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

Episode Date: September 21, 2020

World-renowned lipidologist Tom Dayspring returns to give an update on the current thinking in lipidology as a follow-up to his 2018 five-part podcast series. In this episode, Tom discusses the growing consensus that atherogenic lipoproteins are essential drivers of atherosclerotic vascular disease. Tom further emphasizes apolipoprotein B (apoB) and lipoprotein(a) (Lp(a)). He provides insights into risk assessment, including which lab metrics to use, how to interpret them, and the appropriate therapeutic targets. Additionally, Tom discusses the most recent developments in lipid-lowering drug therapies—from the continued evolution of PCSK9 inhibitors, to the latest understanding of EPA and DHA, and the most recent addition of bempedoic acid to the list of therapeutic agents. We discuss: The latest in the field of lipidology and cardiovascular disease [3:45]; Apolipoproteins—the key to understanding lipid biology [9:30]; ApoB as a preferred metric over LDL-P [16:30]; Therapeutic goals for apoB concentration [21:45]; Drivers of atherosclerosis [34:15]; Overview and current thinking on high density lipoproteins (HDLs)—Is it a useful metric? [37:00]; Lipoprotein(a)—the most dangerous particle you’ve never heard of [55:00]; Are low density lipoprotein triglycerides (LDL-TGs) a useful metric? [1:13:15]; Tom’s preferred lab measurements [1:17:45]; The latest in lipid-lowering therapies [1:21:30]; The different pathways among various lipid-lowering drugs [1:30:45]; The latest on EPA and DHA [1:38:15]; Fibrates—an underappreciated treatment for hypercholesterolemia [1:49:45] and; More. Learn more: https://peterattiamd.com/ Show notes page for this episode: https://peterattiamd.com/tomdayspring6  Subscribe to receive exclusive subscriber-only content: https://peterattiamd.com/subscribe/ Sign up to receive Peter's email newsletter: https://peterattiamd.com/newsletter/ Connect with Peter on Facebook | Twitter | Instagram.

Hey everyone, welcome to the Drive Podcast. I'm your host, Peter Atia. This podcast, my website, and my weekly newsletter, I'll focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, full stop, and we've assembled a great team of analysts to make this happen. If you enjoy this podcast, we've created a membership program that brings you far more in-depth content if you want to take your knowledge of this space to the next level. At the end of this episode, I'll explain what those benefits are, or if you want to learn

more now, head over to peteratia MD dot com forward slash subscribe. Now without further delay, here's today's episode. I guess this week is Dr. Tom Despray. This name is probably familiar to some of you because back in October of 2018, we released a five-part series with Tom and that set of episodes, despite being quite technical or some of the most popular episodes we've released, especially amongst people who really like to get serious about their understanding of cardiovascular disease. So, we wanted to have Tom back, basically, to pick it up where we left off.

And in this episode, we try to focus on things that have changed in the last couple of years. And that kind of loosely fell into three categories that we probe. The first is digging really deeper into the recognition of the importance of astrogenic lipoprotein. So kind of revisiting the idea of what APOB is, why it matters. And both Tom and I discuss a little bit about how our views have changed with respect to the use of APOB as a laboratory surrogate over LDLP. And we get into all of the nuance around that with respect to the use of APOB as a laboratory surrogate over LDLP. And we get into all of the nuance around that with respect to VLDL, triglycerides, LP little A, etc.

We also get into why HDL cholesterol is a far less relevant metric, at least why we believe that to be the case. We then pivot a little bit and talk about risk assessment. Basically how do you understand these metrics? How do you use these metrics? This is a lot of the clinician type stuff here around APOB and triglyceride-rich lipoproteins. We again revisit the idea of LPLitLA.

And then finally, we bring it home with some discussion around therapies. And in particular, we talk about the continued evolution of the PCSK-9s, the evolving data around omega-3 fatty acids in particular some of the controversy between EPA alone versus EPA and DHA. And obviously we talk about the most recent addition to the lipid drug story,

which is a drug called Bempendoic Acid, which has not been around very long and probably many people are not gonna be familiar with that, but Tom does a great job explaining that. Tom's a diplomat of both the American Board of Internal Medicine and the American Board of Clinical Lipidology. He practiced internal medicine in New Jersey for 37 years, the last 17 of which was devoted to consulting patients with lipid and cardiometabolic disorders.

Between 2012 and 2019, he served as the chief scientific officer at two major cardiovascular bio-marker laboratories. Since that time, he has been working with us in our practice, primarily on the research side of things, but also as a consultant advising on most of our cardiovascular cases. He's both a fellow of the American College of Physicians and the National Lipid Association, the NLA, and he's an associate editor at the Journal of Clinical Lippetology. He was also the recipient of the National Lippet Association 2011 Presidents Service Award. He's authored and illustrated more manuscripts and book chapters related to Lippets than I can count. And so without further

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

neutrally that it makes sense to sit down again. That was amazing. First of all, it's always great to sit down with you, Peter, and chat about my little lipid world. But yeah, I'm shocked every time somebody tells me we've listened to the whole series, and I've done it three times, and I just can't imagine that. But I'm glad it came across pretty good. You know, one of the things I wanted to do today, Tom, and I can promise you, and all the listeners, we are not going to do this for another eight hours today. But what I want to do today is sort of, I think, kind of pick up the mantle from where we were a couple of years ago, and talk about what's different since then. I think the last two years has seen a number of things that are actually pretty exciting

in the field of lipidology and the field of cardiovascular disease. Some of it's been what the really nuanced level scientifically. Others have been, frankly, at the broader level in terms of recognition of certain things that you've been talking about and many others, people like Alan Snyderman have been talking about. A lot of this stuff is very clinically relevant. The way I pose this to you, and I think this, unless you're opposed to it, the way I'd

love to kind of go through this is maybe use our time today to talk about things that are different today than perhaps they were a few years ago, and dive into those things in enough depth that everybody from the lay person to the Efficient Auto will have something that you want. Yeah, that's a perfect strategy for today. Now, there's no doubt we'll reiterate some concepts that we went over in great depth back then, but we won't have that opportunity today. But, and you know, MAPID always lived on the cutting edge of

lipidology science science leading the charge, trying to understand new concepts that come down. But one of the great satisfaction of my career is much of what I've promulgated for the longest time has come to fruition. And that's what's really happened in the last two years. There are certainly some new concepts and some abandonment of some other issues. But it's just the, you know, my whole mantra for a long time, you know, we've known each other a decade probably is that, atherogenic lipoproteins are really the issue behind clinical atherosclerotic vascular disease.

And although many of us have known it for a while, the data has just become so overwhelming that virtually all of the guidelines have signed on to that premise now that atherogenesis is certainly a sterile mediated disease, but steriles are trafficked within APOB containing lipoproteins, which provides the vehicle that transports them into the artery wall,

where they can, in some start a pathological process. So it's the recognition of anthropogenic lipoproteins that is now in the guidelines. And, you know, anthropogenic lipoproteins are still diagnosed using various cholesterol metrics, but there are things beyond LDL cholesterol mounted in the guideline. And even APOB is certainly within every of the contemporary guidelines in the last two years. And that's of course the atlants, the nightmare thing that he's been harping about

for a long, long time. So it's atherogenic lipoproteins. Within that category though, the things that are also emerging is what contributes to the atherogenicity of an APOB particle, triglycerides has really taken center stage, how they affect lipoprotein concentration and quality or functionality, whatever adjective you want to subscribe to. It's the loss of the ability of at least the

HDL cholesterol metric to be terribly informative to us. And it's the emerging significance for a lot of reasons of lipoprotein, little A. So those are the big areas where it changes, really becoming important and is really useful at the bedside. Of course, pharmacology and intensity of pharmacology has also advanced and we'll touch a little bit on that today. I'm sure to sort of summarize that we're going to talk about kind of double clicking on APOB slash LDL particle. Basically, the atrogenic lipoproteins front and center in the pathogenesis of cardiovascular disease. We're going to talk about the modification of our risk

assessment. And I like that you brought up HDL because I want to have a pretty interesting discussion about that. And obviously, we're going to talk about what's happened in therapies. There have been actually quite a number of things, including the continuation, more data around ZMIB and PCSK9 inhibitors, much more data since we last spoke around omega-3 fatty acids. I spoke with Bill Harris about that, but I think we can go a little bit further. And there are a couple of other therapies. So let's start with maybe a little bit of a reminder for people as to what APOB is. People like you and I sometimes use APOB and LDLP interchangeably as

shorthand that's not entirely correct and when we last spoke we probably disproportionately spoke about the number of LDL particles and now we're going to focus on APOB. So do you mind explaining what the difference is both from a biology standpoint but also from a laboratory standpoint. And those are critical points, Peter, because it's one thing to talk about APOB, but almost what you're saying about it depends how did you analyze it? What laboratory metric did you water that you think is telling you something about APOB,

whatever that encompasses? So to make a story very simple and sure, you know, lipids go nowhere in aqueous plasma because they're hydrophobic. So for a lipid to be traffic throughout plasma, it has to attach to a protein. Now a few molecules of any lipid can attach to albumin, but that's not the primary way lipids get anywhere. Serious collections of lipids, hydrophobic substances, attach to fairly significant proteins, which solubilize them. And these apoproteins, as they're called,

proteins that wrap collections of lipids, provide structure and stability to this macro molecule that we're gonna call a lipoprotein. So the main structural protein that enraps lipids in our body is apolipoprotein B. It's a 500-keletal and molecular weight protein, so it's pretty big, and it has a great ability to attract a lot of lipids to bind to it. But once the lipids are bound to it, this is a water soluble lipid transportation vehicle. There's basically one other class of lipoproteins, and that is the

HDL particles that you mentioned. And they have no APOB on them. Their structural protein is APO-IPO-Protein A1, capital A, dash, either Arabic or Roman number one. So right away we have a double classification of lipoproteins, the apob containing, they're often called beta lipoproteins or the apo A1 are called the alpha lipoproteins. So now within that apob family, it always gets a little more complex than lipidology. The two tissues in your body that can make apoby are the liver of parasites. And of course the small intestine which is absorbing a lot of lipids so it has to put them in something if those lipids are going to get into your plasma. So the apob that's made in the liver is a big 500-keletal protein that I mentioned and it's called APO B100. Now why do they add

the 100 on it? Because the intestine also produces APO B but it produces a truncated version that has 48% of the molecular weight of the hepatic produced APO B. So that's called APO B48. So if the liver makes an APO B particle full of lipids, it's got one molecule of ApoB100 on it. If the intestine makes a big lipoprotein, and it does, they're called chylamicrons, that has one molecule of ApoB48. The intestine component in your lymphatics, it enters the systemic circulation, the liver just secretes it directly. So those are the two types of apobly. We're not going to talk a lot about column microns. They're in most people without a genetic pathological issue.

It's not your column microns that are the major problem here. They're a post-prandial lipoprotein. So the liver makes these APOB 100 particles, and they can go out, the liver can secret them, but some of the particles that the liver secrets can be catabolized into smaller and smaller versions, even though they're still APOB proteins. So if we're going to talk about the APOB 100 family, and I'm probably not going to use the term 100 anymore, we're talking about very low density lipoproteins intermediate density lipoproteins and low density lipoproteins.

