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

00:00:00.000 Hey, everyone. Welcome to The Drive Podcast. I'm your host, Peter Atiyah. This podcast,

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00:00:41.960 head over to peteratiyahmd.com forward slash subscribe. Now, without further delay, here's

00:00:48.080 today's episode. My guest this week is Benoit Arsenault. Benoit is an associate professor at

00:00:55.620 University Institute of Cardiology and Pulmonology of Quebec at Laval University. He's also a research

00:01:02.460 scientist in the cardiology axis at the Quebec Heart and Lung Institute in Canada. His research

00:01:09.780 background is in understanding the risk of cardiovascular disease, such as atherosclerosis

00:01:14.640 and aortic stenosis, in relation to lifestyle and inherited risk factors. This includes extensive

00:01:19.960 research in the unraveling of the role of LP little a, HDL metabolism, PCSK9, and lipid lowering

00:01:27.480 therapies. In this episode, we really dedicate our focus to that of LP little a, something that many

00:01:34.040 of you are aware of, especially if you've been listening to this podcast for some period of time.

00:01:39.140 This is a subject, of course, that we've gone into great detail, but we haven't had a dedicated

00:01:43.400 podcast on this subject matter since I did an AMA on it many years, and a lot has changed

00:01:48.800 since then. So you may be asking, why should I care about this? Well, as Benoit points out in the

00:01:53.560 podcast, while it varies by race, about 20% of the world's population is in a high-risk category of

00:01:59.120 LP little a. This is actually higher than I thought. I had always cited the number of somewhere between

00:02:03.720 8 and 12%. On top of that, most doctors aren't checking LP little a with their patients, and I see a

00:02:09.820 lot of my patients who show up who have never heard of this or had it tested. So that means there's

00:02:14.360 going to be some of you listening to this who may not realize they have a high LP little a,

00:02:18.580 and of course that means you're at risk. In fact, LP little a is the single highest genetically 0.74

00:02:24.460 inherited trait that confers high risk of ASCVD. All of this is to say this is a very important

00:02:31.780 topic for everyone to understand, because even if you don't have an elevated LP little a, chances are

00:02:36.440 you know somebody who does. Now in this discussion, we talk about a bunch of things. Of course, we go

00:02:39.620 back to the basics. What is LP little a? We talk about the epidemiology of it, the basic biology of

00:02:44.220 it. How is it inherited? How is it measured? How does it impact things besides ASCVD, such as aortic

00:02:50.060 stenosis, and of course, ultimately, myocardial infarction. We talk about the importance of measuring

00:02:54.040 it in order to get the risk factors, how to manage lipids around it, etc. We also talk about what we

00:02:59.120 know about the possible current therapies and treatments for LP little a, including niacin, statins,

00:03:03.880 PCSK9 inhibitors, as well as the possibility on the horizon for things called antisense oligonucleotides.

00:03:09.200 So without further delay, please enjoy my conversation with Benoit Arsenault.

00:03:18.920 Hey Benoit, wonderful to sit with you today and talk about a subject matter that,

00:03:23.400 you know, honestly, I think five, certainly 10 years ago, nobody would have a clue what we were

00:03:27.880 talking about. And yet today we get so many requests to go back and revisit this subject matter.

00:03:34.600 So again, delighted to have you here and look forward to talking about something that

00:03:39.760 probably impacts a lot more people than most might appreciate. So let's take a step back and

00:03:44.360 give me a sense of where your interest in this little lipoprotein LP little a came from.

00:03:50.400 So first, Peter, thank you so much for the wonderful invitation. I'm really excited about our discussion

00:03:55.620 today. So I got involved in LPA research actually during my postdoc years. I trained here at Laval

00:04:03.960 University in Quebec City, did some work in the field of lipids looking at LDL particle size,

00:04:11.340 triglycerides, APOB, etc. on cardiovascular outcomes. So that was in 2006 to 2009. And that was really at

00:04:21.680 a point where not that many people talked about LP little a because there had been so many negative

00:04:28.400 studies on LPA and the risk of cardiovascular disease like MIs and stroke and so on. And it's

00:04:35.540 really the genetic association studies that have kind of resurrected the field of LPA. And these were

00:04:41.420 published in 2009 to 2011. And that was during the time I was a postdoc in Amsterdam. And I was working

00:04:49.600 over there with John Castelline. And he was working on the Treating to New Targets trial,

00:04:55.340 the TNT trial, which is one of the first trials that showed that if you reduce low-density lipoprotein

00:05:01.300 levels by increasing the statin dose, you'll get an incremental benefit in cardiovascular outcomes.

00:05:07.380 So we were working on a bunch of sub-analyses in that trial. And they had just measured a whole panel

00:05:15.160 of emerging biomarkers that could be associated with cardiovascular events like CRP, antiproBNP,

00:05:23.660 other markers, inflammatory markers, other biomarkers of insulin sensitivity, and LPA. And it turned out

00:05:31.940 that of a huge list of 18 biomarkers that they had measured in thousands of individuals, LPA was actually

00:05:38.880 the strongest of them that was predicting residual cardiovascular risk. So that was, I think, the first

00:05:46.220 paper I published on LPA in those years. And at the time, we were also wondering if there was any

00:05:54.480 genetic variants that could explain a statin response, because statin works well in most people,

00:06:01.300 but there's a huge inter-individual variability in terms of LDL lowering associated with statin. So

00:06:08.180 this came at a time where genome-wide association studies were increasingly used, and they were

00:06:14.360 used to, well, they were first used to identify genetic variants associated with specific diseases,

00:06:20.440 but they were beginning to be used in pharmacogenetic studies. So we were part of a big genetic consortium

00:06:27.600 that was called the GIST consortium, so Genomic Investigation of Statin Therapy. And it turned out

00:06:33.960 from that big analysis that LPA was the most important genetic risk factor that explained

00:06:41.020 a statin response. So we'd shown that if you have high LPA, then your LDL wouldn't be lowered as much

00:06:48.420 as if you didn't have a high LPA. Well, we're going to talk about that in some detail, because right now,

00:06:54.180 I think many people will not understand exactly why that's the case, because they won't necessarily

00:06:58.500 understand the relationship between LDL and LPA and why what you just described is completely

00:07:03.520 intuitive today based on all the work that's been done in the last decade. But let's take a step back

00:07:08.520 into that epidemiology so that for the people who aren't familiar with LPA, we can give them a sense

00:07:14.080 of why this is such an important topic. So we'll start with an observation, right? So we'll start with

00:07:20.240 the epidemiology, which is elevated levels of this particular lipoprotein, which occur in about what

00:07:28.140 fraction of the population? Depending on ethnicity, actually, it can be very high, for instance, in

00:07:34.860 individuals of African ancestry who have the highest level, and all the way down to Chinese and Japanese

00:07:42.440 that probably have the lowest levels. But we can say like in the ballpark that about 20% of the

00:07:49.700 world population has an LPA level that puts them in a higher risk category. So if we go down in time,

00:08:00.040 LPA was discovered in 1963 by a Swedish scientist named Cary Berg. And he was one of the first to show

00:08:08.500 in the late 70s and at the beginning of the 80s in different European cohorts that LPA was associated

00:08:14.360 with cardiovascular events. And LPA was measured probably more currently at that time in these big

00:08:21.240 epidemiology studies. The thing is, however, that the assays that they were using were probably not

00:08:29.060 the best. They were certainly not as good as they are today. There was a lot of variability. And a lot of

00:08:35.320 these studies published in the 90s and in the early 2000s came out negative. So that really was

00:08:42.920 really tough for the field because nobody talked about LPA at that moment.

00:08:47.920 Tell people what you mean about the studies came out negative, negative with respect to what hypothesis

00:08:52.740 and why?

00:08:53.920 The hypothesis was that high LPA was associated with cardiovascular events like myocardial infarction,

00:09:00.800 stroke, etc. So the hypothesis was that people with higher LPA levels were at the highest risk.

00:09:08.380 And it turned out not to be the case in many, many of those studies. So we realized afterwards that

00:09:15.800 the assays that had been used were probably not very good. So the assays really did not correctly

00:09:23.400 identify people with high LP little A. And I think this has to be attributable to the complex structure

00:09:30.180 of lipoprotein little A, which has in the LPA genes, there's a copy number variation. And the antibodies

00:09:38.300 that are used against that, sometimes they can bind to different epitopes of LPA. So now we have

00:09:45.160 antibodies that are binding to LPA on other regions. So we get a much better sense of the number of LPA

00:09:53.640 particles in the bloodstream. But back in the days, the assays that were used, they were overestimating

00:10:00.260 the isoform size that was bigger, and they were underestimating the small LPA isoform size, which is

00:10:08.220 associated with high LPA. So a lot of research has been done on that. And now we have better assay, we don't

00:10:15.360 have like optimal assays now, but most of these problems have been solved. And you can really see in the

00:10:22.060 literature the interest on LPA that actually match this effect because the LPA gene was cloned in the

00:10:30.220 80s by the group of Angelos Escanu at the University of Chicago. And you can see it, if you just look at

00:10:37.900 the PubMed search, you would see like a straight line from the 70s to the mid 80s. And when these studies

00:10:45.360 came back negative, you would see like the number of PubMed searches would go down. And they came back up

00:10:51.200 in 2009 and 2010 when genetic association studies were beginning to be published. Because the great

00:10:58.880 thing about genetic studies is that you don't necessarily need to measure lipoprotein A level.

00:11:03.960 So you can look at genetic variants, at common genetic variants that are associated with diseases. And

00:11:10.460 there were three big studies published in 2009 that very convincingly shows that genetic variants

00:11:16.780 associated with high LPA levels were tracking with cardiovascular events. And now you can see

00:11:22.440 the PubMed searches on LPA going back up again, and they haven't been as high as they are today.

00:11:28.780 Yeah. And we should make sure people understand some of the semantics. So LPA is the gene that codes for

00:11:35.400 apolipoprotein little a, which then binds to an LDL and then turns an LDL from being just a garden

00:11:43.100 variety LDL into an LP little a. And I think once people understand that, it becomes easier,

00:11:48.960 I think, for us to communicate in this way. So I'm going to restate that. And I really want everyone

00:11:52.440 to understand this. So there's a gene, LPA is the gene. And this gene, everybody has this gene,

00:11:59.360 but we have different variants of it. And so a subset of the population, and it varies considerably by

00:12:05.220 ethnicity. So African, East Asian, also quite high, down to Caucasian, and as you mentioned,

00:12:11.640 Chinese, Japanese, et cetera. So you're going to see different expressions of the apolipoprotein

00:12:17.600 little a. This apolipoprotein little a, which we'll talk a lot about and what it looks like and

00:12:23.360 its structure and what its heterogeneity is all about, but it wraps onto a low-density lipoprotein.

00:12:29.920 And then it becomes kind of a supercharged low-density lipoprotein. It becomes a particularly

00:12:33.940 nefarious LDL. And we're going to talk about all the reasons why it's not responsive to the same

00:12:38.400 treatments, et cetera. So would you add anything to that? I don't want to make it too complicated

00:12:42.740 yet, but I want to make sure everybody understands when we talk about the LPA gene, which is identified

00:12:47.760 during the GWAS experiments, how the genotype allows us to not know everything about the phenotype,

00:12:55.680 but we can start to get into trying to impute causal relationships. And eventually we're going to

00:13:01.420 talk, of course, about Mendelian randomization, where we can go even deeper.

00:13:05.500 So anything you would add to that, just even though we're kind of going to keep it at the

00:13:09.700 101 level for a moment, just to make sure that the listeners are following as we get into the

00:13:14.020 more nuanced part of this? No, I think you've explained it perfectly, Peter. Maybe the only

00:13:18.960 thing I would add is that part of the genetic heterogeneity among different people is the

00:13:25.000 apolipoprotein A isoform size. So people express different LPA isoforms. Some are bigger than the

00:13:33.520 other. And that actually plays an important part of the equation, explaining why some people

00:13:38.200 have a higher LP a little later than others. I'm glad you reinforced that point because,

00:13:44.040 and this is going to get into a little bit of chemistry, which I know some people will understand

00:13:47.620 and some might not. One of the big challenges here, as you've now alluded to twice, is the

00:13:52.740 difficulty in measurement. Now, when we look at something like ApoB, and people who listen to this

00:13:57.720 podcast a lot will be very familiar with ApoB, we talk an awful lot about it. One of the things we

00:14:03.060 talk about is that by measuring the concentration of ApoB, you can completely and accurately measure

00:14:09.320 the concentration of the atherogenic particles, the majority of which are LDL. And the reason for

00:14:14.860 that is twofold. The first is that every LDL has one and only one ApoB 100 particle on it. The second is

00:14:23.340 that all ApoBs are the same size. Therefore, they have a molar weight. And by knowing the mass,

00:14:30.000 you know the number. Now, I always like to point out two contrasts to this, right? The HDL particle,

00:14:36.100 by contrast, has multiple ApoAs on it. And this is totally different from Apo little a. So we're not

00:14:43.180 going to talk about that other than to say it's Apo big A. And therefore, you don't have a unique

00:14:48.100 number. And then of course, with LP little a, you have the problem that you raised, which

00:14:53.280 creates enormous challenges. There is no molar weight for Apo little a. This is the fundamental 1.00

00:15:00.220 problem in the assay of trying to measure this thing. Exactly. And we're really moving in the

00:15:05.640 right direction in terms of getting the LPA measurement in nanomoles per liter. And there's

00:15:12.840 more and more labs that are doing this. And this is clearly the way to go. We have to move away from

00:15:18.720 measurements in milligrams per deciliter, which is really influenced by the isoform size of LPA.

00:15:25.780 And the measurement in nanomolar will actually give you a much better sense of the number of

00:15:32.000 LPA particles in the circulation. Now, will that require electrophoresis?

00:15:36.920 How will that actually be measured? Or will it use NMR?

