#03 - Ron Krauss, M.D.: a deep dive into heart disease

Hey everyone, welcome to the Pia Tia 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 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 with a higher quality, more fulfilling life.

If you enjoyed this podcast, you can find more information on today's episode and other topics at piamd.com. In this podcast, I'm speaking with Dr. Ron Krauss. 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. 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 and lipidology. He wears a ton of hats.

He's a clinician. Obviously, lipidologist. His interest in nutrition, genetics, drug research is quite profound. I believe both his college degrees and medical degrees from Harvard.

He's board certified in internal medicine and technology and metabolism. Currently, he's a senior scientist and the director of atherosclerosis research at the Children's Hospital in Oakland. In this episode, we talk 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 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 Obviously, some of that's a little bit outdated. 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. I think I'm going to run 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 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 Mignon Journal of Medicine that largely shaped his career. This is the stuff we talk about with Friedrich and 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 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. So 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. So 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. And 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 and 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. And finally we end with a discussion of PCSK9 inhibitors which I suspect will have a completely dedicated podcast at this topic at some point and 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. Okay so 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 Peter at tiamd.com forward slash podcast so without further ado here's my conversation with Dr. Ron Krauss.

Well I'm here with Dr. Ron Krauss today and this is a really exciting topic for me and 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 LAD calcifications that's the artery in the left side of the heart but he was very hesitant to do any treatment and he wanted a second opinion so I thought we should involve Ron and Ron I remember I was sitting in my kitchen we spoke for probably half an hour and 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?

First of all thank you Peter for asking me to talk to you today and address this topic which is you know I have a deep and long standing interest in hopefully I can address the issues that you're also interested in and will have a good conversation. What atherosclerosis of course is the underlying process that leads ultimately to vascular disease particularly clinically advanced heart attack and stroke. It starts in childhood is 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 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 cells in the artery wall that deliver various inflammatory molecules things 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 relevant 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 atherogenic 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 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. 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 other hands and says chest pain left shoulder pain shortness of breath and he said no no no no it's sudden death that was a little over 20 years ago is that still true today? As I've heard and I think this is arguable because these are really rough rule of thumb calculations somewhere in the range of 30 percent passing past the opposite 30 percent 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 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 permanitori symptoms sometimes in retrospect they are there and 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 percent. Right upon further querying there was some exercise in tolerance. You recognize it yeah and three hearts 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 a hundred percent certainty use any kind of risk predictor to know if somebody's destined to have heart attack with certainty.

One thing at the outset which is this is a disease that begins in infancy and I have very few textbooks and or papers that are 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 hold 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 Dase bring a great mentor Alan Snyder and a great mentor and Alan gave me this textbook of pathology I think a little bit starry is the author and while I believe the data represented or somewhat dated because it was largely based on the Vietnam cohort and in Korea yes where obviously smoking would have been a higher prevalence than today. The fact remains that when you look at autopsies of young people who died of unrelated reasons homicides accidents etc 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 have been done. I have linked all of the usual risk factors smoking semi diabetes hypertension and disability me all of them in a lipid disorder all of those have been associated with the more advanced lesions in those individuals so even even even the 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 compound nature of the disease. 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. Is it smoking? Nope.

Is it high blood pressure? Nope. It's age. It's age.

Why is it age because it's exposure? It's in time it's area under the curve. Age, regardless of age is a risk factor that cuts across many of the diseases, chronic diseases that we have to deal with cancer, for example. That's right.

It's a cumulative process that can progress at various rates depending on the conditions. So people as you know, we talk about genetically elevated, severely elevated, cost or levels will have that process accelerate and have the disease sort of clinically early on. Sometimes these syvigeneic 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, 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 normalized for a few things, the only disease that increased monotonically by decade in risk of atherosclerosis.

From childhood? Yeah. Even cancer actually, I think by the ninth decade it started to come down. Yeah.

Yeah. Yeah. Yeah. No, it's definitely the latency period for cancer also is a factor there as well.

So there's a sort of latency period where nothing happens and then all of a sudden the older age pops up. I'm sure a lot of people listening to this are going to say, okay, well, 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 a protein. We throw those terms around interchangeably but I think it's probably important to give the average person a sense of understanding.