And of course part of the LDL family is lipoprotein little A if you happen to produce that, not everybody does to significant amounts. The names of those particles as you know, they were originally discovered via ultracentification. So the ones that float it on top of the tube with a very The names of those particles, as you know, they were originally discovered via ultra-centrification, so the ones that float it on top of the tube with a very low density, the ones that sank to the bottom were the high density and the in-between were the IDLs and LDLs. Now, so the APOB family is VLDLs plus IDLs plus LDLs plus LP little A if you have it. Well, that's true, but here's the reality.

We have to look at plasma residence times. How long do these things float around? How long are they in your system? Because that's important because these are the particles that have the potential to crash your artery wall and traffic, star rolls, and whatever else into the artery wall. The columnar crons I mentioned are half-life is in minutes.

Their plasma residence time a few hours. The VLDL particles, their half-life is two to four to six hours, depending on how rapidly they're catabolized. The ideal particles are transient in between particle, between a VLDL and an LDL. They're around for an hour or two. They're not other under the unusual genetic condition a player in this APOB game we're talking about. And finally, we have the LDL family. Now LDLs have a plasma residence time of two to five days.

And there are other attributes to the LDL that determines, is it gonna just hang around for two days or five days? Clearly, the longer it hangs around, you're going to have a lot more LDL particles than if you could rapidly clear them. So when we talk about whatever APOB metric you're doing, technically, you are measuring VLDLs, their remnants, their smaller VLDLs, IDLs, plus LDLs, plus LPL,

little A, but because of the half life, 90 to 95% of your APOB particles are LDL particles. So that's why many people say, Hey, APOB is just another way of getting an LDL particle count. And that's true. Even in people who might have a lot of remnants, the remnant particle number is quite small. It is still way more LDL particles floating around in these people who might have these remnant VLDLs that cause issue. Not to say a VLDL remnant might not be a very injurious, apobet-containing particle. It certainly isn't some people.

But if we're looking at the number, which is the primary driving force as to how an APOB particle enters the artery wall, LDL is king. And that's why our metrics of APOB or LDL particle count are what are at the top of all the guidelines. And of course, the metric most people use are LDL cholesterol and non-HDL cholesterol? I mean, Tom, on a personal level, the reason I have switched to APOB in our practice, which is obviously heavily influenced by the work that you've discussed, the work that people like Alan Snyderman have been doing for many years, frankly comes down to a consistency factor. So we had historically relied on LDL-P, LDL particle number, as a concentration

count, but frankly in the span of eight years went through three technologies to do that, right? Two generations of NMR coupled with electrophoresis. And while in the end we felt the electrophoresis provided the most accurate measurement, you always have a problem when you don't know what you're comparing it to. So if we have Gen1 NMR, which is probably still being used by LabCore and Quest today, that is probably quite inaccurate compared to Gen 2 NMR, but the percentiles, meaning the populations of people that were measured, are still what we use to understand where someone lies. It puts you in a bit of a dilemma as a clinician or as a patient you want to continually upgrade

your technology. In other words, if you're talking about getting a new iPhone, you don't really care that your phone is so much better than two generations ago's phone, because all your metrics are better, and there's nothing to be gained by comparing yourself to how much better you are. But when you're talking about diagnostics,

it does matter where your reference range is and if you're moving it. So do you agree with my logic for switching to APOB a year ago as now being a much more homogeneous way to assess patients Even across labs. So especially now in light of COVID, we can't always use the same lab to measure APOB So you know, I might be sending a patient to one lab versus another lab, and I just feel like we're getting better results this way. Does that drive with you? No, that makes total sense.

And a real important take home point for listeners is pick your favorite metric. Peter's right now is APO B. Mine right now is APO B. And stick with it. Don't do APO B this time in an LDO particle count via NMR. Peter didn't even mention Quest has a particle number technique called ion mobility transfer that people are not comparable. All biomarkers you should consistently try and use, of course the same lab not always possible, but the same assay. And the APOB immunosay is pretty standard throughout the industry. It's not like everybody's got their own APOB assay. The animal can vary widely. The other big reason to do that and consistency of results over time is sooner or later,

yourself, you're going to read the guideline or maybe your patients are going to go, all the guidelines talk about APOB. There is no guideline telling you to do an NMR, LDLP, or an IAM ability LDLP. So it's another reason to just stick with the APOB. And I think there are less false positives with the APOB. It's just been my personal experience. I've been an NMR guy all my life. And as we got better and better,

we just so often saw a totally unexplainable discordance between LDLP and APOB. The data is overwhelming for APOB. So I think that's where you should be in today's world as your marker of Athergenic lipoproteins. Yeah, I think we saw that, especially with the second generation NMR. It was almost like it had become too sensitive.

We were seeing discordance that far exceeded what the framing ham or Mesa data predicted the discordance should have been. That's really actually what took us to the ion mobility assay. But again, I'm actually very from a diagnostic and management standpoint. I'm actually quite comfortable with where we are. I think the final point I'd add to that time is just the economic one. You know, frankly, I think the cost of an APOB is, you know, at least in Canada, and the only reason I know that is because Alan Snydermann is at McGill and, you know, he's been pounding this

for a while. I mean, we're talking about a three or four dollar test. So there is no excuse for any physician to say, we're not going to order your fancy APOB because it costs too much. I'm going to order the LDL cholesterol. I think that excuse has lost all of its water. It's so true, and Alan just published a beautiful paper where he's researched the course of APOB assays. Because even some of the people in the guidelines always, oh, we can't say APOB, it's so expensive.

That's an old excuse that is no longer applicable to 2020. So all the technologies to quantitative, anthropoprotein, APOB is the most affordable. And even, you know, look, lab sometimes change crazy. But if you tell a lab you want to pay a cash price, it's really pretty cheap. Yeah. Let's go back to kind of the macro point here around APO B, which is a greater coalescing around the idea that APO B concentration matters. So I think it's very well understood that two of the biggest risk factors for cardiovascular

disease are smoking and hypertension. I don't think there is any ambiguity that cigarette smoking and high blood pressure increase the risk of cardiovascular disease. And they both appear to do so through a mechanism that weakens the endothelium or creates an injury to the endothelium. The question now becomes, as you put it, Tom, how ironclad is the story that it's the APOB bearing particle in the presence of injured endothelium that is the Trojan horse that begins this destructive trajectory of taking that cholesterol into the subendithelial space, becoming retained, undergoing this chemical oxidation process, which then kicks off an inflammatory

response that paradoxically, as an attempt to repair the damage results in what can be a fatal injury. There are other hypotheses, for example, there are people who note, and we have, I mean, look, I have a patient in our practice, Tom, you've weighed in on her case, walks around with a total cholesterol of 300 and something, an LDL cholesterol of 220 milligrams per desoleter,

an APOB of 170 milligrams per deciliter. She's in her late 60s and her coronary artery calcium score is zero. We have elected to not treat her with any lipid lowering therapy. In other words, there are exceptions to this. How do we reconcile that? Well, it's the human body in medicine. As you know, not all smokers are going to come down with lung cancer or chronic obstructive lung disease.

Why not? If that's such a horrible risk factor. I try to explain this and I've certainly seen cases like you say where, oh my God, if I was just going to say, give me your apobie or whatever cholesterol metric, you're going on three drugs right now, you got no choice. And maybe the old days we approach people that way, but no more. I think you have to individualize your whatever risk factors you discover that might wind up causing atherogenesis and then figure it out.

So particle number is certainly a major factor that might force it in, but not always, and the tally of function, although you can certainly, if you review the history of this, and how do you really determine ended tileo function? Not everybody has serious ended tileo dysfunction who winds up with death or scars. So particle number itself, and some people can just make the particles go in.

I think if we take most adults who's not going to have a little bit of endotelial dysfunction. So I agree with you, it's a combination of something about atherogenic particles, be it their number, endotelial dysfunction. But I'm talking more and more now when I discuss any type of lipoprotein. I don't care which subgroup you want to talk about. I think we certainly have to know its particle concentration, but I like to talk about particle quality. So what are the other attributes of any lipoprotein

that might contribute to its atherogenicity or in some perhaps not understanding, make it relatively, it's not going to generate atherosclerosis and there certainly have to be things like that going on. So as we're getting smarter, we're looking at other components of the lipoproteins that could be other proteins that are on them, that could be their complex lipidome. And trying to see, ah-ha, can that help us discern

whether in you a given particle concentration is more worrisome than it is in the next person. So there's a lot going on. And also from the gist of this conversation listeners will know atherosclerosis, atherogenesis is a multi complex, multi-fectorial disease. And that's why even when Peter and I, if we consult on a case and we realize in this person we have to beat up APO B and get their particle numbers to a more physiologic range, we don't stop once we do that. We examine in great detail for other things that might be injuring the endotelium or the arterial wall and see are any of those treatable or so. So we're getting a little bit smarter on lipoproteins,

but there's certainly more to it than just particle number. Do we think that there's a limit to where the benefit of reduction becomes diminishing or even J curves in the other direction? So we discussed it in the first episode significantly. We did so again with Ron Kraus. It wouldn't be you know the worst idea in the world a couple of years from now to sit down and do it again and re-examine the data. But again, I think the causal relationship between ApoB and atherosclerosis is as strong as virtually anything we see in medicine, for which you can't do the perfect experiment where you have to rely on natural experiments.

perfect experiment where you have to rely on natural experiments. Nevertheless, maybe it's not entirely clear what the dose response looks like. So if you have somebody whose APO B is 160 milligrams per desoleter, there's a risk reduction that comes to lowering it from 160 to 100 and lowering it from 180 to 60. What do we know about the risk reduction in lowering it, say from 60 to 40 to 20? And I ask both what we could infer pharmacologically and non-pharmacologically. In other words, from the Mendelian randomization versus the pharmacologic.

Well, even using pharmacologic trials, and Mendelian randomization, the concept you're going to come across with is lower is better. And with the pharmacologic thing, we're modulating things that either have clinical trial proof that if you lower them, it's good, or the Mendelian randomization, looking at genes where that drug might be doing something, it works. Now you do need a few hypobcontaining lipoproteins. They do traffic other lipids.

They traffic fat soluble lipoproteins. But we must never confuse a beta lipoproteinemia where nobody, or that person can't make them, or a hypobatal lipoproteinemia where they make a few, enough to traffic those other things that a lipoprotein might have to traffic. But even the guidelines where they examine people looking at their baseline, APO, B or LDL cholesterol, the first thing they suggest, at least in the higher risk people, is try and get a 50% reduction.