00:15:39.980 It's going to be measured through immunoturbidometric assays. So not by NMR. NMR can

00:15:47.940 actually give you a pretty good estimate of LDL particle number, but you have to use antibodies to

00:15:54.500 measure LPA. Okay. So we got a little in the weeds there. I apologize. We'll come back to that

00:16:00.040 stuff later. But let's pick it up back about a decade ago when the GWAS studies were able to

00:16:07.200 distance themselves from the limitations of the assay and focus instead on the genotype and the

00:16:13.560 heterogeneity of the genotype. These GWAS studies now found a much stronger association between

00:16:20.900 the variants of this genotype that produced high copy numbers of apolipoprotein little a

00:16:28.640 and insipid cardiovascular events. Correct?

00:16:31.420 So there were, I think, three studies that were all published in 2009. The first one was the one

00:16:39.760 by Robert Clark from the UK. They used the Procardis Consortium, which were, if I recall well,

00:16:47.520 there were 3,000 people with heart disease and 3,000 controls. And they've identified two SNPs in the

00:16:54.140 LPA regions that are completely different from one another. And you really saw the dose response

00:17:00.480 effect of these SNPs on LPA levels with a proportional effect on the risk of heart disease.

00:17:07.740 So it was like kind of the first Mendelian randomization study where they nicely showed that

00:17:13.480 if you had one LPA-raising allele, you had higher LPA levels. Whereas if you had two or more LPA-raising

00:17:21.900 variants, then you had even higher LPA levels and the risk was proportionally higher.

00:17:27.940 It's also worth explaining how important this type of analysis is, because it really is the bridge

00:17:34.500 between observational epidemiology and clinical trials. And of course, we're going to talk about

00:17:39.600 clinical trials, many of which are ongoing. But the importance of what you just said, Benoit,

00:17:44.720 is the following. There are a handful of assumptions that make this type of Mendelian randomization

00:17:49.920 essential. One is the assumption that the sorting of these genes is random, right? So in other words,

00:17:56.560 you know, we look at a population and we can look at this as though nature did an experiment and it

00:18:02.600 randomized the population to different copy numbers of these alleles that are going to produce different

00:18:09.700 amounts of the protein. But the second important piece of a Mendelian randomization, being able to

00:18:15.880 link something causal, is the assumption that the gene of interest is not doing something else that

00:18:22.500 you're unaware of, right? In other words, if the LPA gene was on the one hand responsible for making

00:18:30.140 apolipoprotein little a, which it is, but on the other side, it also changed your, I'm making this up,

00:18:38.540 your susceptibility to secondhand smoke. And people who had that gene would be debilitated by secondhand

00:18:47.100 smoke. People who didn't have that gene had complete immunity to secondhand smoke. Imagine

00:18:51.780 such a gene existed. Well, all of a sudden the Mendelian randomization wouldn't be very helpful

00:18:55.860 because those people who are at an increased risk of cardiovascular disease from having more copies of

00:19:01.980 Lp little a, you don't know if it's that or if it's the exposure or susceptibility to secondhand smoke.

00:19:08.440 So do you have a sense? I mean, I think in the case of Lp little a, it's pretty straightforward 1.00

00:19:12.520 because it's a relatively simple gene. But when that type of analysis was done, was it relatively easy

00:19:17.560 to demonstrate that that gene wasn't doing anything else, both in its coding and non-coding regions?

00:19:23.940 Yeah. First, let me say that I think that a lot of geneticists would disagree that Lpa is a relatively

00:19:29.400 easy gene. I mean, there's like, I think 2000 different variants that are associated with Lpa and

00:19:35.960 you add in the isoform and each isoform has a specific set of different variants. So that being

00:19:42.280 said, I think you really nicely explained it. And the beauty of working with Lpa, but also

00:19:48.120 with most proteins in the circulation is that you're looking at cis-acting SNPs. So cis-acting

00:19:55.240 means variants that are acting within the window of the gene that expressing their protein as in

00:20:02.820 opposition to like a trans-acting SNP would be, for instance, a SNP in the CTP gene, for instance,

00:20:10.960 which we know might be associated with Lpa. But CTP does a lot of other things. It regulates HDL

00:20:18.660 cholesterol levels. It regulates triglycerides. So we don't use CTP genes when we do Mendelian

00:20:25.460 randomization on Lpa. And the example that you mentioned, you know, a specific gene being

00:20:30.620 associated with an intermediate phenotype that could, on the other hand, influence Lpa would be

00:20:36.180 reverse causality. And in the case of Lpa, we're very, very confident that we're using the correct

00:20:42.940 genetic instruments to infer a causal relationship between Lpa and a wide range of atherosclerotic

00:20:51.080 cardiovascular diseases. So to put a bow on that, we really have two independent types of analyses now

00:20:58.200 that make it very clear that Lpa is playing a causal role in the development of atherosclerotic

00:21:06.880 cardiovascular disease independent of LDL, which you referred to earlier by commenting and using the

00:21:13.420 term residual risk, which I think people might not appreciate residual risk, meaning what is the risk

00:21:19.840 that remains in terms of ASCVD in the presence of LDL lowering? And of course, Lpa would be one such

00:21:27.920 example. And those two pieces of information are now the regular observational epidemiology,

00:21:34.240 provided that the assays more accurately capture the measurement of Lpa, and now these Mendelian

00:21:41.140 randomizations that effectively are nature's randomized experiments, provided those two criteria we discussed

00:21:48.460 can be met. Is that a fair synthesis of the state of the art today in terms of our understanding?

00:21:54.220 Yes, I think you can also add a third assumption, which would be that the effect of the variance on

00:22:00.720 the outcome, so the effect of Lpa variance on cardiovascular disease, are explained by higher Lpa levels.

00:22:07.780 And I think for Lpa, it's a fairly fair assumption to make.

00:22:11.860 Okay, so let's talk about how this is done clinically today. Over the past decade, I've seen three different

00:22:18.180 types of commercial assays for measuring Lpa. I don't believe two of them are in existence anymore.

00:22:24.520 One was the Lpa cholesterol content. So I assume that this was an assay that was looking at the

00:22:31.880 cholesterol content of the Lpa's, which means the LDLs that had apolipoprotein little a on them,

00:22:39.440 you just measure the cholesterol content. So it was analogous to measuring LDL cholesterol,

00:22:43.560 but for this narrow subset. Is that assay still in existence?

00:22:47.760 Well, I think there are certain labs that still use it, but it's really not the way that the

00:22:53.160 field is moving to because the cholesterol, and you can make the same argument for LDL,

00:22:57.900 the cholesterol within certain lipoprotein does not necessarily tell you a lot of information

00:23:03.560 about the number of particles that are in the bloodstream, which is the most important thing

00:23:09.740 to measure if you want to estimate risk. So for LDL, ApoB, there's some discordance, but for Lpa,

00:23:17.220 the discordance is even higher. So what you really want to do is try to find a lab that will give you

00:23:23.140 an Lpa measurement in nanomoles per liter.

00:23:26.120 Right. Now there are some labs that have done that. I've seen a lot of those labs. So one of them

00:23:30.420 was called Health Diagnostics Labs. I think that was the name of the lab. They no longer exist.

00:23:36.180 They did calculate an LP little a in nanomole per liter. I don't know what their methodology was.

00:23:42.860 Most labs are using milligrams per deciliter. So they are simply telling you, I say simply,

00:23:48.600 they are telling you the mass of LP little a. Now, just to be clear, are we in that assay looking at

00:23:57.580 the mass of the entire LP little a, or are they just trying to estimate the mass of the

00:24:01.980 apolipoprotein little a's? It's the mass of the particle. So it's a much better measurement than

00:24:08.640 Lpa cholesterol that you just referred to. And we shouldn't, you know, let good be the enemy of

00:24:15.300 perfect here. If you have an Lpa measurement in milligrams per deciliter, and it puts you in a high

00:24:22.440 risk range. So let's say it gives you an Lpa level above 50, then the chances of the Lpa assay

00:24:30.300 that will give you a result in nanomoles per liter, it will also give you a high level. So if

00:24:35.520 you have an Lpa measured in milligrams per deciliter, you can obviously try to get a second

00:24:41.700 measurement in nanomoles per liter. But, you know, if you have a Lpa in a high range, both methods will

00:24:48.040 give you the same information that you have an Lpa in the higher range. Now, you have to keep in mind

00:24:53.380 though, that if you have an Lpa, for instance, of 50 milligrams per deciliter, the measurement in

00:24:59.000 nanomoles per liter will be around 125 nanomoles per liter. So some people have measurements using

00:25:06.340 both methods, and they just say, well, for some reason, my Lpa doubled. Well, that's not the case.

00:25:11.680 The Lpa didn't double. And it's remarkably stable over time. So most guidelines will probably tell

00:25:18.960 you just to measure Lpa once in a lifetime, and it's relatively stable.

00:25:22.820 Yeah. I mean, I think that's the take-home point here is unlike LDL and ApoB, which are so modifiable

00:25:30.440 and therefore it really matters that you know what you're measuring because you're going to be

00:25:34.840 measuring it over and over and over and over again. With Lpa at this point in time, and this is going

00:25:40.940 to be changing, but at this point in time, it's basically something we measure to determine risk,

00:25:46.280 after which point we don't really need to measure it. We've established risk,

00:25:50.300 and now we need to take measures elsewhere. So let's now kind of talk a little bit about the

00:25:55.740 biology of Lp little a. We'll include figures in the show notes to the podcast. So we'll be able to

00:26:03.080 show people exactly what this thing looks like and how it intersects with and binds to the LDL particle,

00:26:11.920 how it's distinct from the ApoB, et cetera. But let's talk a little bit about the production of this

00:26:18.820 thing. Is it hepatically produced? It's produced in the liver?

00:26:22.240 Yes, exactly. So all the lipoprotein A particles originate from the Apo lipoprotein little a that's

00:26:30.460 pretty much only expressed in the liver. So it's not entirely clear in the literature how or where

00:26:38.980 specifically an Apo lipoprotein little a will become an LP little a, so where it will bind to ApoB and

00:26:47.900 ultimately an LDL particles. There's multiple hypotheses that have been tested. So some people

00:26:54.500 say that the Apo lipoprotein little a, which is like a glycoprotein, is secreted in the bloodstream,

00:27:01.220 and there it will bind to whichever LDL is closer to it to form LPA. There's another hypothesis that

00:27:10.140 suggests that it's probably at earlier after the secretion of LPA, so not entirely in the

00:27:17.240 bloodstream, but when it leaves hepatocyte in the space of this in the liver, that the binding of

00:27:22.660 Apo lipoprotein little a with LDL. But now I think we have very good evidence to suggest that

00:27:28.680 this happens within a liver cell, the binding of Apo A to Apo B to eventually form LPA. So there's

00:27:37.080 good evidence to suggest that as soon as the Apo A is produced, it can form an LPA when it meets

00:27:44.640 with an Apo B particle. And for whatever reason, that just seems a bit more intuitively obvious

00:27:50.140 given the mechanics of it, right? You're bringing so many LDLs to the liver, you're making Apo lipoprotein

00:27:56.900 little a in the liver. It seems like a more obvious place for the marriage to occur than in

00:28:01.480 the periphery. But again, it remains to be seen, although it seems like it's more likely that that

00:28:05.960 is the case, correct? Correct. And so the levels of LPA are determined by the rate of production of

00:28:13.060 LPA particle and little by its catabolism. We're still not entirely sure of how the catabolism of

00:28:21.480 LPA occurs. Most of it is by the liver. There's a little bit of catabolism by the kidney as well.

00:28:27.280 But identifying like the receptor at the surface of hepatocyte that will remove LPA from the blood

00:28:33.340 stream has been challenging. So there's some evidence suggesting that the LDL receptor might

00:28:39.220 be one of them. There's some evidence for and against that. And there's also the plasminogen

00:28:44.140 receptor. And I think we're going to eventually talk about the homology between Apo lipoprotein

00:28:50.340 little a and plasminogen. So let's go back to this point, which is that it's really the production

00:28:57.320 of Apo lipoprotein little a that determines the concentration of LP little a. And if that weren't

00:29:03.860 the case, it might be that by simply reducing the amount of targets for it, i.e. reducing the amount

00:29:10.020 of LDL, you might reduce the amount of LP little a. But in fact, that does not appear to be true,

00:29:14.880 with one notable exception that we will get to down the line. In other words, if you give somebody

00:29:20.280 a statin, which is a very potent drug to lower LDL, the primary mechanism by which it does so

00:29:28.320 is by increasing hepatic clearance of LDL. So you have more and longer lasting LDL receptors on the

00:29:37.560 liver, and they're pulling those LDL out of circulation, which is lowering the plasma

00:29:41.840 concentration. And yet that does nothing to offset the amount of LP little a, which goes back to the

00:29:48.120 explanation that started your journey here, which was why is it that some people respond really well

00:29:54.600 to statins and some don't. And obviously it would be the higher your LP little a, the worse your

00:30:01.280 statin response, because there's a subset of your LDL that are not responding to the statin. So maybe

00:30:08.180 let's start by explaining how a statin takes an LDL out of circulation, and why this doesn't work

00:30:15.420 for an LP little a, which is basically just an LDL with this one other little thing covalently bound

00:30:21.520 to it. Exactly. So the statins actually reduce LDL particles in the circulation by upregulating the

00:30:30.400 LDL receptor at the surface of the hepatocyte. So the density of the LDL receptor at the surface of the

00:30:38.660 hepatocyte is super important. The more LDL receptor you have, the higher the catabolism of

00:30:45.080 APOB containing lipoproteins will be because APOB binds to the LDL receptor. So under the assumption

00:30:51.340 that LPA is catabolized by the LDL receptor, you would think that statins would actually reduce

00:30:59.140 LPA levels. Whereas we see that there's not really a lowering effect of statins on LPA. And there's even

00:31:07.360 been more than one studies that have shown that if you put somebody on a statin, you'll even have a

00:31:13.200 small increase in LPA levels. Now, that shouldn't be a reason not to put someone on a statin, of course,

00:31:20.340 because there's been trials like the heart protection study that have shown that a treatment

00:31:25.620 with statin is beneficial in patients with high LPA levels, maybe even more so than patients with low

00:31:33.500 LPA levels. So one should not like, don't prescribe a statin because you're afraid of a small LPA level.