So what is LDL C versus LDL P versus APO B 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 clacks.

So cholesterol is indeed an important component of the plaque and it gets into the plaque by uptake of cholesterol from lipoprotein particles. 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 a capsule around the lipid. And so let me interrupt you for one second.

Is it just a point of clarification? The reason we even need these lipoproteins is the cholesterol is hydrophilic, a perniphytic 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. Right, right, right, right, and for the techno files here, it's the cholesterol ester.

So there's a 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 lipoprotein, not just cholesterol, of course, but triglycerides as I mentioned, even perhaps more importantly for many functions, energy, metabolism and other compounds such as phospholips. It's 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, that's sort of 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 lipoprotein. 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 a lot of fat in anything that causes the thing to float and that's very degrees, defines different classes of lipoprotein. Since 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 causes the plaque to develop and it brings the cholesterol with it.

So the LDL particle, the low density lipoprotein itself is spherical molecule or macromolecule, which carries around cholesterol, astrol, esterol, lipid, triglyceride. It has a signature on it, doesn't it? It's 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 Apoprotein 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 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 deciliter, 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. In frequent cholesterol, 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, I was interested in diet effects and drug effects and heart disease. 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 the LDL particle. But there's only one APO-B per LDL. So APO-B represents a pretty good signature for an LDL particle. This found on some other particles, but it's primarily on LDL.

But the amount of cholesterol attached to that APO-B as part of this particle can vary, as can other lipoproteins. 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 APO-B protein B. So there can be an important clinical consequence of focusing on LDL cholesterol to the exclusion of APO-B 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 APO-B or APO-B, which is a much better measure of the number of particles. And individuals have smaller particles because of this variation in lipid content. They are actually 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 measurements of LDL cholesterol may under-represent the number of particles, and furthermore, those particles themselves are considered by many, so there's still not total consensus on this point, but 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, I measured directly, not even calculated, and the LDL cholesterol is 100 milligrams per deciliter. 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 1400 or 1300 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 multiethnic 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 have particles somewhere in the middle of the LDL size intensity 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 APOB will tend to have disproportionately less heart disease risk 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, the particles associated with the discordance at the local cholesterol, the APOB 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's some pretty, I think pretty widely accepted data now, I think 10 years ago, this was a little more obscure. 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 on my blog that talks about how, based on anywhere from zero to five of the characteristics that an individual has in 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 hyperinsulinemia, which itself may contribute to optimal damage, inflammation, and other things.

It's absolutely possible and likely to be true. So this brings up a pattern, a lipoprotein pattern that I will take some credit for having to find in my own way about 25 years ago, 27 years ago now, called the atherogenic, dyslipidemia, atherogenic lipoprotein 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 lipoproteins 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 criteria for metabolic syndrome, which is for the listener would be low HDL cholesterol, high triglyceride, high fasting, glucose, high blood pressure, and girth, basically it'll be a tricolobese.

Yeah, so I remember being part of the discussion is where that metabolic syndrome was defined. Cinex. It's very interesting. Yeah, well, that started with insulin resistance, the centerpiece.

You can put various molecules in various processes through the center. They all contribute and see point out in hyperinsulinemia, 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 written by increased growth.

I mean, it's 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 cholesterol fat. This is all fat around the internal organs. And you can have metabolic syndrome without that, but the vast majority of people that...

Certainly Caucasians. Yeah, and non-caucasians, populations such as the Citi Stations who don't have increased weight 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 the dyslipidemia is probably both clinically and pathologically, the one that I think has the most substance in terms of a direct colosseal connection to cardiovascular disease. Yeah. And I'll tell you, it's a very interesting historical footnote, Gary Tobs, a mutual friend of ours. 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 Framingham study, which I'm talking about the very, very first Framingham 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-part area, metabolic syndrome was high LDLC. It's low HDLC 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, that I'm blank on the name of the trial, the first trial, there was the LRCCP, but then there was the one before it had a funny name, like, improve it or something. It wasn't, it was like, yeah. It was a trial of, the five-bray trial was LRCCP. No, that was close to everything.

Oh, okay. I think you're thinking of the LRC. Yeah. That's where I got my training in the LRCP.

