This episode is a deep dive into Lipoprotein a with Dr Steven Nissen from the Cleveland Clinic. He and Dr Nero discuss the genetics of Lp(a), its pathophysiology, current treatment strategies and research into lowering Lp(a) levels. This is a fascinating conversation that also discusses the role of coronary inflammation in the work of Dr. Paul Ridker as well as the role of CT angiography in future clinical trials.
This episode is a deep dive into Lipoprotein a with Dr Steven Nissen from the Cleveland Clinic. He and Dr Nero discuss the genetics of Lp(a), its pathophysiology, current treatment strategies and research into lowering Lp(a) levels. This is a fascinating conversation that also discusses the role of coronary inflammation in the work of Dr. Paul Ridker as well as the role of CT angiography in future clinical trials.
[00:00:00] Dr Thomas Nero: Good morning and welcome to Future Pulse. I'm Dr. Tom Nero. Today we're going to be talking with Dr. Steven Nissen about lipoprotein little a. Dr. Nissen is the chief academic officer at the Cleveland Clinic. He is the former president of the ACC. He has authored countless papers and is currently either the study chair or on the steering committee of four of the five ongoing lipoprotein little a trials. This is going to be a very deep dive into lipoprotein a, including its genetics, the pathophysiology, current treatment options for patients with elevated lipoprotein a, as well as the ongoing clinical trials. Enjoy. Good morning, and welcome to Future Pulse. Uh, good morning, Dr. Nissen. Thank you for joining us today.
[00:00:51] Dr Steven Nissen: It's my pleasure to join you and look forward to our discussion.
[00:00:54] Dr Thomas Nero: So we have a lot to talk about with lipoprotein little a, , I think it's finally getting on everyone's radar. , I initially started looking into this, uh, Almost exactly 30 years ago when I was doing some work at the university of Chicago.
It's been, , a long time coming. , and for everyone out there, , just to get background on all of this, , the ESC document, by Kronenberg was an excellent review and there's been a number of reviews. It seems like every week there's another paper, including the one that, uh, you wrote recently on Lepodisiran.
Dr. Nissen and the other one on the , oral LPA antagonist with Dr. Nichols. So I would have everyone take a look at those.
[00:01:35] Dr Steven Nissen: Silence.
[00:01:50] Dr Thomas Nero: of increasing atherosclerosis, inflammation, and thrombosis.
, but yet right now we don't seem to have a effective treatment, although that's what we're going to be talking about today. , it also , seems to be involved in aortic stenosis, , which is a topic that I also want to get into. , but first we're going to talk, we're going to jump into the weeds here a bit and talk about the genetics of LPA, , how it evolved.
It seemed to have evolved, Convergently along with the plasminogen gene, although it plays no physiologic function and seems to be related to both plasminogen as well as the SLC22A3 genes. From your background with this, how do you see the genetic background of this abnormality, how it sort of plays out in the way that we're looking at it, both for pharmaceutical research as well as clinically?
[00:02:40] Dr Steven Nissen: Well, first of all, , thank you again for, , inviting me, the. Genetics are actually interesting. First of all, we believe that the gene, most people believe the gene evolved out of our ancient ancestors in Africa. If you follow where the gene is most present, it actually proximity to the diaspora, to the movement , of ancient humans out of Africa is a pretty good predictor of the levels.
So in the middle East, it's higher. The farther away you get from Africa, the little bit less you see, although it is certainly global. It is in about 20 percent of the population. If you use a cut point of 60 or 70 milligrams per deciliter or around 150 nanomoles per liter, you're going to see this in about 20 percent of the population.
You will see it in more people. With coronary disease, which of course is why, how we begin again to understand it as a risk factor. It is just a terrible problem that it is not being measured. I published in, uh, in Heart, a manuscript where we studied LPA globally in 48, 000 people. And they all had coronary disease.
They all had atherosclerotic cardiovascular disease. And only 13%. had had an LPA level obtained by their physician. And we're talking about it in virtually every country in the world. It wasn't any better in the United States than it was anywhere else. So it's really a huge problem.
[00:04:24] Dr Thomas Nero: Yeah, we do seem to be behind globally on, , the LPAs that we're drawing here. , I think that the, , ESC guidelines recommending that it be drawn at least once in a lifetime in patients is a very
[00:04:35] Dr Steven Nissen: Good, good guidelines, good guidelines. Now the genetics here. , so both genetic alleles contribute. So here's the way to think about it. , You could get an allele from one parent that, , is associated with high levels. , you can get an allele from both parents. So , your, plasma levels relate to what you get from both alleles.
So. You know, clearly you could have two parents that have moderate levels, and then your effect is going to be higher. You're going to have an additive effect. So the genetics are complicated, but they're clearly there. Now, there's been some interesting work done recently on concordance among relatives, and it is really quite interesting.
But if you take, uh, somebody with a high LPA level and you take first degree relatives, you're going to see about 50 percent of them will actually have. If you go to second degree relatives, about a third will have elevated LPA levels. So it's important for everybody to recognize that when you find an index case, somebody with very high levels, When I see them, the first thing I do is to have your first degree relatives, your children, parents, sometimes, uh, siblings.