00:31:41.160 It might be an interesting thing to do to measure LPA levels before and after the initiation of a

00:31:47.300 statin. But overall, we have so much experience with statin that we know they work in the overwhelming

00:31:55.040 majority of individuals, and especially even better in patients with high LPA.

00:31:59.700 Yeah. I mean, one hypothesis for that might be that the statins are bringing a higher influx of LDL

00:32:07.620 to the site of the production of the apolipoprotein little a. And that might possibly be why you're

00:32:14.260 seeing an increase in LP little a. If that were true, that would make it even more likely the scenario

00:32:19.940 that that's the source of the merger between apolipoprotein little a and LDL.

00:32:24.620 What's the magnitude by which LP little a would go up in the context of a statin?

00:32:30.600 Well, that depends on the study. There's been a lot of studies that have shown that statins

00:32:35.400 don't have an effect. And most of the studies have shown like a 10% increment in LPA levels.

00:32:42.920 So if you have low LPA levels and you're treated with a statin, you'll still remain with a low LPA

00:32:49.860 level. And if you have high LPA level, then you'll obviously still remain with a high LPA level,

00:32:55.900 although it's going to be a little bit higher. So it's important to say that as we move forward

00:33:01.520 with the LPA lowering drugs that are being tested on top of statin therapy at the moment.

00:33:07.200 So we have published a paper in patients with aortic valve stenosis at the astronomer trial,

00:33:12.720 where you can actually get, I think it was a 20% increment in lipoprotein little a. So

00:33:17.740 it might not be trivial. So the signal is there, but let me restate that the statins are very

00:33:24.540 effective in patients with LPA, even though there's a small increment of LPA.

00:33:29.800 Yeah. And an easy way to think about this would be if you give a statin and let's say in the most

00:33:35.600 aggressive case, the LP little a goes up by 10%, but the ApoB comes down by 60%, you'd have to make

00:33:43.540 the case that an LP little a is six times more atherogenic on a particle for particle basis for

00:33:51.420 that to be an equivalence maneuver. So that begs the question, what is it about LP little a that's

00:33:58.060 so virulent? What is it about LP little a that makes it, I assume, more atherogenic on a particle

00:34:04.920 for particle basis than its garden variety ApoB bearing cousin?

00:34:09.680 Yeah, there's no question about this, Peter. I mean, on a per particle basis,

00:34:15.560 LPA is much more atherogenic than an equivalent LDL particles. Well, first of all, an LPA has an LDL

00:34:24.020 particle on it. So by definition, it's, you know, as atherogenic just to start with. There's also

00:34:31.520 evidence that LPA might influence the rates of thrombosis because LPA has a sequence homology,

00:34:39.660 with plasminogen, which plays a role in clotting and has antifibrinolytic activity. But I think the

00:34:47.880 most important thing is the number of oxidized phospholipids that are transported by lipoprotein

00:34:55.720 little a, which is much higher than the amount of oxidized phospholipids that you see on LDL particles.

00:35:03.380 And oxidized phospholipids have effects on a wide variety of cells, endothelial cells, smooth muscle

00:35:11.660 cells, macrophages, cells of the aortic valve, like valvular interstitial cells. Now they're sending

00:35:20.420 in signals that will drive pro-inflammatory, maybe pro-thrombotic and pro-calcifying signals to these

00:35:28.540 cells. So that is probably the most important reason why on a per-particle basis, LPA is more

00:35:36.540 atherogenic than LDL, sorry. So let's talk about these oxidized phospholipids. I think most people

00:35:44.720 might not be familiar with what a phospholipid is. But before we do that, let's explain to people

00:35:50.580 what an LDL looks like physically in relation to an LDL. So if an LDL is a largely spherical compound

00:36:00.580 that has on its surface a single lipoprotein called ApoB100 that wraps around it, how does that

00:36:09.960 now interact with the apolipoprotein little a to become an LP little a? Okay, so to answer this

00:36:16.560 question, I'm going to tell you a little bit about the structure of apolipoprotein little a. And to

00:36:24.180 explain that, I'm going to talk about plasminogen for a minute. So plasminogen is a gene that's

00:36:29.900 expressed on chromosome 6. It has five Kringle repeats. It's called a Kringle because it resembles

00:36:37.460 a Danish pastry. So it's a little round of proteins and you have five of them that are one another in

00:36:44.180 the protein. Now LPA is the gene right next to plasminogen on chromosome 6. And we have reasons

00:36:52.360 to believe that along the lines of evolution, it probably emerged from a duplication of the

00:36:58.340 plasminogen gene. Which would have been very important tens and hundreds of thousands of years

00:37:04.220 ago because trauma was such a threat to our species, much more than it is today. And of course,

00:37:10.800 trauma carries with it in the short term, an immediate risk of hemorrhagic shock, blood loss,

00:37:17.440 ultimately septic shock probably would have killed just as many people from the infection.

00:37:22.080 But anything that would have reduced your risk of hemorrhagic shock would have been generally

00:37:27.860 positive thing up until a hundred years ago or a couple hundred years ago. So tell people exactly

00:37:34.600 how plasminogen would have played a role in that and why this is something that if a duplication was

00:37:39.900 created probably worked to an evolutionary advantage, again, until we lived long enough for it not to.

00:37:46.940 Yeah, there's a lot of hypotheses out there and the effect of LPA on wound healing is certainly one of

00:37:54.540 them. And this is being studied ex vivo. So that might be one of the reasons why we have high LPA levels

00:38:02.080 in 20% of the population and why before that even there was the duplication of the plasminogen gene.

00:38:08.640 Now, when we're talking about that duplication, it's only the Kringle 4 and Kringle 5 that remain

00:38:15.360 in the LPA gene. And the Kringle 4 is even separated in 10 different subunits. So there's

00:38:24.060 the Kringle 4 type 1 all the way to the Kringle 4 type 10. Now, the most important is probably the

00:38:30.540 Kringle 4 type 2, which is where the copy number variation is. So one can have one Kringle 4 type 2

00:38:38.520 or only a couple. And you can also have the way all up to 40 Kringle 4 type 2 repeats. So this is where

00:38:45.980 when we talk about LPA isoform size, it's due to variation in Kringle 4 type 2. So there's other

00:38:53.120 Kringle parts that are important. Kringle 4 type 10 is probably the most important for the binding of

00:39:00.960 oxidized phospholipid. And to answer your question, Peter, about the interaction between ApoA and ApoB,

00:39:09.820 you have to look at the Kringle 4 type 9, which contains cysteine residues, which are important to do

00:39:17.120 a disulfide bridge with ApoB. So it's a covalent bound that's happening because of the cysteine

00:39:25.240 residues on Kringle 4 type 9. So interesting sort of thought experiment. The reason I'm asking this

00:39:31.720 question is not just to be difficult, it's to try to understand the pathophysiology a bit better,

00:39:37.060 especially as it pertains to the oxidized phospholipid. If you could create a drug that

00:39:42.160 would cleave that disulfide bond, so it wouldn't lower ApoB and it wouldn't lower apolipoprotein

00:39:50.040 little a, it would just prevent their union and therefore it would eliminate LP little a. But you

00:39:56.620 still had a high concentration of apolipoprotein little a floating around by itself, dragging with

00:40:05.000 it oxidized phospholipids. Would you guess that it would still be problematic or would your guess be

00:40:11.940 that no, because it wouldn't be able to gain residence in the tissues such as the subendothelial

00:40:20.360 space, the interstitial space of the aortic valve, all the places where it wreaks havoc?

00:40:25.820 Yeah, I'm only going to speculate here, Peter. Of course, I don't think there's solid data on the

00:40:31.760 form of ApoA that's not bound to LDL particles. So we know that ApoA can still have oxidized

00:40:40.160 phospholipids. And we are not entirely sure how, if you're talking about LPA, how it gets inside

00:40:48.140 the cells, if it gets inside the cells. Now we have some evidence and we've published that with

00:40:54.520 a colleague of mine, Patrick Mathieu here, who's a heart surgeon. We've looked at an LPA receptor in

00:41:02.000 the valvular interstitial cells. So these are the types of cells that are very abundant in the

00:41:08.540 aortic valve. And just to remind our audience, LPA is also associated to a very significant extent to

00:41:15.920 aortic valve stenosis. And when I'm talking about LPA receptor, I'm not talking about the receptor for

00:41:22.060 lipoprotein little a, I'm talking about the receptor for lysophosphatidic acid, which is generated

00:41:30.060 by LPA, by an enzyme called autotaxin, which is actually carried by LPA in the blood. So on top of

00:41:38.340 oxidized phospholipids, ApoB, LDL, LPA has its specific proteome. So it carries a lot of different

00:41:46.760 proteins that have different function that makes LPA even more atherogenic. Now these oxidized

00:41:54.000 phospholipids can have a signaling effect in the aortic valve. And that might be totally independent

00:42:01.780 from LDL. So we don't know. I'm only speculating here, but there are some signaling effects of

00:42:07.540 oxidized phospholipids that I think are very important. And they activate a lot of different

00:42:13.540 inflammatory processes and also osteoblastic processes, because these types of valvular

00:42:20.460 interstitial cells are becoming like osteoblasts, which are the cell types that make bones. So

00:42:27.060 it makes a lot of sense, you know, when you're talking about aortic valve calcification, that

00:42:31.420 there's a bone-like process that's happening within this tissue. Yeah. For all of our patients

00:42:36.980 that have elevated LP little a, one of the first tests we do is get a baseline look at their aortic

00:42:43.980 valve. So typically we'll do it with an echocardiogram. If we can get a good enough view, if not, we use a

00:42:49.140 cardiac MRI, but it's for exactly this reason. What's the approximate hazard ratio? How much does

00:42:55.480 risk go up for aortic stenosis in an individual with elevated LP little a? And how much does it

00:43:02.100 depend on whether or not they have a normal aortic valve to begin with, which has three leaflets,

00:43:07.060 a so-called tricuspid valve, versus if they have a relatively common anatomic variant with only two

00:43:14.300 leaflets, which is called a bicuspid valve, which even outside of LP little a would increase,

00:43:19.140 your risk for stenosis? Exactly. So there's not really good evidence showing that LPA is associated

00:43:26.860 with bicuspid aortic valve stenosis, because we're studying genes that are associated with

00:43:31.960 bicuspid aortic valve stenosis, and we don't see really an effect of LPA there. Now, that being said,

00:43:38.140 it might accelerate the formation of aortic stenosis in patients with bicuspid aortic valve.

00:43:45.360 Who are already at risk? Exactly. So LPA is probably an initiator of aortic valve stenosis,

00:43:53.880 and we've known that since 2013, when George Tanasoulis and Wendy Post published this genome-wide

00:44:02.180 association studies of aortic valve calcification in the CHARGE consortium, and they've shown that LPA,

00:44:09.180 that one variant associated with high LPA level, was the most important variant associated with

00:44:15.720 aortic valve disease. Now, we had known for a few years that LPA was present in the valve, and in the

00:44:22.220 valve, it actually co-localizes with oxidized phospholipids. So we knew this, but that study

00:44:28.780 was really, I think, a game changer for our understanding of aortic valve stenosis.

00:44:34.360 Now, when we're looking at the effect of high LPA on aortic valve stenosis, it really depends on the

00:44:43.560 level of LPA. So if you're looking at patients that have high-ish LPA levels, such as, let's say,

00:44:50.120 50 milligrams per deciliter or 125 nanomolar, the risk can be increased by 50%, maybe 100%,

00:44:58.240 or double, but when you're going and you look at patients that have very high LPA, the risk can

00:45:04.960 increase quite substantially. So if you have patients with very high LPA level, then what you're doing,

00:45:10.460 looking at the aortic valve, especially by ECHO, because it's probably the most widely available

00:45:16.400 tool to investigate this. In our lab, we performed sodium fluoride PET-CT, so positron emission

00:45:24.240 tomography coupled with computed tomography using a radio tracer that's called sodium fluoride.

00:45:30.700 And in patients that have high LPA levels, but these were patients from the general population,

00:45:36.700 we can already see like a signal before the onset of aortic valve calcification using this radio tracer.

00:45:46.420 So this really tells you that there's an effect of LPA on the initiation of the process of aortic

00:45:52.900 valve stenosis. So you're seeing before any gradient appears, before any flow-related metric,

00:46:01.240 you're seeing a metabolic change at the valve? Yeah, exactly. So the sodium fluoride will actually

00:46:08.260 bind to a chemical called hydroxyapatite, which is literally a complex of calcium and phosphorus,

00:46:16.000 which will eventually be involved in the pathophysiology of aortic valve stenosis. And we see

00:46:22.720 that process happening at the earliest stage of the disease. And we also see an effect of LPA on the

00:46:28.900 later stage of the disease. So the data that's available so far that have looked at the progression

00:46:34.260 rates of aortic valve stenosis has shown that patients with high LPA might even progress more

00:46:42.240 rapidly than patients who have low LPA, especially within younger patients that have high LPA. Because

00:46:48.740 when you're looking at patients, you know, that are above 75 or 80, there's a lot of calcium that's

00:46:56.420 already present in the valve. And the mechanism might be very different in younger patients compared

00:47:02.600 to older patients when we're investigating the progression of aortic valve stenosis.

00:47:08.080 Yeah. And if we're going to create a public service announcement here for primary care physicians,

00:47:13.100 it's so important to identify aortic stenosis in its earliest stages because the outcome data

00:47:18.920 are quite clear that the earlier you intervene, the better the outcome. So, you know, I think 25 years

00:47:26.480 ago, we had a certain threshold in terms of surface area of the valve and gradient of pressure across

00:47:32.380 the valve, at which point you would replace the aortic valve. If you look at the literature today,

00:47:37.380 it seems that you're getting better and better outcomes when you proceed earlier and earlier

00:47:40.940 before the heart is overly taxed based on that pressure head that it faces. And of course,

00:47:47.260 the increased risk of spontaneous cardiac death and other things that goes up with aortic stenosis.