And that's where most of the bang for the book is going to be. Now if you still have options that you can lower it further, yeah, the trial show, yeah, there is incremental reduction events, but it's a much smaller, absolute risk reduction and dropping it the 50% or so. So I don't know if that answers your questions. So most people don't have the type of levels where with modern therapeutics, with modern lifestyle, we can more often than not attain physiologic concentrations. And if I want to talk about APOB, that's probably under 50 milligrams per deciliter, if we

can get there. That's what the newborns have. That's when you go in clinical trials. If you take it down that low, you see your most risk reduction. And so far, at least with pharmacologic lowering of ApoB with the currently FDA approved drugs, there is no signal of harm. Yeah, again, it's funny because I was just about to say with the current crop of drugs, specifically the PCSK-9 inhibitors, we are routinely seeing patients who easily can get an APOB into the 20 to 40 milligram per desoleter range.

You and I actually sat down a couple of months ago and did a calculation to estimate how much cholesterol is actually contained in the circulating lipoproteins versus that, which is in cell membranes. Do you remember doing this with me? Not per se, but I, and where we're developing equations, you're the master of that. Well, it was one of these things, right? It was sort of like, look, you know, when you look at a person's plasma glucose level, you realize pretty quickly it represents a tiny fraction of total body glucose. And similarly, there's such a concern about plasma cholesterol level, but you know,

given how essential cholesterol is, it's understandable why people would be concerned that low cholesterol could be problematic. But once you do the calculation and realize virtually all of the cholesterol in the body is contained within the cell membrane or within the steroidal producing tissue, the circulating amount is a very narrow window into the total amount of cholesterol. And therefore, a reduction of, say, 60 milligrams per desoleter to 50 milligrams per desoleter of APOB, or even something more extreme, like a full 50% reduction of total cholesterol, 200 milligrams per desoleter to 100 milligrams per desoleter, does not

represent a significant reduction in total body cholesterol. That's a very important point. All right, let me repeat it. You have a total body cholesterol that you measure in the plasma that says, oh, it's 200 milligrams per desoleter, that goes down to 100 milligrams per desoleter. Let's say the LDL fraction reduced from 150 to 75 or something. Someone might say, God, you just cut cholesterol in half, that can't be good for you,

given the importance of cholesterol. But my point is, no, you simply cut the amount of cholesterol being carried by the lipoproteins in the plasma in half, that doesn't capture the majority of the cholesterol. Yes, thanks for refreshing my memory. What you're talking about now, it's really pools of cholesterol throughout the body. And I think I'm so glad you brought this up because this is just not even understood,

even in the lipidology community. We have a total body cholesterol. There are basically three pools. There's your brain and nothing we're talking about today has anything to do with brain cholesterol. It's a separate system. It doesn't interact with the other cells in your body or certainly with the cholesterol in your plasma. So if it's not in your brain, where is cholesterol in your body? Well, it's either in all your peripheral cells,

perhaps some more than others, or it's circulating in your plasma. And if it's in the plasma, where is it? There's an easy-wean C-amount bound to albumin. There's more bound within all of the lipoproteins that are trafficking in your body, meaning your APOB and your APOA1 particles. But believe it or not, if I wanted to search down blood cholesterol for you, I would suck out your red blood cells and extract cholesterol for them. Red blood cells carry far, far more cholesterol than all of your lipoproteins put together. And the other crucial point you made subtly, and I hope everybody understood you, the amount

of cholesterol within your lipoproteins has no correlation with your cellular cholesterol or even your red blood cell cholesterol. So whatever, however you're modulating some LDL total cholesterol, HDL cholesterol metric, that tells you nothing about what might you be doing to the cholesterol content of your cells. So don't have a panic attack if you're making LDL cholesterol 30 because I can assure you virtually every cell in your body even if that's your plasma LDL cholesterol has more than enough cholesterol because it can denoubo synthesize it

it can put it in its cell membranes or other organelles that require cholesterol if it's a starrygenic starrygenic tissue can produce a little more or perhaps de-lipped a similar. So there's no cell that's being deprived of cholesterol in the periphery when you're modulating lipids through lifestyle or drugs. Tom, what's the best explanation for why it's not the red blood cell that is the primary driver of atherosclerosis, given the fact you just stated, which is red blood cells contain within them a lot of cholesterol within their membranes, and red blood cells clearly traffic to and from past the endothelium. I certainly have my own answer for this question. I think

the histology makes it abundantly clear, but is there any thought you would add to that? No, I think histologically, we know it's foam cells. And where do foam cells get their sterile content from ingesting oxidized lipoproteins, carrying cholesterol? Is the vase of a serum, which supplies the arterial intimate with blood cells, dumping red blood cells in here that are contributing cholesterol. Maybe a few molecules, but I don't think we have any evidence. That's a driver of cholesterol that's resulting in arterial wall pathology. Yeah, this is one of those moments where sometimes a picture just serves a thousand words. This will be one of the best.

We're going to obviously accompany this podcast with a lot of figures and diagrams of yours. But what we're basically talking about is you have to differentiate from the vase of a soram side, which is the non-luminol side of the vessel, where, of course, you have to have blood vessels to keep the artery itself alive, versus the luminol side where the endothelial lining is damaged by everything, including just daily life, but certainly high blood pressure, smoking, uric acid, high glucose, high insulin, shear forces, you name it. And that's what's allowing these lipoproteins in.

But you're right, it's really this histologic examination that makes a very clear, unmistakable case, that it's not the cholesterol in the membrane that's doing this. It's this trafficked cholesterol that ultimately becomes a foam cell through the macrophages ingestion of the lipoprotein that is the insult. That's a pretty good tour to force on this topic. One more little caveat, Peter, with that vase of a sore, as you know, as you have an evolving plaque, it gets bigger and bigger, and it becomes prone to erosion or rupture and the coagulation system. So there's nothing to say that even in a minuscule histologic rupture

of a plaque that the vase of a sore can't be contributing some clotting factors or something else to that pathological process. It almost assuredly does. At some point, once you have damage, I would fully expect coagulation factors to be coming from both sides, the luminal side and the vase of the soram side. It's an all hands on deck war. And the uric acid too, probably, you know, which can crystallize just like cholesterol. You touched on it in the outset, which is what have the guidelines stated with respect to other lipoprotein? So if we take a step back and we went back to the early 1980s, right? In the early 1980s, when we were just beginning to talk about the sub-fractionation of cholesterol.

So, little history lesson for people. It's 1959-ish early 1960s. Ansel Keys is clearly on to something, and he is identifying a relationship between serum cholesterol and coronary artery disease. He's correctly identifying a relationship between serum cholesterol and coronary artery disease. He's correctly identifying a relationship. And at the time, they're doing very rudimentary assessments saying, hey, if you take the people who are in the top 10% of serum cholesterol and you compare them to the people in the bottom, 10% of serum total cholesterol, there's a profound difference in atherosclerosis.

Most people are familiar with how that history went, and then where it got taken off the rails a little bit by what might be the root cause of those things. But nevertheless, it was pretty clear into the 1960s and 70s that something about serum cholesterol mattered. Eventually, people began to, as you pointed out, Tom, begin to fractionate those things, so it wasn't just about total cholesterol. It became about different densities of those cholesterol. And these lipoproteins, some of them were lighter, some of them were heavier and really light and heavier.

The wrong words, they had different densities. But one that emerged pretty quickly as a contrast to the low density life of protein was the high density life of protein. And through all of the epidemiologic work that emerged in the late 70s and into the early 80s, and that also, by the way, continued into the 90s through the work of Jerry Reven, as he was in the early stages

of identifying what would be called metabolic syndrome at the time called syndrome X. It became clear that higher levels of cholesterol in the HDL particle, which unfortunately is erroneously often referred to as high good cholesterol, had a positive association, the opposite of what we have just been describing, which is high levels of cholesterol in the LDL particle. There's a lot less talk of that today, at least amongst the people who know what they're talking about. Unfortunately, there's still a lot of people who talk about that in social media. But why is it that we aren't sitting here in the guidelines talking about HDL cholesterol?

The so-called, quote unquote, I hate to use this word good cholesterol. And you know, I'm in your corner. I'm out one. Folks, there's one cholesterol molecule. I don't care whether it's in your cell, whether it's in any lipoprotein in your brain. If I drew you the structure of cholesterol, it's identical. So how dare we put an adjective on it like that's good and that's bad. How do you know? So you don't. So there's silly terms, but they sort of evolve for a good reason. And this is a wonderful historical journey that you really have to do to figure out why did HDL have like such importance. And now it's an afterthoughtod. Although it's an aftertod, I must say virtually all of the current risk algorithms that are used

to classify you as are you at high, very high, moderate, or low risk still use the metric HDL cholesterol to determine that because data is just 40, 50 years old. The problem with HDL cholesterol as a metric is all those studies that seems to suggest a higher is better, lower is worse, were never adjusted for anything else. So you know observational type data. I found the answer. Here it is. You got blue eyes and everybody with blue eyes gets this that or whatever. And of course you never adjusted for, oh, wait a minute, everybody with the blue eyes has this lethal thing going on also. So in retrospect, it turns out that the overwhelming majority of people who might have low HDL cholesterol have a high APOB level,

and that's what drives their atherosclerosis. So all guidelines, even though they might do your baseline risk using an APOB metric like total or LDL cholesterol, they'll use HDL cholesterol as trying to figure out the lipid component to your risk. They use smoking and blood pressure and other things. Peter talked about also. When they get to goals at therapy, though, only because we have multiple trials now where for decades, people have been trying this and everything to raise HDL cholesterol because if high is better than low, raising, it has to be fantastic. And not a single trial has ever panned out that what you do to HDL cholesterol results in

cardiovascular benefit. Let's pause there for one sec, Tom, and just make sure people understand that there have been multiple trials using at least two, maybe more technical approaches to raise that number that is unambiguously associated with better outcomes. Is that correct? No, there are no clinical trials that would support raising. No, no, no, no, no, I'm sorry. There have been multiple clinical trials that have attempted to raise HDL cholesterol.

That's true. Yes. And it's more than two drugs. There are other drugs that... Yeah, I think more than two mechanisms of action. Correct. At least two that I can think of. There might be...

Yeah. There's probably three mechanisms of action that have been... That would all raise HDL cholesterol. But the point that you made that should not be lost on anyone is, at best, those trials have been neutral. As have the Mendelian randomization trials, looking at genetics, surrogates of HDL and cardiovascular outcomes, yes. And at worst, those trials have been harmful. Yeah, there are plenty of people, and you know them, you've seen them in your practice. Certainly I have, when I was practicing with high HL cholesterol, who are full of plaque,

and we do see people with low HL cholesterol, who, just like you said, you see some people with high LDL or total cholesterol don't have plaque. There are plenty of people with low HL cholesterol, who, my God, you don't seem to have much cardiovascular risk. So there has to be, if HDLs are important to the cardiovascular system and I maintain they are, the metric HDL cholesterol is useless. Yeah, and this is really where I think I want to go with this. And just, I mean, there's so much we could say on this, but I think it's worth maybe even just explaining this very important point, right, which is HDL cholesterol, the number that everybody sees when they look at their lipid panel,

that if it's below 40 milligrams per deciliter is probably flagged as being too low. If it's above 70, your doctor gives you a high five, that is measuring the concentration of cholesterol within an HDL particle. Now, it doesn't tell you anything about the functionality of that particle. And this is where I think, I don't remember if it was Ron Kraus that said this, but someone said this to me, and I've never forgotten it. It might have been Alan, actually. They said, this LDL biology stuff is trivial. All you got to do is lower it. They said, this LDL biology stuff is trivial.