Before I came out to Berkeley, actually, that's where I got my first dose. And that study was going on at that time, and there was a lot of nail biting. Well, 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 Niacin, 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 the table, I'll be happy to pick it up when you're ready.

I'm ready to mention that. I cannot wait. We're definitely going to do that. 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. And what was the conclusion of that paper?

Or more of the point consensus statement? It was more than just a paper. It was really a four to four. So this paper assembled a multiple lines of evidence addressing the question, does 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 that 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.

That was my understanding that led to the coming together to counteract that perception that lowering LDL was not beneficial. But 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 LDL cholesterol is a myth. Like heart disease has nothing to do with this.

And the problem is, and it's a common 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. And speaking to causality, and the second one was relating all of this information to the role of LDL in the pathophysiology of atherosclerosis.

And that paper is the work in progress, but it could be those two papers assemble just about all the evidence, one needs to support the use of LDL cholesterol. And when will that second paper be on? I can't tell you don't even know if we thought. We don't even know if we thought.

Well, we'll certainly link to the first one in the show notes because that was published in early 2008. Yeah, we expected the 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 in certain populations with certain approaches, 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 brain misleading, because it's not the fact is that LDL is causal, but there are other circumstances that modify that causality, 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 get benefited. And we know there's heterogeneity in the clinical response when one looks at cardiovascular protection with LDL lowering treatments. So I have to absolutely extend the simple notion of LDL causality to saying that one has to look very carefully at the arguments against LDL causality because they latch on to pieces of information that I really mislead you. Just because lowering LDL cholesterol is not always beneficial, it 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 just 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, the temporal sequence, the specificity, consistency, coherence, and then the relative risk reduction or risk reduction with 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 PCSK9 mutations, both hypo function or gain a function loss of function PCSK9, 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've been in the field for decades, started with being impressed with the role of genetic elevations of LDL.

Very, very strongly. I would put that probably right at the top. And you talked about this condition, familiar hypercholesterolemia, when there's two doses of an abnormal gene, the LDL levels in skyrocket. I referred to that a little while ago as the condition that can be too 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 extensively, which I think, by the way, was quite a good exercise for both of us who did it and people hopefully will read it. What you have to do is look at an eight-year-old child with cholesterol levels that are eight or nine times normal, who's a candidate for liver and heart transplant, and that's it. That's causal.

But the genetic support is beyond that. Right. Now, in those cases, the genetic defect is one of the LDL receptors. So closing the loop on how this works, the body makes cholesterol.

So every cell in the body makes cholesterol, then cholesterol gets recirculated, ends up mostly back in the liver. It gets secreted. Some of it in bio gets reabsorbed, and this process continues. But it's 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. So it 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 the 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, delivered 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 onto able B. It's able B that is the key that binds to the lock that snaps up the LDL in the liver and he grades it and then he greets it into the biome. And that's the way we just spoke, one of the ways we just spoke of cholesterol.

There are other mechanisms involving HDL. 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. I'm just going to connect that concept to something you brought up earlier. And that is the duration of exposure to, in this case, high levels of LDL.

We talked about it as a function of age, the longer the, the longer the years of exposure. But there's also a dynamic aspect to LDL metabolism that we just touched on. That is particles are produced actually precurs of LDL, which are called VL, which is carried mostly, right? And able protein V as well.

Those particles are being actively secreted. They interact with peripheral tissues and receptors and other transporters that handle various lipids in various ways and liping enzymes. There's a lot of processing that goes on. And then what's left comes back to the liver throughout the other 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's less time for the arteries to be exposed to any other pathological 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, the 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 VLDL particle? So very low density, like protein, 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 text. Well, directionally though. So for particularly for larger VLDL, the triglyceride, the half-life is half an hour an hour, two hours, it's pretty rapid because that particle is rapidly subject to enzymatic digestion.

Well, let me just jump to the LDL. So the LDL that are formed from those precursors, you know, more like 12 to 24 hours or longer. So it turns out that smaller particles have a longer rest of its time because they are less avidly removed by LDL receptors. So there's a range of circulation times for LDL in some cases, days actually.

