ordinarily, if one bruises oneself or has some sort of an injury, those inflammatory processes cause redness and accumulation, in some cases, of clotting factors. When that happens in the artery, that can convert this fatty streak into something that is much more mildly. And then there is a process that kind of feeds on itself, and it does involve platelets and clotting factors in an important way, and involves a number of inflammatory molecules. And if there's continuing input of these bad, anthropogenic, if you will, lipoprotein particles, that can actually change the nature of the plaque. And inflammation comes into play in a very serious way when that results in a breakdown of the surface of the plaque, which ordinarily protects it from any kind of serious consequences. So even fatty streak can develop, which can develop into a plaque. And a plaque in this case is essentially a larger fatty streak. The plaque has a cholesterol, but it also has all these other cells. It's a much more complex phenomenon. So that plaque is ordinarily under relatively benign conditions encapsulated by a fibrous layer. But inflammation in the release of various molecules can cause that fibrous cap, that protective cap, to weaken and ultimately potentially rupture. And when that rupture occurs, that is the beginning of the end, in terms of the process that we're talking about here. Most cases of heart attack and stroke involve this type of acute rupture and ultimately formation of a clot that blocks the arterial flow. So starting from a relatively benign process, this can develop into something that's much more serious. Now, when I was in medical school, I remember in first year pathology lecture, the pathologist said, let's see a show of hands. What is the most common first presentation of heart disease? And you know, everybody puts up their hands and says, a chest pain, a left shoulder pain, shortness of breath, and he said, no, no, no, no, no, it's sudden death. That was a little over 20 years ago. Is that still true today? Estimates, I've heard, and I think this is arguable because these are really rough rule of thumb calculations. Somewhere in the range of 30%, passing past be upwards of 30%, which is still a huge number. It's staggering. It means that one third of people's first brush with the knowledge that they have atherosclerosis is death. And I have patients, and I'm sure you do as well, who will have died and come back. And so there is this process where there's an acute event that causes an irreversible change. But for some people, fortunately, we can bring them back. But together that represents really the basis for calling this disease the silent killer. Because, as you were saying, we don't, in those patients, have promedatory symptoms. Sometimes in retrospect, they are there. And I think that's the important reason for educating the public as organizations like the American Heart Association does, as to the first signs of heart disease, because it may be, and it probably is true, that a significant component of that 30%, right? Upon further querying, there was some exercise intolerance. And recognize it. Yeah. And it's very hard sometimes. One of the things that we'll be talking about is ways of assessing risk. And those are still imperfect. And we can't, with 100% certainty, use any kind of risk predictor to know if somebody's destined to have a heart attack with certainty. Yeah. You said something at the outset, which is this is a disease that begins in infancy. And I have very few textbooks and/or papers that I refer to so frequently that they actually sit on my desk in my office so that every time I'm with a patient, I can pull them out. But one of them was a book that was given to me by one of my mentors. I consider you a great mentor, Tom Daye, spring a great mentor, Alan Snyder, and a great mentor. And Alan gave me this textbook of pathology. I think believe it's Stari is the author. And while I believe the data represented there are somewhat dated because it was largely based on the Vietnam cohort. And Koreans. Yes. Where obviously smoking would have been a higher prevalence than today. Right. The fact remains that when you look at autopsies of young people who died of unrelated reasons, homicides, accidents, et cetera. And you look at the histologic sections of their coronary arteries, it's amazing how many of them have lesions that are type three or beyond. Type three meaning obviously a type of pathological region where you go beyond fatty street. Yes, indeed. That's right. So a subset of these use will have more advanced lesions. And the studies that have been done have linked all of the usual risk factors. Smoking, certainly diabetes, hypertension, and this lipidemia, all of, in a lipid disorder, all of those have been associated with the more advanced lesions in those individuals. So is your point out even even a more significant plaque development in a current childhood? I think the thing that's hard for people to understand. And I think it's true of most chronic diseases. But I don't think any disease in any disease. It is as clear as it is with atherosclerosis, which is the compounding nature of the disease. You know, another great example of one of those questions that the professor asks that gets everybody stumped, which is what's the greatest risk for heart disease? You know, is it smoking? Nope. Is it high blood pressure? Nope. Is it dyslipidemia? Nope. It's age. It's age. I mean, and why is it age because it's exposure? It's time. It's area under the curve. Yeah, that's exactly true. Age, regardably, is a risk factor that cuts across many of the diseases, chronic diseases that we have to deal with cancer, for example. And yeah, that's right. It's a cumulative process that can progress at various rates, depending on the condition. So people, as you know, when we talk about who have genetically elevated, severely elevated cholesterol levels, we'll have that process accelerated and have a disease so up clinically early on. Sometimes with these severe genetic disorders and the teens, whereas others, most of the population, fortunately, who do have risk factors, show a gradual increase in the manifestation of disease as a result of those risk factors as a function of their age. You know, at last check, and I can't remember if it was JAMA or another journal, but it was about a year ago. And they looked at some actuarial data for people out through being past centenarians. And the only disease, once you normalize for a few things, the only disease that increased monotonically by decade in risk was atherosclerosis. From childhood. Yeah. Even cancer, actually, you know, by think by the ninth decade, it started to come down. Yeah. Yeah. Yeah. Yeah. It's right. It's definitely the latency period. If we're cancer, also, is the factor there as well. So there's this sort of latency period where nothing happens and then all of a sudden an older age pops up. I'm sure a lot of people listening to this are going to say, okay, well, God, I'm really confused by half the terms you guys just used. So let's unpack some of them beginning with we use the term sometimes lipid cholesterol, like the protein. We throw those terms around interchangeably, but I think it's probably important to give the average person a sense of an understanding. So what is LDLC versus LDLP versus APOB of things like that? Sure. The underlying concept that we are going to address is cholesterol because that's really the compound. It's the molecule that winds up causing plaques. So cholesterol is indeed an important component of the plaque. And it gets into the plaque by uptake of cholesterol from lipoprotein particles. And so lipoproteins are complex, spherical macromalcules, big guys, which come in varying sizes and are composed of cholesterol along with other lipids, such as triglyceride. And most importantly, perhaps for distinguishing the various types of lipoproteins, is their protein content. So there's a variety of different proteins that form the package that actually capsules around the lipids. And let me interrupt you for one second. Is it just a point at clarification? The reason we even need these lipoproteins is that cholesterol is hydrophilic, pardon me hydrophobic, it repels water. And so therefore, to move cholesterol through the bloodstream, you have to package it in something that is hydrophilic or dissolves in water, is that correct? Right. Yeah. And for the techno files here, it's the cholesterol ester. So there's two forms of cholesterol. And it's the fatty form of cholesterol is cholesterol ester. The other form is more waxy. So the fatty form is transported right from one tissue to another. And that is the purpose of lipoproteins, not just cholesterol, of course, but triglycerides, as I mentioned, even perhaps more importantly for many functions, energy metabolism and other compounds such as phospholipids, as well as passengers on the truck, certain vitamins, etc. So these are packages that serve an important biological function. They're not here to cause heart attacks. We divide them into various categories, but the common parlance, the most typical way that we think about cholesterol as a pathologic factor is when it's on LDL. So that's called LDL cholesterol. And that measures the amount of cholesterol on an LDL particle. And LDL is low density lipoproteins. So this is a form of lipoprotein that is characterized by size and it's also characterized by its density, which is related to its capacity to float, because there's when there's fat in anything, it causes the thing to float. And that's to varying degrees defines different classes of lipoproteins. And it's the LDL that is the most strongly connected to cardiovascular disease, risk and the cholesterol in LDL, which is measured commonly clinically as LDL cholesterol, is what has been most widely associated with cardiovascular risk and forms the basis for many of our recommendations for lowering risk. But it's important to recognize that this is a tag on a much more complex substance, a particle. And this will talk about, I think very shortly, particle is what classes are the plaque to develop, and it brings the cholesterol with it. So the LDL particle, the low density lipoprotein itself, the spherical molecule, or macromolecule, which carries around cholesterol, astral, phospholipid, triglyceride, it has a signature on it, doesn't it? Something called APOB100. That's right. The key protein that holds this particle together, that allows it to form a sphere and to encapsulate the lipid cargo, is called APO protein B. There are two major forms of APOB. The one that's found in LDL particles is called APOB100. And oftentimes, that is used as a surrogate for measuring LDL particle concentration, as we'll talk about. And this is a big clinical distinction. I think it is safe to say, at least in my, you know, relatively modest sampling of physicians. Most physicians, let alone most patients, are not really clear on the distinction between the number when they say LDL is 100. They don't necessarily realize what they're saying is, the LDL cholesterol is 100 milligrams per desoliter, meaning if you took all of the LDL particles in the body, smashed them apart, gathered the cholesterol ester. The mass per unit volume is 100. And that's, yes. And that's very different from saying, how many of these particles do we have? That's right. And that's important. So that observation really forms a very significant component of my history in this field, because I entered the field as a young fellow, knowing about LDL cholesterol. It's interested in diet effects and drug effects and heart disease. But I learned about lipoproteins actually from a group of investigators in Berkeley, California, who were part of a team that initially identified lipoprotein particles. And over the course of the next 10 or so years, I dug into that knowledge and discovered that there are subtypes of the various forms of LDL, as well as other lipoproteins, which we can talk about perhaps in a few minutes. But focusing on the LDL, there can be variation in the amount of cholesterol that is carried on LDL particle. But there's only one APOB per LDL. So APOB represents a pretty good signature for an LDL particle. It is found on some other particles, but it's primarily on LDL. But the amount of cholesterol attached to that APOB as part of this particle can vary, as can other lipid components. And that results in variation in both the size, as I mentioned, and the density, so that some forms of LDL have less cholesterol, and some have more cholesterol. The ones that have less cholesterol are smaller, generally, and the ones that have more cholesterol are larger, but they all have one APOB protein B. So there can be an important clinical consequence of focusing on LDL cholesterol to the exclusion of APOB, because it's the particle that is really the agent of damage in the artery. And measuring LDL cholesterol can under-represent the number of LDL particles compared with the measurement of APOB or APOB, which