All you got to do is lower it. It's the HDL biology that is really complicated. That's what the 21st century is going to be about. We don't have a clue what we're talking about with HDL. We've been using this idiotic crude metric of how much cholesterol it contains. It is now completely clear that that was the wrong metric than any attempts to increase it were futile. We've count the number of particles, we can even measure the size of them. That also appears to be almost as crude as what the cholesterol

concentration is. But to come up with an assay that truly measures functionality may be beyond the scope of laboratories. Whereas with the APOBL, the L side of the equation, it really appears to be a stochastic problem. The more of these things you have, to the first order, the more problems you have. You've already alluded to other attachments to them that can add second and third order terms. But I mean, do you agree with my assessment, Tom, that this HDL problem is way harder and we don't have a clue what we're talking about? Oh, it's just so perfect. What you've just said in the last few minutes, it's, you know, we all use laboratory metrics to try and figure out what a given biomarker tells us and what we can do about it. And the only metric

that's really available to the world world now is HDL cholesterol, which Peter says that's the collective cholesterol mass within all the HDLs that exist in a deciliter of your plasma. If you are doing ion mobility or NMRs, you can get an HDL particle count, but that, although it might be a tad better than HDL cholesterol telling you something, there's so many exceptions to that rule that it's not a useful bedside metric either.

But presuming again, HDLs must perform some function in the human body, and part of that function might be either preventing or putting out arterial wall plaque fires that have many ideologies, how can we measure what Peter referred to as the functionality of the HDL particle? You know, being a fireman's son, if you listen to that last podcast, I look at HDL's as fire engines, but I know any fire department has about 10 different types of different fire trucks, and they also apply something different that firefighters can use to extinguish a fire. Some might carry chemicals, some might carry ladders, axes, water, some carry more firemen and others. So what type of fire truck do you need at a given scene? Well, it depends what the heck the scene is all about. So what do HDLs do?

They certainly traffic some degree of cholesterol, which it turns out is probably just their first though ecometric reasons, make it a spherical particle, to which other things can attach. The other things that are in that HDL, remember, HDLs are tiny, so they don't carry a lot of cholesterol. Here's a stat that will astound a lot of people. If I took the average HDL particle, the average size HDL particle out of your plasma, how many molecules of cholesterol would be inside of it? About 45. How many molecules are in the average size LDL particle? About 1500, 2000. So the volume of a spear is the third power of the radius. What might

influence even the cholesterol content of 45 cholesterol molecules within an HDL? Well, it's a spear. There's only so much can go in there. What if that HDL was carrying extra triglycerides for whatever reason? Well, it couldn't carry very many cholesterol molecules. So that would be a cholesterol depleted HDL. What if that HDL, if I had five groups of HDL particles, same size, same cholesterol content, but they all had different phospholipids on their surface lipidome, or they all were trafering different proteins, they all have APOA1, but what else are they carrying? And those proteins have a multitude of functions. Dan Raider years ago, he's told me, Tom, H.L.s are part of the DNA immune system.

They're little fire engines, they're carrying God knows what that could go into wherever there's inflammation in your body, a swollen knee, any incis-ungury or your arterial wall, and they could maybe help what's going on there because they're trafficking immunomodulatory functionality molecules, or they could go in because, oh my god, these are corrupt HDLs, they're carrying bad junk, which is further inflaming it. We have no way of measuring those now. I mean, researchers can do lipidome analysis of the phospholipids, this thingo lipids, the ceramides that are in HDLs. We can, you know, they've identified

over 150 different proteins that might be on an HDL. Now, they're not all on one given HDL, but some HDLs may have two of this protein none of that. And you have different groups of HDLs. In my analysis, there are different types of fire engines carrying different things. Peter in our lifetime, you will never be in affordable, reproducible, a high throughput way of evaluating any of this. People are hanging their hats now on the ability of HDLs to efflux cholesterol from a cell. And hey, if an HDL can suck some starrows out of your foam cells, yeah I'm kind of thinking that's pretty good, but it's probably a minuscule function of the hundred other functions that HDLs can do. So what if the HDL is pulling out some cholesterol but it's dumping other crap in the

process. So if we ever had an HDL function panel it's going to be a dozen or more type tests which we're not going to see because of nobody's going to pay for them. The research to be done to prove that these have relevance in a large clinical trial is just not going to be done. So that's the dilemma. There are such panels, right? I mean, I think I feel like I've seen a couple of commercial panels that attempt to subdivide the HDL particles even further.

I've never personally been able to know what to do with such panels. And these days, I don't even look at APO A1 anymore. I'm really focusing most of my efforts on VLDL cholesterol as a poor man's proxy for remnant triglyceride, basically as a strategy for how to lower APOB, APOB, LP, little A. And then focusing just frankly much more on the metabolic stuff that we've talked about, the obviously glucose, insulin,

humus, cysteine, uric acid, much more aggressive stance on blood pressure. But in some ways, my lipid world has become a little bit easier in light of this discussion we're having. It is because you've got the ability based on analysis and understanding of things to not order the silly focus focus HDL panels that are being offered by people as a way to generate revenue and I look I've been associated with labs all my life I'm not at the present time I don't work for any lab that does or doesn't do any of these tests you're talking about. But mostly those panels that you look at, they're looking at, they're reporting HDL size,

they're reporting APOA1. Peter knows there can be from one to five molecules on APOA1 on your various HDL species. So you have just a few HDLs carrying a lot of APOA1 or do you have a ton of HDLs that carrying little APOA1 and that could be a misleading metric. People are looking at some of these phospholipids. Now some labs are offering ceramide levels or singacine levels. But again, you can find something that might support that, but then you have to weigh it against the APOB and the things that are almost beyond discussion.

And you would realize this is contributing nothing to me. Why am I even ordering this? Am I trying to impress some patient that I can use big words? And this means anything. So they're silly. I'm an offer doing research on HDL functionality and looking into it. So we all get a better comprehension of it. I'd love to have a test that tells us what I talk about the flux of HDL particles, how do little incy-wincy HDLs mature fill up, then what do they do with that cholesterol, and are they catabolized, are they not catabolized, are your HDLs pulling cholesterol out of an R&W and then sharing it with an LDL that might take it right back

into the R&W. So there's just so many phenomenal issues to get into with HDL, but right now don't waste your money. You're going to get an HDL cholesterol. Everybody's going to be doing a lipid panel. Do not waste your money time or your brain energy on trying to figure out these HD on metrics. So let's at that junction pivot now to more of the risk assessment stuff. We have talked probably on at least two podcasts about LP Little A. You and I spoke about it during our marathon podcast.

I think we had an AMA segment where Bob Kaplan asked me a lot of questions about LP Little A. It's still on my list of things to do. I'd love to have Sam Tameekis on the podcast for people who don't know. Sam is certainly among close to the world's experts on LP Little A. And I think, frankly, a dedicated podcast on this topic

is warranted, given that directionally, one in 10 people listening to this podcast has an elevated LP little A, and it represents, unless you correct me Tom, I believe it would represent the single greatest genetic driver of atherosclerosis. So here we have this thing called LP little A that tragically most people don't know they have. I'll tell you a funny story. Have you ever heard of this reality TV show called Alone?

No. I don't think I've watched TV in 12 years, but it now shows up on Netflix, and I do watch Netflix from time to time. So a friend of mine mentioned to me the other day, he goes, you gotta check out this show called Alone. It's right up your alley. People, they take these people

who have remarkable survival skills and they throw them out in the world's worst environment, ten of them separately of course. And basically the person who last calls uncle wins half a million bucks. So I'm into season six right now, which is, it's the first one I've watched, but it's clearly into a really nasty part of the Arctic. So I'm watching this and I'm just humbled by the fact that these people can survive any length of time. Anyway, one of the guys in the show, you learn their backstory and this guy looks as impressive as anybody I've ever seen, but somehow it comes up that part of his motivation

for doing this is he had a heart attack like the year before. And I think he's 39 on the show, implying that he had his heart attack like the year before and I think he's 39 on the show implying that he had his heart attack at the age of 38 or thereabouts. Now if you looked at this guy, Tom, you wouldn't think this is the kind of guy that could have a heart attack. I mean, he looks, he is a specimen. And of course, what's the first thing that comes to my mind? Well, I've seen this story play out 50,000 times, right?

I mean, my wife's grandfather died at 40. He was a firefighter. The first thing that comes to my mind, well, I've seen this story play out 50,000 times, right? I mean, my wife's grandfather died at 40. He was a firefighter. Fit as a fiddle dropped dead of a heart attack at 47 in my mom's dad's arms when he was 16. So I know the story very well. And to me, it's LP Little A until proven otherwise. Anjato Conner wrote a great story about this in the New York Times several years ago,

disclosing that he himself found he's a carrier of LP Little A. So always wanna make sure everybody stops, reevaluates, make sure that they aren't a high LP Little A carrier. What else is on our list of real risk assessment here? And by the way, feel free to just pile on to more LP Little A stuff, because this, to is, I mean, this, this is interesting stuff. And I do

think, unlike my pessimism around HDL where I don't think we're going to learn a whole heck of a lot about it, I think we're just scratching the surface of differentiating between really aggressive LP little a's versus not as aggressive LP little a's and I'm optimistic there. Well, you're right. And of course, on the favor of LP little a be in dangerous is a bunch of Mendelian randomization trials, which don't exist for any HDL metric or so. So right away, it's a market that requires more serious evaluation or so. You want to remind people again what it is? I guess I glossed over that, you know.

Sure, for those new to this. Low density lipoprotein is a collection of cholesterol, triglycerides fossil lipids wrapped by single molecule of apolipoprotein B because of the size and density. It falls within a certain fraction of that centrifuge tube and it's called low density.

But all lipoprotein subclasses are heterogeneous. They consist of big particles, small particles, or maybe a particle carrying something else that doesn't really change its density that much, so it separates with the LDLs. And LP little A is basically, you have your LDL part of this macro molecule, but coattached to the APOB structural protein is another protein that shouldn't be there. And it's called APO-protein-Lyll-A.

And by Lyll-A, we mean small case, not a capital A. And that molecule that attaches APOA, can vary in molecular way, size, length, etc. but that's beyond this discussion. So it's in LDL, it's carrying an extraneous passenger. And here's the problem. We know people with high LP little aid. God, they don't seem to be bothered. They're not coming down. There's no premature family history in them. And other people's, the example Peter just gave my God, there are athletic rex at young ages. So I also just, as I've sort of iterated about other lipoproteins, I think when we're talking about LP, little A in the year

2020, we aren't talking about all right, let's, what's its mass, what's its LP little A particle number, but I also think we have to be smarter on understanding the quality or other attributes of this LP little A particle. What makes this APO little A attachment maybe terrible for that guy who had his heart attack at age 38? But here are other people who are coming in and age 80 and they got a lot of LP little A and they're not full of plaque or so.