Have they been tested? They often have not been, and I know you know what's, what's coming is if they get tested, you find out they may even have levels that are higher than the levels you see in the, in the patient you see with the disease.
[00:06:24] Dr Thomas Nero: And in a little bit, we're going to get on to how we approach that, because that's been one of the, um, big barriers for people being tested is that they just don't know what to do with the information and they're concerned about. Well, now that I know now, what do I do? Although I do think that there's, there's some, there may be some clear answers to that.
[00:06:41] Dr Steven Nissen: Yeah, there are.
[00:06:42] Dr Thomas Nero: So as far as the alleles are concerned, it's interesting. So one allele increases your risk by about 50%. Two alleles increase your risk up to 2. 5 times your baseline risk. , but then when you look at those alleles, you look at the genetic variants, , and genetic risk scoring, and it doesn't seem to increase your ability to, , diagnose outcomes or diagnose risk beyond the LPA level.
, so beyond our purely research question, do you think there's importance for clinicians, , to be looking at genetic variants specifically.
[00:07:15] Dr Steven Nissen: I don't think so. I think right now we would be delighted. If we could just get people to measure serum and plasma levels in patients and what you said, I completely agree with that. Getting it once in a lifetime. I tell people, you know, look, you know, your early 20s or whatever, get, get your level tested and then don't get it again.
And I'm always seeing patients referred to me that I've had. Have it done five times. Every time they come in for a lipid panel, they get an LP little a well, it doesn't change. So, you know, you don't need to get it over and over again. Just get it once. That's
[00:08:18] Dr Thomas Nero: both which are associated with a little bit different risks as far as thrombosis versus atherosclerosis.
And, you know, the, the paper's a little, uh, a little wonky, even more wonky than this conversation.
, so back to the LPA particle itself, , it's made up of a protein that's bound to APOB. Um, it has a number of Kringle formations and those Kringle formations are part of what.
Mimics the plasminogen. , and that , the main size of this LPA, , is associated with the Kringle 4 repeats.
[00:08:50] Dr Steven Nissen: right.
[00:08:51] Dr Thomas Nero: Talking about that specifically, because I found this very, very confusing. The number of Kringle 4 repeats is actually inversely proportional. To the mass that we're seeing.
[00:09:02] Dr Steven Nissen: That's right. Yeah, both mass and concentration. And by the way, we need to have an understanding here about what we're measuring. So, two unit systems are used, as I think many people know. Mass units, which are milligram per deciliter and concentration units, which are nanomoles per liter. Virtually everybody who works in this field believes that concentration measurements are better, but that's not what happens.
I mean, in our hospital, we're measuring milligrams per deciliter. The conversion is not a perfect calculation, but on average, and this is based upon the 48, 000 people that I studied. The ratio of 2.45 to one is about the average, so that if you're at a hundred milligrams per deciliter, then you're gonna be about 2 45, uh, for your nano moles per liter.
This happens to me all the time. I get patients from all over the world, set up a virtual appointment with me or whatever, and I, I see them and they say, my. My LPA level is 200 and they don't tell me what it is. They don't tell me, they don't know whether it's milligrams per deciliter or nanomoles per liter.
And so I think it's important for all of us to, to start to think alike about this. And we got to get people to switch to concentration.
[00:10:32] Dr Thomas Nero: And as a sidebar, would you also recommend that for LDL measurement? We've moved over to using, to looking at a lot of LDL subparticle, uh, formations and subparticle numbers. I know in Europe that they're using a lot more in nonamoles per liter.
[00:10:45] Dr Steven Nissen: Yeah, I, I am vehemently against measuring particle numbers in it with LDL, uh, mainly because we don't have the data. Uh, to suggest that targeting. those numbers make a difference. What we do have pretty good data for is ApoB. So I was off topic here today, but I think if you're not sure measure ApoB, don't spend all the money on the NMR particle.
[00:11:15] Dr Thomas Nero: Yeah, I do. I do think that in the future as, as, as our research does develop, that we should be using APOB as the target for the outcomes of the trials are rather than just LDL measurements. So , we were talking a little bit about. The fact that LPA has a number of different pathologic mechanisms, pro athelosclerosis, pro inflammatory, and prothrombotic.
, so if you don't mind just going in a little bit on your view of , what about this particle makes each of these pieces individually. Important
[00:11:46] Dr Steven Nissen: Well, I think, you know, most people believe, and again, there's still evolving research here, that , what we really have is a particle that has ApoB LDL and has ApoA. And most people think that the APOA is pro thrombotic and, uh, in part, by the way, there is some evidence that even deep venous thrombosis is increased in people with high LpA, which is another piece of evidence that it is a pro thrombotic particle.
The APOB component, which is really LDL. is very atherogenic. We talk about atherothrombosis. And so here we have in a single particle, something that is pro atherosclerotic and pro thrombotic together. And that's clearly one of the reasons why it is so risky.
