210 - Lp(a) and its impact on heart disease | Benoît Arsenault, Ph.D.& Peter Attia, M.D.

1. 0:00 – 0:08

   Intro

   1. PAPeter Attia0:00

      [upbeat music] Hey, everyone. Welcome to "The Drive" podcast. I'm your host, Peter Attia.

2. 0:08 – 4:43

   How Benoît came to study Lp(a)—a new marker for cardiovascular risk

   1. PAPeter Attia0:09

      Hey, Benoit. Wonderful to, uh, to sit with you today and talk about a subject matter that, you know, honestly, I think, uh, five, certainly 10 years ago, nobody would have a clue what we were talking about. And yet today, we get so many requests to go back and revisit this subject matter. Uh, so again, delighted to have you here and, um, look forward to talking about something that, you know, probably impacts a lot more people than, uh, than, than most wight might appreciate. So, like, let's take a step back and give me a sense of where your interest in this little lipoprotein Lp (a) came from.

   2. BABenoît Arsenault0:48

      So first, Peter, thank you so much for the wonderful invitation. I'm really excited about our discussion today. So, um, I got involved in Lp (a) research actually during my, uh, postdoc years. Uh, I trained here, uh, at Laval University in, uh, in Quebec City. Uh, did some work, uh, in the field of, uh, of lipids, looking at, uh, LDL particle size, uh, triglycerides, apoB, et cetera, on cardiovascular outcomes. So that was in 2006 to 2009, and that was really at a, a point where not that many people talked about, uh, Lp (a) because there had been so many negative studies on, on Lp (a) and the risk of, uh, cardiovascular disease like MIs and stroke and so on. Uh, and it's really the genetic association studies that have, uh, kind of resurrected the field of Lp (a) , and these were published in 2009 to 2011. Uh, and that was during the time I was a, a postdoc in Amsterdam, and, um, I was working, uh, uh, over there with, uh, with John Castelli. Uh, and he was working on the Treating to New Targets trial, the TNT trial, which is the, the trial that-- one of the first trial that have sh- that, uh, that, that showed that if you, uh, reduce, uh, low-density lipoprotein levels, uh, by increasing the statin dose, you'll get an incremental benefit in, in cardiovascular outcomes. So we were working on a bunch of, uh, sub-analyses in, uh, in that trial, and, uh, they had, uh, just measured a, a whole panel of, of emerging biomarkers that they thought was associated with, uh, that could be associated with cardiovascular events like, uh, like CRP, uh, NT-proBNP, uh, other markers, uh, inflammatory markers, other biomarkers of insulin sensitivity, and Lp (a) . And it turned out that, uh, of a huge list of 18 biomarkers that they had measured in thousands of individual, uh, Lp (a) was actually the, the strongest, uh, of them that, that was predicting, uh, residual, uh, cardiovascular risk. So that was, uh, I think the first paper I, I published, uh, on, uh, on Lp (a) in, uh, in those years. And at the time, we were also, uh, wondering if there was, uh, any genetic variants that could explain a statin response because, uh, statin work well in, in most people, but there's a huge, uh, interindividual, uh, variability in terms of LDL lowering associated with statins. So this is, uh, this came at a time where, uh, genome-wide association studies were, uh, increasingly used, and they were used to, uh, als- well, they were first used to identify genetic variants associated with specific diseases, but they were beginning to be used in pharmacogenetic studies. So we were part of a big genetic consortium that was called the JIST consortium, so Genomic Investigation of Statin Therapy. And it turned out from that big analysis that Lp (a) was the most important, uh, genetic risk factor for-- th- that explain, uh, statin response. So, uh, we'd shown that if you have high Lp (a) , then your, uh, LDL would be, uh, w- wouldn't be lowered as much as if you didn't have, uh, high Lp (a) .

   3. PAPeter Attia4:26

      Well, we're gonna talk about that in some detail because right now, um, I think many people will not understand exactly why that's the case because they won't necessarily understand the relationship between LDL and Lp (a) and why what you just described is completely intuitive today based on all the work that's been done in the last decade.

3. 4:43 – 15:08

   The relationship between Lp(a) and CVD risk

   1. PAPeter Attia4:43

      But let's take a step back into that epidemiology so that for the people who aren't familiar with Lp (a) , we can give them a sense of why this is such an important topic. So we'll start with, um, an observation, right? So we'll start with the epidemiology, which is, uh, elevated levels of this particular lipoprotein, which occur in about what fraction of the population?

   2. BABenoît Arsenault5:08

      So, uh, depending on, uh, ethnicity, actually, it can be, uh, very high as, for instance, in individuals of, uh, African ancestry who have the highest level, uh, and all the way down to, uh, Chinese and Japanese that probably have the lowest levels. But we can say like in the ballpark that, uh, about 20% of the world population has an Lp (a) level that puts them in a higher risk, uh, category. So if we, uh, go, go down, uh, in time, uh, Lp (a) was discovered, uh, in 1963 by a Swedish scientist called, uh, named Kary Berg, and he was one of the first to show in the late '70s and at the beginning of the '80s in different European cohorts that Lp (a) was associated with, uh, with cardiovascular events. Um, and Lp (a) , uh, has been measured, uh, was measured cur- more, more, probably more currently at that time in these big epidemiology, uh, studies. Uh, the thing is, however, that the assays that they were using were probably not the best. They were certainly not as good as, as they are today. There was a lot of variability. Uh, and a lot of these studies published in the '90s and in the, uh, in the early 2000 came out negative. So, uh, and that really, uh, was really tough, uh, for, for the field because nobody, uh, talked about, uh, Lp (a) at that point.

   3. PAPeter Attia6:43

      W- tell people what you mean about the studies came out negative, and what w- negative with respect to what hypothesis and why?

   4. BABenoît Arsenault6:50

      The, the, the hypothesis was that high Lp (a) was associated with, uh, with cardiovascular events like, uh, myocardial infarction, stroke, uh, et cetera. So, uh, the hypothesis was that people with higher Lp (a) levels, uh, were at the highest risk, and it turned out, uh, not to be the case in many, many, uh, of those studies. Uh, and so we realized after- afterwards that the assays that had been used were probably, uh, not very good. So the assays really, uh, did not, um, correctly identify people with, uh, with high Lp little a. And I think, you know, w- this has to be, this has to be attributable to the, the, the complex, uh, structure of, of lipoprotein little a, which has, uh, in, in the Lp (a) genes there's a, a copper-- a copy number, uh, variation. Uh, and the antibodies that are used against that, sometimes they can, uh, they can bind to different epitopes of, uh, of Lp (a) . And, uh, so now we have, uh, antibodies that are, uh, binding to Lp (a) , uh, on other regions. So we get a much better sense of the number of Lp (a) particles in the, in the bloodstream. But back in the days, uh, these -- the, the assays that were used, they were overestimating, uh, the, uh, isoform size that was bigger and they were underestimating the, uh, small, uh, Lp (a) isoform size which is associated with, uh, with high Lp (a) . So, uh, a lot of research has, uh, has been done on that and now we have better assay. We don't have, uh, we don't have like optimal assays now, but, uh, uh, these, these problems -- most of these problems have been solved. And, and you, you can really see in the literature the interest on, on Lp (a) that, uh, that actually match, uh, this, uh, th- this effect because the, uh, Lp (a) gene was, uh, cloned in the '80s by the group of Angelo Scanu, Scanu at, uh, the University of, uh, Chicago. And, uh, and you can see it, uh, if you just look at the PubMed search, you would see like a straight line from, uh, the '70s to, uh, the mid-'80s. And when these, um, studies came back negative, you would see like the number of PubMed searches would go down and they came back up in, uh, 2009 and 2010 when, uh, genetic association studies, uh, were beginning to be published because, uh, the great thing about genetic studies is that you don't necessarily need to measure, uh, lipoprotein A levels. So you can look at genetic variants, at common genetic variants that are associated with diseases. And there were three big studies published in, uh, 2009 that have, uh, very convincingly shows that, uh, genetic variants associated with high Lp (a) levels were tracking with, uh, with cardiovascular events. And now you can see the, the PubMed searches on Lp (a) going back up again. Uh, and they haven't been as high as they are today.

   5. PAPeter Attia10:09

      Yeah, and we should make sure people understand some of the semantics. So Lp (a) is the gene that codes for apolipoprotein little a which then binds to an LDL and then turns an LDL from being just a garden variety LDL into an Lp little a. And I think once people understand that, it becomes easier, I think, for us to communicate in this way. So I'm gonna restate that, and I really want everyone to understand this. So there's a gene, Lp (a) is the gene, and this gene, everybody has this gene, but we have different variants of it. And so a subset of the population, and it varies considerably by ethnicity, so African, uh, East Asian also quite high, down to Caucasian and, uh, and, and, and, um, um, uh, as you mentioned, Chinese, Japanese, et cetera. So you're gonna see different expressions of the apolipoprotein little a. This apolipoprotein little a which we'll talk a lot about and what it looks like and its structure and what its heterogeneity is all about, but it wraps onto a low-density lipoprotein and then it becomes kind of a supercharged low d- low-density lipoprotein. It becomes a particularly nefarious LDL. Um, and we're gonna talk about all the reasons why it's not responsive to the same treatments, et cetera. So, um, would you add anything to that? Like I would-- I don't wanna make it too complicated yet, but I wanna make sure everybody understands when we talk about the Lp (a) gene which is identified during the GWAS, uh, experiments, how the genotype a- allows us to not know everything about the phenotype, but we can start to get into trying to impute causal relationships and eventually we're gonna talk, of course, about Mendelian randomization where we can go even deeper. An- anything you wanna add to sort of the, the basics of this?

   6. BABenoît Arsenault12:00

      No, I think you've explained it, uh, perfectly, Peter. Maybe the only thing I would add is that, uh, part of the genetic, uh, heterogeneity among, uh, different people is the, the apolipoprotein A isoform size. So, uh, people express, uh, different, uh, Lp (a) isoforms. Some, some are bigger than, uh, than the other and that, that probably, uh, that -- well, that actually plays an important part of the, uh, equation explaining why some people have, uh, higher Lp little a than others.

   7. PAPeter Attia12:33

      I'm, I'm glad you reinforced that point because, and this is gonna get into a little bit of chemistry which I know some people will understand and some might not. One of the big challenges here as you've now alluded to twice is the difficulty in measurement. Now, when we look at something like apoB, and people who listen to this podcast a lot will be very familiar with apoB. We talk an awful lot about it. One of the things we talk about is that By measuring the concentration of apoB, you can completely and accurately measure the concentration of the atherogenic particles, the majority of which are LDL. And the reason for that is twofold. The first is that every LDL has one and only one apoB 100 particle on it. The second is that all apoBs are the same size, therefore they have a molar weight, and by knowing the mass, you know the number. Now, there are-- I always like to point out two contrasts to this, right? The HDL particle, by contrast, has multiple apoAs on it, and this is totally different from apo little a, so we're not going to talk about that other than to say it's apo big A, and therefore you don't have a unique number. And then of course with Lp little a, you have the problem that you raised, which creates enormous challenges. There is no molar weight for apo little a, right? This is, this is the fundamental problem in the assay of trying to measure this thing.

   8. BABenoît Arsenault13:58

      Exactly. And, uh, we're, we're, we're really moving in the right direction in terms of getting the Lp (a) measurement in, uh, nanomoles per, per liter. And, uh, there's, there's more and more labs that are, that are doing this, and this is clearly the, the, the way to go. We have to move away from measurements in, in mis- milligrams per, per deciliter, which is really influenced by the, uh, isoform size of Lp (a) , and the measurement in, uh, nanomolar will actually give you a much better sense of the number of Lp (a) particles in the circulation. And that's what we should be, uh, aiming at because the, the risk of-

   9. PAPeter Attia14:37

      Now will that require electrophoresis? How will that actually be measured? Or will it use NMR? I mean ...

   10. BABenoît Arsenault14:43

       It's going to be u- measured through, uh, immunoturbidimetric, uh, assays, so not by, uh, by NMR. NMR can actually give you a, a, a pretty good estimate of, uh, LDL particle number, but you have to use, uh, antibodies to, to, to measure, uh, to measure Lp (a) .

   11. PAPeter Attia15:04

       Okay. So we got a little in the weeds there. I apologize. We'll come back to that

4. 15:08 – 21:54

   What genome-wide association studies (GWAS) revealed about Lp(a)

   1. PAPeter Attia15:08

      stuff later. But let's pick it up back about a decade ago when the GWAS studies were able to, uh, distance themselves from the limitations of the assay and focus instead on the genotype and the heterogeneity of the genotype. These GWAS studies now found a much stronger association between the variants of this genotype that produced high copy numbers of apo little pro- apolipoprotein little a and incipient cardiovascular events, correct?