And one of the things we're beginning to understand is look, APOA has potentially some thrombogenic properties which perhaps get expressed in some people more than others, but more, more one of the functions perhaps even of APOA wide, even evolved is a little scavenger protein that attaches to oxidized lipid moieties, specifically oxidized phospholipid oxidized sterols. They bind to it with great affinity and maybe that little garbage truck full of oxidized particles, if it could bring it back to the liver or some other tissue that could catabolize it, those oxidized lipid moieties, which tend to be destructive to cells, are

not getting to cells. So we are beginning to have metrics that are starting to appear and available in the real world, that we can measure the oxidation, the oxidized lipid moieties that are on apolidil A. They're actually, it's called oxidized PL fossil lipids on APOB. And if you say, well, these oxidized fossil lipids are on all the APOB particles to a minuscule degree for because of the affinity of oxidized lipid moieties to APOA, the overwhelm, if you have a positive oxidized fossil lipid APOB, the overwhelming majority of APOB particles, trafficking

those oxidized lipids are LP little APOB particles. So two people came to consult me tomorrow. They both have an elevated LP little A metric. One has a normal oxidized phospholipids on APOB, but the other one is elevated. Based on Sam Simeckis and others' work, I'm going to be a little more worried about that person who's, my god, not only do they have this undesirable particle, but this particle is loaded down with injurious other lipids that are potentially very harmful. So that's one aspect of it. We're nowhere near being able to test for the thrombogenicity, if that's a big factor of April, little A and everything. So there are other ways of doing this.

I mean, all the time when I get my weekly email from Peter T, here's the podcast this week. I'm waiting for Sam Simeka. So, but for those of you still waiting for Peter to nab him, he's pretty active on Twitter. And he really tweets a lot of good information on the cutting edge of what's coming down with LP.

I think it's LP, little a dash underscore doc something like, but go on Twitter and Sam Samek is T S I M I K S and you'll be happy you followed him. So there's just a lot to understand Peter. So it's who has it. And by the way, the new guidelines are the European guidelines suggest that everybody ought to have it once in their life as they approach adulthood. And you never need repeat it unless somehow you're trying to modulate it or maybe you go through Metapol as where it can go up a little bit, but it's genetically determined marker you have it or you don't have it. If

you don't have it at age 18, you're not going to have it at age 68. So it's a one time test. And it helps us before we talk. Let's do thorough cardiovascular risk assessments, no matter what your APOB is. And this would be one of the tests that at least the Europeans have signed on to now, the National Lipid Association, other people have issued guidelines to it. And they're still telling you, well, do it for unexplained heart attacks or strong family history of heart disease. To me, it's, again, it's not a very expensive test, get it once or for all, but there's so much to talk about this, Peter,

and in the future, I mean, there are ways, what would you do for somebody with high LPL in the late? We have strategies, which is mostly attacking APOB right now and any of the other cardiovascular risk factor, but there are drugs in the pipeline that may give us better alternatives to perhaps stop your liver from making APO, little A. Let's talk about that a little bit. So up until I would say a few years ago, the only strategy for patients, let's assume that we've confirmed that a patient's LPLidilay is elevated. And furthermore, let's confirm that we have reason to believe that in that patient, the LPLidilay is also problematic.

And again, this usually shows up in family history. It's not a subtle thing. A lot of times, I'm taking the family history from a patient before I've got the blood test that'll be there. Those could be offset by weeks. And it's because we give our patients the template to work on this, they come in with a very thorough family history. They really know what happened to, you know, the mother's older sister and the grandfather and all of these other things.

And, you know, you usually just see this history of history of lots of heart attacks before the age of 60. Obviously it can be confounded by people who are heavy smokers and things like that. But. Yeah, let me just interrupt you for one second. It'll be a minute because published yesterday in the Journal of the American College of Cardiology is a study and a fantastic editorial.

And they looked at people with terrible family histories of heart disease and people who had LP little A issues or they didn't and the conclusion was simple. Don't have high LP little A if somehow you can avoid that which you can't. Don't have as terrible family history of coronary arteries and I don't know how you avoid that. But if you want the worst scenario, don't have both LP littleP. Little Amphus. Peter, what Peter is just saying is, now backed up by a nice study. Yeah, I love the best advice is choose healthier parents. So let's assume we're in that situation, which is we have high L.P. Little A,

and we have the family history that is not favorable, or something else that's even more germane to the patient, which is a positive calcium score, something to that effect. Well, again, historically, our best bet would be remove all other risk to the extent that it is possible. So we lower all other APOB maximally, pharmacologically. We optimize completely all of the metabolic parameters that we've discussed briefly here, but touched on in greater detail elsewhere. And that includes everything from modulating blood pressure as aggressively as it needs to be to controlling all of these other factors that don't get enough attention in my book, the

uric acids, the homocysteins, things like that. But then as you point out, there's a strategy now that says, wait a minute, what if we knock out the liver's ability to make apolidol A? And all of a sudden, you wouldn't have an LP little A. So what does that strategy look like? And where is that strategy in the pharmacologic pipeline? In pretty early trials. And of course, any cell, we're talking about the liver here, if the liver is the primary side of production of April, little A, and it is, if we could mess with the genes to ASO therapy, we could probably stop a cell from making a given protein, if we can stop the liver from making April proteinin little A, if you don't have that, you certainly the liver can't secrete it so it can attach to LDL particles, transforming them into LP-little A particles. So that's almost like a no-brainer.

The Mendelian randomization trials don't have high ApoA or LP-little A. So let's just interpret it synthesis. That's what we've done with other things that contribute to coronary order disease, and that has to work. Yes, provided that protein doesn't screw or that ASO treatment doesn't screw up something else or cause a downside to it. And that's why you ultimately have to do large clinical trials, looking at not only event reduction, but safety.

But those drugs are in early, you know, and like anything else, the first generation of those anti-sense oligosaccharide drugs that came around, they've perfected them. So there's a second generation of them now that they've made even more hepatoselactive so they can dose less of it. And it goes right into the liver but there phase one, phase one, dash two trials and Novartis, I believe, has now acquired the product that they're going to put it in a major which has just started enrollment of phase three trial on, let's not. But here's the problem. Peter knows the billions that probably you have to be invested when you're

developing a drug of that type of magnitude to reduce something. You're not going to do it on every time that can harry who has a trivial LP, little A. You want that first trial to work. Because if it doesn't, that's it. The drug is dead. It'll never be tested in lesser risk people.

So the only way you can get into this current apolidil A synthesis modulator drug is you have to have had an atherosclerotic clinical event in myocardial infarction stroke, blah, blah, blah, stents, and you have to have an astronomical, like upper quintile concentration of LP, little A. Because Bendelline trials suggest if you're going to get benefit by lowering April little A or LP little A, it has to be a pretty significant drop in it. So you're not going to take somebody with a trivial LP little A elevation and, you know, if you're chested 50,000 of them, maybe it would work. So if they go through this first trial,

and it'll probably take three, four, five years to show efficacy and safety, then they're gonna have to maybe do some sub-trial analysis. And then is anybody even gonna fund the primary prevention trial with this drug, with the cost that that takes? I don't know. So even if you're, somebody who's had a heart attack

because of LP little lane, you're waiting for the stroke, you got five, ten years to wait. And for primary prevention, go on to other ways that clinicians are attacking this problem right now because you're not going to have anything. Why is it that statins, which are probably the most potent drug until five years ago to lower LDL and by definition, then lower APOB concentration have virtually no effect on LP-little A. But this new class of drug that's been around for five years called PCSK-9 inhibitors, well, even more potent in lowering LDL seem to also be able to lower LP little A.

I think there's two reasons there. And one, we've gotten enough trials now that seem to show, depending on your APOA makeup, do you produce the large high molecular weight APOA or the smaller low molecular weight APOA, which in epidemiologic trials seems to be way more associated with atherosclerosis, that if you're one who does produce the low molecular weight, short APOA, which means because it's

such a small protein to make, the liver can make a ton of it, see, create it. So they actually, even though they're molecular weight of apolilay is lower, they have much higher LP little A particle counts. If you have that isopharmate LP little A, statins can induce the synthesis at statins do not affect the synthesis of the larger APOA moiety. So in some people, Peter says statins do not much to LP little A concentrations, but there is a small component where statins do not much to LP little A concentrations,

but there is a small component where statins will actually raise it a little bit. And people get scared, they go, well, I'm lowering LDL cholesterol, LDL particle counts of tab, but I'm raising LP little A. Even Sam Semykas will tell you, don't worry about it.

LP little A, if you learn nothing else about our LP little A discussion is a minority LDL particle. So even though if you have the small isoform a statin, maybe raising LP little A a tad, it's so blowing away the LDLs that don't have APOA attached to it, that at the end of the day, you have less cardiovascular risk. And that little excursion in L.P. Lidelae concentration is probably meaningless. Now, to go on to the second part of the questions, the PCSK 9 inhibitors don't have an effect on the synthesis of ApoA in the body. So at least they're not aggravating it in some people. But we're still in our infancy trying to understand how LPLidLA particles

are. Intercontabularized are cleared, and it's probably due to multiple receptors. The LDL receptors part of it, and a PCSK9 can give you more LDL receptors than a statin probably can, putting aside the synthetic interference with it. But PCSK9, their finding has effects now on APOE receptors and three or four other lipoprotein, clearing receptors that are expressed in liver and other cells or so. So, I mean, there's got to be better clearance

of the particles with PCSK9 inhibitors. Then there is with LDL receptor expression with statins or statins, plus whatever other APOB lowering drug you're going to add to it or so. So I think that's where we're at right now. Most of the time these people are going to wind up on statins, plus PCSK9 unless they can't tolerate a statin or there's another reason not to use a statin. So that's my explanation right now, Peter. I think we touched on that a little bit in the last podcast and we still don't have a

lot of info and clearance of the LP and L.A. particles. And as you said, it's quite variable. I mean, we've seen patients where they're on a PCS and I inhibitor for other reasons. And every time I put somebody on, when I recheck their LP, LLA, just different other reason than to gather our own data on how much of an effect the drug, either probably went to Repatha, is having on LP, LLA.