00:47:51.400 So aortic stenosis is a very serious problem independent of ASCVD, atherosclerotic cardiovascular

00:47:58.120 disease, which is what most people think of when they think of LP little a, assuming they know

00:48:02.100 something about what we're talking about in terms of this molecule. So let's go back to another point

00:48:07.180 you raise. And again, I think when people look at the diagram, this will be much easier. We get into

00:48:12.480 the anatomy of the fourth and fifth region of these Kringle repeats and which of the subunits

00:48:17.920 can create this vast heterogeneity. Why two people can have an LPA gene that overexpresses,

00:48:26.880 well, LPA through apolipoprotein little a. One of them can have a molar mass that's very high.

00:48:32.160 One can have a molar mass that's very low because of these number of Kringle repeats.

00:48:37.080 What does the number of these repeats tell us about the pathophysiology of this?

00:48:42.960 Well, if you had asked me that question 10 years ago, I would have said a lot. But our understanding

00:48:49.460 of the pathophysiology of LPA is increasing every week now, basically. So maybe 10 years ago,

00:48:58.060 there was this debate about LPA as to whether or not it was the LPA concentration that mattered or

00:49:05.220 if LPA concentration didn't matter at all because it's the APOA isoform size that mattered. Small

00:49:12.300 isoform size being associated with higher LPA levels. And there has been some epidemiological

00:49:18.340 studies that have measured APOA isoform size, either through PCR or immunoblotting, etc. So in

00:49:26.480 the same patient, you can have LPA levels measured and you can have the APOA isoform size. And using

00:49:34.600 the techniques that were available back then, they did multiple adjustment, adjusting LPA concentration

00:49:40.300 for the APOA isoform size and looking at the association of APOA isoform size with outcome

00:49:47.560 adjusting for LPA levels. And the data back then was going all over the place, basically. So

00:49:53.600 some studies were saying it's the concentration, some other studies were saying it's the APOA

00:49:58.280 isoform size that matters. Once again, these questions were ultimately resolved by looking

00:50:04.680 at genetics. So there's one variant that's associated with small LPA isoform size, but that's also

00:50:14.800 associated with a low LPA. So you can see this was our way to do a discordance analysis by looking

00:50:21.660 at that specific SNP. And that genetic variant was not associated with cardiovascular diseases

00:50:28.180 at all. And in many studies now, it's been shown that probably the best study that has investigated

00:50:36.600 that is a study from the DECODE cohort, which is a cohort from Iceland. They did whole genome sequencing

00:50:44.220 in, I think it was 15,000 individuals. And they've shown unequivocally that the LPA isoform size,

00:50:52.120 even though you can sequence it, really was not associated with the risk of heart attacks and

00:50:59.060 strokes once you take into consideration LPA level. So it's really the LPA number that matters. And

00:51:06.380 that's actually very positive for the field because there's so many puzzles that we still need to figure

00:51:11.860 out in terms of the association between LPA and risk. So at least we can convincingly say that it's

00:51:18.340 the number of LPA particles that matter and not necessarily the isoform size and that the isoform

00:51:23.780 size matters because it's associated with different levels of LPA and not through an independent effect.

00:51:31.120 So really this, for once, creates a beautiful symmetry here, which is it mirrors ApoB.

00:51:35.420 The first, second, and third order factor in the harm caused by an LDL particle is the number of the

00:51:42.340 particles. The size, all of those things only factor into the number. So why is it that smaller particles

00:51:49.820 are more often associated with a poor phenotype? Because when you have smaller particles, you generally

00:51:56.000 have more of them. So that's good to know. Do we have a sense of the complexity in why some families,

00:52:06.860 because again, we didn't talk about the inheritance of this. So before I ask this question, let's go back

00:52:11.220 and explain the inheritance of this. It's a very important piece of the puzzle. How is this gene

00:52:15.920 inherited and what are the implications for people who have elevated levels of this as far as their

00:52:23.120 offspring? That's a very good question. So the pattern of inheritance is true autosomal dominant

00:52:30.140 pattern of inheritance. So like, for instance, if you compare it with a monogenic disorder, let's say

00:52:35.980 femoral hypercholesterolemia. In Quebec, we have a very famous mutation, which is a 15 kilobase deletion

00:52:43.380 in the LDL receptor. So if you inherit at least one copy, you know you'll have FH. For LPA, if you

00:52:51.260 inherit a genetic variant that's associated with high LPA, chances are you'll have high LPA as well,

00:52:57.860 because you only need one variant and not necessarily two. So you'd need either the allele

00:53:02.940 from your father or your mother that will rise LPA. But it's a bit more complex than that, because

00:53:09.600 we cannot necessarily consider it monogenic disorders, because there's 2,000 different variants

00:53:16.620 in the LPA region that are associated with high LPA. So your father can have a high LPA because of a

00:53:25.100 specific variant, and your mother can have an LPA variant that lowers LPA. But it depends on the

00:53:32.060 combination of SNPs that you will ultimately get. So it's not as clear as any monogenic disorder, even

00:53:40.100 though it's a dominant mode of inheritance, it's been shown that the children, they have very different

00:53:47.220 LPA levels than their mothers and fathers. And you cannot really estimate it. So you really have

00:53:52.400 to measure it. And for people that are asking the question, at what time I should get an LPA

00:53:58.540 measurement, let's say if I had a heart attack at an early age, and I want to prevent that in my

00:54:04.000 children, then we know that the LPA gene is fully expressed by age 2 in the liver, of course, and

00:54:12.620 that the levels that you will get at 5 years old are probably going to remain, well, maybe not the

00:54:20.520 same levels, but if you have high levels by age 5, it will increase through adulthood, but very, very

00:54:27.900 slowly. Yeah. So again, some very important information there, right? Piece one of that is

00:54:33.660 you cannot predict the phenotype of the offspring from the phenotype of the parents. And let's contrast

00:54:41.240 this with APOE, the gene. By the way, there's a lot of parallels between APOE and LPA. APOE is a gene

00:54:48.820 that today doesn't seem to serve much of a purpose. All it seems to do is increase your risk of

00:54:54.660 Alzheimer's disease and even increase your risk of cardiovascular disease independent of that.

00:54:59.520 There are three isoforms, the 2-3-4 type, and it's this fourth type that's high risk. So you can argue,

00:55:04.660 how in the world does this gene exist? And of course, the answer is evolution wasn't really

00:55:10.180 thinking about Alzheimer's disease. So therefore, there must have been some benefit of it. And of

00:55:14.160 course, we now know there is, right? This genotype was associated with protection from parasitic

00:55:19.420 infections in the brain, which would have been far more to our advantage 100,000 years ago,

00:55:24.660 50,000 years ago, 10,000 years ago, than the downside of Alzheimer's disease in your 70s or 80s.

00:55:32.660 But with APOE, because you have these three discrete isoforms, you only have six combinations.

00:55:40.020 And therefore, if you know what the parents' isoforms are, you can probabilistically give a

00:55:46.960 distribution for what the children will be. You still would need to measure it, of course,

00:55:50.660 but there's a finite number of outcomes. Now, of course, there you're measuring genotype and not

00:55:56.320 phenotype. We don't measure the phenotype of APOE yet. So here, you have so many genes that are

00:56:03.820 associated with this thing that if the parents are both elevated, the probability that the offspring

00:56:09.300 are going to be elevated seems pretty high. If one parent is elevated and the other is not,

00:56:14.160 there's a pretty decent chance that the offspring will not. Tell me about the situation in which

00:56:20.160 both parents are not elevated, but yet could carry variants of LPA that when combined could

00:56:26.860 elevate. Has that been observed? Or does one safely say if both of your parents are below 30 milligrams

00:56:34.940 per deciliter, the probability that you are going to be north of 50 is very small?

00:56:40.480 I think it's very small, but you still have to measure it. To be honest, I don't think I would

00:56:45.480 know the answer to that. Most guidelines will tell you to measure it in everybody at least once in

00:56:51.500 their lifetime. And when do the guidelines suggest that that start? Do the guidelines suggest doing it

00:56:56.680 in adolescence when you have a long enough runway to take action if the LP little a is elevated? Or do

00:57:03.440 they not specify? I don't think they specify that. And the guidelines are actually just starting to

00:57:09.360 advise for LPA measurements. So some guidelines, like the American Heart Association guidelines,

00:57:15.440 which are probably the less favorable for LPA measurement, they'll tell you to measure,

00:57:21.800 I don't remember exactly, but in patients with atherosclerotic cardiovascular disease or with a

00:57:26.760 family history of atherosclerotic cardiovascular disease, in patients with familial hypercholesterolemia,

00:57:32.460 or in patients with aortic valve stenosis.

00:57:34.440 So in other words, measure the LP little a once they've demonstrated that the disease

00:57:40.300 that it causes is present.

00:57:42.480 Pretty much.

00:57:43.620 That's fantastic advice. That's excellent insight.

00:57:47.320 Yeah. But if you look at the Canadian guidelines, they'll tell you to measure it

00:57:50.640 in everybody at least once in their lifetime.

00:57:53.720 And by the way, this is where Canadians also stand out over Americans. Canadians have long adopted

00:57:59.240 the measurement of ApoB as the superior measurement to quantify LDL risk. And yet here in the United

00:58:06.520 States, the guidelines still favor the use of LDL cholesterol, which is clearly inferior to ApoB.

00:58:13.340 Yeah, absolutely. So I would like to comment on that. I think that the Canadian guidelines are

00:58:19.260 much more up to date with the recent literature on that. There's clearly no doubt about it.

00:58:24.200 As are the European guidelines while we're on the topic, right? The European guidelines,

00:58:28.580 the Canadian guidelines are in line with the available evidence and the United States guidelines

00:58:34.000 are, you know, just 40 years out of date, but that's all.

00:58:37.980 Yeah, absolutely. And the European guidelines actually advise to measure LPA in everybody for

00:58:42.900 a different reason. It was to identify patients who have very, very high LPA levels because we realize

00:58:51.260 throughout the years that having a super high LPA might be a cause for familial hypercholesterolemia.

00:58:59.420 You need to measure LDL to diagnose familial hypercholesterolemia. And after mutation in the LDL

00:59:06.000 receptor, variation in the LPA gene might even be the second cause of familial hypercholesterolemia.

00:59:12.920 And the reason for that is quite simple, because when you measure LDL, you also measure LPA cholesterol.

00:59:21.640 So if you have a very high LDL and also a very high LPA, there's a very good chance that the

00:59:29.380 high LDL cholesterol will actually be high LPA cholesterol. I think it's really underappreciated.

00:59:36.800 And actually, that's the reason why it's in the European guidelines. But now I think most of the

00:59:43.220 guidelines that will be put forward will just simply for whatever reason to measure LPA at least

00:59:49.700 once. And I don't know if it's in the pediatric guidelines because I don't really follow that

00:59:55.040 literature. But maybe in children who have strokes at a young age, many of them have high LPA.

01:00:03.540 So it's not as clean as the literature in adults, but there's been a lot of studies looking at high

01:00:11.020 LPA and stroke in children. So if you have a family history or relatives that had a stroke at a

01:00:18.360 young age, it might be a good idea to measure LPA as well. Yeah, that's actually a terrifying thought,

01:00:23.660 by the way. You know, my view on these things, of course, is just the amount of energy that goes into

01:00:28.080 debating it is so ridiculous compared to the relatively low cost of simply measuring the

01:00:33.460 thing. People who debate why would you spend $14 on an ApoB test. It's like, if your life isn't worth

01:00:40.400 $14, we shouldn't be having this discussion. Same is true for measuring LP little a. So I think it

01:00:45.880 should be done on everybody, non-negotiable, certainly before your 18th birthday. That would

01:00:51.480 be my thinking on this. So let's go back now. What's the greatest that you've seen number of LP little a

01:00:59.280 to LDL? I had a patient once when we were measuring both in nanomole per liter who had an LP little a of

01:01:05.840 690 nanomole per liter in the context of an LDL particle concentration of about 1800 nanomole per

01:01:14.000 liter. So a little over one third of his LDL were LP little a. I assume you've seen numbers even in

01:01:22.500 excess of that. Yeah. Well, just to be clear, Peter, I don't see patients. I'm a biochemist and

01:01:29.360 I've seen some very interesting case reports on children that have FH and high LPA. Some of them

01:01:36.500 even had to have liver transplant because the lipids were just so high and they were having events in

01:01:44.060 children years. But those are only case reports, of course. It's not mainstream and I wouldn't want to

01:01:49.940 scare anybody, but this is as dangerous as it can get. So let's talk about other therapies that have

01:01:56.380 been proposed. So there was certainly a day, and sadly, there are still a number of physicians that

01:02:02.600 I interact with, including those who carry the title of lipidologist, who are recommending the

01:02:08.640 use of niacin to lower LP little a. Can you talk a little bit about the history of that and at the risk

01:02:14.580 of spoiling the punchline, why we do not believe that is a good idea? Well, it was even in the

01:02:20.500 latest guidelines of the European Atherosclerosis Society to advise niacin treatment in some patients

01:02:27.180 with high LPA. We did not have large cardiovascular outcome studies on literally any effect of niacin

01:02:35.140 therapy. Now we know that niacin therapy will actually reduce LPA levels. It will increase HDL,

01:02:41.980 it will lower triglycerides. So the effects on plasma lipids are actually pretty good. However,

01:02:49.220 you know, if you're looking at LPA, the mean reduction will probably be about 20 or 30% with

01:02:54.800 niacin. And there are, as you say, some lipidologists that have seen like very important reductions of LPA

01:03:01.300 with niacin that they've decided to keep those patients on niacin. And I don't see any problem with

01:03:07.700 that. The thing is, however, when you look at the actual evidence, we have two large cardiovascular

01:03:13.500 outcomes trials. We have the AIM-HI trial and the Heart Protection Study 2-TRIVE trial that have shown

01:03:21.560 that there's no cardiovascular benefits in treating anyone with niacin. And we see a lot of side effects

01:03:29.000 as well. Flushing being the most important side effect of niacin. So we have those risks and we don't

01:03:34.620 have that many benefits. So that's why niacin is not as prescribed as it once was. There are still

01:03:41.380 people that are using it. Niacin reduces the production of LPA. And LPA still predicts the

01:03:47.660 risk of events in patients treated with niacin. So we know that from the AIM-HI trial. So when you're

01:03:53.640 looking at the cost to benefit ratio for niacin, the evidence really isn't there to support niacin

01:04:00.300 treatment. Why do you think this is? If we look at the effect of niacin on raising HDL, which it does,

01:04:08.060 right? HDL cholesterol goes up with niacin administration at a high enough dose. But the

01:04:12.880 outcome trials are very clear that that does not translate into benefit. It makes you think a little

01:04:18.840 bit of the CTEP trials where you give a CTEP inhibitor, HDL cholesterol goes up. In some cases,

01:04:24.840 you actually saw more events, but usually at best you see no effect. There it's a little easier to

01:04:30.880 argue why that could be happening when you look at the complexity of HDL biology. And you understand

01:04:38.680 how much we don't understand. And therefore that HDL functionality is what really matters. And we

01:04:45.720 don't have an assay for HDL functionality. So these things that we measure, like the amount of

01:04:50.900 cholesterol in an HDL particle is a pretty useless measurement in that it tells us nothing about how

01:04:57.060 the HDL actually works. Especially when you consider that you can have high cholesterol in an

01:05:02.520 HDL particle because of all the cholesterol that's entering it, or you could have high cholesterol in

01:05:07.380 an HDL particle because not much cholesterol is leaving it. Those would be two completely different

01:05:11.340 states of affairs. And again, it makes sense why you can dismiss the notion that raising HDL

01:05:19.140 cholesterol is valuable pharmacologically. In the case of LP little a, it's a bit more confusing

01:05:24.360 because as you said, niacin actually inhibits the production of apolipoprotein little a.