is a much better measure of the number of particles. And when individuals have smaller particles because of this variation in lipid content, they are actually at high risk of heart disease because those particles have properties that render them more pathologic, more toxic. So there's a double whammy. If you have small particles, first of all, clinical measurement of LDL cholesterol may under-represent the number of particles, and furthermore, those particles themselves are considered by many, although there's still not total consensus on this point, to have greater pathologic properties. So let's use a specific example. So if a patient has a blood cholesterol level, and let's just assume it's LDL calculated, a measured directly, not even calculated, and the LDL cholesterol is 100 milligrams per desk a liter. At the Framingham population, that would place them at about the 20th percentile. But let's say that patient has an LDL particle number of 1,400 or 1,300 nanomole per liter. And of course, in the units that tells you it's a number per unit volume, that places them at the 50th percentile. Now, at least to me, the literature is very clear on, in the case of discordance, which of the two is driving risk. I think both the Mesa population, the multi-ethnic study of atherosclerosis, and the Framingham and Framingham offspring study, make it very clear that risk is tracking with the number of particles, not the cholesterol concentration. Do you agree with that, or am I missing something? No, the data are out there. And just to take a step back, LDL cholesterol, that clinical measurement, has worked reasonably well for a significant subset of the population as a marker for LDL particles, because most individuals may have particles somewhere in the middle of the LDL size and density range, and the cholesterol content in those particles is fairly proportional to the number of LDL particles. But where things break down is the increasing proportion of the population who have different LDL particle distributions. You need to consider that higher LDL particles with normal LDL cholesterol, which I will answer your question, yes, is associated with an increase in risk that's not reflected by LDL cholesterol. So that is the discordance we're talking about on the high end, and conversely, individuals who have high LDL cholesterol, but normal levels of April B will tend to have disproportionately less heart disease risks than would be predicted from the LDL cholesterol. So that's the discordance, which I think is pretty well demonstrated in a significant subset of the population at both ends. But underlying that, and again, there's some debate on this issue, it certainly reflects the numbers of particles, and that is the bottom line. But it also reflects the types of those particles. So there's really two features at both ends of that distribution. Smaller cholesterol, two particles associated with discordance, at the low cholesterol, the April protein B ratio, and conversely, larger LDL particles associated with less risk at the other end. And there may be systemic factors here at play, because there are some pretty, I think, pretty widely accepted data now. I think 10 years ago, this was a little more obscure, but one of the greatest drivers of the discordance in the wrong direction, meaning the LDL particle is disproportionately higher than the LDL cholesterol, is metabolic syndrome. In fact, there's a very beautiful graph that I've written about at some point in my blog that talks about how, based on anywhere from zero to five of the characteristics that an individual has of metabolic syndrome, the proportion of discordance goes up. So it also could be that as discordance rises, risk rises because of the other factors, such as hyper-insulinemia, which itself may contribute to entomal damage, inflammation, and other things. Is that possible? It is absolutely possible and likely to be true. So this brings up a pattern, laparotene pattern, that I will take some credit for having to find, in my own way, about 25 years ago, 27 years ago, and now, called the atherogenic dyslipidemia, or atherogenic laparotene phenotype, which is a constellation of lipid changes that includes higher triglyceride, lower HDL cholesterol. So that's the cholesterol in the protective form of laparotene being deficient, and a predominance of smaller LDL particles. And so that triad, that lipid triad, has defined atherogenic dyslipidemia, and it folds right into the metabolic syndrome. Right. Two of those three make up two of your five. That's right. Criteria for metabolic syndrome, which for the listener, might be low HDL cholesterol, high triglyceride, high fasting glucose, high blood pressure, and girth, basically obesity. Exactly. Drunken obesity. Yeah. So I remember being part of the discussions where that metabolic syndrome was defined as a syndrome. It's very interesting. Yeah. Well, that started with insulin resistance as the centerpiece. You can put various molecules in various processes toward the center. They all contribute. And as you point out, hyperincentenemia, associated with insulin resistance is likely another marker of another process related to glucose, metabolism, and its consequences. And then the blood pressure connection is an intriguing one, but that's also part of it. But a lot of that is driven by increased girth. I mean, it's sort of of the five conditions. The one that I think is the most prevalent underlying factor that leads to the development of metabolic syndrome is increased abdominal fat, which is associated with increased weight. Specifically cholesterol fat. This role fat around the internal organs. And you can have metabolic syndrome without that, but the vast majority of people that certainly Caucasians, yeah. Yeah. And non-calculations, populations such as these Asians who don't have increased waist still can have increased fat internally as part of the syndrome. But it's probably acting on an underlying genetic predisposition, which is very common. And so, and there's many other factors that come into play as part of the syndrome. But I would say that just lipidemia is probably both clinically and pathologically the one that I think has the most substance in terms of a direct causal connection to cardiovascular disease. Yeah. And you know, I'll tell you, it's a very interesting historical footnote, Gary Tops, a mutual friend of ours. And I don't know if this actually was any of his books, or I might have read this in one of the outtakes, but it was an interesting footnote, which was basically at the time of the Framing Him study, which I'm talking about the very, very first Framing Him study, which was really a two-part study, of course. One of the things that came out of that study was that low HDL cholesterol and high triglycerides was four times more predictive of atherosclerosis than elevated LDL cholesterol. Now, that rings true with what we just said about metabolic syndrome. Nowhere in the five criteria of metabolic syndrome was high LDL C. It's low HDL C and high trig. But it's interesting that the LDL cholesterol story really took off, and at least Gary argued, I believe, if I'm remembering the argument, that part of that had to do with the fact that the, God, I'm blanking on the name of the, the first trial. There was the LRCCP, but then there was the one before it had a funny name, like, improve it or something, but it wasn't, dude. It was like, you know, it was a trial of the Fibrate, the Fibrate trial, do you think? The Fibrate trial was LRCCP. No, that was, that was close to what I mean. So I think that's when you're thinking. Oh, okay, okay. I think you're thinking of this LRC. Yeah. I was, I was, and so part of my training. Yeah, that's where I got my training in lipids before I came out to Berkeley, actually. That's, that's why I got my first dose. And that study was going on at that time, and there was a lot of nail biting. Well, and, and the argument here was, look, we kind of spent, we lost a decade and a half between, say, 1980 and 1995, when we missed the role of insulin resistance, because we really went down this LDL cholesterol rabbit hole and didn't necessarily see the bigger picture. And, one of the things I hope we have time to talk about today, because it's actually something that I spend more time scratching my head about than anything else is you look at a drug like Niasin, which lowers APOB LDLC and raises HDLC. So in theory, it's doing everything in the right direction. And yet, when it comes to outcomes, it's a very confusing picture. So maybe later on, this afternoon, we can get to that, because I think that's, there's going to be some rich info in there. If you put that on a table, I'll be happy to pick it up when you're ready. I'm ready to lunch with that. I cannot wait. We're definitely going to do that. So okay. Let's talk a little bit about a paper that you were an author on this year. It was the European Atherosclerosis Society consensus statement. Now, you and I were joking about this a while ago that you almost couldn't believe this paper needed to be written, but sometimes there's a benefit in writing it in. What was the conclusion of that paper or more to the point consensus statement? It was more than just a paper. I mean, it was really a tour de force. So this paper assembled a multiple lines of evidence addressing the question this LDL cause heart disease is LDL a causal factor for heart disease? And just to be clear, the counter argument is sure people with high LDL are more likely to get heart disease that can't be disputed. The epidemiology is clear. The counter argument is but LDL is not a causal role. That's right. And it's associated with that efforts to lower LDL cholesterol are not fully justified as a means of attacking the cause. I don't want to be responsible for having stated that incorrectly because I still can't quite believe anybody would hold that opinion. But that was my understanding that led to the coming together to counteract that perception that lowering LDL was not beneficial. But there are there are many people. I mean, not that I spend terrible amounts of time on Twitter, but it's a pretty commonly held view at least in the vocal minority that love to write about this and talk about this that, hey, LDL cholesterol is a myth like heart disease has nothing to do with this. And the problem is and it did come out in the paper to some extent, but I'll tell you there is a second component to that effort that is still being written. It was planned and will be a two-part series. The first part is assembling all the evidence from epidemiology, clinical trials, genetics, etc. that speak to the causality. And the second one was really relating all of this information to the role of LDL and the pathophysiology of atherosclerosis. And that paper is a work in progress, but it could likely be those two papers assemble just about all the evidence when needs to support the use of LDL cholesterol. And when will that second paper be out? I can't tell you. You don't even know. It has taken longer if we thought. Well, we'll certainly link to the first one in the show notes because that was published in early 2018. Yeah, we expected it next year or so. But one thing I do want to say because there's a caveat and part of my life as a researcher as well as a clinician is recognizing the complexity of what we're dealing with. In discussions such as this, it's important to keep the concepts straightforward and understandable to the best to be possible. But the flip side of that is the risk of oversimplifying a complex situation. So when I just said that the evidence is that lowering LDL cholesterol is beneficial, that's not always true. And so when it can point, if one is so inclined to the evidence that under certain conditions and certain populations with certain approaches, the only LDL cholesterol does not result in reduced heart disease risk. And to the extent that you consider that to be a fatal flaw in the argument, that can be, I think, very misleading because it's not the fact is that LDL is causal, but there are other circumstances that modify that causality to the extent that some forms of LDL under certain conditions, and this may not be uncommon, can be elevated without pathologic consequences. And so lowering LDL in those cases may not give benefit in that. We know that there was heterogeneity in the clinical response when it looks at how to ask your protection with LDL lowering treatment. So I have to absolutely extend the simple notion of LDL causality to saying that when it has to look very carefully at the arguments against LDL causality because they latch on to piece of piece of information that are really misleading. Just because lowering LDL cholesterol is not always beneficial, doesn't mean that LDL is not pathological. And the second component of that is the focus on LDL cholesterol that goes back to our initial discussion here today as a marker for a causal mechanism, but it's the particles that are causal. And LDL cholesterol, as