And then ideal are somewhere in the middle. The intermediate density of lipoproteins are ideal. That's 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. And so 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 and they can be subject to various pathologic effects involving oxidation in the position of partial digestion products of various lipids that cause them to be more toxic.

And those particles can be damaging even with a shorter residence time because there's so toxic. So that gets into what I was referring to earlier as somebody greater complexity of beyond thinking just about LDL cholesterol, thinking about LDL particles, thinking about the types of LDL particles in terms of pathophysiology, and then also thinking about the role of these remnant lipoproteins. They all participate in this potential risk. And 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.

And this VLDL, cholesterol VLDL remnant problem is one that is unfortunately very often missed even by relatively astute clinicians. You know, your textbook case is these type 3s, these hypertroglyceridomias who have normal lipob, normal LDL-C, you think they're relatively low risk, you sort of miss the fact that their VLDL cholesterol is 75 milligrams per deciliter. And they have these just devastating atherosclerotic plaques. And that was, again, one of my learning experiences when I was at the NIH, at a time, working with Dr.

Sredex and the Levy, when the various... Just for the listener, it's important for them, I think, to understand the luminaries that you just described. Right? Sredex and Levy and Lee's, I mean, let's put these guys in context, right?

This is... 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-part goals. 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 prints 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, Fredericks and Levy and Lee's, that completely transformed me. It was epiphany because those five articles describe lipid disorders in terms of genetic, genetic types, different like a protein profiles that had different metabolic effects, different consequences, and were influenced differently by various diets.

I thought this was absolutely the most important lead I could imagine. I made up my business when it came to deciding what I was going to do after my medical training is to come back into an animation work with those guys. I was fortunate enough to be able to do that. It was really in the era where what was called the Fredericks and Typing System identified these various forms.

The one you just refer to is genetic forms of lipids that you don't often always consider. It was called Type 3, and that was characterized by abnormalities in receptor-mediated clearance of these remnant particles through a mutation in April protein E or variant of April protein. That also was fascinating. I happen to be in California when the April E's were discovered.

I sort of feel like one of these characters that just shows up at the appropriate time. It was called the Orange Rich Bepdried, and there's the history. We wrote a review actually of the early history of Lipoprotein D. Search, which I would commend to the 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 after that paper was published. I got an email from Joe Goldstein who was the other one. Oh, yeah, another one.

I got an icon in the field that said everybody that goes into the lipid research should be this paper. It's not a book. I don't make any money off of it. We're going to make sure that the people who want to get smarter.

Anyway, paying back to these remnants, I think for particle, the remnants are probably the most pathological as well because of this rampant atherosclerosis when there's elevation of remnants. Unfortunately, this condition of Type 3 is fairly rare. It's like 1 in 10,000. But it does illustrate the biology.

I've seen several. You've seen several. What I was trying to say, actually initially, I was trying to say, when I was at NIH training, I said, all these things. You collected them.

Yeah, we had patients who had the Type 3. We had Type 1, which was a serious elevation of triglyceride. Type 2 was from the hypercholesterinium. It goes on and on.

Yes, and it's really striking. I call my students. I've lectured around this too. I've shown the pictures of what are called xanthomas, which are the deposits of cholesterol and lipids and tissues.

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. These are just very striking illustrations of the whole genetics. It gets back to your earlier question about causality.

There's so many situations where genetics helps in establishing causality. This certainly is one of them. After that, you asked me, one, two, and three. You asked me, how many of you might talk to me about that?

Before we leave FH, I think the other nice thing about the PCSK9 mutation, FH is only showing you the change in one direction. With PCSK9, you see both directions. I believe the hyperfunctioning were the first people identified, correct? These people had an enzyme PCSK9.

They had hyperfunction, therefore, this enzyme, one of its roles is to degrade the LDL receptor. They had fewer LDL receptors. They had more LDL. They looked a lot like FH patients, correct?

Yeah. I just began for the technical word we said on the phone. It's actually not an enzyme. It behaves like an enzyme, but it actually drives LDL receptors into the garbage disposal machinery in the cell called lysosomes.