   2. BABenoît Arsenault15:42

      Exactly. So there were, I think, three studies that were all published in 2009. Uh, the first one was, uh, the one, uh, by, uh, Robert Clark, uh, from the UK. They used the PROCARDIS consortium, uh, which were, if I recall well, there were 3,000 people with, uh, heart disease and 3,000 controls. And they've identified two SNPs in the Lp (a) region that are completely different, uh, from, from one ano- uh, from one another. Uh, and they-- you really saw the, the, the, the dose response effect of these SNPs on Lp (a) levels with a proportional, uh, effect on the risk of, uh, heart disease. So it was like the f- kind of the first Mendelian randomization, uh, study where, um, they, they, they nicely showed that if you had one Lp (a) ri- raising, uh, allele, you had higher Lp (a) levels, whereas if you had two or more Lp (a) rising variants, then you had even higher Lp (a) levels and the risk was proportionally, uh, higher.

   3. PAPeter Attia16:47

      Also worth explaining how important this type of analysis is because it really is the bridge between observational epidemiology and clinical trials. And of course, we're going to talk about clinical trials, many of which are ongoing. But the importance of what you just said, Benoit, is the following. There are a handful of assumptions that make this type of Mendelian randomization essential. One is the assumption that the sorting of these genes is random, right? So in other words, y- y- you know, we look at a population and we can say -- we can look at this as though nature did an experiment and it randomized the population to different copy numbers of these alleles that are going to produce different amounts of the protein. But the second important piece of a Mendelian randomization being able to link something causal is the assumption that the gene of interest is not doing something else that you're unaware of, right? In other words, if the Lp (a) gene was on the one hand responsible for making apolipoprotein little a, which it is, but on the other side, it also changed your, I'm making this up, your susceptibility to secondhand smoke. And people who had that gene would be debilitated by secondhand smoke. People who didn't have that gene had complete immunity to secondhand smoke. Imagine such a gene existed. Well, all of a sudden, the Mendelian randomization wouldn't be very helpful because those people who are at an increased risk of cardiovascular disease from having more copies of Lp little a, you don't know if it's that or if it's the exposure or susceptibility to secondhand smoke. So do, do you have a sense-- I mean, I think in the case of Lp little a, it's pretty straightforward because it's a relatively simple gene. But whe- when that type of analysis was done, was it relatively easy to demonstrate that that gene wasn't doing anything else, uh, both in its coding and non-coding regions?

   4. BABenoît Arsenault18:50

      Yeah. First let me say that I think that a lot of geneticists would disagree that Lp (a) is a relatively, uh, easy gene. I mean, uh, there's like I think 2,000 different variants that are, uh, associated with Lp (a) , and you add in the, uh, isoform, and each isoform has a specific sets of, a specific set of different variants. So, so, so that being said, uh, I think you, you really nicely explained it. Uh, and the, the, the beauty of working with Lp (a) , but also with most proteins, uh, in the circulation, is that you're, you're, um, you're, you're looking at cis-acting SNPs. So cis-acting means, uh, variants that are acting within the window of the gene that expressing their, their protein as in opposition to like a trans-acting SNP would be, for instance, a SNP in, uh, the CTP gene, for instance, which we know might be associated with Lp (a) , but CTP does a lot of other things. It regulates HDL cholesterol-

   5. PAPeter Attia19:51

      Right

   6. BABenoît Arsenault19:51

      ... levels, it regulates triglycerides. So we don't use, uh, CTP genes when we do, uh, Mendelian randomization on, uh, on, on Lp (a) . And the, the example that you, that you mentioned, you know, uh, a specific gene being associated with an intermediate phenotype that could, on the other hand, influence, uh, Lp (a) would be reverse causality. And, uh, in, in, in the case of Lp (a) , it's we're, you know, we're very, very confident that, that we're using the, the, the correct, uh, genetic instruments to infer a causal relationship between Lp (a) and a wide range of, uh, atherosclerotic cardiovascular diseases.

   7. PAPeter Attia20:32

      So to put a bow on that, we really have two independent types of analyses now that make it very clear that Lp little a is playing a causal role in the development of atherosclerotic cardiovascular disease independent of LDL, which you referred to earlier by commenting and using the term residual risk, which I think people might not appreciate. Residual risk meaning what is the risk that remains in terms of ASCVD in the presence of LDL lowering? And of course, Lp little a would be one such example. And those two pieces of information are now the regular observational epidemiology, provided that the assays more accurately capture the measurement of Lp little a, and now these Mendelian randomizations that effectively are nature's randomized experiments, provided those two criteria we discussed can be met. Is, is that, is that a fair synthesis of the state of the, of the art today in terms of our understanding?

   8. BABenoît Arsenault21:36

      Yes. I think you can also add a third assumption, which would be that, uh, the effect of the variants on the outcomes or the effect of Lp (a) , uh, variants on cardiovascular disease are explained by higher Lp (a) levels. And I think for Lp (a) it, it's, it's a fairly, uh, fair assumption

5. 21:54 – 26:11

   Clinical tests to measure Lp(a)

   1. BABenoît Arsenault21:54

      to make.

   2. PAPeter Attia21:54

      Okay. So let's talk about how this is done clinically today. Um, most-- I mean, uh, the-- Over the past decade, I've seen three different types of commercial assays for measuring Lp little a. Um, I don't believe two of them are in existence anymore. One was the Lp little a cholesterol content. So I assume that this was an assay that was looking at the cholesterol content of the Lp little a's, which means the LDLs that had apolipoprotein little a on them, you just measure the cholesterol content. So it was analogous to measuring LDL cholesterol, but for this narrow subset. Is that assay still in existence?

   3. BABenoît Arsenault22:34

      Uh, well, I think there are certain labs that, that still use it-

   4. PAPeter Attia22:38

      Okay

   5. BABenoît Arsenault22:38

      ... but it's really not the way that the, the, the field is moving to because, uh, the cholesterol... And you can make the same, uh, uh, the same argument for LDL. The cholesterol within a certain lipoprotein, uh, does not necessarily tell you a lot of information about the number of particles that are in the bloodstream, which is the most important thing if you-- to, to measure if you want to estimate risk. So for, for LDL apoB, there's some discordance.

   6. PAPeter Attia23:07

      Yep.

   7. BABenoît Arsenault23:08

      Uh, a- but for Lp (a) the, the discordance is-

   8. PAPeter Attia23:11

      Just enormous

   9. BABenoît Arsenault23:11

      ... even higher.

   10. PAPeter Attia23:12

       Yep.

   11. BABenoît Arsenault23:13

       Exactly. So, uh, so, so y- what you really wanna do is, uh, try to find a lab that will give you, uh, an, an Lp (a) measurement in, in nanomoles per, per liter.

   12. PAPeter Attia23:23

       Right. Now, there are some labs that have done that. I, I've seen a lot of those labs. So one of them was called, um, God, Health Diagnostics Labs. Um, I think that was the name of the lab. They no longer exist. They did calculate an Lp little a in nanomole per liter. I don't know what their methodology was. Most labs are using milligrams per deciliter, so they are simply telling you... I say simply, huh. They are telling you the mass of Lp little a. Now, just to be clear, are we in that assay looking at the mass of the entire Lp little a, or are they just trying to estimate the mass of the apolipoprotein little a's?

   13. BABenoît Arsenault24:04

       It's the mass of the p-

   14. PAPeter Attia24:05

       The whole particle

   15. BABenoît Arsenault24:05

       ... of the particle. So, so it's a, a much better measurement than Lp (a) cholesterol that you, that you just referred to. So, uh, and, and we shouldn't, you know, uh, let, uh, good be the enemy of perfect here. If you have an Lp (a) measurement in milligrams per deciliter and it puts you in a high-risk range, so let's say your, your-- it, it gives you an Lp (a) level of above 50, uh, then the chances of the, uh, Lp (a) assay that's, uh, that will give you a result in, in nanomoles per liter, it will also give you a high, uh, a high level. So if you have, uh, uh, an Lp (a) , uh, measured in milligrams per deciliter, you can obviously try to get a second measurement in, in nanomoles per liter. But- You know, if you have a, a Lp, a Lp in a high range, it'll-- both methods will give you, uh, the, the s- the, the same information that you have an Lp in the, in the higher range. Now, you have to keep in mind, though, that if you have an Lp, for instance, of 50 milligrams per deciliter, the measurement in nanomoles per liter will be around 125 nanomoles per liter. So some, some people have measurements, uh, using both methods and they just say, "Well, for some reason my Lp doubled." Well, that's not the case. The Lp didn't double and, and it's remarkably stable, uh, over time. So, uh, most guidelines will probably tell you just to measure Lp once in a lifetime and it's relatively, uh, relatively stable.

   16. PAPeter Attia25:39

       Yeah. I mean, I think that's the take-home point here is unlike LDL and apoB, which are so modifiable and therefore it really matters that you know what you're measuring because you're going to be measuring it over and over and over and over again. With Lp (a) , at this point in time, and this is going to be changing, but at this point in time, it's basically something we measure to determine risk, after which point we don't really need to measure it. We've established risk and now we need to take measures elsewhere. Um,

6. 26:11 – 29:52

   The biology of Lp(a)

   1. PAPeter Attia26:12

      so let's now kind of talk a little bit about the biology of Lp (a) . Um, we'll include figures in the show notes to the podcast so, um, we'll, we'll be able to show people exactly what this thing looks like and how it intersects with and binds to the LDL particle, uh, how it's distinct from the apoB, et cetera. But let's talk a little bit about the production of this thing. Is it hepatically produced? It's produced in the liver?

   2. BABenoît Arsenault26:44

      Yes, exactly. So all the lipoprotein A particles originate from the apolipoprotein little A that's pretty much only expressed in, uh, in the liver. Um, so there's a, there's-- it's not entirely clear in the literature how or, or where specifically, uh, an apolipoprotein little A will become an Lp, uh, little A, so where it will bind to, uh, to apoB, uh, and ultimately an, an LDL particles. There's multiple, uh, hypotheses that, that have been, uh, that have been tested. So some people say that the apolipoprotein little A, which is like a gly- a glycoprotein, is secreted in the bloodstream and there, uh, it will bind to whichever LDL, uh, is closer to it to form, uh, Lp (a) . There's another hypothesis that suggests that it's probably, um, at earlier after, uh, the secretion of, uh, of Lp (a) , so not entirely in the bloodstream, but when it leaves hepatocyte in the space of this in the, uh, in the liver that the, the binding of apolipoprotein little A with, uh, with LDL. But now I think we have very good evidence that to suggest that this happens, uh, within a liver cell, the binding of apoA to apoB to eventually form, um, uh, Lp (a) . There's-- so, so there's good evidence to suggest that as soon, uh, as the, uh, Lp (a) , uh, the apoA is produced, uh, it can form an Lp (a) when it meets, uh, with, uh, an apoB particle.

   3. PAPeter Attia28:29

      And for whatever reason, that just seems a bit more intuitively obvious given the mechanics of it, right? You're, you're sec- you're bringing so many LDLs to the liver. You're making apolipoprotein little A in the liver. It seems like a more obvious place for the marriage to occur than in the periphery. But again, um, it, it remains to be seen, although seems like it's more likely that that is the case, correct?

   4. BABenoît Arsenault28:53

      Correct. And, uh, the, the-- so the levels of Lp (a) are determined by the levels of production of-- by the rate of production of, uh, of Lp (a) particle and little by, uh, by its catabolism. We're still not entirely sure of how the catabolism of, uh, Lp (a) occurs. We, we-- it's probably by... Well, most of it is by the liver. There's a little bit by the, a little bit of catabolism by the kidney as well. Uh, but identifying like the receptor, uh, at the surface of hepatocyte that, um, that, that will remove Lp (a) from the bloodstream has been challenging. So there's some evidence suggesting that, uh, the LDL receptor might be one of them. There's some evidence for and against that. Uh, and there's also the plasminogen, uh, receptor and I f- I, I, I think we're, we're gonna eventually talk about, uh, the homology, uh, between apolipoprotein little A and, and plasminogen.

7. 29:52 – 35:20

   How statins lower LDL-cholesterol and why this doesn't work for an Lp(a)

   1. PAPeter Attia29:52

      So let's go back to this point, which is that it's really the production of apolipoprotein little A that determines the concentration of Lp (a) . And if that weren't the case, it might be that by simply reducing the amount of targets for it, i.e. reducing the amount of LDL, you might reduce the amount of Lp (a) , but in fact, that does not appear to be true with one notable exception that we will get to down the line. In other words, if you give somebody a statin, which is a very potent drug to lower LDL, the primary mechanism by which it does so is by increasing hepatic clearance of LDL. So you have more and longer-lasting LDL receptors on the liver, and they're pulling those LDL out of circulation, which is lowering the plasma concentration. And yet that does nothing to offset the amount of Lp (a) , which goes back to the explanation that started your journey here, which was why is it that some people respond really well to statins and some don't? And obviously it would be the higher your Lp (a) , the worse your statin responds because there's a subset of your LDL that are not responding to the statin. [lips smack] So, um, maybe let's start by explaining how a statin takes an LDL out of circulation and why this doesn't work for an Lp (a) , which is basically just an LDL with this one other little thing covalently bound to it.