we just talked about, does not always mirror the number of LDL particles. Now I don't think we should necessarily take the time to go through the paper in incredible detail, but it did touch on eight criteria for causality, plausibility, strength, biological gradient, temporal sequence, the specificity, consistency, coherence, and then the relative risk reduction or risk reduction with an intervention. Among those, I found the Mendelian randomization to also be very compelling. So when I talk about this with people, I generally talk about the natural experiments, such as the people with PCS-K9 mutations, both hypofunction or gain-of-function loss-of-function PCS-K9, the FH patients, the Mendelian randomization and the intervention. If you were going to bring up three points from the paper that you think probably are most relevant, what would they be? Well, you've just touched on probably the number one strongest argument. And it's really where we, those of us who have been in the field for decades, started with being impressed with the role of genetic elevations of LDL, very, very strong evidence. I would put that probably right at the top. And you talked about this condition, familiar hyperclestrolemia. When there's two doses of an abnormal gene, the LDL levels can skyrocket. I referred to that a little while ago as the condition that can lead to heart disease early in childhood. It's unequivocal. In fact, the reason I got a little bit taken aback by the need to do this more extensive review, which I think, by the way, was quite a good exercise, both for those of us who did it and people, hopefully, who read it. But all you have to do is look at a eight-year-old child with cholesterol levels that are eight or nine times normal, who's candidate for liver and heart transplant to know that that's it. That's causal. But the genetic support is beyond that. Right. Now, in those cases, the genetic defect is one in the LDL receptor. So closing the loop on how this works, the body makes cholesterol. So every cell in the body makes cholesterol. Then cholesterol gets recirculated. It ends up mostly back in the liver. It gets secreted, some of it in bile gets reabsorbed, and this process continues. But it's this LDL clearance, mostly via LDL receptors in the liver, that seems to be where a lot of these genetic things go awry. That's right. Yeah, the liver really is the factory as well as the disposal plant, if you will. Most of the cholesterol that winds up in the blood is released in terms of in lipoproteins that are synthesized by the liver. And then they come back to the liver ultimately after they've done their thing, so to speak, deliver their cargo or interacted with cells in various ways and come back to the liver. And a large portion of that return is mediated by these receptors that latch on to able beat. It's able be that is the kind of the key that binds to the lock that snaps up the LDL in the liver and he grades it and exweats it into bile. And that's the way we dispose, one of the ways we dispose of cholesterol. There are other mechanisms involving HDL. But the receptors are a key determinant and do represent a mechanism by which most of the drugs that we use to lower cholesterol act to increase LDL receptor mediated disposal of LDL particles. And I'm just going to connect that concept to something you brought up earlier. And that is the duration of exposure to, but in this case high levels of LDL, we talked about it as a function of age longer in the reviewers, the longer exposure. But there's also a dynamic aspect to LDL metabolism that we just touched on. That is particles are produced actually precursors of LDL, which are called LDL, it's carried mostly try this right, and April protein B as well. Those particles are being actively secreted. They interact with peripheral tissues and receptors and other transporters that handle various lipids and various ways. And enzymes set us a lot of processing that goes on. And then what's left comes back to the liver through LDL receptors. Now if that process happens briskly, if there is a nice fast turnover, if you will, of those particles, you can just see that there is less time for the arteries to be exposed to any of those pathologic forms of lipoproteins. They can be scooped up. But what underlies, at least to me, a common concept, a common underlying factor that connects various lipid traits to heart disease risk is the extent to which they influence the circulation time. That is the length of time that a particle is circulating in the blood so that particles are not being cleared by LDL receptors efficiently. They will circulate longer and have more opportunities for mischief. What is the typical half-life of a LDL particle, so very low-density lipoprotein, ideal intermediate density and low density? I'm probably going to get this wrong, and this is where I don't want to have to go back and look at the textbook. Well, directionally. Yeah, so particularly for a larger LDL attract this right, the half-life is half an hour, an hour, two hours. It's pretty rapid because that particle is rapidly subject to enzymatic digestion. Let me just jump to the LDL. The LDL that are formed from those precursors, more like 12 to 24 hours, or longer. It turns out that smaller particles have a longer risk in its time because they are less avidly removed by LDL receptors. There's a range of circulation times for LDL in some cases days actually. Then ideal are somewhere in the middle. The intermediate density lipoproteins are ideal, is what you're referring to. That's the step between VLDL and LDL that is involved in their metabolism. So it's these longer exposure times, and these intermediate particles can include and do include very pathologic forms as well. There are disorders and metabolic syndrome coming back to that is one of them where the clearance of those intermediate particles, which also comprise what we call remnants, partial breakdown products of VLDL on the way to forming LDL. Those intermediate particles can have much longer exposure times. They can be subject to various pathologic effects involving oxidation, the position of partial digestion products of various lipids that cause them to be more toxic. Those particles can be damaging even with a shorter residence time because they're so toxic. That gets into what I was referring to earlier as a somewhat of a greater complexity of beyond thinking just about LDL cholesterol, thinking about LDL particles, thinking about the types of LDL particles in terms of the pathophysiology, and then also thinking about the role of these remnant lipoproteins. They all participate in this potential risk. It comes down in my view in the end to the length of time that a particle with certain pathologic effects is circulating in the blood. This VLDL cholesterol, VLDL remnant problem is one that is unfortunately very often missed even by relatively astute clinicians. Your textbook case is these type 3s, these hyper-trageless radimias who have normal APOB, normal LDL C, you think they're relatively low risk. You sort of miss the fact that their VLDL cholesterol is 75 milligrams per desk a liter, and they have these just devastating atherosclerotic plaques. That was, again, one of my learning experiences, when I was at the NIH at a time working with Dr. Fredrickson and Levy. Just for the listener, it's important for them, I think, to understand the luminaries that you just described. Fredrickson and Levy and Leese, I mean, let's put these guys in context. You had people that figured out that there was this thing called cholesterol, but it was really those three that did the pioneering work in the 1970s that laid the groundwork for fractionating, figuring out all of the different sub-particles. Late 60s. Late 60s, early 70s. No, it was late 60s. I'll just give you a slight anecdote since you paused me on this. I've always been interested in heart disease because it rents in my family. As a medical student, I read a series of five articles that was published in the New England Journal of Medicine and I think you're referring to the three authors, Fredrickson, Levy and Leese, that completely transformed me. It was a epiphany because those five articles describe lipid disorders in terms of genetic types, differing lipoprotein profiles that had differing metabolic effects, differing consequences, and burn influence differently by various diets. And I thought this was absolutely the most important lead I could imagine. So I made it my business when it came to deciding what I was going to do after my medical training is to come back, it's to come then I used to work with those guys and I was fortunate enough to be able to do that. And it was really in the era where what was called the Fredrickson typing system, identified these various forms. And the one you just referred to, the genetic forms of lipids that you know and often always consider, it was called type three and that was characterized by abnormalities in receptor mediated clearance of these remnant particles through a mutation in apoprotein E or variant of aprotein. And that also was fascinating. And I happened to be in California when the apoees were discovered. So I sort of feel like one of these characters that just you know shows up at the appropriate time. It was called the Arge Ridge peptide and the history is just I wrote a we wrote a review actually of the early history of lapoprotein research, which I would commend to let's put that on your list. There was no general lipid research in 2016. In fact, I just got a fan letter for that article because anybody that's seriously interested in this field should probably understand the origins. In fact, I got a letter. We have that paper was published. I got an email from Joe Goldstein who is the other one. Oh, yeah. Another laminar icon in the field. He said everybody that goes into lipid research should be this paper. So I'm going to it's not a book. I don't make any money off of it, but we're going to make sure that people get smart on that. Anyway, paying back to these remnants. I think particle for particle, the remnants are probably the most pathologic particles of all because of this rampant atherosclerosis when there's elevation of remnants. Unfortunately, this condition of type three is fairly rare. It's like one in 10,000. Yeah, but it does illustrate. I've seen myology. Yeah, I've seen so you've seen so right. So yeah, when I was starting to say, I actually initially what I started to say when I was at NIH in my training, I saw all these things. You know, all the types were there. You collected them. Yeah. We had patients who had the type three. We had type one, which was a serious elevation of triglyceride. Type two was familiar hypercholestrenia. It goes on and on. So yes, and it's really striking. I tell my students, I lecture on this to students at Berkeley. I show them pictures of what are called xanthomas, which are deposits of cholesterol and lipids and tissues. And you have these very characteristic lesions that used to be rampant in patients before we had adequate recognition and treatment as a manifestation of the underlying pathology that also affects the arteries. The cholesterol that winds up in the arteries can also break into the skin. And these are just very striking illustrations of the role of genetics. So it gets back to your earlier question about causality. There are so many situations where genetics helps in establishing causality. And this certainly is one of them. After that, you ask me, what are you know, one, two, and three, right? You ask me how many my top three are. I didn't answer that. And before we leave FH, I think the other nice thing about the PCS-K9 mutation, you know, FH is only showing you the change in one direction. But with PCS-K9, you see both directions. That's right. I believe the hyper functioning were the first people identified, correct? Yes. So these people had an enzyme PCS-K9. It hyperfunctioned. Therefore, this enzyme's one of its roles is to degrade the LDL receptor. And so they had fewer LDL receptors. They had more LDL. They looked a lot like FH patients, correct? Yeah. Yeah. I just to be again for the technical where it was on the phone. Oh, it's actually not. It's not an enzyme. It kind of behaves like an enzyme. But it actually drives LDL receptors into the garbage disposal machinery in the cell called lysosomes. And it causes the LDL receptors to be broken down. But it's the same in basaltus. You get less LDL receptors higher, LDL cholesterol. And then the mutations in the other direction are the ones that led to the development of PCS-K9. The loss of function, antibodies to PCS-K9 mimic the loss of function mutations, which lower LDL. And that's one of my, you know, when I get to tell these stories one day, I'll look back and say that was my aha moment because I think that paper came out in 2006 in the New England Journal of Medicine. It was either O4 or O6. But I remember this well, which was the discovery of those families with the hypofunctioning