It causes the LDL receptors to be broken down, but it's the same end result as you get less LDL receptors higher LDL cholesterol. Then the mutations in the other direction are the ones that led to the development of PCSK9. The loss of function antibodies to PCSK9 mimic the loss of function mutations, which is lower LDL. That's one of my—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 04 or 06, but I remember this well, which was the discovery of those families with the hypofunctioning PCSK9. These people walked around with an LDL cholesterol between 10 and 20 milligrams per decil, 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.

One of those patients classically, I think a physical therapist or somebody that was reactive had an LDL of the teens, which is one sixth normal and is doing fine. 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 are healthy. We have very little evidence to the contrary. Do you want to say anything about the Mendelian randomization?

I think it's not the most intuitive concept of people, but it is actually a very powerful concept. Right. The principle of Mendelian randomization, first of all, mental, regramental, was a 19th century monk who discovered the principle of inheritance of traits and teas, actually. The idea is that these genetic variants are randomly distributed in the population, so that assumption underlies this concept of name and randomization, because then you can say that the occurrence of a genetic variant in the population or even 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.

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 PCSK9. So the PCSK9 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 genetic association with outcomes.

That relationship parallels very closely the relationship with that variant to LDL cholesterol. The difference is that the risk associated with the genetic variant 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 risk. So a genetic marker like this in the Mendelian minimization model tells you that lifelong exposure to a genetic variant that either races 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 overestimating long-term risk. So the paper that you referred to that came out of the European consensus, there was a heavy dose of Mendelian minimization, either the main author or one of the key authors, did a very good job of showing how the genetic markers for their connected LDL receptor levels, both so PCSK9, others associated with higher receptor activities, well, predict cardiovascular risk much more robustly than do the results of clinical trials. Clinical trials only last four or five years. So that risk reduction, which is parallel, but is displaced because the magnitude of that effect is blended 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 10 years ago, I don't remember when Jim Ophos'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, a moment ago, you said that your intuition is that actually that's not correct, that particle for particle, a small particle is more atherogenic.

Is that a fair assessment of your thought? It is definitely an assessment, I thought. And unlike what we've just been talking about, we don't have a weight 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 and that is the reason particle size got on the map was that the paper, I think in the 80s actually, probably three plus years ago, in which the only test we have was particle size measurement.

We showed the particle size, small particle size is related to risk, but we also said it was associated with lower HCl and hydroglycerides. 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 independent of the 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 different sizes. That's a similar concept.

So there are techniques that measure, they give a number for whether most of the LDL in the blood is larger or smaller. And you 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, I'm going to say 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's just, that says that there's something going on that tips in a quantum way towards this 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 Afros 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 a message. It's what I recall as long as something is less than 70 nanometers, it can enter the seven to three of you'll say so any small, any larger small LDL can enter the space. That's a residence time.

Yes. How long do they say how long do they do? So it turns out it's going to be a little bit complicated, but I'm going to try. Maybe we have an audience that's willing to handle complicated.

How can you work through this with you? Because I know what I want to say and I just want to make sure that I say 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 of 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 area well is very low. Now, if you have an LDL receptor defect, it also causes large LDL accumulates.

FH patients have large LDL particles. So 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's to say that large LDL are not. The other thing is that large LDL is not associated with risk. And the other thing is that large LDL is not associated with risk. So there's no question about that.

The question is, are they equally atherogenic? Two 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, the United Rest of all it said was that you can show that this large LDL are associated with risk. And then the second thing is that if you adjust 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, the smaller LDL carry more atherogenic risk. But 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 region of the genome which is responsible for synthesizing a protein called sorrelin, SORT-I-L-I-N. 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 in 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 effective 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 in 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 affects. It's not affecting clearance. Well, we don't know about clearance. I can't tell you about clearance.

I can't tell you about clearance. I can say it's not LDL receptor-mediated clearance. Maybe we don't know. This could even pick one like one clearance.

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 world 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 we can measure in the usual risk factor range exclusively with small and very small, it's even a subtype of small LDL. That's that collection of smaller particles that is somehow affected by this variant. Now, those patients have elevated triglycerides from the HGLC.

No, no. So that was an account as 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 example is the subject.

So this gets into what you might consider a new one. 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 get a talk, a couple of talks actually at 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. 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 intelligent and experienced people in the field.