And the range is zero to 60, 70% reduction. I mean, that's literally how broad it is with probably a median reduction of a third. Yeah, so two important points here. One, LP little A is not an acceptable goal of therapy because there wouldn't be trial daddy. So even though we all think that's probably going to be good, but I think most people like Peter when he prescribes it, I don't sort of like to at least see what happens to get

his own information or so, but realize that's not what you're making a therapeutic decision on per se is the LP little a concentration. So just keep that in mind when you're following up on these people. One last thing I want to circle in on you with that you and I spoke about a couple of years ago, it was an experimental metric that was being bandied about. In fact, I remember you guys ran it at THD on some of my serum, but I don't know that I'd ever saw the commercial light of day, which was, I think it was like LDL triglyceride concentration. Have those tests ever seen the light of day? I think if you look around enough, you might find a lab. It's a very easy assay,

Denka makes it where you could get an LDL triglyceride level. And by the way, just another thought jumped into my brain on that LP little A. As I told you, there are other things that attach to even LDLs and HDLs that make them less clearable or more atherogenic and a very recent study show believe it or not there are LP little ap articles that carry apoc3. You're not going to clear that particle if you make it so double whammy. Yeah, oh my god. But anyway, back to LDL triglycerides. People I often tease Dan with, you said, you know what, we're really cost effective. We're only going to allow you to have one lipid concentration on this person. Nothing else. I would tell him, give me an LDL triglyceride level, certainly

not an LDL cholesterol level. And remember, apobesal, lipoprotein metric, not a lipid metric, so that's what I would really take. But the triglyceride part of the core of any lipoprotein has a lot to do with plasma residence time of that particle, what else might be attached to that particle, even I alluded to it a little bit in my brief HDL discussion before. Dan Raider calls him fat HDLs. What if your HDL particle is not carrying very many cholesterol molecules, it's carrying triglycerides. Well, he's shown, God, that was a decade ago,

to those fat HDLs, meaning triglyceride and rich are dysfunctional. They're carrying some of the bad stuff that HDLs are carried at, don't allow them to do their cardio protective functions. So if triglycerides gets into an LDL, number one, what happens to an LDL that's floating around? And it might still be a big LDL because it's full of triglycerides, it's not cholesterol, but it has a very great affinity for light-paced enzymes that line our arteries or the surface of the liver. So a hepatic light-paces of very potent triglyceridase phospholipase that is just like a fly trap looking for flies. It's looking for triglyceride enriched HDLs. And if it binds to it, it will extract

hydrolyze the triglycerides. So if I had an LDL full of triglycerides and I pulled the trig out, what am I left with? Well, that's an LDL particle. It's lost a lot of surface phospholipid as well as a lot of core triglycerides. I have the so-called small LDL or dense LDL. I try not to use both adjectives together because they're redundant. And we have plenty of evidence that, yeah, it's no good to have an increased total LDL particle count. But if try not to have too many small LDL particles, because the evidence has certainly emerged that particle for particle, they're probably more arogenic than the more buoyant, larger LDL particles for a variety of reasons.

And the bigger non-traglistered rich LDL, it might be a better fit for an LDL receptor. It's going to clear it. So LDL triglycerides, basically, if you told me it was high, I know you probably got a high LDL particle count, APOB. I know you have the small LDL particles. I know where those triglycerides probably came from. Your VLDL triglyceride rich particles, your chylamicron particles,

and when they transfer to triglycerides to LDLs, they become remnant lipoproteins, which Peter has alluded to. And you can bet those same triglycerides are invading the HDL particles, contributing to HDL functionality. And last but bet those same triglycerides are invading the HDL particles contributing to HDL functionality. And last but not least in the studies where they've looked at LDL triglyceride, many of the

inflammatory markers are high because those particles settle off the inflammatory zone and various endodelial cells and elsewhere. So it's a really simple, easy to do metric that could tell us so much. And I think if I saw it was up the first thing I'm saying up, I'm dealing with an insulin resistant person because that would be the most common cause, not some genetic triglyceride problem. Right.

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

for the additional VLDL by adding the VLDL cholesterol. What is your take on the idea of non-HDL cholesterol versus APOB as they are somewhat proxies for the same problem? Well, I'm an SNYDerman school, and he's published on this extensively. I find it, All right, it's probably gives you a little bit more information for the reason you just described versus LDL cholesterol. Yeah. Beyond LDL cholesterol, but as Snoterman has clearly shown in several studies, even though non-HDL cholesterol correlates with APOB a little bit better than does LDL cholesterol, there's still 20, 30% of the population in our diabetics insurances, and we're there discordant, and where there is discordance, even with non-HL

cholesterol and APOB, risk follows APOB. So why am I wasting my time with it? It's all useful. It might help you pick what therapy you want to use, but at the end of the day, I see no need to follow your non-HL cholesterol and following APOB because I'd be a fool if I told you I normalized your non-HL cholesterol and I eliminated your lipoprotein mediated risk. Until you measure or re-quantitate of these particles, and if we ever got a quality test, that's a silly thing to say to a patient. Yeah, exactly. We saved $3.

Yeah. And we might spend a little time or you're very good at explaining it. How do you determine VLDL cholesterol in your patient's peter? You're not dividing triglycerides by five, the old three-to-world formula. No, so we use a lab that is actually giving a VLDL cholesterol. And even if they didn't do that, we would still take total cholesterol and subtract from it LDL cholesterol and HDL cholesterol, not perfect either because in that situation, sometimes the LDL is calculated. But I always do a back at the envelope trig divided by five. It's not close enough. No, that's true. And listen, you made a key point here,

which maybe you went over people's heads. You cannot do that calculation. If you have a calculated LDL cholesterol, you must have a directly measured LDL cholesterol. Because total cholesterol is LDL cholesterol, V LDL cholesterol, and HDL cholesterol. So if you subtract a directly measured LDL cholesterol, VLDL cholesterol and HDL cholesterol. So if you subtract a directly measured HDL cholesterol, I directly measured HDL cholesterol. In effect, you have a directly measured VLDL cholesterol, which in our current world is

as bad as close as you're going to get to an evaluation of remnants. I think in our last podcast, we talk why there are exceptions to that rule, and that's a more complex discussion. But please, you can't get VLDL cholesterol using the free to world calculated, healthy, alcohol, cholesterol. All right, let's talk a little bit about therapies. Statons have been around forever. They still take up most of the air in the room. They are the workhorse of lipid lowering therapy. Is there anything new and exciting to talk about? I would say that there's no new statin on the market today that wasn't there two years ago. Is the most recently

introduced statin live-alow? Yeah, and that's probably 10 years ago. live a low. Yeah, and that's probably 10 years ago. Yeah. What was it? What do you make of that, Tom? Why are we not seeing more statin innovation? Two things, I think third party payers would never pay for a new branded statin. They're going to always insist you use the cheapest generic that's appropriate to the degree of LDO lowering that you need. So there are seven of them on the market now. So I don't think a bean counter at some farm is looking for, let's get a new statin. We're well aware of potential downsides to statin,

things we have to look for, who tolerates and who doesn't. I don't know that there's somehow going to invent a new statin that brings none of the potential downside of a statin to the equation. So they're looking at other therapies that will now that we understand it's after a genoclypo proteins that will reduce that. And if your investment pays off, you'll have a branded product for X number of years and you might get a little return on your investment. So I don't think we're going to see another statin right now. The biggest thing that's happened with statins and in a guy, you know,

any old days when we had nothing else to do and we didn't know a lot about all this life of protein stuff is, hey, you got that most trivial elevation of some LDL metric, mostly LDL, you're going on a statin, I want them in the drinking water. Any old days, oh Tom, I just took a statin because they just reduced heart attacks, you and I know there is an event reduction, but there's plenty of residual risk, even if you're aggressively using a stat. And so there always is more to the story. But I take the newer guidelines, give you a lot more ability to ascertain in a given individual, after you do your thorough cardiovascular risk assessment, you and I do our own risk assessment,

which is a little different than what the guidelines might offer. But then once a person crosses a certain threshold of athletic risk, then it becomes plausible to consider a stat. And there's more to it than per se the LDL cholesterol level. There's all those other factors that go into risk assessment. And there are other adjunct of diagnostics now. Earlier, we briefly alluded to coronary calcium scoring, LP, L.A. They would be things that current guidelines says, if you're hemorrhoon, should I give

a statin, should I not, or the patient, I don't want to take it, at, hemmin or horn, should I give a statin? Should I not or the patient? I don't want to take it at least to a CAC, at least to an LP, little A. Look at the family history, as you mentioned, look at the blood pressure, other concomitant risk factors. In fact, at that end to do I want to use a statin or other APOB lowering therapy. So that's the biggest change with statins. Nobody's saying, hey,

they belong in the drinking water. You should carefully choose who you're advocating stat and therapy to any sort of rules of thumb just in terms of the alchemy of this. You mentioned that there are seven out there. You know, in our practice, we really only pick from four of them, live a low crest or lipitor and prevastatin. I mean, most of these are generic now. And if you listen to the podcast with Catherine Eban, which I know you did, we are actually still pushing for branded whenever we can get it. And if we're not getting a branded version of those, we cross check with who the generic supplier is. And we've seen differences,

right? We've seen that a two versions of Razoova statin can produce different outcomes. So, our default position is that all generics are crap until proven otherwise, and that's why we use a tightly controlled list of meds. But I don't think I've ever prescribed Symba statin, for example. What's your take on some of the older statins versus the... I mean, the reason I think we look at preva and live-alow is mostly for the sensitive patient and then crestor and lipitor, resuvestatin and retorvestatin being kind of the workhorse. Yeah, well, you're just too young, Peter, and all foggy's like myself. A low-the-statin or mevacore was the first statin that came around, send the stat and was next and in Pravastatin, Pravacol came.

So, we have a lot of experience with those drugs, but as time went on, and pretty early on, there was a pretty rational thing that whatever the reason, Pravastatin is a safer stat and to use then, send the stat and or low the statin. And it turns out that was mostly related to drug drug interactions where Travis statin is pretty clean. Subsequent to that, the only statin

that is even cleaner than Travis statin on drug drug interactions is the live-alow. So, Patavastatin would be its generic name. So that's in today's polypharmacy world where we're not only even talking about prescription products, but the multitude of supplements or God knows what people wind up taking. We have no way to check on drug-jog interactions. So you're probably going to get into less trouble with Pythagestatin or Pythagestatin. Of course, a long came Resuvastatin, many years later after Pravastatin,

and it shared some at least pharmacokinetic attributes with the Pravastatin, and that it was a hydrophilic statin, kinda hepatoselactive, but it was way more potent on a milligram basis than Pravastatin. So it became an over that evolution of all those early stands, you know, every three years we had lower and lower and lower LDL metric goals, which weren't

there when we first started. So what used to be acceptable is no longer acceptable. So it was very easy to transform from the hydrophilic pravastatin to the way more potent hydrophilic, Resilva statin. And that pretty much was my statin of choice thereafter, unless you had a putts around because of statin intolerance, where you would try some of those other things. Personally, once all this was known and once Resilva statin hit the market, I don't think I ever prescribed another lipitor dose again, unless, you know, third party payers are influences here.