PCS-K9s. These people walked around with an LDL cholesterol between 10 and 20 milligrams per desolate. Two things about them stood out. The first, they never got heart disease. The second, they didn't seem to suffer any other consequences that you might concern yourself with. Right. Yeah, one of those patients, classically, I think a physical therapist or somebody that was very active and had an LDL of and the teens, which is, you know, 1/6 normal and is doing fine. Yeah, so that's another use of genetics in a way to confirm that lowering of LDL, not necessarily using all the ways that LDL can be lowered, but at least certainly that form of LDL lowering is healthy. And probably most forms of LDL lowering a healthy. We have very little evidence to the contrary. Do you want to say anything about the Mendelian randomization? It's, it's, you know, I think it's not at the most intuitive concept to people, but it is actually a very powerful concept. Right. So the principle of Mendelian randomization, first of all, Mendel, regular Mendel was a 19th century monk who discovered the principle of inheritance of traits in p's actually. The idea is that these genetic variants are randomly distributed in the population. So that assumption underlies this concept of negative randomization because then you can say that the occurrence of a genetic variant in the population or or a collection of variants can be either single or multiple variants that are associated with a biomarker such as LDL cholesterol can be used to test the causality of LDL by looking at another relationship. And that is the association of those genetic variants with the disease process. So for example, and so I'm going to give you an example because it's really a little bit abstract without an example, and we'll talk about PCS K9. So the PCS K9 loss of function mutation causes a lowering of LDL. There is independent evidence that that mutation is associated with reduced cardiovascular disease risk. Nothing to do with LDL, just the genetic association with outcomes. That relationship parallels very closely the relationship of that variant LDL cholesterol. The difference is that the risk associated with the genetic variant, the risk of heart disease, is actually less than would be predicted from the LDL cholesterol using standard risk relationships because this is lifelong exposure. This gets back to the exposure issue. So a genetic marker like this in the many randomization model tells you that lifelong exposure to a genetic variant that either raises or lowers risk has effects that can be attributed to LDL because that the LDL change predicts that risk relationship. Yeah, whereas a lot of the conventional risk models are basically looking at maybe a decade of risk or something like that and they're always going to fall short both under and over estimating long-term risk. So in the paper that you referred to that came out of this European consensus, there was a heavy dose of Mendelian manimization. Either the main author or one of the key authors did a very good job of showing how the genetic markers for they're connected to LDL receptor levels, both so PCSK9, others they're associated with higher receptor activities. Well, predict cardiovascular risk much more robustly than do the results of clinical trials. Clinical trials only last five to ten years. So that risk reduction, which is parallel, but is displaced because the magnitude of that effect is blunted because it's not a lifelong exposure. So it's very instructive. Yeah, let's go back to something else you said a few moments ago that I think is, I would say ten years ago, I don't remember when Jim Ottvost's analysis came out, but Jim, who's an incredibly thoughtful person in this field, wrote a paper that basically said, "Once you normalize for the number of LDL particles, the size doesn't matter." Now, moment ago, you said that your intuition is that that actually that's not correct, that particle for particle, a small particle is more authentic. Is that a fair assessment of your thought? It is, it is definitely an assessment of my thought. And unlike what we've just been talking about, we don't have a way showing incontrovertibly that that's true. So when tries to sort of dance around this question by using statistics, can you use statistics to factor out everything with which the particle size, and let me clarify one other thing before I go on a net is, the reason particle size got on the map was that I wrote a paper, I think in the 80s, actually, probably 30 plus years ago, in which the only test we had was particle size measurement, and we showed the particle size, small particle size, which related to risk, but we also said it was associated with lower HDL and higher triglycerate, so that was the definition of this triad that we just talked about, and we never said that the particle size was independent. We never actually said that. We never said it was related to, independently, to risk. It was a marker for this whole syndrome. The particle size context that I was referring to early on in our discussion today was not the size of particles, but the numbers of particles of differing sizes. That's a somewhat different concept. So there are techniques that measure, they give a number for whether most of the LDL and the blood is larger, small. It may typically bifurcate this at like something like 20.5 nanometers or something like that. And the other thing I'm going to say because this is a lot, I'm going to say it because there's an opportunity to say it. If you measure those particle sizes correctly, the distribution in the population is bimodal. That means there is a discrete subset of the population that has smaller LDL particles. Now that says nothing about their heart disease risk. That says that there's something going on that tips in a quantum way towards the small LDL trait. And that is the marker for the metabolic syndrome. So that's not about heart disease risk. That's a metabolic marker. The heart disease risk depends on the magnitude of that small LDL mode. If you have a lot of, if you have a lot of LDL particles that are small, that's bad. Now the argument that outvotes and others have made using statistics that I will come back to in a minute as to why I think this is a flawed approach, is that if you knew certain statistical corrections for interrelationships of various particles with each other, there is a significant relationship to risk of larger LDL as well. So that's not untrue. A larger LDL can be. I mean if I recall, as long as something is less than 70 nanometers, it can enter the subenditheal space. So any small, any large or small LDL can enter the space. So it gets back to residence time. Yes. How long do they stay? That's right. So it turns out, so this is going to be a little bit complicated, but I'm going to try, maybe we have an audience that's willing to handle complicated. I don't need to work through this with you because I know what I want to say and I just want to make sure that I say it clearly. Let's talk about larger LDL. So this, in this large LDL mode, that signifies sort of the flip side of metabolic syndrome. It generally identifies people who have not only larger LDL, but higher HDL cholesterol and lower triglyceride. So that's a low risk syndrome and often low insulin. That's right. And so quite apart from the question, are these particles that are worse, they signify a metabolic profile where there's a pretty brisk circulation of those particles and the exposure to the artery wall is very low. Now if you have an LDL receptor defect, it also causes large LDL. The large LDL accumulating FH patients have large LDL particles. So why is that? Why is that bad? It's because of the residence time is much higher. Right. And so neither I. Well, there's some people that have taken some of my own work and taken it to an extreme that I don't feel is justified. And that is to say that large LDL are not anthropogenic at all. They certainly can be. There's no question about that. The question is, are they equally anthropogenic to smaller particles or any other particles in the LDL spectrum? And I'm just. I'll just say this, the work that you're referring to did not address that. All it said was that you can show that the large LDL are associated with risk. And then the second thing is that if you adjust the total LDL particles for the peak size of LDL, the peak size is not associated with risk. So those are two different statistical manipulations, neither of which, neither of which disprove the hypothesis that smaller LDL carry more anthropogenic risk. And we have an example of something I'm going to tell you again genetically, which may or may not be something that your audience is familiar with. There's another genetic syndrome that involves a variant that affects a vision of the genome, which is responsible for synthesizing a protein called sordeln, SOR-T-I-L-I-M. That genetic variant was discovered, probably six or seven or eight years ago now, and was associated with both high risk of cardiovascular disease and high LDL cholesterol. And in fact, the association of that genetic variant with cardiovascular disease was as strong, if not slightly stronger, than the associations of genetic variants and the LDL receptor itself. So this was a new player in the spectrum of causal factors, again, relating a genetic mechanism that raises LDL to an effect on cardiovascular disease risk through a pathway that doesn't involve the LDL receptor. This is not an LDL receptor story. What we published as part of the initial description of this variant and this relationship to cholesterol metabolism is that in two independent populations using two independent methods, it's specifically associated with small and very small LDL, not large LDL at all. So here's a genetic variant that as far as we can tell effects. So it's not affecting clearance? Well, we don't know about clearance. I can't tell you about clearance. All I can say is it's not LDL receptor mediating clearance. There may be, we don't know. This could be Neiman-Pixil, one like one clearance for all. So if you can ask me later on, what one of the experiments that I would do if I had all the resources in the role that would relate to this mechanism, because the genetic association, it's not clear exactly what's being affected by the genetic variant. It's not clear how it works, but what's definitely clear is that that variant is associated in terms of lipoprotein changes or anything else that we can measure in the usual risk factor range exclusively with small and very small and very small. It's even a subtype of small LDL, but it's that collection of smaller particles that is somehow affected by this variant. Now, do those patients have elevated triglycerides or low HGLC? No. No, it's exclusive. So that counters the argument that I would say, gosh, maybe these small particles ultimately are just a marker for an inflammatory metabolic dysregulation. They largely are, but this is a subtype. So this gets into what you might consider a new one. So I'll tell you another anecdote. When I first kind of discovered that people had all these different forms of LDL, this is again in the 80s. I don't know how many, this is 35 years ago now. I was invited to give a talk, a couple talks actually, various meetings, one of which was in San Diego actually, and others where I presented this data. And it was using not the current methodologies, but a very elaborate procedure involving the ultra centrifuge, which separates these particles into various fractions. And I have a picture of what I showed on the wall of my office, because it's so emblematic of the existence of these discrete forms of LDL. And I remember talking about this to very intelligence and experience people in the field. And it was considered as oteric. And for about 15 years, nobody paid any attention to it, because it was felt, nobody else had methods to show what we had been showing in large populations. Fortunately, later on, that was remedied by more widely available methodologies that we were partly responsible for. But the bottom line is that the recognition of these various forms of LDL, we tended to simplify to avoid having people think it was too esoteric. So we talked about large and small as if there were only two forms in these two modes, etc. And all that's true, but within both of those, but the small LDL, there's yet another subtype. And it's this very small LDL. So the garden variety, small LDL, that is generally measured by techniques that are being used, such as NMR and I'm a ability method. Largely measures the small LDL that you're talking about, it's part of this generalized metabolic syndrome. But this very small guy looks like it's another pathway, it's another pathway. And it's a pathway that has a strong genetic association with risk. And we are, I'll just say this to this audience, we are trying to do some studies and this gets back to the studies I'd love to do to test the hypothesis, these particles may be secreted directly. So this might be a