And it was considered as a terric. 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 practically 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 of it as a terrace.

So we talked about large and small as if there are only two forms in these two modes, etc. And all that's true. But within the small LDL mode, within both of those, but the small LDL, there's yet another sometime. 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 our Pan-Mabili method, largely measures the small LDL that you're talking about as 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 the 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.

I went through the VL pathway. That's a hypothesis that we're not. 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. I'm not like, I'll do it later. Well, we were signed to learn how to lower up.

We're not going to get to LP little. That's another topic. But yes, 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 particle slash APOB be too low?

And 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 very low LDL are genetics syndrome, which is associated with very low LDL. We just talked about one of them.

So PCSK9 loss of functional mutations are an example of what you're asking. Those individuals have lifelong exposure to very low 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 a start to these things that live longer. So this is the genetic evidence for the safety and the benefit really of having very low 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 nanobis or 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 nanobis. They 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 with PCSK9 inhibition probably does. And that either risk may 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. 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, thereby 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 up regulates 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 errors of metabolism that are uniformly stable. Yeah, yeah, yeah. But sort of outside of those people, are people walking around with low cholesterol where 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 variance.

There are genetic variance in the rate limiting enzyme, HNG, Choreadar-Taste, that is the target of statins that affect LDL levels and heart disease risk in the expected direction. But those variants have a modest effect size. They are not big time players to knock down LDL to those same real level. That's what makes the BCS9 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 LDLs 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 significant family history and a very elevated LP little A, just as an example.

So you've got, and you know, I've seen to collect these patients. So you've got these folks and they've got a clinical burden of disease. So they've, you know, they're CT-NG grams shows off plaque. They're calcium scores shows that they've got calcifications.

They're LP little A's through the roof. And they're tolerating their statins, meaning they don't have the myelgis or 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 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 the Smosseval levels and it found that if the level was below 0.5, which is 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 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.

Like proteins 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 a degree of cholesterol synthesis. Do you think I'm paranoid? You've opened up a big topic on myself.

I think that is the off target effects of cholesterol. If we consider the target, that's not even the proper term. It's the off tissue target because it's the tissue targeting of stay out of the brain. So that's the way we get to the liver inhibiting HMG-CoA reductase and 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. Well, that's right. So there's something called pharmacokinetics.

So 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 this session, but I wanted to listen to understand this. The point you just made is so important. In an ideal world, a statin would be a dream drug if it only inhibited cholesterol synthesis and 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 and the muscles, etc.

Unfortunately, that's not the case. So... Right. So this has to do with me, with these my exposure to this set of issues through the world of pharmacology.

So I had been hanging out with pharmacologists 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 in the permanence of clinical outcomes. So the disposition, that term refers to getting it to the tissue, if any of the tissues, but you want it to get statins to the liver. And most parts of 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 statin disposition. The nature of the statin itself is chemical composition. The presence of a certain genetic variance, when in particular, that's been well studied, that affects the amount of statin in the blood that prevents it from getting the liver.

Under those conditions, there's 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 the other tissues. And part of my research experience right now is delving in to all of these other effects that go beyond the desired inhibition of HMB-quary duct-taste and liver that are actually quote on target 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 described, and I'll come back to that.

But there's a condition that's even more, I think, clearly connected to an unexpected effect of 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? If you talk to cardiologists, I'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 trials. It's about 6 or 7 years.

Yeah, up to 6 or 7 years. But we've published that risk can be significantly higher in women than men, perhaps it's 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.

It'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. 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 cells that produce insulin and or the tissues that insulin acts on. It's just a muscle being important. Right.

Right. So it's the reason I haven't been more specifically at this. We really don't know. There's a number of theories, all of which collectively could be true in different individuals.

But the net effect is not trivial. It's... Is it dose-dependent? Yes.

Well, there are some evidence that are glycemic. There's just glycemic effect that was dependent. In fact, this was very limited information on this, actually. But there is some...

Are there some evidence that seem to be... So, for example, when you look at Simvis satin, it seems to have a much higher incidence of myalgia as a CK elevation. When we look at the entire suite of satins, 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 satins that's most recently been introduced is something called the Patavus statin. It's not that livolo. Yeah, livolo.