01:05:31.820 And for all of the nastiness associated with LDL and LP little a, their biology is actually easier

01:05:38.820 to understand. In other words, the things that they're doing to hurt you are easier to understand

01:05:43.040 than what HDL is doing to help you. So why do you think there is not a more clear signal

01:05:47.820 between the use of niacin and the reduction of events?

01:05:52.540 Yeah, it's a very good question. The Mendelian randomization studies have been very clear that

01:05:59.380 you will need a very large reduction in LPA to produce cardiovascular benefits. The first study

01:06:07.620 has suggested that because it's basically only modeling, right? There's no trial data, so we can

01:06:12.740 at best estimate the treatment effect. So it's suggested that you needed 100 milligrams per

01:06:18.320 deciliter reduction in LPA to get a benefit in a trial that would be comparable to a statin

01:06:26.080 treatment, like a 20% reduction. Over what period of time? You'd need to see that in a five-year

01:06:31.600 window? Yeah, well that's actually the problem because when you're looking at Mendelian randomization

01:06:36.360 studies, you're looking at primary prevention and we're looking at lifelong reduction. So it's very

01:06:41.560 hard to estimate a trial. Oh, so the MR says if you want to take that mortality curve down

01:06:48.640 to the next rung, it's a hundred milligram per deciliter reduction and lifetime exposure.

01:06:54.740 There was one study that showed that. There's other study that came out after that that said,

01:06:59.920 well, it's probably not a hundred. It might be around 50 milligrams per deciliter, but it's still

01:07:05.660 high. So you need a large effect. So it's not a 20% reduction. But there's a bigger point there.

01:07:11.360 Which you alluded to, that's over the course of your life. That means over five years,

01:07:16.200 you might have to basically obliterate it if you're going to want to see a benefit.

01:07:20.440 Yes. And well, that's what the antisense oligodonucleotides will do. And I guess we'll

01:07:24.720 come back to that later. But when they compare it to LDL though, they also compare it to lifelong

01:07:29.900 exposure to lower LDL. So they're not necessarily comparing lifelong reduction to trial data that,

01:07:36.660 you know, with statin trials, we have between two and seven years length of treatment in patients

01:07:41.640 that already have disease. So you cannot really compare apple and oranges. But when you compare

01:07:45.680 the lifelong effect, and that's obviously a caveat of those studies, because you're trying to estimate

01:07:51.240 the results of a trial using lifelong effects. So you have to take some and leave some for those

01:07:56.820 kinds of studies. But I want to come back to something that you said about CTP inhibitors,

01:08:01.120 because we do have evidence, at least for the anacetrapib, that it might lead to cardiovascular

01:08:07.800 benefits. Was that the Merck one? Yes, it's the Merck one. And they stopped the trial even though it

01:08:13.720 was trending in a positive direction. Is that correct? Exactly. So there's one reason for that was

01:08:20.460 that they saw a lot of drug accumulation in adipose tissue, which is not something you want if you want

01:08:27.100 to prescribe a lifelong treatment. And the second thing is that while the treatment effect was not

01:08:33.340 spectacularly high, I think it was a 6% reduction in the rate of events. I'm saying this because you

01:08:41.620 talk about HDL and functionality. And in that trial, I don't remember the name of the trial. It was a

01:08:46.820 revealed trial. Yeah, that was stopped about two years ago. It was relatively recent, maybe three years

01:08:51.640 ago, right? Maybe a little bit more than that. But it was a big trial, I think 30,000 patients.

01:08:56.960 So this is why we need big trials in that arena. So what they showed is that it was the reduction in

01:09:03.740 the number of ApoB lipoproteins that actually mattered. It really didn't matter. Like the risk

01:09:10.820 was not proportional to the HDL rising effect. It was proportional to the ApoB lowering effect. And when

01:09:18.500 you're looking and if you plot all the clinical trials together, if you plot the ApoB lowering

01:09:25.080 effect to the reduction in cardiovascular disease, you can see that all these trials line perfectly on

01:09:31.520 the line. And even that specific trial with anacetrapib, it fell right on the line. Same

01:09:36.960 with PCSK9 inhibitors, same with ezetimibe, any LDL lowering drug that's out there, maybe a few

01:09:44.660 exceptions, but it will land on this line. So it's really not about HDL so much. When they developed

01:09:51.340 the drug, they thought it was about HDL, of course, but it's really funny because actually it just

01:09:56.240 further convinced us to hit on ApoB containing lipoproteins as hard as we can.

01:10:03.280 Yeah, it is kind of the silver lining in all of this. Sometimes it's easy,

01:10:06.240 if you think about this stuff too much philosophically, to lament the fact that we even

01:10:10.080 have ApoB, right? Because there's no real need for ApoB. We could survive with no circulating ApoB

01:10:16.500 and we wouldn't have any atherosclerotic disease. So every time you get a little depressed and have

01:10:20.980 that thought, you can also realize how fortunate are we that the biology of ApoB is so much more

01:10:25.960 well understood than that of ApoA. Now I'm talking ApoBigA. And that eradicating ApoB is becoming

01:10:33.680 easier and easier and easier and safer and safer and safer. And it's the single most important thing

01:10:39.280 that you can do in the plasma to reduce the risk of atherosclerotic disease. I mean, all of these

01:10:43.940 things make for a very fortunate turn of events for our species. And that's why turning to this

01:10:49.540 pesky LP little a is so important because of what you described at the outset, which is this residual

01:10:55.800 risk in the individuals. And it's interesting, you talked about 20%. That's higher than the number I

01:11:01.940 quote my patients. I usually tell my patients it's 10%. So I've been understating this for some time.

01:11:07.780 I didn't realize it. So all comers, 20% of the population would be over 50 milligrams per

01:11:13.220 deciliter? Yeah, depending on ethnicity. So it's certainly above 15%. No doubt about it. And in some

01:11:20.000 population, especially in populations of African ancestry, they have the highest LPA levels. And

01:11:26.820 they also have the highest LPA levels adjusted for LPA isoform size as well. So in most individuals,

01:11:34.780 if you look at the distribution of LPA in the population, it's really skewed towards the null.

01:11:41.220 So it means that there's a lot of patients, most individuals have very low levels of LPA. And there's

01:11:48.560 some individuals, as we mentioned, 15 to 20% that have high LPA levels. Now in individuals of African 0.99

01:11:55.600 ancestry, it's a more like a Gaussian distribution. So that's one of the reasons why they have higher LPA.

01:12:01.920 Does that mean they have higher risk if they have a higher LPA? Not necessarily because the risk is

01:12:09.300 really proportionate to the level. So there's nobody within shouting distance of what I'm about to say,

01:12:16.320 I believe, which is LP little a is hands down the most common hereditary driver of ASCVD. Correct?

01:12:24.380 I mean, FH wouldn't even get within the same zip code when you think about genetic things that are

01:12:30.320 driving atherosclerotic cardiovascular disease, correct? It is by far the most prevalent form of

01:12:36.840 dyslipidemia. So you can argue that, and we have to talk about penetrance as well. So the penetrance is

01:12:43.520 the proportion of individuals with a certain genotype that will have the disease. So the penetrance is

01:12:50.340 obviously not 100%, right? So when I hear people say that, you know, LPA for the pharmaceutical

01:12:56.580 industry is a market of 1.4 billion people, I say, well, hold on a second. It's not everyone that has

01:13:03.440 a high LPA that will have an event. And we need to figure out what are the drivers of risk in patients

01:13:10.800 with high LPA. And we're starting to study that. And we see that there is some residual risk effect,

01:13:17.480 even in patients with high LPA. So we see that, for instance, if you have a high LPA, but have lower

01:13:23.540 CRP levels or lower inflammation, you might not have a risk that's as high as if you have high CRP.

01:13:31.200 So you can argue that residual inflammation is very important. But there need to be more studies on this

01:13:39.280 because one can make the case that, well, it might be the same for smoking, or type 2 diabetes,

01:13:44.360 or any other cardiovascular risk factor that you can think of. But even then, even if LPA is not

01:13:51.480 fully penetrant, it is so common that it is by far the most important form of dyslipidemia that will

01:13:59.200 explain a lot of cardiovascular events at the population level.

01:14:04.380 And what I find so tragic about that statement is the number of good physicians out there,

01:14:11.500 really great doctors that are working hard, taking care of patients, frontline physicians,

01:14:16.140 family medicine physicians, internists, who have no idea what it is. You know, you ask them about it,

01:14:22.200 and they look at you as though you've asked them something in a different language.

01:14:26.580 I still struggle to understand that disconnect, given its urgency. I wonder if that's a uniquely

01:14:32.180 American phenomenon. Do you have any insight? I know you're not a clinician, but do you have an insight

01:14:37.000 as to whether or not the literacy around this in Canada and Europe is higher?

01:14:43.500 I don't have any reasons to believe that the literacy in Canada or Europe is higher than it is

01:14:49.620 in America. Even with your guidelines being more forward-leaning?

01:14:54.440 Oh yeah, but these guidelines are new, and it will take a lot of time before they implement it. Sometimes

01:14:59.660 it takes a full decade before it's transmitted to younger generation of physicians, and people actually

01:15:05.960 talk about it. So that's one of the reasons I'm so glad that we get to do this podcast. Hopefully this

01:15:11.220 will raise awareness for the physicians out there that didn't have any information about LPA, and you

01:15:18.240 know, you can't blame them because, well, it's obviously in the guidelines, but you know, not all

01:15:22.600 physicians read all the lipids guidelines. There's so many guidelines out there that you can't blame

01:15:27.480 them for that. But I mean, that's why we have to do more education to physicians. And I think one of the

01:15:33.160 reasons that people are reluctant to measure LPA is that because there's no treatment. Any medical

01:15:39.660 procedure that you do, even if it's asking for a measurement of any labs that you can mention,

01:15:44.920 it has benefits, but it also has consequences. You don't want to stress anybody saying, hey,

01:15:49.620 you have this risk factor, it's super important, and you don't want to do like an over-diagnosis,

01:15:55.220 an over-treatment. I used to think that a lot, but now, you know, we're in the age of

01:16:00.600 shared decision-making. We can communicate the correct information to patients, tell them what

01:16:06.940 we know. And even though there's no specific therapy for high LPA, it doesn't mean you can't

01:16:12.900 do anything. There's trial data showing that if you prescribe, for instance, a statin, and if you

01:16:19.620 lower LDL cholesterol levels in patients that have some risk factors for cardiovascular disease,

01:16:25.340 you'll reduce the risk of events. So in patients with high LPA, you need to manage LDL, you need to

01:16:31.040 manage LPA, you need to manage lifestyle, smoking cessation, and etc. And we've actually shown that.

01:16:38.340 I've been working for more than 15 years with investigators in Amsterdam and Cambridge on

01:16:44.780 the EPIC Norfolk study. So the EPIC Norfolk study is the European perspective investigation into

01:16:51.340 cancer and nutrition. And they have a LPA measurement in 18,000 individuals. And we've

01:16:57.900 looked in that population at the effect of LPA on the risk of events, but according to what the

01:17:05.420 American Heart Association calls the Life Simple 7. So smoking, having a healthy diet, being physically

01:17:14.400 active, having low body weight, LDL cholesterol, no diabetes, and blood pressure that's on target.

01:17:22.380 And if you look at patients that have high LPA and that manage all of these risk factors,

01:17:29.460 it's observational study, of course. But if you consider it a causal relationship, you could

01:17:34.640 reduce your risk by two thirds. So that's not trivial. So that's one reason why we should measure LPA.

01:17:40.760 If it's just to target the other risk factors, we'll have a lot of benefits in terms of prevention

01:17:47.000 of cardiovascular diseases at the population level. And I think this is another great example of the

01:17:52.880 parallel with APOE, the genotype. As recently as even a couple of years ago, I would have enormous

01:17:58.400 arguments with physicians about patients that we were co-managing, right? So this would be

01:18:04.240 a patient who has both of us as their physician. And the patient would say, look, I want to have my

01:18:10.040 APOE genotype measured. I would say, I completely concur. The other physician would say that's an

01:18:14.760 absolutely horrible idea. What good comes of that if they discover that they have an APOE4 gene and

01:18:19.800 their risk is higher? All you've done is create anxiety, to which I would argue, perhaps in some

01:18:24.920 individuals, sure. And that's why it should be something that is done with consent. But that

01:18:29.340 assumption assumes you can do nothing about it. And while you can't change the gene, the evidence that

01:18:34.920 you can modify behaviors that will lower the risk is enormous. Now, in the case of APOE, it's even

01:18:40.540 more complicated because we now know what we didn't know a few years ago, which is there are so many

01:18:45.340 other genes that will either amplify or attenuate the risk of APOE. So frankly, today, knowing that

01:18:51.740 you're APOE4 positive, in my opinion, carries much less information than it once did. So I want to ask you

01:19:00.140 about something parallel with LP little a. I've had patients who have had modest LP little a, meaning

01:19:08.120 150, 125 nanomole per liter, 60 milligram per deciliter, who have had the most devastating

01:19:19.340 ASCVD that you can shake a stick at. I mean, six vessel disease, calcium scores of 2000.