mechanism that spits out a pathologic form of LDL without going through. - Through the VLDL pathway. - Without going through the VLDL pathway. That's a hypothesis that we're now. So it sounds like almost like an LP little A type issue. In a way it is. Yeah, that's a good point. It's a particle that we don't know how to lower, like an LP little A. Well, we were signed to learn how to lower up. That's another topic, I guess. We're not going to get to LP little A. That's another topic. But yeah, so it's a genetic factor that is associated with risk that we don't yet know what to do with. So let's go back to something that you've kind of touched on a little bit, which is, can LDL cholesterol slash LDL particles slash APOB be too low? I'm referring specifically to a pharmacologic intervention. So I think we've already established that the people so genetically blessed to have hypofunctioning PCSK9 seem to be completely fine. But if someone came along and said, "Look, I'm walking around at the 30th percentile of the population. I want to walk around at the first percentile of the population. I'm going to pharmacologically lower it." Is there a downside? Right. So I guess I'm hung up on genetics today because I think the best scenario to consider in evaluating the pros and cons of RALO LDL, our genetics syndrome was associated with RALO LDL, and we just talked about one of them. So PCSK9 loss of function mutations are an example of what you're asking. Those individuals have lifelong exposure to RALO LDL. And as far as we can tell, do fine. There are people who have abnormalities in the APOB protein that results in impaired production of LDL, ultimately, and most people do very well. Now we have less heart disease, they think it's a live longer. So this is the genetic evidence for the safety and the benefit really of having RALO LDL. That doesn't imply that we can extrapolate those genetic observations to all treatments. Now for the PCSK9 inhibitors, if we assume that the use of the antibodies to lower PCSK9 therapeutically mimic the genetic effect, then one would have the same confidence that this would not be hazardous. You don't yet know that they're not other effects of these antibodies. It may not necessarily fully mimic the genetic effect. But by and large, I think it is a vote of confidence that those treatments that lower that particular treatment will PCSK9 inhibition probably does. Not only lower risk, but have no significant downsides. But we don't know the clinical trials of any of the drugs that lower LDL have not been long enough to know what the lifelong effects might be. So if you look at the most widely prescribed class of drugs for lipid lowering, it's obviously going to be statins. And statins really do two things. You know, they have a direct effect, which is they inhibit the first committed step of cholesterol synthesis. And so that directly lowers the burden of cholesterol there by lowering the burden of lipoprotein. But in many ways, their indirect effect is at least as strong, which is the liver in response to this, upregulates the LDL receptor and you get enhanced clearance. Now the latter, we certainly have a genetic model to look at. Do we for the former? Do we know of people who have deficient cholesterol synthesis? Outside of the extreme, we know that there are certainly inborn areas of metabolism that are uniformly fatal. But sort of outside of those people are the people walking around with low cholesterol or the defect is in cholesterol synthesis that would give us confidence that, hey, inhibiting cholesterol synthesis can't be that bad. I'd have to say I don't know that there is such a genetic variant. There are genetic variants in the rate limiting enzyme, HMG query ductase that is the target of statins that affect LDL levels in heart disease, risk in the expected direction. But those variants are have a modest effect size. They are not big time of players to knock down LDL to those same relative. That's what makes the PCSK9 story so exceptional. It's just nothing quite like it. So the answer is to my knowledge, no, we don't have that kind of evidence that would apply to very low LDL that are induced by genetic factors. And that's a scenario that I think I clinically struggle with. And I suspect there's going to be at least one other person listening to this that's going to share that struggle, which is I do get a little bit nervous when I have a patient whose risk of atherosclerosis is so high, for example, a patient with a significant family history and a very elevated LP little A, just as an example. And you know, I seem to collect these patients. So you've got these folks and they've got a clinical burden of disease. So their CT&G Gram shows soft plaque, their calcium score shows that they've got calcifications, their LP little A is through the roof. And they're tolerating their statins, meaning they don't have the myelges, their CK elevations, or any of those things. But to get their LDL where it needs to be in a patient like that, I'm going to put to the fifth or 10th percentile. I have effectively by all means that I can measure almost shut off cholesterol synthesis. In those patients, I panic because of a couple of papers that I've seen that look at the opposite end of the spectrum, which is, you know, they look at markers of cholesterol synthesis in patients who are medicated and then the risk of dementia. In particular, there's a paper that looked at those mass law levels. And it found that if the level was below 0.5, which is, you know, generally very low on the scale we look at. And they use that as a cutoff on the receiver operating characteristic curve. The area under that curve, which again, can vary from somewhere between about 0.5 to 1, 0.5, meaning it's a useless test. It's a coin toss. One is a perfect test. You know, they're coming in with AUCs of the ROC at 0.87, 0.89. That's quite suggestive of this. And certainly biochemically, there's a plausibility to this, right? We understand that every tissue in the body has the ability to borrow cholesterol from elsewhere. That doesn't appear to be the case in the brain. The lipoproteins don't seem to, you know, be able to traffic across the blood-brain barrier. So I guess that's just one area where I certainly don't know an answer, but I've become, I think, clinically much more quick to move people to PCSK9 inhibitors when I get uncomfortable with the degree of cholesterol synthesis. Do you think I'm paranoid? You've opened up a big topic all by itself. I think that is the off-target effects of cholesterol. If we consider the target, and that's not even the proper term, it's the off-tissue target, because it's the tissue targeting of statins to the liver, inhibiting HMG clear reductase in the liver. That is the therapeutic goal. That's right. That's actually all you're really trying to do. That's right. But we can't. We have to hit all of these peripheral tissues as well. Oh, that's right. So there's something called pharmacokinetic. So, if the last 16 or 17 years, I have been leading a program in studying statin pharmacogenetics, which is. I just want to explain this again, because I know you and I are sitting here in the discussion we understand this, but I want to make sure the list of understands the point you just made. It's so important. In an ideal world, a statin would be a dream drug if it only inhibited cholesterol synthesis, meaning HMG-CoA reductase activity in the liver, such that the liver would up-regulate, and you wouldn't impact peripheral tissue metabolism, cholesterol metabolism, for example, in the brain, in the muscles, et cetera. Unfortunately, that's not the case. So, I'll let you continue. So this has to do with me, with at least my exposure to this set of issues through the world of pharmacology. So I've been hanging out with pharmacologists for the last 15 years through this pharmacogenomics program. It's obvious, even without that experience, that factors that affect the disposition of statins, like any other drug, are important determinants of clinical outcomes. So the disposition, that term, refers to getting it to any of the tissues, but you want to get statins to the liver. For the most parts, statins are very efficiently removed by the liver. So fortunately, so that tends to offset some of the concerns that you have. However, there is variation in the genes, as well as other factors that affect a statin disposition. The nature of the statin itself, it's chemical composition. The presence or absence of certain genetic variants, when in particular, that's been well studied, that affects the amount of statin in the blood that permits it from getting the liver. Under those conditions, there is a greater likelihood that the statin will wind up somewhere else. And that can be muscle, which is the most common symptom, but it can be all of the other tissues. Part of my research experience right now is delving in to all of these other effects that go beyond the desired inhibition of HMU-chloriductase in the liver that are actually, quote, "ontarative effects." So I'm going to come back to the brain in a minute, because I've been extremely interested in the issues that you describe, and I'll come back to that. But there is a condition that's even more, I think, clearly connected to an unexpected effective statin, and that is its tendency to increase blood sugar and increase the risk of diabetes. That's been demonstrated now. What's the relative risk? It's about, if you talk to cardiologists, they'll say the relative risk is small because the benefit is much greater. Well, that risk is about 10% on average. We have published a paper over what period of time? Over duration of the clinical trial. Up to six or seven years. But we've published that risk can be a significantly higher in women than men. Perhaps this higher 30% or plus. And do we think that that effect is due to dysregulated glucose uptake in the muscle? There is evidence, and we're deeply involved with these studies, of direct pathologic effects on muscle energy metabolism. That's more closely connected with, obviously, with muscle symptoms than with diabetes. But insulin resistance is certainly another factor that could be involved, and the muscles could be involved. The liver could be involved. So that's one situation where there may be on-target effects, even in the liver that might contribute to this. We think it's probably not liver. We think there's probably effects either beta cells and but cells that produce insulin and/or the tissues that insulin acts on, such as the muscle being the most important. Right. So the reason I haven't been more specifically at this, we really don't know. There's a number of theories all of which sort of collectively could be true in different individuals, but the net effect is not trivial. Is it dose-dependent? Yes. Well, there are some evidence that a glycemic effect is those dependent. In fact, this was very limited information on this, actually, but there is some evidence that seem to be. So, for example, when you look at symbastatin, it seems to have a much higher incidence of myalgyz or CK elevation. When we look at the entire suite of statins, do we see some that seem higher risk for diabetes, some that seem lower risk? Yes. And again, this is sort of a collection of observations from various sources. One of the statins that's most recently been introduced is called pitavistatin. Levelo. Yeah, levelo. That group in France has shown pretty convincingly recently that this is not associated with diabetes risk. This is kind of my go-to statin before I move to a PCSK9. This is my last line statin. Yeah. It's not that potent, as you know. That's the problem. You sort of, you know, but once in a while you'll save someone. You'll get a guy who can't tolerate anything, but he tolerates this and you're off to the races. Same here. Exactly. So, it's probably the lower potency, and it's probably its chemical characteristics. Again, what I'm saying right now is still not established in a conclusive way, but it does suggest that there is differences in the statins. And that being one that has less association with risk. And the one that's probably most commonly associated with risk. And we've seen this in studies that we've not yet even published all of them as a torment statin. It appears to be a higher risk. So, there's interesting. And we don't think that that's just due to the fact that it's so ubiquitous. No. So, would that be a reason because I got to tell you, I think when I'm confronting a patient for the first time with a statin, I am generally almost tossing a coin between Crestor and Lipitor as a first line agent. Very quick to flip between them if I see any CK bumper, LFT bump. But what you're saying would almost suggest that if it's a person who's not incredibly insulin sensitive, where none of this probably matters, someone who's borderline, you'd lean towards Crestor over Lipitor. Yeah, this is sort of putting on my clinical judgment hat rather than my scientists hat. No, no, but that's