   2. BABenoît Arsenault31:26

      Exactly. So the statins actually, uh, reduce LDL particles in the circulation by upregulating the LDL receptor at the surface of the hepatocyte. So the density of the LDL receptor at the surface of the hepatocyte is super important. The more LDL receptor you have, the higher the catabolism of apoB-containing, uh, lipoproteins will be because apoB binds to the, uh, to the LDL receptor. So under the assumption that, uh, Lp (a) is catabolized by, uh, the LDL receptor, you would think that statins would actually reduce Lp (a) levels. Whereas we, we see that there's not really a lowering effect of statins on, on Lp (a) , and there's even been, uh, more than one studies that have shown that, uh, if you put somebody on a statin, you'll even have a small increase in, uh, in Lp (a) levels. Now, that shouldn't be a reason not to put someone on a statin, of course, uh, because there, there's been, uh, trials like, uh, the Heart Protection study, uh, that have shown that, uh, a treatment with statin is beneficial in patients with high Lp (a) levels, even maybe even more so than patients with low Lp (a) levels. So, uh, one should not like, um, don't prescribe a statin because you're afraid of a, of a small, uh, Lp (a) level. It might be an interesting thing to do to measure Lp (a) levels before and after the initiation of a, of a statin. But, uh, uh, overall, uh, we have so much experience with, with statin that we know they work in the overwhelming majority of individuals and, and especially even, even better in patients with, with high Lp (a) .

   3. PAPeter Attia33:19

      Yeah. I mean, one hypothesis for that might be that the statins are bringing a higher influx of LDL to the site of the production of the apolipoprotein little a, and that might possibly be why you're seeing an increase in Lp (a) . Um, again, that would be... If that were true, that would make it even more likely the scenario that that's the source of the, the merger between apolipoprotein little a and LDL. [lips smack] What's the approximate magnitude by which, um, LDL or apoB, let's be specific, I guess, because that's really the metric we care about. What's the magnitude by which apoB would go up in the presence of a statin for an Lp (a) ? Pardon me, [lips smack] let me state, restate that. What's the magnitude by which Lp (a) would go up in the, um, context of a statin?

   4. BABenoît Arsenault34:07

      Uh, well, that depends on the study. Uh, there's, there's been a lot of studies that have shown that statins don't have an effect. Um, and most of the studies have shown like a 10% increment in, in Lp (a) levels. So if you have low Lp (a) levels at, you know, if, and you're treated with a statin, you'll still remain with a low Lp (a) level. And if you have high Lp (a) level, then you'll-

   5. PAPeter Attia34:34

      You'll still remain high

   6. BABenoît Arsenault34:34

      ... obviously still remain with, with a, with a high Lp (a) level, although it- it's going to be, uh, a, a little bit higher. So, so it's important to, uh, to, to say that, um, uh, as, as we, you know, move forward with, uh, uh, Lp (a) lowering drugs that, that, that are being tested on, on top of statin therapy at the moment. Uh, so we, uh, we have, uh, published a paper in patients with aortic valve stenosis at the ASTRONOMER trial, where you can actually, uh, get a, a, I think it was a 20% increment in, in, in lipoprotein little a. So it might not be trivial. So, so the signal is, is there, but let me restate that, uh, that statins are, are very effective in, uh, in patients with Lp (a) , even though, uh, there's a small increment of

8. 35:20 – 46:00

   The structure of LDL-p and Lp(a) and what makes Lp(a) more atherogenic than an equivalent LDL particle

   1. BABenoît Arsenault35:20

      Lp (a) .

   2. PAPeter Attia35:20

      Yeah. And an easy way to think about this would be if you give a statin and let's say in the most aggressive case, the Lp (a) goes up by 10%, but the apoB comes down by 60%, you'd have to make the case that an Lp (a) is six times more atherogenic on a particle for particle basis for that to be an equi- an equivalence maneuver. So that begs the question, what is it about Lp (a) that's so virulent? What is it about Lp (a) that makes it, I assume, more atherogenic on a particle for particle basis than its garden variety apoB-bearing cousin?

   3. BABenoît Arsenault36:05

      Yeah. There, there's no question about this, uh, Peter. I mean, on a per particle basis, Lp (a) is much more atherogenic than an equivalent, uh, LDL particles. Uh, well, first of all, uh, an Lp (a) has an LDL particle on it. So, uh, by definition, it's, you know, as atherogenic just to s- to start with. Um, there's also, uh, evidence, uh, that Lp (a) might, uh, influence the rates of thrombosis because Lp (a) , uh, has a sequence homology with, with plasminogen, which plays a role in, um, uh, in, in clotting and has, uh, antifibrinolytic, uh, activity. But, uh, the, the, I think the most important thing is the number of oxidized phospholipids that are, uh, transported by lipoprotein little a, which is much higher than the amount of oxidized phospholipids that, uh, that you see on, uh, LDL particles. And Oxidized phospholipids have effects on a wide variety of cells, endothelial cells, smooth muscle cells, macrophages, cells of the, uh, aortic valve like valvular interstitial cells. Now, they're sending in signals that will drive pro-inflammatory, um, pro- maybe pro-thrombotic, uh, and pro-calcifying signals to, to these cells. So that is probably the most important reason why on a per particle basis Lp (a) is more atherogenic than LPL-- than LDL, sorry.

   4. PAPeter Attia37:49

      So let's talk about these oxidized phospholipids. I think most people might not be familiar with what a phospholipid is. Um, but before we do that, let's explain to people what an LDL looks like physically in relation to an LDL. So if an LDL is a largely spherical, uh, compound that has on its surface a single lipoprotein called ApoB 100 that wraps around it, how does that now interact with the apolipoprotein little A to become an Lp little A?

   5. BABenoît Arsenault38:27

      Okay. So to answer this question, I'm going to tell you a little bit about the structure of, uh, apolipoprotein little A. And to explain that, I'm going to talk about plasminogen for, uh, for a minute. So plasminogen is a gene that's, uh, expressed on chromosome six. It has, uh, five kringle repeats. Now, a kringle is, uh, a-- it's called a kringle because it resembles a Danish pastry. So it's a, a, a little, uh, round of, of proteins, and you have five of them that are, uh, one another in the protein. Now, Lp (a) is the gene right next to plasminogen on chromosome six, and we, uh, have reasons to believe that, uh, along the lines of evolution, it probably emerged from a duplication of the, of the plasminogen, uh, gene. Um, so Lp (a) , uh, has-

   6. PAPeter Attia39:23

      Which, which would have been very important tens and hundreds of thousands of years ago because trauma was such a threat to our species, much more than it is today. And of course, trauma carries with it, in the short term, an immediate risk of hemorrhagic shock, blood loss. Ultimately, septic shock probably would have killed just as many people from the infection. But anything that would have reduced your risk of hemorrhagic shock would have been a generally positive thing up until a hundred years ago or a couple hundred years ago. So tell people exactly how plasminogen would have played a role in that and why this is something that if a duplication was created, probably worked to an evolutionary advantage, again, until we lived long enough for it not to.

   7. BABenoît Arsenault40:13

      Yeah. There's, uh, there's a lot of hypotheses, uh, out there, and the effect of Lp (a) on wound healing is, is certainly one of them, and, uh, this is being studied, uh, ex-ex vivo. So that might be one of the reason why, uh, why we have, uh, high Lp (a) levels in twenty percent of the population and why before that even there was the duplication of the, um, of the plasminogen gene. Now, when we're talking about that duplication, uh, it's, it's only the kringle four and kringle five that remain in the Lp (a) gene, and the kringle four is even separated in, uh, ten different subunits. So there's the kringle four type one all the way to the kringle four type ten. Now, the most important is probably the kringle four type two, which is where the copy number variation is. So you can have-- So one can have, um, one, uh, kringle four type two or only a couple, and you can also have the way all up to forty kringle four type two repeats. So this is where when we talk about Lp (a) isoform size, it's due to variation in kringle four type two. Um, so there's an other kringle, uh, repeats that are, uh, or parts that are, uh, important. Uh, kringle four type ten is probably the most important for, uh, the binding of oxidized phospholipid. And to answer your question, Peter, about the, uh, interaction between apoA and apoB, you have to look at the kringle four type nine, which contains cysteine residues, which can be, uh-- which are important to do a, a cy- uh, a disulfide bridge with, uh, with apoB. So it's a, a covalent, uh, bound that's happening because of the cysteine residsu- residues on the kringle four type nine.

   8. PAPeter Attia42:15

      So interesting sort of thought experiment. If, if... And, and this is really-- The reason I'm asking this question is not just to be difficult. It's to try to understand the pathophysiology a bit better, especially as it pertains to the oxidized phospholipid. If you could create a drug that would cleave the dos- that, that disulfide bond, so it couldn't-- it wouldn't lower apoB and it wouldn't lower apolipoprotein little A. It would just prevent their union, and therefore, it would eliminate Lp little A. But you still had a high concentration of apolipoprotein little A floating around by itself, dragging with it oxidized phospholipids. Would you guess that it would still be problematic, or would your guess be that no, because it wouldn't be able to gain residence in the tissues such as the subendothelial space, the interstitial space of the aortic valve, all the places where it wreaks havoc?

   9. BABenoît Arsenault43:20

      Yeah, I'm, I'm only going to speculate here, uh-

   10. PAPeter Attia43:22

       Of course

   11. BABenoît Arsenault43:22

       ... Peter. Of course, there's... Uh, I don't think there's, uh, solid data on the lo- uh, the, the, the form of apoA that's not bound to, to LDL particles. Um, so, so we know that, uh, apoA can still have, uh, oxidized, uh, phospholipids. And we are not entirely sure how, uh, if you're talking about Lp (a) , how it, it gets inside, uh, the cells, if it gets inside the cells. Now, we have some evidence, uh, and we've, we've published that, uh, with a colleague of mine, uh, Patrick Mathieu here, who's a, who's a heart surgeon. Um, we've looked at, uh, the, uh, an Lp (a) receptor in the, uh, valvular interstitial cells. So these are the types of cells that are, uh, very abundant in the, uh, in the aortic valve. And just to, uh, remind our, our audience, Lp (a) is also associated, uh, to a very significant extent to aortic valve stenosis. And when I'm talking about Lp (a) receptor, I'm not talking about the receptor for lipoprotein little a, I'm talking about the receptor for lysophosphatidic acid, which, uh, is m- generated by, uh, by Lp (a) , by an enzyme called autotaxin, which is actually carried by Lp (a) in, in the blood. So on top of oxidized phospholipids, apoB, LDL, Lp (a) has its specific proteome, so it carries, uh, a lot of, of different proteins that have different function that makes, uh, Lp (a) even more atherogenic. Now these, um, oxidized phospholipid can have a signaling effect, uh, in the, uh, in the aortic valve. Uh, and that might be totally, uh, independent from, from, from LDL. So, so we don't know. I'm, I'm only speculating here, but there are some signaling effects of, uh, of oxidized phospholipids that I think are very important and they a- they, um, they activate a lot of, of different inflammatory processes, uh, and also, uh, uh, osteoblastic, uh, processes because these types of, uh, valvular insert- in- interstitial cells are becoming like, uh, osteoblasts, which are the cell types that, that, that make bone. So it makes a lot of sense, you know, when you're talking about, uh, aortic valve calcification, that there's, uh, a, a bone-like, uh, process that's, that's happening within this tissue.

9. 46:00 – 52:24

   The role of Lp(a) in aortic valve disease

   1. PAPeter Attia46:00

      Yeah. For all of our patients that have elevated Lp little a, one of the first tests we do is get a baseline, uh, look at their aortic valve. So typically, we'll do it with an echocardiogram if we can get a good enough view. If not, we use a cardiac MRI, but it's for exactly this reason. What's the approximate hazard ratio? How much does risk go up for aortic stenosis, um, in an individual with elevated Lp little a, and how much does it depend on whether or not they have a normal aortic valve to begin with, which has three leaflets, a so-called tricuspid valve, versus if they have a relatively common, uh, anatomic variant with only two leaflets, which is called a bicuspid valve, which even outside of Lp little a would increase your risk for stenosis?

   2. BABenoît Arsenault46:48

      Exactly. So there's not really good evidence showing that Lp (a) is associated with bicuspid aortic valve stenosis because we, uh, we're studying genes that, that are associated with bicuspid aortic valve stenosis, and we don't see, uh, really an effect of, uh, of Lp (a) there. Now that being said, it might, uh, accelerate the, uh, the formation of aortic stenosis in patients with, uh, bicuspid aortic valve.

   3. PAPeter Attia47:17

      Who are already at risk.