01:19:28.480 And I mean, these are people who are having coronary artery bypass surgery in their fifties and their

01:19:35.820 LP little a is, you know, a little elevated. And by the way, their LDL and APOE4 were not through the

01:19:41.440 roof. They're not smokers. They're not hypertensive. They're not type two diabetic, et cetera. Hard to

01:19:47.620 explain those ones. Similarly, I've had patients whose family histories do not suggest advanced

01:19:55.320 or premature ASCVD. And I told you about one of them earlier, 690 nanomole per liter LP little a.

01:20:04.680 Now, this person had a zero calcium score. Admittedly, they were in their 40s. So,

01:20:09.760 you know, a calcium score of zero in your 40s doesn't generally tell you anything,

01:20:13.340 but at least tells you that this person isn't having advanced atherosclerosis.

01:20:17.900 Their family history is very uninspiring. And at least one of their parents had to have

01:20:23.240 an elevated level. Grandparents, nothing. And I scratched my head and I think,

01:20:28.600 why is it that this person seems somewhat immune from their very elevated LP little a,

01:20:35.720 whereas this other person who's elevated, but not through the roof, is ravaged by it?

01:20:42.560 Well, you're describing my next grand proposal, Peter. So,

01:20:45.600 this is exactly what we're trying to study. I alluded earlier to the penetrance of high LPA,

01:20:52.000 and that's exactly what you're referring to.

01:20:54.520 Oh, I misunderstood, Benoit. I thought you were referring to the penetrance

01:20:58.060 in terms of the expression of the protein. You were referring to the penetrance of the disease.

01:21:04.580 Yes, exactly. Exactly. But, you know, we can say a lot about that. In our lab, we isolated

01:21:10.180 the LPA particle from the blood of donors and patients with aortic valve stenosis.

01:21:17.480 So, the reason being that, well, we're going to study those particles because those patients,

01:21:23.260 they were matched for age, sex, statin therapy, smoking, etc. So, they're the same people,

01:21:29.500 demographically speaking, but one of them has a disease and the other one doesn't.

01:21:34.500 They all have high LPA and they were matched for LPA levels. So, we thought, well, maybe there's

01:21:39.680 something happening in the particle. Maybe they have more oxidized phospholipids. Maybe

01:21:44.400 they have different proteins. So, we've studied that and we realized that these patients might have

01:21:51.380 more cell adhesion molecules that are transported by LPA, which make them more quote-unquote sticky

01:22:00.060 to endothelial cells or fibrin clots or maybe even macrophages because patients with high LPA also have

01:22:09.160 activated macrophages, which can penetrate much more easier in the vessel wall. There's more apoptosis

01:22:17.000 in the macrophage. There's more cytokine production like IL-6, IL-8, etc. So, there might be something

01:22:24.620 that's different in the LPA particle. That's just an hypothesis. This was a study of, I think,

01:22:31.140 there were 20 patients in each study arm because it's not easy to remove LPA from the blood and have

01:22:37.160 it in a sufficient quantity that you can actually do proteomics on it. So, this is, it took a PhD

01:22:42.520 student of mine at least one year just to recruit the patients and isolate their LPA and there were

01:22:47.220 40 of them. And that's just because the electrophoresis is complicated? Is it getting

01:22:51.880 it out of the body that's complicated or isolating it once it's ex vivo? Well, once it's ex vivo, you have

01:22:57.480 to isolate it. It's not difficult to isolate it because you need to do ultracentrifugation. But

01:23:03.200 it has the same size as LDL and the same density as HDL. So, you have to do chromatography columns to

01:23:10.660 just basically separate it from LDL particles and also HDL particles. So, you need to do a size

01:23:17.560 exclusion chromatography and an affinity-based chromatography. So, it took a lot of time just

01:23:23.780 to set up that technique. And we worked with a great colleague of mine, Marlis Koshinsky, who's at the

01:23:29.660 Robards Research Institute in London, Ontario. And she's been doing this for ages, but she helped us

01:23:36.240 doing that. And we're actually, I think, one of the first to actually isolate LPA from the blood of

01:23:41.420 patients. So, that might be an explanation for this different expression of the disease in people that

01:23:47.740 have all high LPA, but some that are lower than others. So, that's just a hypothesis. You need to look

01:23:54.240 at other risk factors. Maybe there's another gene that's out there that might code for a receptor

01:24:01.380 of LDL. There's labs that are really devoted to finding other genes aside LPA that might explain

01:24:09.720 this. And the GWAS hasn't identified any? Because that would be your first tool. Before I'd go looking

01:24:15.500 for that gene or that receptor, rather, I would be trying to just find out what the association is,

01:24:21.060 right? Absolutely. And those studies have been done. Probably the best GWAS on LPA levels was

01:24:27.220 published, I think, last year by the group of George Stanisoulis and McGill in Montreal and James

01:24:35.460 Engert. What they showed is that, well, obviously, the biggest hit was at the LPA locus. And we had

01:24:41.820 known this for a while, that ApoE actually also regulates high LPA levels. So, that's another reason why.

01:24:48.620 Is there some concordance with ApoE and LPA?

01:24:53.080 Yeah. So, ApoE allele that will rise, the risk of heart attacks will also rise LPA levels. So,

01:24:58.960 you have that, you have the CTP gene. And then we haven't talked about the LPA lowering effect of

01:25:05.480 CTP inhibitors, which is actually higher than what you can get with niacin therapy. So, some have

01:25:12.860 suggested that the quote-unquote benefits of CTP inhibition might be due to a certain extent

01:25:18.780 to high LPA levels. But the problem with niacin trials and CTP trials is that they weren't done,

01:25:26.200 particularly in patients with high LPA. So, I guess we'll never know.

01:25:30.320 So, they're probably underpowered, at least when it comes to trying to understand that.

01:25:33.920 Yeah. Because you would have to recruit only patients that have high LPA, which would mean

01:25:38.620 to get rid of 80% of the trial population. So, these trials will be very hard to do. And when

01:25:44.540 you look at the other genes, you have CTP and you also have ApoH, which is on another chromosome. And

01:25:50.840 ApoH codes for beta-2 glycoproteins. And that protein might actually influence the presence of

01:26:00.040 oxidized phospholipids on ApoA. So, that might be interesting. And I can't think of a study that

01:26:06.200 have tried to look at that locus with high LPA to see if it has a modulatory effect on outcomes. But

01:26:13.180 that would be a very interesting study to do. So, these are the genes that I can think of.

01:26:19.480 Interestingly, the LDL receptor and also the most probably important regulator of LDL receptor,

01:26:27.300 PCSK9, they did not pop up in that GWAS, which was a little bit surprising to me given the effect

01:26:34.400 of PCSK9 inhibitors on LPA. Before we get to that, I want to go back to and really make sure

01:26:40.620 we flush out this oxidized phospholipid, plasminogen, basically the atherogenicity of

01:26:46.420 this particle. Is it clear that LP little a's enter the subendothelial space as LDLs do? Or is that

01:26:54.060 unclear? There's not as much research that's been done on LPA. But if you look at post-mortem studies,

01:27:00.880 you can see LPA in atherosclerotic plaques. And you can certainly see it on aortic valves.

01:27:07.280 Aortic valves are much more easier to get than atherosclerotic plaques. You can remove the

01:27:12.240 valve and you can study it under the microscope. So, there's good evidence that the LPA can actually

01:27:18.100 penetrate there. Usually, what they do is they will bind to clots that are in the region of the

01:27:26.520 atheroma. And that's one of the reasons why they might also be present there. And they can also send

01:27:33.400 their oxidized phospholipid to different receptors. Because we don't really know what is the receptor

01:27:39.940 for LPA in those tissue. So, at the surface of macrophages, there are scavenger receptors,

01:27:47.300 toll-like receptors, CD36 that might bind LPA. They bind a bunch of things. But they also might

01:27:53.860 bind NPA, which will ensure that LPA gets trapped in the macrophages and...

01:27:58.940 Myeloperoxidase?

01:28:00.240 LPA, sorry, sorry. I meant LPA, yeah.

01:28:03.040 Oh, LPA. Okay, okay. If I'm hearing you correctly, Benoit, it would almost suggest

01:28:07.160 that LPA plays less of a role in the initiation of atherosclerosis, which is really initiated

01:28:15.660 by the monocyte becoming the macrophage in the subendothelial space and engulfing the oxidized LDL

01:28:24.320 to become that foam cell. That's really the initiating trigger. You're saying LPA might not

01:28:31.300 be playing a role in that, or maybe it is. I want to make sure I'm not misquoting you. But where it

01:28:36.240 really lights things on fire is once you already have a plaque, that's where the ability to form a

01:28:44.540 clot goes up. Potentially, if you say it has more V-cams on it, it's attracting even more

01:28:50.000 macrophages to the site of injury. Am I capturing what you're saying correctly?

01:28:55.320 Absolutely. I think it's actually both. So, the macrophages of patients with high LPA are already

01:29:02.340 deactivated, and they will get, as soon as there's some endothelial dysfunction, they'll get there.

01:29:09.020 They might even cause endothelial dysfunction. So, LPA, it's probably a main driver before the onset of

01:29:17.100 any discernible plaque, but it also has this double whammy where it initiates the disease, but it also

01:29:24.980 is associated with the progression of the disease. And we see it in, for instance, I talked to you a

01:29:31.800 little bit earlier about the PET imaging with sodium fluoride. These studies have also been done

01:29:38.100 by Eric Stroos in Amsterdam. What they showed is that if you don't use sodium fluoride, but you use

01:29:46.400 FDG, so fluorodeoxyglucose, which is basically a marker of macrophage activation. And if you look at

01:29:55.300 the carotids and also the aorta of patients that have no disease, but that are separated on the basis

01:30:04.420 of whether or not they have high LPA, you'll see a lot of light in patients with high LPA. So, that tells

01:30:10.440 you that it's also associated with inflammation, with the inflammatory plaque, even in patients that

01:30:16.180 don't have established disease. So, that's one of the reasons why this kind of particle is so dangerous.

01:30:21.760 And the association is obviously very strong for ASCVD and aortic stenosis. How high is the

01:30:29.840 association specifically for cerebrovascular disease? It's clearly not as high. So, there's

01:30:35.800 obviously a signal. If I would have to rank those atherosclerotic cardiovascular disease,

01:30:42.280 the first one will be aortic valve stenosis. It's obviously less prevalent than MI or stroke,

01:30:49.360 but... But there are fewer contributing factors beyond LPA, the way you have APOB.

01:30:55.400 Exactly. So, the relative risk is actually higher. The absolute risk is lower because there's not

01:31:00.860 that many people that have that. It might be 2% of the population age above 60. But if you look at

01:31:07.840 top quintile versus lower quintile, the biggest risk is with aortic valve stenosis. After that,

01:31:14.260 it depends on the study. Sometimes it's myocardial infarction. Sometimes it's peripheral artery

01:31:20.420 disease. And we haven't talked about that, but LPA is very strongly associated with PAD as well. So,

01:31:28.680 it's aortic valve stenosis, PAD and MI, then ischemic stroke. And it's important to make the distinction

01:31:36.880 between hemorrhagic and ischemic stroke because LPA is only associated with ischemic stroke.

01:31:44.280 It's also associated with chronic kidney disease.

01:31:47.920 So, that's it. Really, it's only associated with aortic stenosis,

01:31:51.940 MIs, peripheral vascular disease, ischemic cerebral strokes, and kidney disease. But aside from that,

01:31:58.100 it really does nothing.

01:31:58.880 Yeah, there was some literature maybe 15 or 20 years ago on deep vein thrombosis and LPA. And there

01:32:08.200 has been new studies published on that. There's been genome-wide association studies. And we really

01:32:13.260 don't see a signal for LPA being associated with deep vein thrombosis too. So, that was part of the

01:32:20.080 conversation for a while. But now, I think it's pretty clear that it's really more closely associated

01:32:26.940 with atherosclerotic cardiovascular diseases and less with thrombolic events.

01:32:34.100 We do have an assay, I believe, for OXLDL, correct?

01:32:38.600 Yeah.

01:32:39.080 Is that assay picking up the oxidized phospholipid of LP little a included in that calculation?

01:32:47.080 Absolutely not. So...

01:32:48.700 Totally different.

01:32:49.940 Yeah. Well, there is actually an assay to measure oxidized phospholipids on

01:32:55.040 ApoB-containing lipoproteins.

01:32:57.640 Is that Sam Tamikas' assay?

01:33:00.620 Exactly. So, they have an assay that measures OXPLs on ApoB, including LPA, of course,

01:33:07.760 and also OXPLs on apolipoprotein little a. But the correlation coefficient between these two is

01:33:15.480 very high. And the correlation between LPA levels and OXPL on ApoB is also very high. So,

01:33:24.700 of course, that can provide some information. And obviously, Sam Tamikas has measured OXPL on

01:33:31.780 ApoB in all of the cohorts that he could put his hands on. And it's a good predictor of all of the

01:33:39.900 diseases that we've just mentioned.

01:33:42.100 But is it a predictor beyond the level and the number of LP little a particles?

01:33:47.240 No. I don't think there's good evidence to suggest that it's a better marker or it predicts

01:33:53.240 above and beyond LPA. I think we should advise people to measure LPA. That would be a gigantic

01:34:00.160 step. And then we can see if at some point we have convincing evidence that measuring oxidized

01:34:05.780 phospholipid will bring an added value. But I haven't seen much data that suggests that.