unfortunately, like for many of us, we still look, we have to make decisions. You like to use evidence-based criteria? Well, this is actually one of the things that I struggle with the evidence-based criteria. We don't have the evidence that allows me to give an answer to that other than saying, yes, I agree that that's what I would do. And I'm also going to back up a little bit and make sure that I have not conveyed the impression that a turbostatin is a diabetogenic drug. It's still a minority of the population and we think through genetic factors that contribute to that we try and we can measure it. I mean, that's sort of the other thing that I sort of sell patients is that this isn't going to sneak up on a one day we wake up with diabetes. I use plenty of a turbostatin, and I have at least been concerned about it in the patient whose risk merits statin treatment. And because as the cardiologists are quick to point out, the benefits of statin treatment with any of statins, cardiovascular risk and patients with diabetes far outweighs the risk of actually developing diabetes. And there's even some evidence that the microvascular complications might be improved. So you can argue that statins are not causing a damaging effect through this mechanism, but it does raise just a little bit of a caution. In fact, it's a caution. I think it should lead to more widespread monitoring of glucose on stands just so that when it can detect those individuals who may have an adverse effect, but it's still a minority of the population and it's not something that should be considered a hazard of diabetes far from it. Yeah, I think for me, I am, I mean, I sort of, you know, talked to patients and I say, look, I think there are short-term things that we're generally going to figure out in three months, which is my algeost plus or minus a CK elevation. So either your muscles are going to get sore with or without an elevation in CK, which is a way that we can measure the breakdown of muscle, and changes in your liver function test. We look for those elevations. I don't know about you, but I see a lot more LFT bumps when combined with Zedia than just statin alone. I find a lot of patients I have that tolerate any dose of a statin and then you add a Zedia, it seems to me like 20% of people just immediately have an LFT bump. I haven't seen it that often, but I have seen it, yes. And then I talk about the long-term stuff, which is actually, I think in many ways, what we should be more concerned with, because the short-term stuff, like you figure that out in 10 seconds, right? But it's the, and the diabetes doesn't worry me as much for all the reasons you've said, which is it doesn't sneak up on you and you can measure the progress. But for maybe I'm being overly cautious and I've had many an argument with many a cardiologist that I share patients with who, you know, will have a patient on a maximum dose of a statin. I'll give you one example. I've got a patient who came to me on 80 milligrams of lipitor. Still wasn't quite at goal. We added the 10 of Zedia, so then he was at goal. And given his burden of disease, goal for this guy is about 700 an animal per liter of LDLP. But, you know, he had no cholesterol synthesis that we could speak of. So put him on a PCS K9 inhibitor. That took his LDL down to like 200 animal per liter. So I said, great, let's back off the lipitor. And his cardiologist just thought, like, this was malpractice. And, you know, it took many a discussion to just even get that back to 40. And my goal is to hopefully get him down to maybe 20 of lipitor so that I can actually see some cholesterol synthesis come back. But again, now we're also a little outside of evidence based medicine, and this is more the art than the science. That's right. And it's a fascinating issue to deal with because we are conducting an experiment in the global populations, certainly in the US, that has never been done before. And that is prescribing statins to millions of people as a lifelong treatment without knowing what the downstream effects are beyond the clinical trial data that we have, which is limited. And we can, you know, call in genetics, but it doesn't necessarily mimic the effects of using a statin drug for 40 years. And so I'm just going to say very briefly that I don't want to open the lid on the discussion that many of the naysayers have used to say that statins should be avoided because they can have long-term effects. But I will say-- That's like saying driving should be avoided because driving has negative effects. But there are things that we don't know that certainly I would like to learn and hopefully our own research project will contribute to this, as to what may be affecting certain subsets of the population with prolonged use by understanding the mechanisms that might be operating in tissues like the muscle, pancreas, and the brain. And so that by understanding those mechanisms and perhaps developing markers for people that may have increased likelihood of these undesirable effects that we may be able to guide our treatment more effectively. That's the way the goal of this pharmacogenetics. Do we understand the mechanism of the myologists? I tend to give patients, you bet, when all. But honestly, the trials are, and I explained to them, I said, look, I use it as a practice, but I can't point to amazing data. What do we think is going on there? We just talked earlier about the European consensus group that I was on, whether it was the second one that I was on, and it was-- Stat and side effects. Stat and side effects. And so the first paper, and that series came out with a year or so ago, and that was on myopathy. The second paper is I think just out, and it describes the data as the related diabetes, cognitive function, etc. The first paper attempted to address the question you asked among other things, and that is what's going on here. And all we have is a diagram that has many points of attack, where one of the things that we're actually working on, one of my colleagues in my research program, is mitochondrial targeting of statins. There may be on-target effects. That is a normal response to statins in some people, or maybe in a significant percentage of population, may affect mitochondrial function in ways that generally are not clinically important, but which in some people could be magnified and lead to changes in muscle function and muscle number, muscle cell number. That's a hypothesis, but what I'm speaking to now is the lack of a clear single mechanism that we can point to. That's just one of several possibilities. The effects on a coenzyme cube, you can know what you mentioned, and it's certainly been out there, but as you say, very high placebo. I'm trying to reverse that, that's right, has not been that successful. One of my patients, I said, "Dr, actually, I'll say this for whatever it's worth. This is one of the clinical pros." I have a doctor who was really a very good observer who wound up getting a liquid form of coenzyme cube as opposed to a capsule. A capsule didn't work. His muscle symptoms dramatically disappeared or improved for the liquid form. So, maybe there's issues of absorption. Who knows? Well, I do think there is, actually. We've just empirically used a wheat test co-Q10 levels in the blood. I've noticed, for what it's worth, that virtually every version doesn't show up. The only one I have found, just to be clear, I don't get paid by this company at all, but there's a brand made by Jero, which I think is probably the best supplement maker I've seen. We've had some other stuff tested, but Jero's ubiquinol is so readily absorbed, because the clinical trials call for 600 milligrams. I don't think I have a patient on more than 400. In fact, most people at 200 milligrams of the Jero variant reach systemic levels that are above our on-statant target. Again, does that mean anything? I actually have no clue, but for what it's worth, I've noticed that on most other versions and variants of ubiquinol, we just do not measure it in the blood. There you go. Yeah. I certainly don't have that experience. It's very interesting to learn. But again, how does that work? How that's working? The other thing I've just mentioned along those lines, and again, it deals with diving deeper into the biology of the system. There's about 20 intermediates on the way to ubiquinol. It's just as complicated a pathway as cholesterol synthesis. We don't know whether there may be other targets in that pathway. It just happens to be the end result. There's lots to learn about how statins impact biology in ways that could affect health. It's in part because we have such a large population who is doing this experiment, basically. It's also because of the centrality of mechanisms that statins affect. It's not just cholesterol, it's precursors of Jero variant hormones that are in this pathway. It's these other pathways that can affect intermediates, like ubiquinol and other pharma seals. There's lots of other downstream products that are affected by statins that may have biological effects that tell us something about what the drug is doing in a physiological way, but may also have pathologic consequences in some people. What do you make of the evidence for and against the case that, and this is not a common argument, but it is one that shows up enough, which is, okay, statins do reduce events, but it's not by lowering LDL. That's an unintended consequence or an intended consequence that is truture and unrelated, but the benefits of statins actually come from the endothelial health and/or inflammatory reduction. This is another deep topic, which is obviously clinically important to people understand what it is they're treating and why. It gets back to a couple of issues. One is the causality of LDL, which we discussed a while ago. LDL is causal. That's established beyond doubt. The benefits of drug induced LDL lowering, let's say statins, have to be considered as operating in part through that mechanism. Otherwise, let's at least can see that in part. Otherwise, you're just ignoring reality. That's number one. Number two is, is it the most important factor? Is it the only factor? The answer is, it's certainly not the only factor. There's no doubt in my mind anyway. I'm not sure how much of this is opinion versus evidence, but well, there's only anti-inflammatory effects. There's a lot of work that a friend Paul Ricker has been involved with to help establish Paul Ricker's at NIH. He's in Brigham. Early on, establishing the importance of sea reactive protein as a marker for inflammatory risk, not just to part disease, but. And we should detour on that topic, because it's so important, right? There was a recent trial that looked at low dose of methotrexate, which isn't it? No, it was an I/O. It was an interluctin one. Well, it weren't there, too. There was the I/O one. The methotrexate isn't out yet. Oh, okay. Maybe I'm just. It's the other one. Okay. The other one's out. Yeah. It used an interluctin one or six. It was always one or six, yeah, yeah, yeah, yeah. One. And so that was a very interesting trial. That was a trial. Yeah, that was okay. That's right. So that was a trial that said, "Look, we can make no change to the lipo protein. We reduce inflammation in a subset of patients. These patients had to have an elevated sea reactive protein if I recall, and you reduced events." Yeah. And we may see the same thing with this methotrexate study, and I think that speaks to. We're not. Yeah. Either way, it's an important finding. Exactly. So, you know, the reason I ask the question among others is. Can you be at the statins, right? Yeah. Okay. Because then you can say, "Well, what does statins do to this pathway?" Well, they do lower inflammatory signaling down this same pathway. And again, risker was a pioneer in studies such as the Jupiter trial and earlier ones as well that were he analyzed the predicted benefit or the associated benefit of LDL lowering against CRP lowering. It's a marker for inflammation. So this goes back to using CRP as a marker for inflammation. And achieving a lower level of CRP at a higher level of LDL was associated with benefit, achieving a lower level of LDL with a higher CRP with benefits. So they both contributed to risk. And so targeting both LDL to less than 70, I think it was in CRP less than I think two milligrams or less later, I think. But targeting those two risk markers together gave the greatest benefit to each contributed. And I think that model stands up pretty well, that it is a double whammy. And one of the reasons statins are so effective is probably because of their unique ability to hit inflammation as well as alcohol metabolism and gets back to PCSK. Right. Doesn't quite have that. That's an intro. That's exactly where I was going to go. Which is, I've got a number of patients that are coming to me saying, look, Peter, I don't care about the cost of the PCSK9 inhibitor. Get me off this statin. I just want to be on a PCSK9 inhibitor to which I say the only issue I take with that