They sometimes tell people you either take this one or here's what you're going to have to pay if you don't go on our formulae. So that can factor into its use. Now lipitor is a potent statin, milligram per milligram. It's not as potent as a result of a statin, but you can get whatever LDL reduction. If you use a higher dose of lipitor as you can with a somewhat lesser dose of a result of a statin, but you can get whatever LDL reduction. If you use a higher dose of lipitor as you can, what if somewhat lesser dose of a result of a statin? So unless the third party payers telling me to use it, I'm probably not going to advocate lipitor. Just do more drug drug interactions and it is lipophilic. There's perhaps other issues at play. You and I have talked about statins ability to get into

the brain and everything where lipophilic statins might be have a little more bit propensity to do that than hydrophilic statins. So the other issues at play that would influence where you're going, the other thing that and I'm going to disagree in it, I think it's the way you practice too, all of the guidelines right now say, okay, you've made a decision to use a statin. Pick the two most statin, the most potent statins, that means you're on lipid or crest or and prescribe it at the maximum dose. Because the weighty striles were designed, you know, lower is better, they all, you know,

they, very few trials where they took people with minuscule LDL cholesterol levels and just statins at them. So they want you to get, hey, the clinical trials shows this statin at that dose works. Maybe there's pleiotropic effects that statin is doing too. So how do you know you have to be evidence based? I don't buy it. I think virtually all of the statins contribution to atherosclerosis reduction is April B reduction. And I think you've known me long enough that rather than maximizing a stat and using the gorilla dose day one, I would prefer to start with a smaller dose. Again, dependent on your risk and your metrics. I mean, if you're coming off in a Q-carner, Sinjome and your LDL metric is off the chart, okay, I'll start with a big one. But I'd rather take

that baby stat and meaning a lower dose of a stat, and perhaps optimizing it with a second APOB lowering drug. And for the longest time, we had a Zedemaib, which has since been proven in clinical trials to further reduce benefit and also in Mendelian randomization trials, looking at the Neiman pick protein. And now we have the new guy on the street, this Ben Padolec acid, which is a weaker cholesterol synthesis inhibitor affecting an early on, cholesterol synthesis step, also that has Mendelian randomization support. And if you can't use

a statin, or if you can use a statin, if you add distutastatin, or even the triple therapy statin, as I said, Ben Padolec acid, maybe you can avoid the expensive PCSK9 inhibitor. So we have a lot more therapeutic options now, the day after. And then talk about the differences in the synthetic pathways between these two drugs or where are they targeting the synthetic pathways and what makes them different.

Is one more hepatic selective or is it really a question of potency with respect to where they're blocking the chain? Yes. The cholesterol synthesis pathway, something like 37 steps, each step has its own different enzyme, catalyzing, catalyzing the transformation of these precursor products into the next down the stage. Stattons happen to inhibit what's called the rate limiting enzyme. It's the third step in the cholesterol synthesis pathway. And of course, that's modulated by the enzyme HMG, CoA reductase.

Statins pretty significantly in a dose dependent fashion, inhibit that enzyme, so you can seriously slow down cholesterol synthesis in various cells. The one cell we really want to do it in is the lever, because that's the cell that has the greatest propensity to upregulate LDL receptors that can clear our APOB containing particles. So, statins, do that. Now, if you can deplete cholesterol pools beyond what a statin can do in the liver, you will express more LDL receptors. So,

when we use his atomite, we block intestinal absorption of cholesterol or backflux of bioclastral into the liver, further depleting hepatic cholesterol pools, you will get more expression of LDL receptors. So now we have this new bempodobic acid. It's called an ATP citrate liase inhibitor. Well, the first step in cholesterol synthesis is citrate, Nademiroconja coming out of the crebs cycle, is transformed to acetyl-CoA, which then goes down and becomes, after it becomes HMG and then the subsequent things. So this Benpidoric acid is called an acl-atp citrate liason

inhibitor, but it's a pro drug. You swallow it, it's only uptaken by the liver, and it inhibits an enzyme in the liver that you can't make acetyl-CoA. So, hey, the less acetyl-CoA you make, you're going to make less HMG. And therefore, you'll have less substrate for the statin tadon. So, collectively, you get additional APO B lowering. The cool thing is, because one of our biggest downsides to statin is people get these myopathic symptoms, be they weakness, muscle aches, or whatever, you know that. It's a big problem with statin therapy, probably more prevalent than what clinical trials would show us. But this bentoic

acid is not have any uptake in the muscle cells. There's a specific receptor that pulls it into the liver. So it is hepatoselective. Look, Resuba statin is somewhat had a hepatoselective because there is a special cellular receptor that pulls in Reservus statin, but other cells can pull a Reservus statin. Reservus statin can give you muscle aches. So it's not quite as apatocelectic as Ben Padoic acid. Do you know what they saw, Tom, in the trial versus placebo for muscle soreness? Because even PCSK9 inhibitors still had some noise with respect to muscle soreness even though mechanistically it's not entirely clear why whereas at least the stat and there's

some explanation as to why someone could experience muscle soreness I'm just kind of curious as to what the head to head. Yeah no they did look at that and it's not zero so there are still people who but they've also shown studies that you can give you a placebo. And people get muscle likes too. So, but it's, you know, and they did comparative trials versus a statin versus a placebo. And there is definitely less with it or so, but it's not going to be zero. So it's worth a trial if you're really hung up. So I take right now it's use in it. The FDA approved it. The FDA says, look, you've got to go do a big outcome trial, which the company is doing. But Mendelian randomization suggests it would work.

Before we ever had outcome trial, as Adam, I Mendelian randomization data suggests that reducing cholesterol and intestinal absorption would reduce cardiovascular events. That turned out to be so. So they only had to do with a certain amount of Phase 3 safety trial in the FDA led to come on the market. And its use was you can add it to a statin in people with familial hypercholestolemia, who the statin probably is not going to get you to gold by itself. And you can combine it to that, or even very high high risk people where you didn't blow your LDLC

down to 70 or 50, whatever you're trying to do it, you need a junk to build the LDL cholesterol apobelowing. You can co-prescribe the bempidoic acid. And they also allow you to co-prescribe is that amide with it. In fact, the company that manufactures this and the brand names called Nexatoll, they also have been given FDA approval because there are a lot of statin intolerant people out there or people who need triple LDL lowering therapy that we're going to give you a combo product which is Ben Padolic Acid plus Zedamib. I guess it's priced a little cheaper. So rather than swallowing two pills, you could just take that combo pill, you could add it to a statin or not. And look, I think for the nightmare of the little world,

you could ultimately, if you had to add PCSK9 inhibitor, the end of the day, if you're good at individualizing your therapy, I think we have four APOB options now a day. And you're going to go down a fairly standard path because not everybody can afford a PCSK 9 inhibitor, not everybody might be at the type of high level risk that the FDA wants you to be at to or the third party payer wants you to be at. But it's a fun time to be in the April B world. We have a lot of therapies and we're not even talking about addressing triglycerides, which there are therapies that do that that might contribute to April B. Lowering also. This patent works a lot by the hepatic upregulation of the LDL receptor.

Do we think that's the case here as well, or do we think that this is more about the actual reduction of cholesterol synthesis? But remember, if you inhibit cholesterol synthesis, you're going to deplete hepatic pills, a cholesterol which will, through the sterile regulatory element binding protein, upregulate LDL receptor expression, perhaps some VLDL receptors or other things like that, APOE receptor. So who, at the end of the day, probably depleting hepatic cholesterol pools is what you're doing. And still it's primary driver. So really, at least on some level, Bempidoc acid is attractive because it's more hepatic cholesterol pools is what you're doing. It's still its primary driver. So really, at least on some level,

bempidoc acid is attractive because it's more hepatic selective, even if it's less potent. And remind me again, what do we think is the relative potency compared to a set? If you look at its monotherapy trials, it's like a zedabyte. You're going to get anywhere from a 10 to 18% lowering of LDL cholesterol by itself at atlas apob 10 to 12% if you use that as a monotherapy. As you know with a Zedomide which statins there's a wide range of responses. I think with all these drugs there are hyper responders,

middle-iterode responders and hyper responders and I think that probably has a lot to do with how much synthesis of cholesterol, how much absorption of cholesterol, what type of LDL receptors do you make or express? So there's a lot of factors at play, but if you want a generalization, that's what it is. And now you alluded to it, but what do we think about in terms of what's changed in the last couple of years in terms of our thinking about EPA and DHA specifically?

Well two things, and it's been a long time, and nobody has respected triglystides more than I have been lecturing about triglystide rich lipoproteins forever. And I knew, despite all the nonsense that it doesn't matter what you do to trends, you don't reduce events like you do with LDL cholesterol, because of improperly designed trials and enrollment of people basically didn't have triglyceride issues and giving them triglyceride lowering drugs. But anyway, we're far enough down the road that not only does the Mendelian randomization trials certainly suggest, look, there are certain genes that are involved with triglycerides that are seriously involved

with atherosclerosis. So it's very plausible if at least true dose mechanisms we improve triglycerides, you're gonna reduce disease. So for the longest time, what was our other than lifestyle, what was our way to lower triglycerides? We had niacin around forever, we had the emerging fibric acid story, which progress, progress, progress until the terribly improvised trials that were done to, let's

see if fibregal works, they didn't give them to anybody who had triglycerides. So, of course, the fibregal didn't work. But there's always been this, hey Omega-3s really are a potentially triglyceride lowering drug. And maybe we should use them. Anybody who's known Bill Harris for the longest time as I have you have? No, yes Omega-3s. If you really want to get triglyceride lowering from an Omega-3, you better be using serious, serious doses of the... You don't give a gram, you don't give two

grams. If you want to get rid of triglycerides or better yet triglyceride rich lipoproteins. If there are other attributes to omega-3s, we have no way of measuring that. Now, none of them are almost certainly are because omega-3s are a crucial part of cell membranes and cell signaling. But if we're just going to deal in our lipid world and you want to have an omega-3 on board to help you combat triglyceride-rich lipoproteins, you want to have a maximum dose, which looks to be 4,000 milligrams a day. So this was the belief, Bill, you still always listen, don't tell me that you gave somebody a thousand milligrams

of omega three and you didn't reduce heart attacks. The odds are strong. You could never reduce heart attacks with that drug, you know. So now we got confused because as we started to realize this, they started to do trials. Well, okay, let's give four grams of omega trees and let's really not make the vibrate mistake put them in a drinking water. Let's enroll people into these trials have high triglycerides. Many of those people also have concomit and low HDL cholesterol, but that necessarily doesn't have to be an entry criteria. But you better have a triglyceride level above a certain degree.

We're not going to waste our money given omega-3s to people with triglycerides of 42 And lo and behold the first trial it started to come down the pike was done in Japan So God probably almost a decade ago to Japan EPA trial You know in Japanese people eat a lot of Omega-3 so they have higher baseline levels anyway, so they just gave them for for whatever reason, EPA only, on top of a statin. And they didn't necessarily have to have high triglycerides, but many of the people did. And lo and behold, although it was not a blind detrial, evidence was pretty good. Wow, this is really plausible that EPA had high dose, four a day reduces macro vascular outcomes when

given with a stat and that of course is working on the LDL metric you're looking at. So of course people say, that's proving omega-3's work. Nobody was given a lot of credence, perhaps other than the people who produce it, that ODIS is unique to EPA. Most people are taking Omega-3s, are taking some combination of EPA and DHA, but as long as you're going to take four grams of that, why wouldn't it do exactly? So here's what happened. So after that EPA trial, the company that makes the branded EPA medication, which is Visepa, Amarin is the company, did a major clinical trial called Redoosit, where they enrolled people with who were taking whatever statinia had to take to get their LDL cholesterol below 70. And in general, these were high-risk people. They had some

degree of carnage, these are they were full- full blown diabetics or had a lot of cardiovascular So it wasn't a low risk primary prevention type of study You had to have a triglyceride above 137 to get into that trial most people it was 150 but you know to triglyceride assay always varies plus or minus 15 points So they would let you come in if you had a 137 because I thought in a week, you're going to have 150. So they enroll people, that was the cuddle off. You had to have that. And low and behold, and you were maximized on whatever stat

and it took to get your LDLC under 100 at the time. Pretty good. And low and behold, and we haven't come up with much in the world so far. At least it has a big trial saying, we lower residual risk with a stat. Is that a my did it in a QCarnay syndrome survivors to a certain degree?