01:34:10.060 I stopped measuring OXLDL because I didn't see any benefit to it over ApoB. So, it sounds like

01:34:17.320 it's potentially the same thing here. And of course, you'd hope that it would have benefit

01:34:21.260 above and beyond so that it would help you stratify risk further. But interesting that

01:34:25.180 it does not. Very complicated to know what to make of these oxidized phospholipid tails that

01:34:30.900 are sitting around there wreaking havoc and potentially also forming part of this explanation for the

01:34:36.680 differential expression of the disease, right? Yeah. And it's the same for LDL as well. So,

01:34:41.620 the LDL particles, they get oxidized. They also have oxidized phospholipids. And that's one of the

01:34:47.660 reasons why LDL particles cause atheroclerotic cardiovascular disease. But the measuring them

01:34:54.880 in the plasma, it will not tell you how many oxidized LDL particles you have in your plaques.

01:35:01.200 So, that's why we need to stick with ApoB and LPA because you'll get a sense of all of the

01:35:07.480 lipoproteins that cause atheroclerotic cardiovascular diseases.

01:35:12.180 So, you alluded earlier to a PCSK9 protein, which we'll talk about. Tell people, before we get into

01:35:20.740 the drug, tell people about the PCSK9 protein, how it works, what its relationship is to the LDL

01:35:27.300 receptor. Absolutely. So, PCSK9, it means pro-protein, convertase, subtilizin, kexin, type 9.

01:35:36.280 It was discovered in 2003 by a collaboration between Nabil Seda, who's at Montreal, and Catherine Boileau,

01:35:46.200 who's in France. They had identified this family in France that had familial hypercholesterolemia,

01:35:54.900 but they couldn't find a mutation in the LDL receptor gene that explained the familial

01:36:04.060 hypercholesterolemia.

01:36:05.780 By the way, before you get into this, I just want to say this is one of my absolute favorite

01:36:10.140 stories in all of medicine, certainly in the modern era of medicine. You know, if you think

01:36:14.700 the last 20, 30 years, this story is remarkable. So, please indulge us.

01:36:19.580 Thanks for doing me the honor. So, they had identified this family that had FH without a

01:36:24.860 mutation in the LDL receptor, and the paper was published in Nature Genetics in 2003. So,

01:36:32.060 you can think that they had been working on this for a few years. So, that was probably at the time

01:36:36.700 where the human genome was being sequenced. So, that was during the days of... So, that was pre-genome-wide

01:36:44.620 association studies and whole genome sequencing where you were doing linkage analyses with

01:36:51.120 satellite DNA. And yeah, so I was an undergrad at that time. I was learning these techniques and

01:36:58.040 I wasn't in the lipids field. So, I heard that story after. But what they found is that they were

01:37:03.880 able to map the gene in that family to a protein that was at the time called NARC1. So, they didn't

01:37:11.740 know that there was a pro-protein convertase. So, when they identified that family in France,

01:37:17.700 they partnered up with Nabil Seda, who is a world-renowned scientist on pro-protein convertases,

01:37:24.100 and they mapped it to NARC1, which eventually became PCSK9. So, the way PCSK9 works is that

01:37:33.020 it's a regulator of the LDL receptor. So, when the cells make an LDL receptor, it will also make PCSK9.

01:37:41.740 Now, PCSK9 can bind to the LDL receptor. That can happen inside the cell. And when that happens,

01:37:49.820 the LDL receptor gets degraded in the lysosome. That can also happen extracellularly. When the LDL

01:37:58.160 receptor, obviously in the hepatocyte, gets stuck at the membrane, but PCSK9 gets secreted. So,

01:38:04.060 you can actually measure PCSK9 levels in the blood. But when it gets secreted,

01:38:08.820 it can actually bind the LDL receptor. And when that happens, the LDL receptor cannot bind LDL

01:38:16.260 particles. And I told you earlier that LDL receptor density at the surface of hepatocyte is super

01:38:22.640 important for LDL clearance. So, because PCSK9 can be secreted, and by the time that they had

01:38:30.820 realized that, they had shown that there were actually families in Montreal that had gain-of-function

01:38:36.240 mutation in PCSK9 that had familial hypercholesterolemia. And then in 2006, the group

01:38:44.420 of Helen Hobbs at UT Southwestern had shown that there are common variants in PCSK9 that are

01:38:52.240 associated with lower levels of PCSK9, lower levels of LDL, and protection against cardiovascular

01:38:59.740 diseases. Now, the pharmaceutical industry didn't need much more information to develop

01:39:05.560 PCSK9 inhibitors, right?

01:39:07.920 And I remember that paper like it was yesterday. I mean, it's hard to believe it's been,

01:39:12.900 what is that now, 16 years ago. Makes me feel old.

01:39:16.820 I remember I was a master's student at the time, and we were witnessing that. And it was

01:39:22.020 a very exciting time.

01:39:24.020 Let me just make sure we synthesize that for people because it's such a big deal, right? So,

01:39:27.720 familial hypercholesterolemia is a very heterogeneous disease. There are at least

01:39:32.520 3,500 mutations that produce the exact same phenotype. Very, very elevated cholesterol.

01:39:40.240 These are patients that have total cholesterol, typically north of 300 milligrams per deciliter,

01:39:45.480 LDL cholesterol by definition above 190 milligrams per deciliter off therapy and often much higher.

01:39:51.880 This disease is unequivocally linked to accelerated ASCVD. And what was discovered in 2003 was yet

01:40:01.960 another gene that was associated with it. But what made it different is most of the genes,

01:40:08.320 not all, but most of the genes associated with FH directly involve the LDL receptor.

01:40:12.680 This one didn't seem to. Instead, they discovered that it was this protein that wreaks havoc on the LDL

01:40:20.540 receptor when it's overexpressed, either by degrading the LDL receptor in the lysosome before it gets

01:40:26.480 brought to the surface, or frankly, just interfering with the receptor when it's at the surface.

01:40:31.820 Does PCSK9 also degrade LDL receptors or increase their turnover when they are at the surface of

01:40:39.700 hepatocytes? That's exactly what I was going to say. That's the third mechanism through which

01:40:44.400 PCSK9 can influence LDL receptor density. Because what people don't really appreciate is that the

01:40:51.360 LDL receptor, when it does its job of bringing LDL particles within the hepatocytes, gets recycled

01:40:58.540 at the surface of the hepatocyte. And that can happen a hundred times in the life of the LDL receptor,

01:41:04.840 because it takes a lot of energy to the cell to produce the LDL receptor. And once a PCSK9 is bound

01:41:13.000 to an LDL receptor, then it prevents its recycling. So the cell has to make more LDL receptor. And when

01:41:21.480 it does that, because they're under genetic control of the SREBP2 transcription factor, so then the LDL

01:41:28.600 receptor gets produced, and so is PCSK9. So you can have this vicious cycle.

01:41:35.120 And it's interesting to think that if the story had stopped there, it's not clear we'd be where we are

01:41:40.500 today without the 2006 paper, which showed, wow, as bad as that gain of function is, the loss of function

01:41:49.300 is really amazing. Where now you found these people who had the opposite of FH. These are people who were

01:41:56.600 basically missing their PCSK9, not completely, just significantly underexpressed. And these were

01:42:02.540 people that as adults walked around with neonate levels of LDL cholesterol, 10, 20, 30 milligrams per

01:42:11.720 deciliter. Yeah. So the most frequent variant that they look at was present in 2% of the population,

01:42:17.980 and they saw very mild LDL reduction. So 20% reduction in LDL, but it's a lifelong reduction, right?

01:42:26.020 That's right. The MR would still suggest that that's beneficial.

01:42:29.600 Exactly. But there has been some studies on, as you say, individuals that have virtually no LDL because

01:42:37.020 they have no PCSK9, really. And they don't have, of course, atherosclerotic cardiovascular disease

01:42:43.660 because you need LDL for that, but they're perfectly fit, you know, doesn't influence reproduction or

01:42:50.240 hormones or anything. Exactly. No increase in the risk of other diseases. So they have normal risk

01:42:55.860 for cancer, Alzheimer's disease, every other disease, and they just don't have the risk of

01:43:00.400 ASCVD. And their LDL cholesterol is 10, 20 milligrams per deciliter. Very important teaching

01:43:06.420 point here, I think, for the listener, which is it might be tempting to say, how can someone

01:43:11.440 with such little cholesterol in their plasma not have other problems when we understand the importance

01:43:19.480 of cholesterol in creating lipid bilayers of cells and being a precursor to steroidal hormones?

01:43:27.020 And I addressed this in a previous podcast, but I think it's worth stating this again.

01:43:30.900 When you look at how much cholesterol is in the body and isolate that fraction, which is in the plasma,

01:43:37.720 even if you take that to zero, you've maybe reduced the total body pool of cholesterol by about 10%.

01:43:47.040 And there's still some cholesterol in the blood, right? Because the liver will secrete very low

01:43:53.140 density lipoproteins that will not necessarily be targeted by PCSK9. So you have to make the

01:43:58.780 distinction. And there's high density lipoprotein as well. So you still have a total cholesterol

01:44:03.800 that might fall from 180 milligrams per deciliter. It might fall to 70 milligrams per deciliter or 60

01:44:12.860 milligrams per deciliter, but it's not zero. You're right. The point is you still have so much

01:44:18.600 cholesterol in extra ApoB tissue, right? The red blood cells, all of the tissue, the hepatocytes,

01:44:24.940 et cetera. We're seeing that also in the trials because, well, obviously the industry developed

01:44:31.100 antibodies, monoclonal antibodies against PCSK9. And these have been tested in two large cardiovascular

01:44:37.340 outcomes trials. And they've shown that if you reduce LDL through these PCSK9 inhibitors, you get

01:44:44.040 a reduction in cardiovascular events. And now in these trials, now these were all patients that were

01:44:50.200 already treated with statins. And you add on to that a PCSK9 inhibitor, and you really bring

01:44:57.500 LDL cholesterol levels to the floor. And in post-doc analyses of these trials, you can see that the

01:45:06.180 benefit was also correlated with the reduction in LDL levels. So patients that had the lowest LDL levels

01:45:16.080 had the lowest risk of having a second event. I say second event because these trials were done in

01:45:21.980 patients with stable CAD and also acute coronary syndrome. So it really tells us that we haven't

01:45:28.740 identified yet the level of LDL that's so low that it's going to harm any physiological or disease

01:45:36.280 process. It's such an important point. And again, I think, you know, you're referring to Fourier and

01:45:41.440 Odyssey. I got to tell you, this is one of those beautiful moments again, where I was a little worried

01:45:48.180 that Fourier and Odyssey were not going to be positive trials, especially Fourier. Because

01:45:52.940 you'll recall Fourier, the patients had an average starting LDL cholesterol in the 70s. I can't remember

01:46:01.160 if it was 71 or 77. I think the mean was 90, and they brought it back down to 30 milligrams per

01:46:07.740 deciliter. Oh, was the mean 90? I thought the mean at the beginning was in the 70s, but I could be wrong.

01:46:13.000 There was not an entry level of LDL. Sometimes you see that in these kinds of trials,

01:46:17.880 you have to bring the LDL down to a certain level, but that was not the case. So they were

01:46:22.160 just being treated with a standard of care, which is obviously a high-intensity statin.

01:46:27.640 Yeah. So these were on very high doses of statins. So if they came in on a statin maximally and their

01:46:34.400 LDL was 90, that's still very low. That still puts them at the 10th percentile. I thought it was 70,

01:46:41.280 so that would have been at the 5th percentile. But the point is, when patients come in and they

01:46:45.760 already have such a low LDL, you add a drug that lowers them to the 30s, but the trial was only five

01:46:53.020 years. And my thought was, there's no way in five years that's not long enough to see a benefit when

01:47:00.760 the patients are starting out so low. And that turned out to be wrong. So the trial was supposed

01:47:07.320 to last five years, but they saw a benefit at 2.2 years. That's right. It was 2.2 and Odyssey was

01:47:15.040 2.4 years or something. Exactly. So basically they stopped the trial when they knew they had

01:47:20.580 an effect. But when the trial was published, that was in 2017, I think. August of 15, I think.

01:47:29.300 Okay. Well, that long. Okay. Well, there had been postdoc analyses from phase three trials that were

01:47:34.880 very positive in the New England Journal. I don't know if you're referring to these papers, but

01:47:39.500 anyway. Sorry. Yes. I'm referring to the FDA approval, which was on the earliest analysis,

01:47:45.260 which was August of 15. Obviously subsequent analyses came after. But I believe at that point,

01:47:51.160 you had the 2.2 and the 2.4 year data because basically Repatha and Proluent were approved within

01:47:57.980 a month of each other, if my memory serves me correctly. Yeah. Based on their LDL lowering and not

01:48:03.220 necessarily on their effect of cardiovascular disease. So I was actually very surprised because

01:48:08.660 in that trial, the relative risk reduction, if you compare PCSK9 with placebo, was only 15%. So people

01:48:16.320 were kind of expecting like a 20 plus percent reduction. And many people were kind of disappointed

01:48:24.500 by that. But I mean, it happened over 2.2 years only. So that's what's underappreciated.

01:48:31.400 I can't remember if I wrote a blog post about this. And if I didn't, I'm sure I wrote it in an email

01:48:37.840 to a friend. And I hope I could find that email. But it was a friend of mine who worked at a hedge

01:48:42.640 fund. Yeah. So it must've been an email. I don't think I wrote a blog post. He said, because you

01:48:46.980 remember Amgen's price, share price decline with those results. I think it was because they didn't

01:48:53.780 hit the relative risk reduction. It was so modest. And I said to him, that tells me Wall Street doesn't

01:49:00.620 understand atherosclerosis. If you can hit a 15% relative risk reduction, which ultimately turned

01:49:08.700 into a bigger risk reduction in 2.2 years on a group of patients who show up on the maximum dose

01:49:17.080 of a statin whose LDL is already at the 10th percentile, you've changed the field of cardiovascular

01:49:22.900 medicine. I completely agree. And I remember thinking this, that if they really wanted to make

01:49:28.620 a trial to increase their stock price, they would have made it the full four years, right? Because

01:49:34.900 then you would have seen the biggest increase. Because if you look at the Kaplan-Meier curve,

01:49:38.720 they're still going in opposite direction. They haven't stabilized. And I talked earlier about the

01:49:44.720 cholesterol treatment trial is curve. The data from the Fourier and Odyssey trial, they fall exactly on

01:49:51.880 the same curve where you're looking at achieved ApoB levels and reduction in event. It's right there.