is, and I don't have a problem doing it in the patient who is completely statin intolerant. I have a couple of these patients where they absolutely need to be on lipid lowering therapy. And they absolutely can't even tolerate, you know, live alone. So there we just do what we have to do. But the trials don't actually tell us how well PCSK9 inhibitors work in isolation, relative to non-treatment. So that's just sort of the evidence-based reason for, hey, it would be ideal if we could at least keep you on some modest amount of a statin. And then secondly, there's it's not clear the PCSK9 inhibitor attacks that other mechanism. Mechanistic aspect to this. And it's not just inflammation down the interleukin CRP pathway, it's also there's nitric oxide synthesis of nitric oxide being a basic dilator. So I think there is a good mechanistic case as well as the clinical evidence case for not abandoning statins in favor of PCSK9. Unless, of course, the patient's statin intolerant. Where do you think the effect? So one of the things I sort of tried to divide this is men, women, primary, secondary prevention, right? That's a nice two by two square. I don't think there's any, I mean, again, I'm not talking about the blogosphere or Twitter, but like if you actually look at evidence, is there any dispute in the efficacy of statins in secondary prevention for men or women? No. So no, there's no dispute. So we won't even need to talk about that. Let's talk about primary prevention. The variability in clinical trials when you look at primary prevention, especially in women, but I think for men to some extent as well. Both in the NNT, so that means the number needed to treat. So and, you know, the NNT, of course, being the reciprocal of the absolute risk reduction. So when NNT of 100 means you have a 1% risk reduction, you need to treat 100 people to prevent an event. You know, when you look at the summary data on this, it's amazing how all over the map it is. So how would you rate the strength of the evidence? Just a quick question, Ron. I'll just give you 30 seconds to answer this. The strength of the evidence in primary prevention for statins in either men or women. Okay. Well, let me start with women and let me also specify that you need to think about a cardiovascular events and then mortality from cardiovascular disease. Right. So we'll talk about major adverse cardiac events. So myocardial infarction stroke versus death. So the evidence, there is evidence, again, importantly for the Jupiter trial, which had a very large enrollment of women, but collectively in other trials as well, for the benefit of statins for high risk primary prevention in women. And the high risk caveat is really important here because it really speaks to this very fine gradation between high risk primary prevention and secondary prevention because if you're at a high enough risk and haven't had a heart attack, you may be five seconds away from the heart attack. So you may have had a silent MI that was managed. So that distinction could be a little bit fuzzy, but technically at least the evidence is there for primary prevention of cardiovascular events in women. It's not really there, at least to my reading. I may be wrong about this because I haven't gone back and double checked, but I haven't seen evidence for benefit on mortality for primary prevention in the women women. And in men, it's kind of weakish for mortality, but it's certainly present for events. Is it also possible that, you know, one of the things I try to explain to, if I'm giving a lecture or something to students, is you look at a paper and you see no statistical benefit. The first question you must ask yourself was, was this study powered adequately to detect a difference? And it's very often the case that there could have been an effect, but we didn't, you know, it was too small to see with the number of subjects. I feel like in some of the primary prevention trials, duration might be the bigger issue. It's, if you're only looking at seven years, which is probably the outer limits of where these trials look, it might simply be that when you're talking about a 1% absolute risk reduction over seven years, it's not really that interesting. Of course, a 1% risk reduction over seven years over 30 years is an enormous difference. Alan Snyderman is actually working on a paper now that looks at 30-year risk, because of course, all the risk calculators are based on 10-year risk, which I think has value, but also has great limitation. And I guess I think that's part of what I struggle with this clinically, which is, you know, we never want to expose a patient to something unnecessarily. And there's no substance you're going to put in your body, whether it's, you know, vitamin C versus a stat, and that comes with zero risk. So how do you weigh that benefit? Yeah. Well, you know, this really speaks to need for much better markers that could help us predict benefit versus adverse effects, so that we can identify not just the high risk candidate for statins based on conventional markers, but individuals in whom we have evidence for mechanisms that would be benefited by stat and treatment that would argue strongly for benefit. And on the other side, markers, ideally, that could assess risk for adverse effects, not just symptoms, but underlying pathology, for example. And again, without, because I want to come back briefly to your question about kind of defunction, because I sort of escaped talking about that, because I feel this is. Because you forgot, because you're cognitive function. No, it's an effect. But the opposite. I've put it in a part of my brain that has made me not forget that there can be effects that are long term that we simply can't assess easily. And so one of them could be cognitive function, but having said that there's no evidence in our consensus paper that just came out and sat in intolerance, no evidence really. Well, at the population level, I would say it's the opposite. At the population level, I think we see that the risk, if anything, goes down a little bit. Yeah. And there's a cardiovascular. That's exactly right. It's a vascular element that even contributes to classical Alzheimer's disease. But again, the data are really not compelling. They're not compelling. This is the challenge. This is personalized medicine. At the end, I don't care about the population. I care about the one person sitting in front of me at this moment when we have to make a decision. Exactly. Exactly. But what's intriguing and what's your question opened up and FB careful, because I don't want to go down the rabbit hole on this one, to the extent that statins influence mechanisms that interact with cholesterol transport in the brain and able protein E, which we mentioned is a variant that causes type three hyperbidemia, able protein E is a key protein that has a variant, another variant that increases the risk for Alzheimer's disease. But we're looking at ways that cholesterol metabolism intersects with that pathway. And inconceivably, that's just one example of a gene that could interact with statins. And if the statins are getting past the blood brain barrier, in some cases, an inflammation might be a factor that could predispose to that. You could start to have imagined effects that could go either way, but could perhaps potentiate this function. That's just a completely off -- No, no, look. I mean, that's exactly -- I mean, that's sort of the hand waving that I use, right? So when I have patients that have one or two copies of an APOE4 gene, I am that much more careful with them, with statin use, and until proven otherwise. Yeah, and we don't know, and we don't know. I mean, actually, there's a wonderful group of APOE4 carriers that has formed sort of a support very large that I've interacted with. They came to my lab. There's about 30 members of the groups that came, and we gave a talk about APOE protein and nutrition, actually. I had to sort of be careful, because these people were just anxious for advice. What do we do? We've got this APOE4 variant. What do I do with my diet? And we've done a lot of studies along these nights, but we don't know what the effect then disease and disease risk is. But there's one other cumulative effect that I'm going to mention without, again, turning the tables on the value of statins. And that is getting back to the muscle effect, because if there is an adverse effect on mitochondrial function, which we can show that, and others have shown that. And if there are individuals who, for one reason or another, are at risk for muscle wasting, it's called the sarcopenias, muscle wasting, conceivably that on target effective statins, the extent that is affecting muscle tissue, could over decades conceivably impact the rate at which this muscle wasting could occur. And so there may be a time, and this is just turning this out at the, probably near the end of this discussion, as a kind of, just a thought, is it may argue for after a certain age, not worrying so much about high-dose statin treatment, unless the patient is at really high risk, because one may be adding in elderly individuals and exposure. Yeah, you're creating a new risk in the presence of another risk reduction. Right, and it's the experiment that we probably are never going to be able to do. And so it just has to sort of be cognizant. I've had patients, and again, I actually take care of a number of physicians, actually, my clinical work, who asked me, you know, I've each stage of 75 or 80, and, you know, done well if, you know, had family history been to me find out. And it's a difficult question to answer, because we don't have the evidence base behind age 75. That was really where the cholesterol guidelines that came out a few years ago stop, because that's where the evidence stopped. Yeah. We do have benefit in older individuals who are at higher risk, but we don't know what the trade office in terms of adverse effects that people that don't really need to be taking it any longer. Now, you were involved in one of the ATP guidelines, correct? Yeah, well, I was on the ATP for, on the last panel that handed it off to the American Heart Association, American College of Cardiology. I was connected with it when it was part of the NIH. You took issue with something, didn't you? Well, there were some concerns that I and others had regarding the scope of the effort originally. And this is my own personal experience with it. When I was brought on, I was expecting, and we originally talked about having a wide range of topics to discuss, not just LDL lowering, but how we manage triglycerides, the role of HDL, emerging risk factors, alpular lay. We had probably 15 or 16 high priority questions, and I was intending to be involved heavily on the discussion of some of these other risk factors. I thought the LDL story was obviously important, and when I had to address, should we update the guidelines, that's what it was really designed to be. And to turn out in the end, that because of various changes in support of the whole program, the number of questions was reduced down to just three, and they all had to do with LDL lowering and the evidence for it. And it was very heavily dependent on trials that were available to provide evidence-based conclusions. So that means that the effort was really limited to a very strict interpretation of evidence-based guidelines. And that led to an abandoning of the LDL targeting that we had. The LDL levels that have been used to guide management of risk were abandoned because there was no study that actually addressed specifically that question. That is, does reaching a certain target reduce risk. And I personally got rather discouraged at the limitation that we were under. Eventually, it sort of got a little bit softened actually after I left the committee. I think there was a little bit more tolerance of a potential role, but basically by being that narrow, we not only lost a lot of important questions and lipid management that just weren't addressed, triglyceride, et cetera, et cetera. Metabolic syndrome wasn't really touched on at all. So it was disappointing to me, and I dealt with it. And so I thought my role on the LDL lowering side was sort of limited. I'd actually been involved with being consultant to companies that made LDL lowering drugs. So I had to actually excuse myself from even the decision process. So it was really at the point where I just wasn't able to contribute the way I thought I could. So I decided to step off. I could continue this discussion probably for six more hours, but there is one other thing I want to go back to that we did talk about. And I think it's the niacin question. No, I sure have not. So what does niacin do, right? So first of all, I don't think anybody actually really understands the mechanism by which niacin lowers APOB. I mean, is that generally? Yeah, that's right. I would say that's a fear of statement. But niacin is a drug that lowers LDL particle cholesterol. It also raises HDL cholesterol quite significantly. In fact, I've