   4. BABenoît Arsenault47:18

      Exactly. So, uh, so Lp (a) is probably an initiator of, uh, aortic valve stenosis, and we've known that, uh, since 2013 when, uh, George Thanassoulis and, and Wendy Post, uh, they, they published this, um, genome-wide association studies of, uh, aortic valve calcification in the, in the CHARGE consortium, and they've shown that Lp (a) , the, uh, with that one variant associated with l- high Lp (a) level was the most, uh, important variant associated with aortic valve, uh, disease. Now, we had known for, uh, a few years that Lp (a) was present in the valve and w- in the valve it actually co-localizes with oxidized phospholipids. So, so we, we, we knew this, but, uh, that, that study was really, uh, I think a game changer for, uh, our understanding of, uh, of aortic valve stenosis. [lip smack] Now, when we're, you're, we're looking at the, uh, effect of high Lp (a) on aortic valve stenosis, um, it, it really depends on the level of, uh, of Lp (a) . So if you're looking at patients that have high-ish, uh, Lp (a) levels, such as, uh, well, let's say m- 50 milligrams per deciliter or 125 nanomolar, their risk can be increased by, uh, 50%, uh, two, maybe 100% or, or, or double. But when, uh, you're, you're going, uh, into-- and you look at patients that have very high Lp (a) , uh, it, it, their risk can, can increase quite, uh, quite substantially. So if you have patients with, with very high Lp (a) level, then what you're doing, looking at the, uh, at the aortic valve, especially by, by echo 'cause, uh, it's probably the most, uh, widely available tool to, uh, to investigate this. [lip smack] Now in our, in our lab we, uh, perform, um, um, sodium fluoride PET/CT, so positron, uh, emis- uh, emission tomography coupled with computed tomography using a, a radiotracer that's called, uh, that, that's called sodium fluoride. And in patients that have high Lp (a) levels but These were patients from the general population. We can already see like a signal before the, uh, onset of, uh, aortic valve calcification, uh, using this, uh, this, uh, this radial tracer. So this, this really tells you that there's an effect of Lp (a) on the initiation, uh, of the, of the process of aortic valve stenosis.

   5. PAPeter Attia49:56

      And, and what is it you s- so you're seeing before any gradient appears, before any flow-related metric, you're seeing a metabolic change at the valve?

   6. BABenoît Arsenault50:08

      Yeah, exactly. So the, the, the sodium fluoride will actually bind to a, a chemical called hydroxy ha- apatite, which is, uh, literally the, a, a complex of calcium and phosphorus which, uh, will eventually, uh, be involved in the pathophysiology of, uh, of aortic valve stenosis. And we see that process happening very early at the earliest stage of the, of the disease, and we also see an effect of Lp (a) on the later stage of the disease. So the, the data that's available so far that have looked at the progression rates of aortic valve stenosis has shown that patients with high Lp (a) might even progress, uh, more rapidly than patients with, uh, who have, uh, who have low Lp (a) , especially with- in, in younger patients, uh, that have, uh, that have high Lp (a) 'cause when you're looking at patients, you know, that are above, uh, 75 or, or 80, there's a lot of calcium that's already, uh, present in the valve and the mechanism might be very different-

   7. PAPeter Attia51:15

      Yep

   8. BABenoît Arsenault51:15

      ... in younger patient compared to, uh, to older patient when you're, when we're investigating the progression of aortic valve stenosis.

   9. PAPeter Attia51:22

      Yeah, and if we're gonna create a public service announcement here for primary care physicians, it's so important to identify aortic stenosis in its earliest stages because the outcome data are quite clear that the earlier you intervene, the better the outcome. So, you know, I think 25 years ago, we had a certain threshold in terms of, uh, surface area of the valve and gradient of pressure across the valve at, at which point you would, you know, replace the aortic valve. Uh, if you look at the literature today, it seems that you're getting better and better outcomes when you proceed earlier and earlier, before the heart is overly taxed, uh, based on that, based on that pressure, uh, head that it faces, and of course the increased risk of spontaneous cardiac death and other things that goes up with aortic stenosis. So aortic stenosis is a very serious problem independent of ASCVD, atherosclerotic cardiovascular disease, which is what most people think of when they think of Lp little a, assuming they know something about what we're talking about in, in terms of this molecule. So [lip smack]

10. 52:24 – 56:56

    How greater numbers of Lp(a) particles are associated with increased risk of disease

    1. PAPeter Attia52:25

       um, let's go back to another point you raised. So you, you -- and, and again, I think when people look at the diagram, this will be much easier. We get into the anatomy of the fourth and fifth region of these kringle repeats and which of the subunits can create this vast heterogeneity, why two people can have an Lp (a) gene that overexpresses Lp, uh, well, Lp (a) through apolipoprotein little a, but they can have -- one of them can have a molar mass that's very high, one can have a molar mass that's very low because of these number of kringle repeats. What does the number of these repeats tell us about the pathophysiology of this?

    2. BABenoît Arsenault53:07

       Uh, well, if you had asked me that question 10 years ago, I would have said a lot, but, um, our, uh, understanding of the pathophysiology of Lp (a) is increasing every, every week now, basically. So, uh, maybe 10 years ago, uh, there was this debate about Lp (a) as to whether or not it was the L- the Lp (a) concentration that matter or if Lp (a) concentration didn't matter at all because it's the, uh, apo (a) isoform size that, uh, that matter, small isoform size being, uh, associated with higher, uh, Lp (a) levels. And there has been some epidemiological, uh, studies that have measured apo (a) isoform size either through PCR or, uh, immunoblotting, et cetera. So in the same patient, you can have, uh, Lp (a) levels measured, and you can have the apo (a) isoform size. And using the techniques that were available back then, they did multiple adjustment, uh, adjusting Lp (a) concentration for the apo (a) isoform size and looking at the association of apo (a) isoform size with outcome adjusting for Lp (a) levels. And the data back then, uh, was going all over the place, basically. So some studies were saying it's the concentration. Some other studies were saying it's the apo (a) isoform size that matters. And once again, these questions were ultimately, uh, resolved by looking at genetics. Uh, so, uh, there's, there's one variant that's, uh, associated with small, uh, Lp (a) isoform size, but that's also associated with a low Lp (a) . So you can see this was our way to do a discordance analysis by looking at that specific SNP, and that genetic variant was not associated with cardiovascular diseases at all. And in many studies, uh, now it's been shown that, uh, I-- probably the best study that has, uh, investigated that is, uh, is a study from the deCODE cohort, which is a cohort from, uh, from Iceland. They have, uh, they sequenced, uh, they, they did whole genome sequencing in I think it was 50,000-- or sorry, 15,000, uh, individuals, and they've shown unequivocally that, uh, the Lp (a) isoform size, even though you can sequence it, uh- really was not associated with the risk of heart attacks and strokes once you take into consideration Lp (a) levels. So it's really the Lp (a) number, uh, that matters, and that's actually very positive for, for the field that-- because there's so many puzzles that we still need to figure out in terms of, of the association between Lp (a) and risk. So at least we can, you know, um, I think I can-- we can convincingly say that it's the, the, the number of, uh, Lp (a) particles that, that matter and not necessarily the isoform size and that the isoform size matters because it's associated with different levels of, uh, of Lp (a) and not through an independent effect.

    3. PAPeter Attia56:21

       So really this, for one, creates a beautiful symmetry here, which is it mirrors apoB. The first, second, and third order factor in the fa- in, in the, uh, in the harm caused by an LDL particle is the number of the particles. The size, all of those things only factor into the number. So why is it that smaller particles are more often associated with a poor phenotype? Because when you have smaller particles, you generally have more of them. Um, so that's good to know.

11. 56:56 – 1:07:30

    The genetics and inheritance of Lp(a) and how and when to measure Lp(a) levels

    1. PAPeter Attia56:57

       Do we have a sense of the complexity in why some families, because again, we didn't talk about the inheritance of this, so in fact, may- before I ask this question, let's go back and explain the inheritance of this. It's a very important piece of the puzzle. How is this gene inherited, and what are the implications for people who have elevated levels of this as far as their offspring?

    2. BABenoît Arsenault57:24

       Yeah, that's a, that's a very good question. Uh, so the pattern of inheritance is through autos- autosomal dominant, uh, pattern of inheritance. So, uh, it's like any, uh, like for instance, if you compare it with a monogenic disorder, let's say familial hypercholesterolemia. In, in Quebec, we have a, a very famous, uh, mutation, which is a 15 kilobase deletion in the LDL receptor. So if, uh, if you inherit that, then at- if you inherit at least one copy, you know you'll, you'll have FH. For Lp (a) , if you inherit a genetic variant that's associated with high Lp (a) , chances are you'll have high Lp (a) as well because you only need one variant and not necessarily two. So you, you need either the allele from, uh, your father or your mother that will, uh, rise Lp (a) . But it's a bit more complex than that because we c- we cannot necessarily consider it a monogenic disorders because there's 2,000 different variants in the Lp (a) region that are associated with high Lp (a) . So your father can have an high Lp (a) because of a specific variant, and your mother can have an, uh, an, an Lp (a) variant that lowers Lp (a) , but it depends on the combination of SNPs that you will ultimately get. So it's not, uh, it's not as clear as any monogenic disorder. Even though it's a dominant mode of, uh, of inheritance, it's been shown, uh, that, um, that the, the children, you can, uh, they have, uh, uh, very different Lp (a) levels than, than their, uh, than their m- their mothers and fathers. And you cannot really estimate it, so you really have to, to measure it. And for people that are asking the question, "At what time I should get an Lp (a) measurement?" Let's say if I had, uh, a heart attack at an early age and I want to prevent that in, uh, in my children, then we know that the, uh, Lp (a) gene is fully expressed by age two, uh, in the liver, of course, uh, and that the levels that you will get at five years old are probably, uh, going to remain, um, uh, the, the s- well, maybe not the same levels, but if you have high levels by age five-

    3. PAPeter Attia59:52

       But if you're elevated at five, yeah, yeah, yeah.

    4. BABenoît Arsenault59:53

       So it'll probably increase through adulthood, but very, very slowly.

    5. PAPeter Attia1:00:00

       Yeah. So again, some very important information there, right? Piece one of that is you cannot predict the phenotype of the offspring from the phenotype of the parents. And, uh, let's contrast this with apoE, the gene. By the way, there's a lot of parallels between apoE and Lp (a) . ApoE is a gene that today doesn't seem to serve much of a purpose. All it seems to do is increase your risk of Alzheimer's disease and even increase your risk of cardiovascular disease independent of that. Um, there are three isoforms, the two, three, four type, and it's this fourth type that's high risk. So you can argue, how in the world does this gene exist? And of course, the answer is evolution wasn't really thinking about Alzheimer's disease, so therefore there must have been some benefit of it, and of course, we now know there is, right? This, this genotype was associated with protection from parasitic infections in the brain, um, which would have been far more to our advantage 100,000 years ago, 50,000 years ago, 10,000 years ago than the downside of Alzheimer's disease in your 70s or 80s. Um, but with apoE, because you have these three discrete isoforms, you only have six combinations, and therefore, if you know what the parents' isoforms are, you can probabilistically give a distribution for what the children will be. You still would need to measure it, of course, but there's a finite number of outcomes. Now, of course, there you're measuring genotype and not phenotype. We don't measure the phenotype of apoE yet. So here you have so many genes that are associated with this thing that if the parents are both elevated, the probability that the offspring are going to be elevated seems pretty high. If one parent is elevated and the other is not, there's a pretty decent chance that the offspring will not. Tell me about the situation in which both parents are not elevated, but yet could carry genes that-- or could carry variants of Lp (a) that when combined could elevate. Do-- Is that-- Has that been observed, or does one safely say if both of your parents are below 30 milligrams per deciliter, the probability that you are going to be north of 50 is very small?

    6. BABenoît Arsenault1:02:26

       I think it's very small, but you still have to, to measure it, uh, Peter. I, I, I, I-- To be honest, I don't think I would know the answer to that. Uh, so that's why we, we simply, um, suggest to measure Lp (a) . Well, the guidelines now, most guidelines will tell you to measure it in everybody at least once, uh, in their lifetime. But there are people that will-

    7. PAPeter Attia1:02:48

       And when do the guidelines suggest that that start? Do the guidelines suggest doing it in adolescence when you have a long enough runway to take action if the, um, Lp little a is elevated, or do they not specify?

    8. BABenoît Arsenault1:03:01

       I don't think they, they specify that. And the, the, the guidelines are actually just starting to, uh, um, advise for, for Lp (a) measurements. So some, some guidelines, uh, like the American Heart Association guidelines, uh, which are, um, uh, probably the less favorable for Lp (a) measurement. They'll tell you to measure, I don't remember exactly, but in patients with atherosclerotic cardiovascular disease or with a, a family history of atherosclerotic cardiovascular disease, in patients with familial hypercholesterolemia or in patients with aortic valve stenosis. So but the guidelines don't usually tell you when you should-

    9. PAPeter Attia1:03:38

       So in other words, measure the Lp little a once they've demonstrated that the disease that it causes is present.

    10. BABenoît Arsenault1:03:48

        Yeah, pr-pretty much. [chuckles]

    11. PAPeter Attia1:03:49

        That's fantastic advice.