01:49:57.540 At the lower end of the curve, of course, because that's a trial in which they saw the biggest

01:50:01.580 reduction in LDL ApoB.

01:50:04.220 So let's go back and close the loop on one thing before we now talk about PCSK9 and LP little a.

01:50:09.260 So you've explained now why a PCSK9 inhibitor, the drugs we're talking about, are so effective in

01:50:15.000 lowering ApoB because they're basically mimicking the most extreme loss of function of this gene.

01:50:21.460 You're taking away that protein that does those three things to reduce LDL clearance.

01:50:29.960 Why is it, remind us, that statins don't lower LP little a? You would think, well,

01:50:37.120 we know why statins get the LDL receptor to be more dense. That should do it. So the obvious

01:50:43.440 explanation here is LDL receptors don't clear LP little a. But why is that? Isn't an LP little a

01:50:50.260 just an LDL with a little extra thing on it? Why is that causing so much difficulty for the statin?

01:50:57.800 I told you earlier that LPA levels were determined by their rate of production. And one of the players

01:51:04.460 that was an unanticipated player in LPA slash ApoA production is actually PCSK9. Because if you

01:51:13.300 incubate liver cells with PCSK9, you'll see the expression of ApoA going up. And in lipoprotein

01:51:20.380 turnover studies, you also see that. So if you treat people with PCSK9 inhibitor, you will actually

01:51:28.980 see a reduction in the production rate of ApoA. And there was a nice study that's a bit complex to

01:51:36.340 fully appreciate by Gerald Watts, who's in Perth, Australia. He's shown this, but he also showed in

01:51:43.480 a second group that if you treat patients with a PCSK9 inhibitor and the statin, you see, and that's

01:51:51.680 probably where the LDL receptor presence gets maximized at the surface of the liver cells.

01:51:58.000 You can actually see clearance or increment in the fractional catabolic rate of LPA. So there's still

01:52:04.040 so much that we don't know in this area. And it's not totally clear why we see this difference of

01:52:12.660 PCSK9 inhibitors. That's depending on whether or not you're treated with a statin.

01:52:18.120 And I think all comers, we see that a PCSK9 inhibitor is lowering LPA by about 30% is the on

01:52:25.200 average. Yeah. And so the average is probably between 25 and 30% in all comers.

01:52:31.940 But the variability is enormous.

01:52:34.640 Exactly. The variability is very important. And it's another example where we need to study

01:52:41.760 patients that have high LPA because these are the patients that we want to provide an answer to.

01:52:47.340 And there's only been one trial that had tested the effect of a PCSK9 inhibitor in patients with LPA.

01:52:55.300 There have been sub-analyses in Fourier and Odyssey outcomes. And when you look at that trial,

01:53:02.420 it's called the ANICHCO trials. And all these post-doc analyses of randomized controlled trials

01:53:08.360 of PCSK9 inhibitors, you see that in patients with high LPA, the reduction is approximately 15%.

01:53:16.400 So it's not spectacular. And in the ANICHCO trial, what they did is that they've looked at arterial

01:53:25.520 wall inflammation using fluorodeoxyglucose. This is a trial run by Zahi Fayyad at Mount Sinai in New

01:53:32.960 York and Erextrose in Amsterdam. They showed that even though you reduce LDL by, I don't know what

01:53:39.860 percentage, but it was a spectacular reduction in LDL. Very small reduction in LPA of 15%.

01:53:47.140 You don't see any effect on arterial wall inflammation. So that means that, you know,

01:53:53.600 there's an important residual risk that's associated with LPA because if you lower LDL

01:53:59.200 with PCSK9 inhibitors, you know, there's no outcomes data, although they did link LPA with

01:54:04.960 recurrent cardiovascular disease. In these trials, you see that the pro-inflammatory effect

01:54:10.840 of LPA on the vasculature still remains. So we're going to have to go after LPA, even in patients that

01:54:18.280 have very low levels of LDL. There's no doubt about it. Is one interpretation of the fact that

01:54:24.640 PCSK9 inhibitors can lower LpA by 30%, but that might not be sufficient to ameliorate the LpA risk

01:54:32.480 specifically, is that it's just simply not enough. It gets back to what you said earlier.

01:54:37.440 You're going to have to eliminate LpA and it becomes a bit more of a step function than the

01:54:44.280 gradient we see with ApoB. I don't know if we need to eliminate LpA, but we need to take a higher LPA

01:54:51.600 level and bring it down to a lower level. Yeah. So that brings us to where we are today, right? So

01:54:57.480 what's the state of the art today? In 2022, with my patients who have elevated LpA, I take a two-prong

01:55:05.720 effect when it comes to lipid management. Obviously, there's many things we're doing outside of lipid

01:55:10.040 management. The first is absolutely eradicating ApoB. So we're very aggressive on this because

01:55:16.820 it's very clear that you can do this safely and effectively. We target an ApoB of about 30 to 40

01:55:22.820 milligrams per deciliter. So we target an ApoB at what we would call a physiologic level. So the

01:55:28.560 level that a child would have. It's clear that a child can have an ApoB of 30 and have no problems

01:55:35.680 with development, which is the most cholesterol demanding period of their life. So there's

01:55:39.740 absolutely no reason that we shouldn't be able to take an adult there without side effects, meaning

01:55:44.660 provided we can do it without side effects from the medications. But the second thing we do is we're

01:55:48.280 very liberal in the use of PCSK9 inhibitors because even though we don't know the answer yet, our belief

01:55:54.500 is even if it waxes at 30%, which is about what we see, we see on average about a 30% reduction in LpA,

01:56:01.640 it's worth it until we get to antisense oligonucleotides. So let's talk about antisense

01:56:07.940 oligonucleotides. What are they? Before we get into that, I'll tell you that I do the same thing. I mean,

01:56:13.540 I'm going to turn 40 this year. So I decided to have a lipid check and have my LPA remeasured and

01:56:21.200 it's very high. It's at 200 nanomolars. I knew that because I had my genotype done with direct

01:56:27.880 to consumer company and they let you look at your own data. So they'd send you all of your SNP

01:56:33.220 information. So I went and looked at my favorite SNP in LPA and I was a carrier of one of the most

01:56:39.360 famous variants in LPA. And that's exactly what I decided to do. So my LDL was a bit higher than

01:56:45.700 average. My LPA was high. So I just started to take a statin. And of course, I've been on a close

01:56:52.060 to vegetarian diet for more than three years. I'm physically active, but at some points you have to

01:56:58.240 look at your labs and say, well, I need to do more. So even I started taking a statin, even though I'm not

01:57:04.620 40 yet, because I see those studies and I see the importance of going after LDL very early and

01:57:12.520 very aggressively. Now I'm not on a super high dose. I need to check it after three months, but if it

01:57:17.680 doesn't go down, I'll increase the dose. And that's, I think, what people who have high LPA should do.

01:57:23.880 So coming down to the antisense oligonucleotides against LPA. This is a very exciting time for LPA

01:57:30.620 research. So the, probably the first horse in the race will be the compound by Ionis Pharmaceuticals.

01:57:39.160 So it is an antisense oligonucleotide against the LPA gene. Well, all of them will be. And the second

01:57:48.200 one is, and they just released some data on this in the, in nature medicine a couple of months ago,

01:57:54.480 and it's called Olpaciran. It's not an oligonucleotide. It's an SIRNA against LPA. It's the compound by

01:58:02.920 Amgen. And I believe they'll need to do a phase three trial, but with the first one, with the Ionis

01:58:09.760 compound. And Ionis is the company that used to be called Isis, like before it became horrible to

01:58:14.760 have the name Isis. It's a San Diego based company. I remember I used to swim with a guy who worked there,

01:58:18.780 his duffel bag, which was from works at Isis on it. And I was like, yeah, you're probably going to 0.82

01:58:23.940 want to change that. Yeah. You can't board a plane with that. So, so yeah, so they already have phase

01:58:32.900 two data that's been published in 2020 in patients with atherosclerotic cardiovascular disease,

01:58:39.120 a very nice dose ascending study. And they've shown that in the dose that they're going to use in their

01:58:45.180 trial, which is a monthly injection, you can get mean reduction of LPA levels of 80%, even in patients

01:58:55.120 with high LPA. So that's very encouraging because this is what we're going to need to prevent heart

01:59:02.320 attacks and obviously to have successful cardiovascular outcomes trial. And in that study, they also showed

01:59:08.600 that 90% of patients who were treated on that dose had LPA levels below 50 milligrams per deciliter. So

01:59:17.640 it's very potent. It's a second generation antisense oligonucleotide. And they have launched a trial,

01:59:26.260 a cardiovascular outcomes trial that's called Horizon. And they're recruiting a little under 8,000

01:59:34.160 patients with stable cardiovascular diseases, and they will study the effect of LPA in their

01:59:42.320 antisense oligonucleotides in the prevention of major atherosclerotic cardiovascular events.

01:59:50.580 And is this a secondary prevention trial?

01:59:52.600 It is a secondary prevention trial. So this is where you have to take the patients that have the highest

01:59:57.460 risk to have a positive trials. To my knowledge, there's no plan for a trial in primary prevention,

02:00:04.320 but that will eventually have to come.

02:00:06.600 That will be the off-label use. Do you have a sense of how far they are in their enrollment? Because

02:00:10.960 this trial, and maybe it's just because of how emotionally invested I am in this, I have a normal

02:00:16.640 LP little a, but it's just, I think I take care of enough patients that don't. This trial feels to me

02:00:21.520 like the molasses rolling uphill in January trial. And as a Quebecois, you can appreciate the speed

02:00:27.700 with which molasses will roll uphill in January. What is taking so long? This is a trial that feels

02:00:35.560 like it's a year away from being completed every year for the past seven years.

02:00:40.960 Yeah. Well, first of all, being an investigator in a research center at times of COVID was very,

02:00:49.260 very difficult to bring people into the hospital for an exploratory trial. So I don't know for that

02:00:58.180 specific trial, but I can tell you for any lab or any clinical research facility, any patient that

02:01:06.120 were recruited, and especially in our hospital, we're the COVID hospital for the entire region.

02:01:12.240 So people don't want to come here during pandemic. So I'm thinking that this is probably part of the

02:01:19.080 explanation. So we'll have the result of that trial probably in 2025. Because I told you earlier,

02:01:26.360 that trial is going to be 8,000 patients. When I saw that, I thought, well, this is not enough. I mean,

02:01:33.280 they need to do a big trial. And this is kind of risky to do a trial in only 8,000 patients. But

02:01:39.440 the way I understand it is that they're going to use the full four years of their treatment period.

02:01:46.260 So even though you have less patients, and for instance, Fourier or Odyssey outcomes that have

02:01:51.860 north of 15,000, so they're recruiting half for the roughly the same population. So they're going

02:01:58.080 to study it for a longer period. So that might also explain why it's not going to be published

02:02:03.940 anytime soon. And we need to be patient. And I'm really looking forward to seeing the results of that

02:02:09.700 trial because they hold the fate of the entire field in their hands. So really looking forward,

02:02:15.080 especially for the patients. Really looking forward to seeing the results of that trial. And I hope

02:02:20.740 that there will be other companies. I know there's three companies that have antisense oligonucleotides

02:02:26.500 against LPA. So you have Ionis, which is partnering with Novartis for the trial. Amgen has one. And

02:02:33.500 there's also another SI RNA company called Silence Therapeutics that have an LPA inhibitor. I don't think

02:02:41.020 they have released their phase one study yet. But I think we'll see more and more of these companies

02:02:47.380 because there's still money to make, I think, in that area of residual cardiovascular risk, because

02:02:52.980 we can target LDL as low as we want. And there's still an underappreciated amount of residual risk

02:02:59.880 that's associated with different things with triglycerides, inflammation. But the first thing

02:03:05.980 that comes to mind to me is the risk associated with high LPA. It's an amazing decade we're in.

02:03:11.300 If in fact this study is published in 2025, you'll have exactly a decade between the approval of PCSK9

02:03:18.000 inhibitors and potentially the approval of this antisense oligonucleotide for LP little a. And

02:03:23.140 you could argue that those two things will have an outsized effect on human health. So Benoit,

02:03:28.940 I want to thank you very much for spending all this time with me today and by extension with all of our

02:03:33.740 listeners, this is such an important topic that I think of this almost as a public service

02:03:38.100 announcement. If you're listening to this podcast, there's at least a 10 and maybe a 20% chance that

02:03:43.920 your LP little a is elevated. You really need to demand that your physician checks this level.

02:03:50.780 We think that the milligram per deciliter mass measurement is probably sufficient. And if you're

02:03:56.760 elevated on that level, at least at this moment in time, the best thing that we can do is keep

02:04:01.860 ApoB as low as possible and manage all of the other manageable risk factors, hypertension, smoking,

02:04:06.920 insulin resistance, et cetera, that traffic with atherosclerotic cardiovascular disease.

02:04:11.460 The other thing I think we can, at least I would be comfortable recommending, I know you're not a 1.00

02:04:14.880 physician, so you probably wouldn't be comfortable making a recommendation. I would also insist that

02:04:18.700 you at least once have an echocardiogram to look for even the earliest signs of aortic stenosis

02:04:25.960 business as it is imminently more treatable and the outcomes are better if it is addressed earlier.

02:04:31.620 Well, thank you, Peter, for having me and thank you for raising awareness on LPA. It was a real

02:04:35.840 pleasure talking to you today.

02:04:37.420 Yeah, the pleasure was mine. Thanks, Benoit.

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The Peter Attia Drive - June 13, 2022

#210 - Lp(a) and its impact on heart disease ｜ Benoît Arsenault, Ph.D.

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