seen it raise HDL cholesterol more than I've seen anything in those CTEP inhibitors. So it seems like the dream drug. It's doing everything right. Now, it does also create some insulin resistance. And it seems to do that at a higher level than even statins do. But do you think that that's the explanation for why the hard outcome data aren't there and why niacin has fallen so far out of favor that, you know, I actually called in niacin for a patient about a year ago. It was we're kind of doing an experiment. He couldn't tolerate a stat and couldn't afford a PCSK9 inhibitor. You know, we were really reaching for straws. And we couldn't even get niacin for him. I mean, we literally couldn't even get his insurance company to pay for niacin. So it is persona non grata. Help me understand that. Okay. So my disclosure is I still use a lot of niacin. So why do I do that in the light of these trials? So let me just back up then and say that the trials, the high profile trials that led to the dismissal of niacin is a therapeutic option. One was, it came high and the other was it wasn't. It was. Yeah. Yeah. HBS2 both involved the following criterion. And that is niacin was tested as an HDL raising agent in the setting of LDL being at a low level as a result of intensive statin plus or minus sedia to bring LDL cholesterol levels to a low enough level that it would be considered a non factor. That is that the niacin effect due to LDL would be minimized. Whereas the HDL, it's how do we assess the level of niacin exclusively on its HDL raising properties because we've maximized LDL lower. That's right. So it would they were designed to test whether the HDL increase with niacin is beneficial. And the answer is from those trials, I'd say unequivocally know that is the HDL raising effect of niacin is not protective. That that's the conclusion to take away. That in my view was beating, maybe not a dead horse but a pretty sick one because I never really was totally convinced that that raising HDL itself would be beneficial. Even though I was part of the earliest study that showed that if you genetically treat mice with a gene that raises HDL, you can reduce the atherosclerosis. I mean, there is a protective effect. But I was of the opinion that the association of HDL cholesterol across the population with risk fell into the same category as the LDL, small LDL storing the triglycerides. So it's part of a interrelated metabolic syndrome. And I felt that the most important pathologic features of that syndrome were not low HDL, but the high levels of small LDL and triglycerides. And both of those components have been not just the LDL, but the triglyceride related risk have been pretty clearly shown to be causal. And the HDL was a marker for that. That was actually my guess just based on my behavior. And there could be another issue here, right? Which is to raise, I mean, there are known HDL like the proteemias where very high HDL is actually atherogenic because they're so dysfunctional, they can't actually delipidate. Exactly. So the simple-minded idea that raising HDL by any means would be beneficial, just like lowering LDL by any means would be beneficial, was disproven by those studies. Plus all of the CTEP inhibitors. That's right. None of the CTEP inhibitors. So there's something fundamentally pathologic about that effect on HDL that overrides any potential benefit that may be due to other factors. And in the case of the two major niacin trials, there was some lowering of LDL, but as you point out, the HDL increase was fairly substantial. And those particles are basically hung up in plasma. It gets back a little bit to this resonance time issue that I was talking about regarding LDL. Well, here's the situation for HDL. But these particles are just sort of like the toilet is plugged. Yeah. You prevent them from doing their job. Right. So you're not delivering cholesterol efficiently back to the liver for excretion. And those particles are hanging around long enough that who knows what properties they may be acquiring that might possibly override some of the benefits of the LDL lowering effect. So does that mean that niacin has no benefit? Well, there was a study that preceded those two studies that was carried out by Greg Brown actually was one that led to the A&Pi study being funded by the NIH. And that was called HATS, HDO, HATS, HATS, HATS, HATS. And that was almost as good as Mr. Fitt, which I realized now is the one I was forgetting for the LRC. That was a multifactor research. Going back to HATS. So HATS was a statin plus niacin and there was other combination of approach, which included niacin. And that study showed benefit two levels. One was the intended endpoint was quantitative angiographic progression measuring the narrowing of the coordinate vessels, which is now not used. We now realize that's not particularly helpful. It happened to be correlated with that endpoint. And in fact, in that study, even though it was initially underpowered to detect the benefit on endpoints, it did that intervention did reduce risk of events. It was a successful trial. We analyzed data from that study using four different methods to look at live reporting particles. So part of this was to see whether we could learn something more than was in the standard lipid measurements would tell us. And what it did tell us is that the small and very small LDL lowering chief by niacin, which it does do was associated with vascular benefit in that study. Whereas the HDO, to the extent of nothing else was explanatory. And that was independent of all the standard lipids. So we have this in the literature from just one study. And I wish we would have access to other types of data that could support this. But it spoke to a therapeutic effective niacin that would be lost in these larger trials because the statin hammer lowered the LDL low enough so that additional benefit is probably just lost. It's too small. It's underpowered. It's lost in the noise. So the failure of those trials speaks to the success of statins and the failure of HDL raising. Those are those are the two things that take away. But niacin, I think in the patients who have small LDL particles, I still use it. And I like to see. Well, that's what I want to ask you. Let's talk me through the perfect niacin patient. Well, the perfect patient with niacin is actually twofold. And we weren't going to talk about LPA, but you did bring it up earlier and I'll miss it. And so it's a it's this genetic factor that is sort of the wild card in atherosclerosis. It's certainly damaging. And we'd like to lower it. So niacin can lower LPA the lay by up to 25% or so. And there is not conclusive, but to me, clinically impressive evidence that if you have a combination of high LPA and small LDL, you're just a time bomb from atherosclerosis. So if you have high levels, you know, high particle number of the small LDL type plus LPA the lay elevations. And there's always always a strong family history of heart disease. And the patients are going to be at high risk at a young age because niacin lowers LPA and because niacin lowers the small LDL particles. So niacin, you think specifically targets smaller particles over larger particles? Yeah, preferentially. Sorry. Yeah. The lower is the lower is that pathway. It's not clear whether just that's the VLDL pathway or not. Honestly, we don't know it gets back to your earlier statement that we don't know the mechanism. Yeah. Really as well. We just don't know the mechanism. But in that combination, that really is the patient that I've got patients like that who have. And you'd put that patient on that over a PCS canine inhibitor if they could afford it? Well, there's another because you're going to get a 30% reduction on LPA like the PCS canine. That's right. That's right. There's another, that's right. That's another angle. This PCS canine has a similar need of LPA lowering effect plus it has a gangbusters bigger effect than an LDL particle LDL levels. So no, I wouldn't use it over PCS canine. The argument there is largely financial. Yes, and what insurance will cover, you can buy NIS in that the local shop off the shelf, you know, longer acting NIS in a safe, both in the safe form, for pennies. You're going to pay an air-nighter, $14,000 for a PCS canine. I've had patients like you who have been willing to do that, who have been willing to sort of. Just pay out a pocket. That's right. And that is the same category of patient and I probably would consider that even more effective. Although, one other thing, a little tweak here, and that is that both statins and PCS canine inhibitors, because they work, as you said, by upregulating LDL receptors as the case of PCS canine, that's the mechanism. Exclusively, yeah. For instance, it's the part of the mechanism. That effect, primarily lowers medium and larger size LDL particles and has a less therapeutic effect than smaller particles, and none on the very small LDL. So there's a gradation of effect, which relates to the structure of the LDL being more or less capable of interacting with LDL receptors, and the larger particles interact well, and so upregulating LDL results. And this explains why we sometimes see a widening of the discordance in the statinized patient, because they're lowering LDL, see more than LDL P, because you're selecting out the larger more cholesterol density. That's right. And so that applies to any mechanism that operates to LDL receptors, which is what most of the drugs do, even as that of my. So what does that mean? For nice. Well, nice and lowers the small and very small LDL, very nicely. So there's a complementarity there to statins. And I think that's part of what attracts me to using it. Again, I don't use nowadays, because of potency of the statins, the ability to get LDL down to target, and such high proportion of patients, the availability of PCSK9. I'd have to say, there's fewer patients that I'm starting on, nice, but there's still candidates out there that I think would benefit from hitting small LDL, hitting LDL in ways that complement the benefits of statins. You know, the only patient I've put on nice in the last four years is a really interesting case. He's a guy with. He doesn't have FH, but he's clearly got some snips of FH, because his. His LDL is incredibly high, but normal synthesis, normal triglycerides, and normal absorption markers. So, you know, his steriles are normal. This is a clearance problem. Unable to tolerate a single statin, including one milligram of live-alow. So we went to Repatha, and there is no effect. And we switched to Pralulent, no effect. That's really interesting. So he's missing. There's an epitope that's just. I would like the DNA from that patient, because I would be happy to introduce you to a. I have a candidate genetic variant that might explain that, actually. Okay. So you use NIS and that patient. Yeah. I mean, it's like basically going to be what? NIS and Aferesis. I mean, this is a really tough case. Yeah. Well, again, I mean, you know, I think it's legitimate to say that there's probably less. If you were a candidate from NIS and with the availability of this potential for using PCS-K9, and certainly in commission with STANs, but I would say the patients with moderately elevated triglycerides and the 150 to. Yeah, yeah, you get a little fennified, right? Yes, I do, actually, despite. That's another subset question. That is a subset of patients who may benefit based on subset analysis, subgroup analysis of the clinical trials. But unfortunately, it's just not a very potent patient. But NIS and I will use as an alternative approach to lowering the triglycerides. And lowering the small LDL. That's elegant. That's something. I mean, if just on a personal level, that's certainly an amazing and insightful pearl that I've gathered from our discussion today. I appreciate you seeing that. Well, and with that, Ron, I want to say, you know, first of all, just I consider you a great friend and an unbelievable mentor. I feel so fortunate to have benefited from your knowledge and peers of yours over the last decade. And your generosity is unparalleled in terms of any time I can pick up the phone and call you and run a tough case by you. You're always there to do so. So I greatly appreciate that. I also think we need to do this again sometime because I literally have twice as many questions as we've got to. I wanted to get into saturated fat, fructose, apoe. There's all these other things that I know you are just an expert on that I know people are going to want to hear about. So I'm going to have to come back to San Francisco and we'll have to continue this discussion hopefully during the Warriors' off season. I have to do that, Peter. And thank you for your kind words. And it's been a pleasure talking with you. I think the opportunity to help people understand some of these complex issues is something you've been very good at and I'd be able to compete with that. Thank you so much, Rob. Okay. 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