    12. BABenoît Arsenault1:03:50

        So-

    13. PAPeter Attia1:03:50

        That's, that's excellent advice

    14. BABenoît Arsenault1:03:51

        ... so, so if you look at the-- Yeah. But if you look at the Canadian guidelines, though, they'll tell, they'll tell you to measure it-

    15. PAPeter Attia1:03:56

        Yeah

    16. BABenoît Arsenault1:03:56

        ... in everybody at least once in their, in their lifetime. So there is really an-

    17. PAPeter Attia1:04:00

        And, and by the way, this is where Canadians also stand out over Americans. Canadians have long adopted the measurement of apoB as the superior measurement to quantify LDL risk, and yet here in the United States, the guidelines still favor the use of LDL cholesterol, which is clearly inferior to apoB.

    18. BABenoît Arsenault1:04:20

        Yeah, absolutely. So, uh, I, I would like to comment on, on that. [chuckles] I think, I think the, the Canadian guidelines are, are much more up to date with the, with the recent, uh, literature on that. There's clearly no, no doubt about it. But, uh-

    19. PAPeter Attia1:04:34

        As are the European guidelines-

    20. BABenoît Arsenault1:04:35

        ... to come back to the-

    21. PAPeter Attia1:04:35

        ... while we're on the topic, right?

    22. BABenoît Arsenault1:04:36

        Yeah, exactly. Exactly.

    23. PAPeter Attia1:04:36

        The European guidelines and the Canadian guidelines are in line with the available evidence and the United States guidelines are, you know, just 40 years out of date, but that's all.

    24. BABenoît Arsenault1:04:47

        Yeah. Ab-absolutely. And the European guidelines, actually, they, they advise to measure Lp (a) in everybody for a different reason. It was to identify patients who have very, very high Lp (a) levels because we realize, uh, throughout the years that the, uh, having a super high Lp (a) might be a cause for familial hypercholesterolemia.

    25. PAPeter Attia1:05:11

        Hmm.

    26. BABenoît Arsenault1:05:11

        So, um, so and you need to measure LDL to diagnose, uh, familial hypercholesterolemia. And, uh, after the, uh, after mutation in the LDL receptor, mutation, uh, or variation in the Lp (a) gene might even be the second cause of familial hypercholesterolemia. And the reason for that is quite simple, because when you measure LDL, [lip smack] uh, you also measure Lp (a) cholesterol. So if you have, uh, a very high LDL and also a very high Lp (a) , there's a very good chance that the high LDL cholesterol will actually be high Lp (a) , uh, cholesterol. So, um, so yeah, this is-- I th-I think it's really underappreciated. Uh, and, and actually that's the reason why it's in the European guidelines. Uh, but now I think, uh, most of the guidelines that will, that will be, uh, put forward will just simply for whatever reason to measure, uh, Lp (a) at least once. And I don't know if it's in the pediatric guidelines because I don't really follow that, that literature. But, uh, maybe in children, uh, who have strokes at, uh, a, a young age, many of them have, uh, high Lp (a) . So it's not, uh, as, um, as clean as the literature in adults, but th-there's been a s- a lot of studies looking at high Lp (a) in stroke in children. So, uh, if you have, uh, a family history, uh, or relatives that had, uh, stroke at a, at a young age, it might be a good idea to, uh, to, to measure Lp (a) as well.

    27. PAPeter Attia1:06:53

        Y-yeah, that's actually a terrifying thought, by the way. Um, you know, my view on these things, of course, is just that the amount of energy that goes into debating it is so ridiculous compared to the relatively low cost of simply measuring the thing. Uh, the am- the, the people who debate why, oh, why would you spend $14 on an apoB test? It's like, if your life isn't worth $14, we shouldn't be having this discussion. Uh, same is true for measuring Lp little a. So, uh, I think it should be done on everybody, non-negotiable, certainly before your 18th birthday. That would be my, that would be my thinking on this.

12. 1:07:30 – 1:22:46

    Niacin and other proposed therapies to lower Lp(a), apoB, and CVD risk

    1. PAPeter Attia1:07:30

       Um, [lip smack] so, uh, let's go back now. By, by the way, I, I-- what's the greatest that you've seen, uh, number of Lp (a) to, uh, Lp little a to LDL? I, I had a patient once when we were measuring both in nanomole per liter who had an Lp (a) of 690 nanomole per liter in the context of an LDL particle concentration of about 1,800 nanomole per liter, so a little over one-third of his LDL were Lp (a) . Uh, I assume you've seen numbers even in excess of that?

    2. BABenoît Arsenault1:08:05

       Uh, yeah. Well, um, just to, to be, to be clear, Peter, uh, I don't see, I don't see patients. I'm not, I'm not a physician.

    3. PAPeter Attia1:08:11

       Right, right, right.

    4. BABenoît Arsenault1:08:11

       I'm a, I'm a biochemist.

    5. PAPeter Attia1:08:12

       But just through, through your collaborations. Yeah, yeah, yeah.

    6. BABenoît Arsenault1:08:13

       But I, I've seen, uh, and I've seen some very interesting case reports, uh, uh, on, uh, children that have, uh, FH and high Lp (a) . Uh, some of them even had to have liver transplant because, uh, the, the, the lipids were just so high, and they were having events in children years.

    7. PAPeter Attia1:08:34

       Wow.

    8. BABenoît Arsenault1:08:34

       So, uh, so but th- th- those are only, uh, case reports, of course. It's, it's, it's not, uh, not mainstream, and I wouldn't wanna scare anybody, but this is, this is as dangerous as it can get.

    9. PAPeter Attia1:08:46

       So let's talk about other therapies that have been proposed. So there was certainly a day, and sadly, there are still a number of physicians that I interact with, including those who carry the, uh, the title of lipidologist, who are recommending the use of niacin to lower Lp (a) . Can you talk a little bit about the history of that? Um, and at the risk of spoiling the punchline, why we do not believe that is a good idea.

    10. BABenoît Arsenault1:09:13

        Yeah. Um, well, it, it was even in the latest, uh, in the last guidelines of Eu- the European Atherosclerosis Society to, uh, advise, uh, niacin treatment in some patients with, with high Lp (a) . Um, we did not have cardio- large cardiovascular outcome studies, uh, on, uh, on, on literally any effect of, of, of niacin therapy. Now, we know that, uh, niacin therapy will actually reduce, uh, Lp (a) levels. It will, uh, increase HDL. It will lower triglycerides. So the effects on, on plasma lipids are, are actually pretty good. Um, however, and then, you know, if you're looking at Lp (a) the reduction, the mean reduction will probably be about 20 or 30% with, uh, with niacin. And there are, as you say, some lipidologists that have seen like very important reductions of, of Lp (a) with niacin that, that act- so they, they've decided to keep those patients on, on niacin, and I don't see any, any, any problem with that. Uh, the thing is, however, when you look at the actual evidence, the-- we have two large, uh, cardiovascular outcomes trials. We have the AIM-HIGH trial and the, uh, Heart Protection Study Two Thrive trial that have shown that there's no cardiovascular benefits in treating, uh, well, uh, anyone with, uh, with niacin, and we see a lot of side effects as well, um, flushing being the most, uh, the most important side effect of, uh, of niacin. So we have those risk, and we don't have that many benefits. So that's why, uh, niacin is not, uh, as prescribed as it, uh, as it once was. There are still people that have-- that are using it. Niacin reduces the production of, uh, uh, of Lp (a) , uh, but, uh, and, and Lp (a) still predicts the risk of events in patients treated with niacin, so we know that from the, from the AIM-HIGH trial. So when you're, uh, looking at the cost to benefit, uh, ratio for, for, for niacin, the evidence really isn't, is- isn't there to support, uh-

    11. PAPeter Attia1:11:24

        So why, why do you think this is?

    12. BABenoît Arsenault1:11:26

        ... niacin treatment.

    13. PAPeter Attia1:11:26

        I mean, if we look at the effect of niacin on raising HDL, which it does, right? HDL cholesterol goes up with niacin administration at a high enough dose. Um, but the outcome trials are very clear that that does not translate into benefit. It makes you think a little bit of the CETP trials, where you give a CETP inhibitor, HDL cholesterol goes up. In some cases, you actually saw more events, but usually, at best, you see no effect. There, it's a little easier to argue why that could be happening when you look at the complexity of HDL biology, and you understand how much we don't understand, and therefore, that HDL functionality is what really matters, and we don't have an assay for HDL functionality. So these things that we measure, like the amount of cholesterol in an HDL particle, is a pretty useless measurement in that it tells us nothing about how the HDL actually works, especially when you consider that you can have high cholesterol in an HDL particle because of all the cholesterol that's entering it, or you could have high cholesterol in an HDL particle because not much cholesterol is leaving it. Those would be two completely different states of affairs. And again, it makes sense why [lip smack] you can dismiss the, uh, notion that raising HDL cholesterol is valuable pharmacologically. In the case of Lp (a) , it's a bit more confusing because, as you said, niacin actually inhibits the production of apolipoprotein (a) . And for all of the nastiness associated with LDL and Lp (a) , their biology is actually easier to understand. In other words, the, the things that they're doing to hurt you are easier to understand than what HDL is doing to help you. So why do you think there is not a more clear signal between the use of niacin and the reduction of events?

    14. BABenoît Arsenault1:13:22

        Yeah, it's a very good question. Um, the Mendelian randomization studies have been very clear that you will need a very large reduction in Lp (a) to produce cardiovascular benefits. There was-- The first study has, uh, has shown that... has suggested that because it's, it's basically only modeling, right? We-- There's no trial data.

    15. PAPeter Attia1:13:45

        Yeah.

    16. BABenoît Arsenault1:13:45

        So we can-

    17. PAPeter Attia1:13:46

        Yep

    18. BABenoît Arsenault1:13:46

        ... at best, uh, estimate the treatment effect. So it suggested that you needed 100 milligrams per deciliter, uh, reduction in Lp (a) to get a benefit in a trial that would be, uh, comparable to a statin treatment, like a-

    19. PAPeter Attia1:14:01

        O- over what period of time?

    20. BABenoît Arsenault1:14:02

        ... a 20% reduction.

    21. PAPeter Attia1:14:03

        Is that a five-year? You'd need to see that in a five-year window? Or what, what-

    22. BABenoît Arsenault1:14:06

        Yeah. Well, that's actually the problem because when you're looking at Mendelian randomization studies, you're looking at primary prevention, and we're looking at lifelong r- reduction. So it's very hard to estimate a trial.

    23. PAPeter Attia1:14:17

        Oh, so the MR says if you wanna redu- if you wanna take that mortality curve down to the next rung, it's 100 milligram per deciliter reduction and lifetime exposure, which means in a clinical tri-

    24. BABenoît Arsenault1:14:29

        So there was one study that, that, that showed that. There, there's other study that came out after that that said, "Well, it's probably not 100. It might, might be around 50 milligrams per deciliter." But it's still high, so you need a large effect. So it's not a 20% reduction. So the-

    25. PAPeter Attia1:14:44

        But, but there's a bigger point there, which is, which you alluded to. If that, that's over the course of your life, that's, that-

    26. BABenoît Arsenault1:14:52

        Yeah, well-

    27. PAPeter Attia1:14:52

        That means over five years you might have to basically obliterate it if you're going to wanna see a benefit.

    28. BABenoît Arsenault1:14:58

        Yes, and well, that's what the, uh, antisense-

    29. PAPeter Attia1:15:00

        Yes. Yeah, yeah

    30. BABenoît Arsenault1:15:01

        ... uh, the antisense oligonucleotides will do, and we'll, we'll c- I guess we'll come back to that later.
13. 1:22:46 – 1:28:36

    Why awareness of Lp(a) among physicians remains low despite the importance of managing risk factors for ASCVD

    1. PAPeter Attia1:22:46

       And what I find so tragic about that statement is the number of good physicians out there, really great doctors that are working hard, taking care of patients, frontline physicians, family medicine physicians, internists who have no idea what it is. You know, you ask them about it, and they look at you as though you've asked them something in a different language. Um, I still struggle to understand that disconnect given its urgency. I, I wonder if that's a uniquely American phenomenon. Do you have any insight? I know you're not a clinician, but do you have an insight as to whether or not the literacy around this in Canada and Europe is higher?

    2. BABenoît Arsenault1:23:27

       I don't have any reasons to believe that the literacy in Canada or Europe is higher than it is in, uh, in America. And that's one of the-

    3. PAPeter Attia1:23:35

       Even with, even with your guidelines being more forward-leaning.