That a group in France has shown pre-commencing the recently that this is not associated with diabetes risk. This is kind of my go-to statin before I move to a PCS-9. This is my last line statin. It's not that potent, as you know.

That's the problem. You sort of... 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. It starts probably... Or 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's differences in the statin.

And that being one 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, is the tortoise statin appears to be higher. Lipitor by its... I've tried to have 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 bumper. 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 scientist hat. No, no, but that's... But unfortunately, like for many of us, we still... But we have to make decisions.

You like to use evidence-based criteria? But this is actually one of the things that I struggle with with evidence-based criteria. If you 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 tortoise statin is a diabetogenic drug.

It's still a minority of the population. And we think there's genetic factors that contribute to that. And we can measure it. I mean, that's sort of the exact thing that I sort of felt.

So this isn't going to sneak up on it one day. We wake up with diabetes. I use plenty of a tortoise statin. And I have to be 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 the statins, cardiovascular risk and patients with diabetes far outweighs the risk of actually developing diabetes. And there's even some evidence that the microbascular complications might be improved. So we 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, that should lead to more widespread monitoring of what glucose on statins just so that it can detect those individuals who may have adverse effect. But it's still a minority of the population. And it's not something that should be considered a hazard of disease far from it. Yeah, I think for me, I mean, I sort of talked to patients that say, look, I think there are short-term things that we're generally going to figure out in three months, which is my algeus plus or my SCCA elevation.

So either your muscles are going to get slower, wither 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 Zeddia than just statin alone.

A lot of patients I have that tolerate any dose of a statin, then you add a Zeddia, it seems to me like 20% of people just immediately have an LFT bump. I haven't seen that often, but I have seen it yet. 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 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. If 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 Zeddia. So then he was at goal and given his burden of disease goal for this guy is about 700 nanomole per liter of LDLP.

But he had no cholesterol synthesis that we could speak of. So put him on a PCSK9 inhibitor, that took his LDL down to like 200 nanomole per liter. So I said, great, let's back off the Lipitor. And his cardiologist just thought, like, this was malpractice.

And 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 population, 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 downstream effects are beyond the clinical trial data that we have, which is limited. We can 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 a negative effect. Right. Right. 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 facets of the population with prolonged use by understanding the mechanisms that might be operating in tissues like the muscle, pancreas and the brain.

So that understanding those mechanisms and perhaps developing markers for people that may have increased the likelihood of these undesirable effects that we may be able to guide our treatment more effectively, that's the way the goal of this pharmacogenetic situation. Do we understand the mechanism of the myalgias? I tend to give patients eubicone 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- Statinside effects. Statinside effects. And so the first paper in that series came out with a year or so ago, and that was myopathy. The second paper is, I think, just out, and it describes the data as the diabetes, cognitive function, et cetera.

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 those kinds. There may be on-target effects. That is, in normal responses to statins, in some people, or maybe in a significant percentage 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 that 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 Q, you can imagine, and certainly out there. But as you say- Very high placebo effect.

Reverse that. That's right. It's not been that successful. One of my patients- I'll say this for whatever it's worth.

This is one of the clinical pros. I have a doctor who's really a very good observer who winded up getting a liquid form of coenzyme Q as opposed to a capsule. A capsule didn't work. His muscle symptoms dramatically disappeared or has improved for the liquid form.

So maybe there's issues of absorption. Who knows? Well, I do think there is actually. I mean, we've just empirically used a- we 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, and I'm just going 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 it. We've had some of their stuff tested.

Jero's eubic-win-all 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-statten target. Again, does that mean anything?

I actually have no clue. That's right. But for what it's worth, I've noticed that on most other versions and variants of eubic-win-all, we just do not measure it in the blood. Yeah, I certainly don't have that experience.

It's very interesting to learn. But again, how does that- How does that- The other thing I just mentioned along the slides and again, it deals with diving deeper into the biology of the system. There's about 20 intermediates on the way to eubic-win-all. It's just as complicated a pathway as cholesterol synthesis.

So we don't know whether there may be other targets in that pathway. It just happens to be the end result. So 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.