But this high dose EPA, two grams twice a day with food, because it is an ethylester. Theoretically, it needs to be de-astarified before it's absorbed. The oil was almost a 30% residual risk reduction. That's mind-boggling to be on after taking a stat. But there was still say, oh, that's fantastic. We all have to start using omega-3s at the appropriate dose, way more than we ever did.

But a lot of believers, and I think probably Bill Harris and myself said, yeah, but we could also just give four grams of EPA plus DHA because deep down many of us believe DHA is a pretty important omega-3 fatty acid too. If for no other reason in your brain needs it, but I believe also membranes need to a certain extent. And not everybody can convert EPA to DHA, although most people probably can. So AstraZeneca had acquired a free omega-3 fatty acid, meaning it's not an ethyl ester, which means it has a better absorption, better pharmacokinetics, more bioavailability. And it was called epinova, but it was EPA and DHA, but free EPA and free DHA. And A and roll basically the same type of people, high triglycerides, maybe DHA, cholesterol

is low, at risk people. And two years into the study, the company just stopped the study. It's never been published, so we don't know, but the reason was it's futility. We're not seeing a signal at two years that it's going to work. So we're not wasting any more money on this. Yeah, this was last November, right, Tom? Yeah. I got to tell you, this caught everybody off guard, didn't it? Because surely caught me.

It was certainly announced that the study was being stopped. And I would say most observers, myself included, felt, oh, wow, they're stopping it because the signal is so big. And then they announced it, the cardiology meeting actually had stopped because there's no signal. I'm a little surprised it hasn't been published yet, are you? And annoyed, to be honest with you, is there something that are hiding that didn't come out in that press

release or the early discussion about it or so? So are there subgroups in there where maybe, yeah, I understand these trials are super expensive and where they say, hey, we're cutting our losses, we'll have to take this out to five or six years before we ever see a signal. And I wish they had done that, but it's not that. But then they wouldn't have made the announcement.

I mean, I guess to me, the thing I'm trying to understand, they would have announced it if they're stopping it. Yes, yes, yes. Yes, I'm saying, but if they were going to keep running it, they probably wouldn't have and made that announcement. Oh, no. And so the thing that I'm trying to wrestle with, which I shouldn't spend any time on, and I'll just wait till it comes out, is how much of this is the vehicle versus the EPA DHA split?

You know, you got to bring Bill Harris back on. Look, technically, that should, if what we want to do is achieve a certain level of omega-3s in our blood, be it in a red blood cell or a cell membrane, where we would measure the omega-3 index, which they did not measure the omega-3 index, which they did not measure in the reducer trial, or whether you just wanna reduce plasma free fatty acid levels. And by the way, that they did do in the reducer trial,

or no, it's not been published, yet it has been presented, that the efficacy of the EPA-only product highly depends on the level you did achieve with a serum. So, again again to me that supports going with four grams a day. Don't think you can get away with two grams a day. Perhaps unless you're really checking the levels, but even that would be guesswork. So to

take home points right now, people ask me Tom EPA or EPA DHA if I want to be evidence based and you're in a type of risk category, I think you got to go with EPA for grams a day What if triglycerides are below 150? What about the person with trig's 100 who still has residual APO B risk? Yeah, it's an unanswerable question right now. I'm not afraid to keep using EPA DHA Whatever the magical mystery effects of a EPA are, you know, our all theoretical at the given moment, and they're checking a lot of biomarkers to try and explain this, and it's all winding up in this massive inflammatory world that's maybe it's to do something or self-signaling world. Yes, but your brain needs some self-signaling from DHA too. So if I'm gonna throw four grams of EPA at you,

I, as you know, I'm a big advocate of doing the Omega-3 index. So if I'm giving you four grams of EPA only, but your Omega-3 index shows me you have adequate DHA in your system. I know some of that EPA is being converted, so I'm kind of happy. And I don't perhaps necessarily have to co-prescribe

some degree of DHA with you. My worry would be what about somebody who's taken the four grams of EPA and the omega-3 index shows you're still deficient in DHA? Then I think you got to scratch your brain and do what you want to do and might be, hey, let's start giving a little DHA. You know, but I can't buy into the concept that a little bit of DHA is negating EPA. Maybe that's true. And that's what the EPA purists will tell you. Well, hopefully we have some published data in the next six months that can at least give us a hint. I don't think this study had enough in common with reduce it to answer that question, but I think it could

potentially give us a clue. Yeah, and we're getting more and more data. They're doing additional trials with EPA and they're doing more subtrial analysis. They've even shown some angiographic data with, despite that great reduction residual risk, if you actually look at plaque, it looks a lot better when you're taking four grams of EPA. So that's pretty encouraging of that type of study anyway. You know about predicting what a plaque image shows an event reduction, but good nonetheless. Anything else on the pharmacology side Tom, that's really interesting to you, especially in the last couple of years, because I like the way we've sort of at least tried to bring people up to speed on what the big changes have been.

Listen, I still think fibrates are widely underused drug. I think for the right person where you've through whatever method you use have identified triglyceride rich lipoproteins. Perhaps those where you clearly see insulin resistance, their diabetics, their insulin levels are high. That's where the Fibrate Subtrial Analysis shows miraculous things, not only with macrovascular endpoints, but with microvascular endpoints, retina, peripheral nervous system, renal function. So even though you might screw up creatinine a little bit, you're actually improving EGFR because of overproduction of creatinine, which in that case is not reflective of EGFR.

So I think there still is a group of patients right now where fibric acids, the purest fibric acid, which is an approach, drug is that phenofibric acid, still solute, trilypics. So I think if you have to use the fibric acid, it'll all possible. That's the one to use. And the good news is there is a new fibrate, permafibrate, pomephibrate that's being invested in clinical trials.

It's called a sparm, a selective P-PAR alpha receptor modulator that they're really high on and there's big outcome trials going on with that yet. But, you know, nobody's going to be using that to think about it until those trials are stopped for good reasons, bad reasons, or published, of course, and get FDA approval. So I think there's still hope with the fibrates. Nice and as a dead drug, I know there's gonna be a lot of people listening to this who, oh no, it's not, it's out of every guideline.

There's not a single guideline in the world that recommends. You can use anything you want if you're stuck between a rock and a hard place. And I certainly know there are LP little A advocates. If you bring Sam on, he will still selectively use nice in in certain cases, but fuel in the lipidology world still agree with that. Yeah, and back to your point on tri-lippics.

We probably have three or four patients on it, and man, it's a world-beater. I had one patient who was probably, I mean, he looked like he had FH, and he looked like he also had, of course, a familial hypertraglis rademia. You couldn't distinguish them. Even though you knew he was going to end up on both a stat and a fibrate at some point, I just had a curiosity. Wanted to see what APOB reduction we'd get starting with just the tri-lipic.

His trig were about 400 to begin with. APOB was over 200. get starting with just the tri-lipics. So his trigs were about 400 to begin with, APOB was over 200. The tri-lipics took him from a triglyceride of 400 milligrams per deciliter to about 100. My memory serves me correctly. And that took the APOB from wherever it was, high 100s, 200, down to somewhere between 80 and 100.

So that's monotherapy of tri-lpics, which was not the intention, but just in a stepwise progression showed you the potency. And unless you're dealing with a super humongous high risk and a cucumber, I don't think it's irrational to go down that route. There are plenty of people who you have to bat him over the head with whatever to convince him to use a stat. And maybe they'll say, well, I believe in triglycerides, you're giving me a triglycer. I'll work with you.

Well, let's see what the parameter clearly you picked the right person here, where a triglycerides where generating the apobie particles and the multi mechanisms on how fibrate-produced triglycerides had a beneficial effect. I've actually with Peter Jones published data using NMRs, some Resuvistatin and phenophybric acid. And you know, in some people, there were pretty nice reductions in LDL particle counts using phenophybric, always more. But when you looked at the particle analysis, when you were even combining phenophybric acid with the fiber, or excuse me, with the statin, you got way more dramatic remnant reductions

with the fiber rate than you ever did with the statin. So another reason, and almost certainly that person would have triggered 400, there was some contribution from remnants in that person you would think. So just don't forget fiber rates. A tragedy to me or young lipidologists are not being taught about it

Few of them can give you a dissertation on vibrates and how they work and what is their trial history? God there's 40 years of trial history that you can always Garner a little bit from any trial So I find that sad that it's not even being taught anymore and people bad mouthfully condemn it without knowing what they're talking about I always feel lucky to have been trained by dinosaurs or any more and people badmoutherly condemn it without knowing what they're talking about. I always feel lucky to have been trained by dinosaurs. Well, some of us have been around the block for a few times or so, but you know what, all dinosaurs, when we meet you young, brilliant guys,

you keep us, if I want to still talk to this guy, I got to keep up with this stuff because I know things I said 10, 15 years ago are silly now because you gotta keep learning, you know that. Guys like you are really good for me that I just can't rest on my laurels. Tom, this has been a lot of fun. We were supposed to do this last week and we had some technical difficulties.

So we postponed till this week and I'm glad we did because it was worth being able to do it and actually be able to look at each other through a screen as opposed to just have to do it by phone. And so I want to thank you, obviously, for your continued insight. You make a great difference in our practice. I guess I should fully disclose to people you are now basically full-time inside a teometical as a practice.

You're on the back side of things doing mostly research, but we drag you into at least a third of our patient calls and we always consult with you on all of our cardiovascular cases. So I hope you're also enjoying being back to clinical medicine somewhat, even though it's at a much lower volume. We certainly enjoy having you. It's been such a wonderful part of, if this is the finish of my career still being able to do this. And you know, although I know a lot of this lipid stuff to basic science, I've always been what I might David's go to clinical lipidologist. Now that this lipid stuff is meaningful, if you can't use it at the bedside and make individualized things. So I'm just thrilled to be able to contribute to you. And I think one day, as you know,

I'm trying to write and generate and put more and more to center writing, and that will become available to your followers and subscribers. And so folks, stay tuned for that. And I will say, and maybe it's another podcast and are probably better people than me to talk to, but the one thing we didn't get into today is the emerging genetic world genetic analysis of lipoproteins and specifically the genetic lipodosis, FH, who needs that type of testing,

who doesn't, whatever you discover, what can you do for it? It's another whole serious podcast. So other than that, thank you for everything, Peter, meeting you a long time ago in Ring on the Vada was a big day in my life. Mine, too, Tom. Thanks so much. Thank you for listening to this week's episode of The Drive. If you're interested in diving deeper into any topics we discuss, we've created a membership program that allows us to bring you more in-depth exclusive content without relying on paid ads. It's our goal to ensure members get back

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