    4. BABenoît Arsenault1:23:38

       Oh, yeah. But these guidelines are new, and it will take a lot of time before they implement it. Sometimes it's, you know, it, it takes a, a full decade before it, you know, it's transmitted to younger generation-

    5. PAPeter Attia1:23:50

       Yeah

    6. BABenoît Arsenault1:23:50

       ... of physician and it's, and people actually talk about it. So that's one of the reason I'm so glad that we get to do this, this podcast. Hopefully this, this will raise awareness for, uh, the physicians out there that, you know, didn't have, uh, any information about Lp (a) and, you know, you can't blame them because, well, uh, it, it's obviously in the guidelines, but, you know, not all physicians will read all the lipids guidelines. There's so many guidelines out there that, uh, you can't blame them for that. But I mean, that's why we have to do more education to, um, to physicians. And I think one of the reason that, um, people are reluctant to measure Lp (a) is that because there's no treatment, uh, for, for high Lp (a) . So sometimes, um, you know, when you... Any-- So, so any, um, a-any medical, uh, procedure that you do, even if it's asking for, uh, a measurement of, of any labs that you can mention, it has benefits, but it also have, it also has consequences. Uh, so for, for instance, you can, uh, you know, you don't wanna stress anybody saying, "Hey, you have this risk factor. It's super important." Uh, and you don't want to do, uh, like, an over-diagnosis and, and, and over-treatment. Uh, so, so I used to, I used to think that a lot. But now, you know, we're in the age of, uh, shared decision-making. Uh, you, we can communicate the, the correct information, uh, to, to, to patient, tell them, uh, tell them what we know. Uh, and even though there's no specific therapy for high Lp (a) , it doesn't mean you can't do anything. Um, and I mean, there's trial data showing that if you prescribe, for instance, a statin and if you, uh, lower LDL cholesterol levels in patients that have some risk factors for, uh, for cardiovascular disease, you'll reduce their, their risk of events. So in patients with high Lp (a) , you need to manage LDL. You need to manage Lp (a) . You need to manage, uh, lifestyle, smoking cessation, uh, and et cetera. And we've actually shown that. Uh, I, um, uh, I worked-- I've been working for, uh, more than 15 years with, uh, investigators in, uh, in Amsterdam and Cambridge on the, uh, EPIC Norfolk study. So the EPIC Norfolk study is the European Prospective Investigation into Cancer and Nutrition, and they have a Lp (a) measurement in 18,000 individuals. And we've looked, uh, in that, uh, in that population at, uh, the effect of Lp (a) on the risk of events, but according to what the, uh, American Heart Association calls the Life's Simple 7. So, uh, smoking, uh, having a healthy diet, being physically active, uh, having low body weight, uh, LDL cholesterol, no diabetes, uh, and blood pressure that's on target. And if you look at patients that have high Lp (a) and that manage all of these risk factors, it's o-observational study, of course, but you can if you consider it a causal relationship, you could reduce your risk by, uh, by two-thirds. So, so that's not trivial. So, so we're trying to, uh... So that's one reason why we should, uh, we should measure, we should measure Lp (a) . If it's just to, uh, target the, the other risk factors, we'll have, uh, a lot of benefits in terms of, uh, prevention of, of cardiovascular diseases at the population level.

    7. PAPeter Attia1:27:23

       A- and I think this is another great example of the parallel with ApoE, the genotype. Uh, as recently as even a couple of years ago, I would have enormous arguments with physicians about, uh, patients that we were co-managing, right? So this would be a patient who has both of us as their physician, and the patient would say, "Look, I wanna have my ApoE genotype measured." I would say, "I completely concur." The other physician would say, "That's an absolutely horrible idea. What good comes of that if they discover that they have an ApoE4 gene and their risk is higher? All you've done is create anxiety." Uh, to which I would argue, uh, perhaps in some individuals, sure, and that's why it should be something that is done with consent. But it, that assumption can-- assumes you can do nothing about it. And while you can't change the gene, the evidence that you can modify behaviors that will lower the risk is enormous. Now, in the case of ApoE, it's even more complicated because we now know what we didn't know a few years ago, which is there are so many other genes [swallows] that will either amplify or attenuate the risk of ApoE. So frankly, today, knowing that you're ApoE4 positive, uh, in my opinion, carries much less information than it once did.

14. 1:28:36 – 1:37:45

    The variability of disease in patients with high Lp(a)

    1. PAPeter Attia1:28:36

       So I wanna ask you about something parallel with Lp little a. I've had patients who have had modest Lp little a, meaning 150, 125 nanomole per liter, 60 milligram per deciliter, who have had the most devastating ASCVD that you can shake a stick at. I mean, six-vessel disease, calcium scores of 2,000. I mean, these are people who are having, you know, coronary artery bypass surgery in their 50s, and their Lp little a is, you know, a little elevated. And by the way, their LDL and apoB were not through the roof. They're not smokers, they're not hypertensive, they're, they're not type 2 diabetic, et cetera. Ca- hard to explain those ones. Similarly, I've had patients whose family histories do not suggest advanced or premature ASCVD, and I told you about one of them earlier. 690 nanomole per liter Lp little a. Now, this person had a zero calcium score. Admittedly, they were in their 40s, so at least, say, you know, a calcium score of zero in your 40s doesn't generally tell you anything, but at least tells you that this person isn't having advanced atherosclerosis. [tsks] Their family history is very uninspiring, and at least one of their parents had to have an elevated level. Grandparents, nothing. And I scratch my head and I think, "Why is it that this person seems somewhat immune from their very elevated Lp little a, whereas this other person who's elevated, but not through the roof, is ravaged by it?"

    2. BABenoît Arsenault1:30:35

       Well, you're describing my next, uh, grand proposal, Peter. So [chuckles] this is abs- exactly what we're, uh, what we're trying to study. Uh, and I alluded, uh, earlier to the penetrance of, uh, high Lp (a) , and that's exactly what you're, what you're referring to. So th- there might be-

    3. PAPeter Attia1:30:51

       Oh, I misunderstood, Benoit. I thought you were referring to the penetrance in terms of the expression of the protein. You were referring to the penetrance of the disease.

    4. BABenoît Arsenault1:31:02

       Yes, exactly.

    5. PAPeter Attia1:31:02

       I'm sorry. I misunderstood that.

    6. BABenoît Arsenault1:31:03

       Exactly.

    7. PAPeter Attia1:31:04

       Okay.

    8. BABenoît Arsenault1:31:04

       So, so but, you know, we can say a lot about that 'cause, uh, we actually measured, um... So in our lab, we isolated the Lp (a) particle from the blood of, uh, donors and patients with aortic valve stenosis. So the reason being that, well, we're gonna study those, those particles because those patients, they were matched for age, sex, statin therapy, smoking, et cetera. So they're like the same, uh, people demographically speaking, but one of them has a disease and the other one doesn't. So and they have-- they all have high Lp (a) , so and the, the... They were matched for Lp (a) levels. So we thought, "Well, maybe s- there's something happening in the particle. Maybe they have more oxidized phospholipids. Maybe they have different proteins."

    9. PAPeter Attia1:31:51

       Mm-hmm.

    10. BABenoît Arsenault1:31:52

        So we've studied that, and we, we realized that these, uh, patients might have more, uh, cell adhesion molecules that are, uh, transported by Lp (a) , which make them more, quote-unquote, "sticky" to, uh, endothelial cells or, or fibrin clots or whatever. They would make them... Or, or may- maybe even macrophages because patients with high Lp (a) also have activated macrophages which, uh, can penetrate much more easier in the, in the vessel wall. There's more apoptosis in the, in the macrophage. There's more cytokine production like IL-6, IL-8, uh, et cetera. So there might be something that's different in the Lp (a) particle. That's just an hypothesis. This was a study of, I think there were 20 patients in each, uh, in each study arm, 'cause, you know, it's not easy to, uh, measure, uh, to, to remove Lp (a) from the blood and have it in a sufficient quantity that you can actually do proteomics on it.

    11. PAPeter Attia1:32:59

        Mm.

    12. BABenoît Arsenault1:33:00

        So this is-- it took my [chuckles] a Ph.D. student of mine at least one year just to recruit the patients and isolate their Lp (a) and their proteome.

    13. PAPeter Attia1:33:06

        And that's just because the, the electrophoresis is complicated or the isolation after the electro... Is it getting it out of the body that's complicated or isolating it once it's ex vivo?

    14. BABenoît Arsenault1:33:15

        Uh, well, once it's ex vivo, you have to isolate it. It's not difficult to isolate it 'cause you need to do ultracentrifugation.

    15. PAPeter Attia1:33:23

        Yeah.

    16. BABenoît Arsenault1:33:23

        But it has the same density of, uh... Well, I... Well, it probably has... It has the same size as LDL and the same density as HDL, so you have to do, uh, chromatography columns to just basically separate it from LDL particles and also HDL particles. So you need to do a size exclusion chromatography and, um, an affinity-based, uh-

    17. PAPeter Attia1:33:48

        Mm-hmm

    18. BABenoît Arsenault1:33:49

        ... um, uh, chromatography. So, so it's, uh, it took a lot of time just to set up that, uh, that technique. And, uh, we worked with, um, a, a great colleague of mine, Marlis Koschinsky, who's at the Robarts, uh, Research Institute in London, Ontario, and she's been, uh, doing this for, for ages, but she helped us, uh, doing that. And we're actually, I think, one of the first to actually, uh, isolate Lp (a) from the blood of, of patients. So, so that might be an explanation for this different expression of the disease in, in, in, in people that have all high Lp (a) but some that, that are lower than others. So that's just a hypothesis. There's... You need to look at other risk factors. Maybe, um, there's another gene that's out there that, uh, might be-- might code for a, a receptor, uh, of LDL.

    19. PAPeter Attia1:34:42

        Mm-hmm.

    20. BABenoît Arsenault1:34:42

        There's labs that are, uh, really devoted to finding other genes, uh, aside Lp (a) , uh, that, that might explain this.

    21. PAPeter Attia1:34:51

        And the GWAS-

    22. BABenoît Arsenault1:34:52

        And we have some-

    23. PAPeter Attia1:34:52

        ... hasn't identified any-- 'Cause that would be your first tool. Before I'd go looking-

    24. BABenoît Arsenault1:34:56

        Yep

    25. PAPeter Attia1:34:56

        ... for that gene, or that receptor rather, I, I would be trying to just find out what the association is, right?

    26. BABenoît Arsenault1:35:03

        Absolutely. And those studies have been done. Probably the best GWAS on, on Lp (a) levels was published, uh, I think last year by the group, uh, of, uh, George Chatzopoulos in, uh, at McGill, uh, in Montreal and, uh, and James Engert. Uh, what they showed is that, well, obviously the biggest hit was at the Lp (a) locus. Uh, but we-- And we had known this for a while, that ApoE actually, uh, also regulates, uh, l- high Lp (a) levels. So that's another reason why ApoE-

    27. PAPeter Attia1:35:34

        Is there concordance? Is there some concordance with high-- with, with ApoE and Lp (a) ?

    28. BABenoît Arsenault1:35:40

        Yeah. So, so the, the, the ApoE that will-- the ApoE allele that will rise the risk of heart attacks will also rise, uh, Lp (a) levels.

    29. PAPeter Attia1:35:49

        Oh.

    30. BABenoît Arsenault1:35:49

        So you have that. You have the CTP gene. And, and then we haven't talked about the low- the Lp (a) lowering effect of CTP inhibitors, which is actually higher than what you can get with niacin therapy. So some have suggested that, uh, the benefits of-- well, the quote unquote benefits of CTP inhibition might be due to a certain extent to high Lp (a) levels. But the problem with, with niacin trials and CTP trials is that they weren't done particularly in, in patients with high Lp (a) . So I guess we'll never-
15. 1:37:45 – 1:48:05

    Diseases most associated with high Lp(a)

    1. PAPeter Attia1:37:45

       Before we get to that, I want to go back to and really make sure we flush out this oxidized phospholipid plasminogen, basically the atherogenicity of this particle. Is it clear that Lp little a's enter the subendothelial space as LDLs do, or is that unclear?

    2. BABenoît Arsenault1:38:04

       Yeah. Well, there's not as much research that's been done on Lp (a) , but, you know, it's-- if, if you look at, um, uh, postmortem studies, uh, you, you can see Lp (a) in, uh, in atherosclerotic plaques, and you can s- and you can certainly see it on, on aortic valves 'cause there's more easier to-- like aortic valve are much more easier to get than atherosclerotic, uh, plaques as you can remove the valve, and then you can study it in the-- under the microscope. So there's, there's good evidence, um, that, uh, the Lp (a) can actually penetrate there. Uh, usually what they do is they will bind to, uh, to clots, uh, that are, uh, in the region of, uh, of the atheroma. Uh, and that's o- one of the reasons why they might also be present, uh, present there. But, uh-- And they can also, uh, send their oxidized phospholipid through different, uh, through different receptors. Uh, 'cause we don't really know what is the receptor for Lp (a) in those, uh, in those tissue. Um, so at the surface of, uh, macrophages, there are scavenger receptors, uh, toll-like receptors, CD36 that might, um That might bind Lp (a) . They bind a bunch of things. Uh, and they-- but they also might bind NPA, which will, um, uh, ensure that Lp (a) g-get, gets trapped in the macrophages and-

    3. PAPeter Attia1:39:34

       NPA, my-myeloperoxidase?

    4. BABenoît Arsenault1:39:36

       Uh, Lp (a) , sorry.

    5. PAPeter Attia1:39:37

       Oh, Lp (a) , okay.

    6. BABenoît Arsenault1:39:38

       Sorry. I-I meant Lp (a) , yeah.

    7. PAPeter Attia1:39:39

       But if I'm hearing you correctly, Benoit, it would almost suggest that Lp little a plays less of a role in the initiation of atherosclerosis, which is really initiated by [clears throat] the monocyte becoming the macrophage in the subendothelial space and engulfing the oxidized LDL to become that foam cell. That's really the initiating trigger. You're saying [clears throat] Lp (a) might not be playing a role in that, or maybe it is. I, I wanna make sure I'm not misquoting you. But where it really lights things on fire is once you already have a plaque. That's where the ability to form a clot goes up. Potentially, if you say it has more VCAMs on it, it's attracting even more macrophages to the site of injury. So, so am, am I capturing what you're saying correctly?

    8. BABenoît Arsenault1:40:34

       Absolutely. Uh, I think it's actually both. So the macrophages of patients with high Lp (a) are already activated, and they will, uh, get, uh... As soon as there's s-

    9. PAPeter Attia1:40:46

       Mm

    10. BABenoît Arsenault1:40:47

        ... some endothelial dysfunction, they'll get there. They might even cause, uh, endothelial dysfunction. So Lp (a) is, is, is associate-- uh, it's probably a main driver, uh, before the onset of any discernible plaque, but it, it also has this double whammy, where it, it's, it initiates the disease, but it also, uh, is associated with the progression, uh, with the progression of the, of the, of the disease. And we see it in, uh, for instance, I, I talked to you a little bit earlier about the, uh, PET imaging-

    11. PAPeter Attia1:41:24

        Mm-hmm

    12. BABenoît Arsenault1:41:24

        ... of, um, of s- with sodium fluoride. These studies have also been done, uh, by, uh, Eric Stroos in, uh, in Amsterdam. Uh, what they showed is that if you, you don't use, uh, sodium fluoride, but you use FDG, so fluorodeoxyglucose, um, which is, um, basically a marker of macrophage activation. And if you look at the carotids and also the aorta of patients that have no disease but, uh, that are separated, uh, on the basis of whether or not they have high Lp (a) , you'll see a lot of light in, uh, patients with high Lp (a) . So that tells you that it als- it's also associated with, uh, with inflammation, with the inflammatory plaque, uh, in, uh, even in patients that don't have, uh, established, uh, disease. So that's one of the reason why it's, um, it, it's, it, th-this kind of particle is so dangerous.

    13. PAPeter Attia1:42:25

        And the association is obviously very strong for, um, ASCVD and aortic stenosis. How high is the association specifically for cerebrovascular disease?

    14. BABenoît Arsenault1:42:37

        It's clearly not as high. So there's, there's obviously a signal. If I, if I would have to, um, rank those, uh, atherosclerotic cardiovascular disease, the first one will be aortic valve stenosis. That's, um... It's obviously less pre-present or prevalent than, uh, than MI or, or, or stroke, but the-

    15. PAPeter Attia1:43:02

        But there are fewer contributing factors beyond Lp (a) the way you have apoB.

    16. BABenoît Arsenault1:43:06

        Exactly. Exactly. So the relative risk is actually higher. The, the absolute risk is lower because there's not that many people-

    17. PAPeter Attia1:43:13

        Yep

    18. BABenoît Arsenault1:43:13

        ... that have that. It's m-might be 2% of the, of the population age above 60. But if you look at, uh, top quintile versus lower quintile, uh, the, the biggest risk is with aortic valve stenosis. After that, it depends on the study. Sometimes it's myocardial infarction, sometimes it's peripheral artery disease.

    19. PAPeter Attia1:43:35

        Mm.

    20. BABenoît Arsenault1:43:35

        And we haven't talked about that, but Lp (a) is very strongly associated with PAD as well. So it's aortic valve stenosis, PAD and MI, then ischemic stroke. Uh, and it's important to, uh, make the, the distinction between, uh, hemorrhagic and ischemic stroke because, uh, Lp (a) is only associated with, uh, with ischemic stroke. Um, and, uh, yeah, I think that's it. It's also associated with, uh, chronic, uh, kidney disease.

    21. PAPeter Attia1:44:06

        Oh, so that's it. Really, it's only associated with aortic stenosis, MIs, peripheral vascular disease, ischemic cerebral strokes, and kidney disease. But aside from that, it really does nothing.

    22. BABenoît Arsenault1:44:19

        Yeah. There was some, uh, some literature maybe, uh, 15 or 20 years ago, uh, on, uh, deep vein thrombosis and, uh, and Lp (a) , and there has been new studies published on that. There's been genome-wide association studies, and we really don't see, uh, a signal for Lp (a) being associated with, uh, with deep vein thrombosis too. So, so that was part of the consis- uh, part of the conversation for a while, but now I think it's pretty clear that it's really more closely associated with, uh, atherosclerotic, uh, cardiovascular diseases and less with, uh, thrombolic, uh, events.

    23. PAPeter Attia1:45:00

        Do you think-- I mean, we do have an assay, I believe, for OX, uh, OX-LDL, correct?

    24. BABenoît Arsenault1:45:07

        Yeah.

    25. PAPeter Attia1:45:08

        Is that assay picking up the oxidized phospholipid of Lp (a) included in that? ... calculation?

    26. BABenoît Arsenault1:45:15

        No, abso- absolutely not. So-

    27. PAPeter Attia1:45:16

        Totally different. Yep.

    28. BABenoît Arsenault1:45:18

        Yeah. Well, there is actually an assay to measure, uh, oxidized phospholipids on apoB-containing-

    29. PAPeter Attia1:45:24

        Is that-

    30. BABenoît Arsenault1:45:24

        ... lipoprotein
16. 1:48:05 – 2:04:58

    The biology of PCSK9 protein, familial hypercholesterolemia, and the case for inhibiting PCSK9

    1. PAPeter Attia1:48:05

       So you alluded earlier to a PCSK9 protein, which we'll talk about. Um, tell people, before we get into the drug, just tell people about the PCSK9 protein, how it works, what its relationship is to the LDL receptor.

    2. BABenoît Arsenault1:48:23

       Absolutely. So PCSK9, uh, it means proprotein convertase subtilisin/kexin type 9. It was discovered in 2003 by, uh, a, a collaboration between Nabil Seidah, who is at, uh, Montreal, and Catherine Boileau, who is in France. They had identified this family in France that had, uh, familial hypercholesterolemia, but they couldn't find a mutation in the LDL receptor gene, uh, that explain the, the familial hypercholesterolemia. So-

    3. PAPeter Attia1:49:03

       By the way, before you get into this, I just wanna say, this is one of my absolute favorite stories in all of medicine, certainly in the modern era of medicine. You know, if you think the last 20, 30 years, this story is remarkable. So please-

    4. BABenoît Arsenault1:49:16

       Yeah

    5. PAPeter Attia1:49:16

       ... indulge us.

    6. BABenoît Arsenault1:49:17

       [laughs] Thanks for doing me the honor. [laughs] So, so they had identified this family that had FH without a mutation in the, uh, LDL receptor, and the paper was published in Nature Genetics in 2003. So you can think that they had been working on this for, for a few years, so that was probably j- at the time where the human genome was being sequenced. So that was, uh, during the days of, uh ... So that was pre genome-wide association studies and whole genome sequencing, where, uh, you were doing linkage analyses with, uh, satellite DNA and, uh, yeah. So I was, uh, an undergrad at that time. I was learning these, uh, these, these techniques, and I, I wasn't in the, uh, lipids field, so, so I, I heard that story after. But, uh, so, so what they found is that, uh, they, they were able to map the, the gene in, in that family to, uh, a protein that was at the time called NARC1. And so they, they didn't know that the, uh, that, that it was, uh, a, a proprotein convertase. So, uh, when they identified that, uh, that family in France, they partnered up with, uh, with Nabil Seidah, who is, um, a, a world, uh, renowned scientist on, uh, proprotein convertases. And they, uh, mapped it to NARC1, which eventually became, uh, PCSK9. So the, the, the way PCSK9 works i- is that it's a regulator of the LDL receptor. So when the cells m- makes an LDL receptor, it will also make PCSK9. Now, PCSK9 can bind to the LDL receptor. That can happen inside the cell, and when that happens, uh, the LDL receptor gets degraded in the lysosome That can also happen extracellularly, um, when, uh, the LDL receptor, obviously in the hepatocyte, gets stuck at the membrane, but PCSK9 gets secreted. So you can actually measure PCSK9 levels in the blood, but when it gets secreted, it can actually bind the LDL receptor. And when that happens, the LDL receptor cannot bind, uh, LDL particles. And I told you earlier that, uh, LDL receptor density at the surface of hepatocyte is super important for LDL clearance. Um, so, uh, because PCSK9 can be, uh, can be secreted, and by the time that they had realized that, they had shown that, uh, there were actually families in, in Montreal that had, uh, gain-of-function mutation in, in PCSK9 that had, uh, familial hypercholesterolemia. And then, uh, in 2006, the group of Helen Hobbs, uh, at UT Southwestern had shown that there are common variants in PCSK9 that are associated with lower levels of, of PCSK9, lower levels of LDL, and protection against, uh, cardiovascular diseases. Now, the pharmaceutical industry didn't need much more information to develop PCSK9 inhibitors, right? And, and because PCSK9-

    7. PAPeter Attia1:52:37

       And I remember that paper like it was yesterday. I mean-

    8. BABenoît Arsenault1:52:41

       Yeah, me too

    9. PAPeter Attia1:52:41

       ... it's hard to believe it's been-

    10. BABenoît Arsenault1:52:42

        I, uh, yeah

    11. PAPeter Attia1:52:42

        ... what is, what is that now? 16, 16 years ago.

    12. BABenoît Arsenault1:52:45

        16 years.

    13. PAPeter Attia1:52:46

        Makes me feel old.

    14. BABenoît Arsenault1:52:46

        Yeah, absolutely.

    15. PAPeter Attia1:52:47

        Yeah.

    16. BABenoît Arsenault1:52:48

        I, I, I remember I was, uh, I was a master's student, uh, at that time, and we were, we were witnessing that, and it was, it was ve- a very exciting time. Um-

    17. PAPeter Attia1:52:59

        So let me just make sure-

    18. BABenoît Arsenault1:53:00

        And, uh, so-

    19. PAPeter Attia1:53:00

        We, we go-

    20. BABenoît Arsenault1:53:01

        Yeah

    21. PAPeter Attia1:53:01

        ... we, we synthesize that for people because it's such a big deal, right? So familial hypercholesterolemia is a very heterogeneous disease. There are at least 3,500 mutations that produce the exact same phenotype, very, very elevated cholesterol. These are patients that have total cholesterol typically north of 300 milligrams per deciliter, LDL cholesterol by definition above 190 milligrams per deciliter off therapy, and often much higher. This disease is unequivocally linked to accelerated ASCVD, and what was discovered in 2003 was yet another gene that was associated with it, but what made it different is most of the genes, not all, but most of the genes associated with FH directly involved the LDL receptor. This one didn't seem to. Instead, they discovered that it was this protein that wreaks havoc on the LDL receptor when it's overexpressed, either by degrading the LDL receptor in the lysosome before it gets brought to the surface, or frankly just interfering with the receptor when it's at the surface. Does PCSK9 also degrade, um, LDL receptors or i- increase their turnover when they are at the surface of hepatocytes?

    22. BABenoît Arsenault1:54:19

        Yeah, exactly that. That's exactly what I was gonna say. That's the third mechanism-

    23. PAPeter Attia1:54:22

        Yeah

    24. BABenoît Arsenault1:54:22

        ... through which, uh, PCSK9 can influence res- LDL receptor density. Because what people don't really appreciate is that the LDL receptor, when it does its job of bringing LDL particles within the hepatocytes, gets recycled at the surface of the hepatocyte, and that can happen 100 times in the, in the life of the LDL receptor.

    25. PAPeter Attia1:54:45

        Wow.

    26. BABenoît Arsenault1:54:45

        Because it takes a lot of energy to the cell, uh-

    27. PAPeter Attia1:54:48

        To make the LDLs, yeah

    28. BABenoît Arsenault1:54:48

        ... to produce the LDL receptor. And once an, a PCSK9 is bound to an LDL receptor, then it prevents its recycling. So, so the l- the cell has to make more, uh, LDL receptor, and when it does that, because they're under g- genetic control of the SREBP-2, um, transcription factor, so then the LDL receptor gets, uh, produced and so is PCSK9. So, so you can have this, uh, this vicious cycle. So, um-

    29. PAPeter Attia1:55:21

        And it's interesting to think that if, if the story had stopped there, it's not clear we'd be where we are today without the 2006 paper, which showed, wow, as bad as that gain-of-function is, the loss-of-function is really amazing, where now you found these people who had the opposite of FH. These are people who were basically missing their PCSK9, not completely, just significantly underexpressed, and these were people that as adults walked around with neonate levels of LDL cholesterol, 10, 20, 30 milligrams per deciliter.

    30. BABenoît Arsenault1:56:00

        Yeah. So, so the, the most frequent, um, uh, variant that they look at was present in 2% of the population, and they saw very mild LDL reduction. So they-- I don't remember. This is 2006.
17. 2:04:58 – 2:10:38

    The variability in PCSK9 inhibitors’ ability to lower Lp(a) and why we need more research on individuals with high levels of Lp(a)

    1. PAPeter Attia2:04:58

       So let's go back and close the loop on one thing before we now talk about PCSK9 and Lp little a. So you've explained now why a PCSK9 inhibitor, the drugs we're talking about, are so effective in lowering ApoB because they're basically mimicking the most extreme loss of function of this gene. You're taking away that protein that does those three things to reduce LP, uh, LDL clearance. Why is it, remind us, that statins don't lower Lp little a? You would think, well, we know why statins get the LDL receptor to be more dense. That should do it. So the, the, the obvious explanation here is LDL receptors don't clear Lp little a. But why is that? Isn't an Lp little a just an LDL with a little extra thing on it? Why is that causing so much difficulty for the statin?

    2. BABenoît Arsenault2:05:56

       I told you earlier that, uh, Lp (a) levels were determined by their rate of production, and one of the players that was an anticip- unanticipated player in, uh, in apo-- apr- Lp (a) /uh, apoA production is actually PCSK9. 'Cause if you, um, incubate cells, liver cells with, uh, with, with PCSK9, you'll see the expression of apoA going up, and in lipoprotein turnover studies, uh, you also see that. So if you treat, uh, people with a PCSK9 inhibitor, you will, uh, actually see a reduction in the production rate of, uh, of apoA. And there was a nice, uh, study that's, uh, a bit complex to, uh, to fully appreciate by, uh, Gerald Watts, who's in, uh, Perth, Australia. He's shown this, but he also showed in a second group that if you treat patients with a PCSK9 inhibitor and a statin, you see the, um, the... And that's probably what, where the, um, LDL receptor presence gets maximized at the, uh, surface of the liver cells. You can actually see clearance, uh, or increment in the fractional catabolic rate of, uh, of Lp (a) . So there's still so much that, uh, we don't know in this, uh, in this area. Uh, so, um, and it's not totally clear why, uh, we see this difference of PCSK9 inhibitors that's depending on whether or not you're treated with a, with a statin.

    3. PAPeter Attia2:07:39

       A-and I think all comers, we see that a PCSK9 inhibitor is lowering Lp little a by... Is, is it about 30% is the on average?

    4. BABenoît Arsenault2:07:47

       Yeah. And, uh, so the average is m- is probably between 25% and 30% in all comers.

    5. PAPeter Attia2:07:54

       Yeah.

    6. BABenoît Arsenault2:07:55

       Um-

    7. PAPeter Attia2:07:55

       But the variability is enormous. I mean, I-

    8. BABenoît Arsenault2:07:58

       Exactly. The variab- the variability is, is very important, and it's another example where we need to study patients that have high Lp (a) 'cause th-these are the patients that we want to provide an answer to. And there's only been one trial that had tested the effect of a PCSK9 inhibitor on in patients with Lp (a) . Uh, there, there had been sub-analyses in FOURIER and ODYSSEY outcomes. Uh, and when you look at that trial, it's called the ENIGMA trials, and all these post-doc, uh, analyses of, um, of randomized controlled trials of PCSK9 inhibitors, you see that in patients with high Lp (a) , the reduction is approximately 15%. So it's not spectacular. And in, in the ENIGMA trial, what they did is that, uh, they've looked at, uh, arterial wall inflammation using fluorodeoxyglucose. This is a trial run by, uh, Zahi Fayad at, um, Mount Sinai in New York and Eric Stroos in, in Amsterdam. Uh, they showed that, uh, even though you, you reduce LDL by, uh, I don't know what percentage, but it was a, a spectacular reduction in LDL, a s- very small reduction in Lp (a) of 15%. You don't see any effect on arterial wall inflammation. So that means that, you know, there's an important, uh, residual risk that's associated with Lp (a) 'cause If you lower LDL, uh, with PCSK9 inhibitors, uh, you know, there's no outcomes data although they did link, uh, Lp (a) with, uh, recurrent, uh, cardiovascular disease in this, in these trials. You see, uh, uh, that the pro-inflammatory effect, uh, of Lp (a) on the vasculature still remains. So we're gonna g- have to go after Lp (a) even in patients that have very low, uh, very low levels of LDL. There's no doubt about it.

    9. PAPeter Attia2:10:01

       And so is one interpretation of the fact that, um, PCSK9 inhibitors can lower Lp little A by 30%, but that might not be sufficient to ameliorate the Lp little A risk specifically, is that it's just simply not enough. It gets back to what you said earlier.

    10. BABenoît Arsenault2:10:18

        Yeah.

    11. PAPeter Attia2:10:18

        It... You're going to have to eliminate Lp little A and, and it becomes a bit more of a step function than the gradient we see with apoB.

    12. BABenoît Arsenault2:10:29

        Yeah. I, I don't know if we need to eliminate Lp little A, but we need to take-

    13. PAPeter Attia2:10:33

        We need to get it probably below-

    14. BABenoît Arsenault2:10:35

        ... a higher Lp (a) level and bring it down-

    15. PAPeter Attia2:10:36

        Yeah. Yeah. Yeah

    16. BABenoît Arsenault2:10:36

        ... to a lower level.

18. 2:10:38 – 2:13:33

    Peter’s approach to managing patients with high Lp(a), and Benoît’s personal approach to managing his risk

    1. PAPeter Attia2:10:38

       So that brings us-

    2. BABenoît Arsenault2:10:39

       And that's what they're testing.

    3. PAPeter Attia2:10:40

       Yeah. So that, that brings us-

    4. BABenoît Arsenault2:10:41

       And that's what [laughs]

    5. PAPeter Attia2:10:41

       ... to where we are today, right? So what's the state of the art-

    6. BABenoît Arsenault2:10:44

       Yeah

    7. PAPeter Attia2:10:44

       ... today? In 2022, with my patients who have elevated Lp little A, I take a two, two-prong effect, uh, when it comes to lipid management. Obviously, there's many things we're doing outside of lipid management. The first is absolutely eradicating apoB. So we're very aggressive on this because it's very clear that you can do this safely and effectively. We target an apoB of about 30 to 40 milligrams per deciliter. So we target an apoB at what we would call a physiologic level, so the level that y- a child would have.

    8. BABenoît Arsenault2:11:19

       Yeah.

    9. PAPeter Attia2:11:19

       It's clear that a child can have an apoB of 30 and have no problems with development, which is the most cholesterol demanding period of their life. So there's absolutely no reason that we shouldn't be able to take an adult there, um, without side effects, uh, meaning provided we can do it without side effects from the medications. But the second thing we do is we're very liberal in the use of PCSK9 inhibitors because even though we don't know the answer yet, our belief is even if it whacks it 30%, which is about what we see, we see on average about a 30% reduction in Lp little A, it's worth it until we get to antisense oligonucleotides.

    10. BABenoît Arsenault2:11:56

        Yeah.

    11. PAPeter Attia2:11:56

        So let's talk about antisense oligonucleotides. What are they?

    12. BABenoît Arsenault2:12:00

        Yeah. Now, uh, before we get into that, uh, uh, I'll tell you that I do the same thing. I mean, uh, I'm going to turn, uh, 40 this year, so I decide, I decide to have, to have a, a lipid check and have my Lp (a) remeasured and it's very high. It's at 200 nanomolars. I knew that because I had my genotype done with a, a direct-to-consumer, uh, company and, and they l- let you look at your own data. So they, they send you, uh, all of your SNP information. So I went and looked at my favorite SNP, uh, in Lp (a) and I was w- uh, a carrier of one of the most famous mutat- uh, variants in, uh, in Lp (a) . So and that's exactly what I decided to do. So my LDL was a bit higher than, than average. My Lp (a) was high, so I just started to, uh, to take a statin. And of course, I, I've been on, um, close to vegetarian daria- diet for more than three years. I act- I'm physically active, but you know, at some point you have to look at, at your, at your labs and say, "Well, there's... I need to do more." So, so even I started, uh, s- taking a statin even though I'm not 40 yet 'cause I, I, I see those studies and I see the importance of going after LDL very early and v- very aggressively. Now, I'm not on a super high dose. I need to have it to, to check it after three months, but um, but if it doesn't go down, I'll increase the dose. So, so and that's, I think what, uh, people who have high Lp (a) uh, should do.

19. 2:13:33 – 2:24:36

    Antisense oligonucleotides—a potential new therapeutic for Lp(a)

    1. BABenoît Arsenault2:13:33

       So coming down to the, um, oligo- uh, the antisense oligonucleotides against Lp (a) . This is a very exciting time for, uh, for Lp (a) research. So the, probably the, the first ho- horse in the race will be, uh, the, the compound by Ionis, uh, Pharmaceuticals. So it is an antisense oligonucleotide against the, uh, Lp (a) gene. Well, all of them. Uh, all of them will be. And the second one is, uh, the... And they just released some data on this in, uh, in Nature Medicine a couple of months ago, uh, and it's called Olpasiran. It's, uh, it's not an oligonucleotide, it's an siRNA against, uh, Lp (a) . It's a compound by Amgen and, uh, I believe they'll, they'll need to do a, a phase three trial. But with the first one, with the, uh, Ionis compound there-

    2. PAPeter Attia2:14:30

       W- and Ionis is the company that used to be called Isis, like before-

    3. BABenoît Arsenault2:14:33

       Exactly

    4. PAPeter Attia2:14:33

       ... before it became horrible to have the name Isis. It was... It's a San Diego-

    5. BABenoît Arsenault2:14:37

       Yeah

    6. PAPeter Attia2:14:37

       ... based company. I remember I used to swim with a guy who worked there and he had a, his, his duffle bag which was from work, said Isis on it and I was like, "Yeah, you're probably gonna wanna change that."

    7. BABenoît Arsenault2:14:47

       Yeah. You can't board a plane with that. [laughs]

    8. PAPeter Attia2:14:49

       [laughs]

    9. BABenoît Arsenault2:14:51

       So, um, so yeah. So they, they have, they, they already, uh, have phase two data that's been published in 2020, uh, in patients with atherosclerotic, uh, cardiovascular disease. A, a very nice dose ascending study and they've shown that in the dose that they're gonna use in their trial, which is a monthly, uh, injection, you can get mean reduction of Lp (a) levels of 80%, even in patients with high Lp (a) . So that's very encouraging because this is what we're gonna need to, uh, to, to, to prevent, uh, heart attacks and, and, and of- and obviously to have successful, uh, cardiovascular outcomes trial. Uh, and in that study they also showed that, uh, 90% of patients who were treated on, uh, that dose had, uh, Lp (a) levels below 50 milligrams per deciliter. So it's very potent. It's a second generation, um, uh- antisense oligonucleotide, and they have launched, uh, a trial, a cardiovascular outcomes trial that's called HORIZON, and they're recruiting, uh, a little under 8,000, uh, patients with, uh, stable, uh, cardiovascular diseases, and they will study the effect of, uh, Lp (a) in-- of their, uh, antisense oligonucleotides in the prevention of major atherosclerotic cardiovascular events. Now that-

    10. PAPeter Attia2:16:25

        And, and is this a secondary prevention trial?

    11. BABenoît Arsenault2:16:28

        It is a secondary-

    12. PAPeter Attia2:16:29

        Yeah

    13. BABenoît Arsenault2:16:29

        ... prevention trial. So th- this is where you have to start. Uh-

    14. PAPeter Attia2:16:32

        Yeah

    15. BABenoît Arsenault2:16:32

        ... you have to take the patients that have the highest risk-

    16. PAPeter Attia2:16:35

        Yep

    17. BABenoît Arsenault2:16:35

        ... to have, uh, to have a positive trial. There's, uh, to my knowledge, there's no, uh, plan for a trial in primary prevention, but that will-

    18. PAPeter Attia2:16:46

        That will be the off-label use

    19. BABenoît Arsenault2:16:47

        ... that will eventually have to come. Yeah.

    20. PAPeter Attia2:16:49

        So, so-

    21. BABenoît Arsenault2:16:50

        Well, yeah

    22. PAPeter Attia2:16:50

        ... do, do you, do you have a sense of how far they are in their enrollment? Because this trial, and maybe it's just because of how emotionally invested I am in this, uh, I don't-- I have a normal Lp (a) , but it's just I think I take care of enough patients that don't. This trial feels to me like the molasses rolling uphill in January trial, and as a, as a Québécois, you can appreciate the speed with which molasses will roll-

    23. BABenoît Arsenault2:17:13

        Yeah

    24. PAPeter Attia2:17:13

        ... uphill in January.

    25. BABenoît Arsenault2:17:14

        [chuckles]

    26. PAPeter Attia2:17:15

        What is taking so long? This is a trial that feels like it's a year away from being completed every year for the past seven years.

    27. BABenoît Arsenault2:17:25

        Yeah. Well, uh, first of all, uh, be- being, uh, an investigator in, uh, a research center at times of COVID was very-

    28. PAPeter Attia2:17:36

        Mm

    29. BABenoît Arsenault2:17:36

        ... very difficult to bring people into the hospital for an exploratory trial.

    30. PAPeter Attia2:17:43

        Mm.

Episode duration: 2:24:36