[00:12:41] Dr Thomas Nero: And part of the, , increased athero atherosclerosis portion appears to be because of increased oxidative phosphorylation of the ApoB. , and whether or not there is a, it is promoted directly from the LPA portion, , or is it because of some other co-promote? , do you have any sort of thoughts about that?
[00:13:03] Dr Steven Nissen: Yeah, I really don't, you know, for me. The, the, the questions that we're really going to try to answer here, that is the pivotal question, which is not how does it cause disease, but can we modify outcomes? And that's an unanswered question. Uh, there is no really good evidence one way or the other. Uh, we're doing multiple trials.
The first to report will be the trial with an antisense. oligonucleotide. Now, Pelacarsin, this is a Novartis drug actually developed by Ionis Pharmaceuticals in California and acquired by Novartis. And that trial is currently scheduled to end sometime next year, whether it does or doesn't, of course, with event driven trials, you end when you get the number of events that you need, but we're, we're closing in on getting an answer.
For the first of these drugs to actually have an outcome trial.
[00:14:06] Dr Thomas Nero: And hopefully that will be followed by the Olpasiran trial, which will, I think, is going to hopefully end in 2026, uh, and
[00:14:14] Dr Steven Nissen: I think that's very, very doubtful based upon the design.
[00:14:18] Dr Thomas Nero: then the Lepodisiran trial, , which is going to be, , beginning, , in the spring. So, uh,
[00:14:24] Dr Steven Nissen: It's moving along.
[00:14:25] Dr Thomas Nero: , and then there's the oral, , medication, , is that yet going towards phase three or are they
[00:14:31] Dr Steven Nissen: It's in, it's in phase 2 and phase 2 will be, we will see data from phase 2 relatively soon. Um, and, uh. That will be very interesting. Now, there's a little bit , of a wrinkle here, , in the drug, the oral drug, Muvalaplin, because, , the current assays for lipoprotein A are actually measuring ApoA and what happens with Muvalaplin is it prevents the association.
There's a, there's a disulfide bond between the lipoprotein. the APO A and the APO B components of the particle. Well, if you prevent that association, then you have some free APO A around, and you're measuring that. And so, and so the effect size for Muvalapin is probably substantially larger than what we reported in the JAMA manuscript, because We're going to need a different assay in order to understand how much muvalapalin actually reduces a lipoprotein.
[00:15:46] Dr Thomas Nero: And for the Muvalapin, , , I believe that that study showed that it had a, was it a 60 percent decrease in the,
[00:15:53] Dr Steven Nissen: you know, it depends on when you look. It was a very short term trial. It was still going down, you know, so, you know, there's lots of uncertainty based upon phase one. for the Muvalaplin trial that will be considerably clarified by phase two, and that could then ultimately lead to a decision to proceed with phase three.
[00:16:16] Dr Thomas Nero: And so the, uh, Pelacarsin is also a, um, uh, SAO, an antisense oligonucleotide, and what is its target?
[00:16:26] Dr Steven Nissen: Its target , is the intact, lipoprotein A particle. It's basically preventing, , the, , translation, , by interfering with messenger RNA for ApoA. And, uh, all of the, uh, therapies other than muvalapalin work by a relatively similar mechanism. Now, Antisense Nucleotide is a single stranded, DNA.
It gets into the liver because it's associated with asialoglycoprotein, or GalNAc and GalNAc. There's a receptor in hepatocytes, the a asialoglycoprotein receptor. And so what happens is it's administered subcutaneously. Uh, it is DNA based, short segment of DNA with GalNac. It gets taken up rapidly by the liver in the hepatocytes.
It interferes with translation and APOA isn't formed. You don't form APOA. You don't make that particle, which is APOA plus APOB. And so it lowers levels. And in phase 2, New England Journal of Medicine, NICE paper by Sam Samikis, uh, 80%. And obviously, that's a very substantial reduction. Uh, and the question is.
What will happen when we do that to patients with, , previous atherosclerotic vascular disease
[00:17:58] Dr Thomas Nero: Yeah, certainly the development of GalNAc to bring it into the hepatocyte was really a dramatic improvement because what before that. You know, the amounts of drugs that you had to get in order to get a clinical response was so much greater and had so much,
[00:18:10] Dr Steven Nissen: was as much as 30 fold greater. I mean, we're talking about an enormous breakthrough, you know, about 10 years ago, the understanding that you could get, and it's going to be, by the way, be involved with CRISPR and all these other. approaches. And we, we may not get to it, but you know, there are CRISPR based approaches to taking on this disease, which are pretty exciting.
[00:18:35] Dr Thomas Nero: well, , I can save some time for that regardless, , , so, , Olpasiran and Liepodisiran uh, are smaller fearing RNA molecules, which , of the RNA, , variants of the gene variants, are they associated with it?
[00:18:48] Dr Steven Nissen: Yeah, it doesn't have, the gene variants don't seem to make any difference at all. Um, because basically what you're doing is you're interfering with Translation . Now this is a double stranded RNA. I usually it's a small segment anywhere from 19 to 23 or so nucleotides and each of the therapies are different.
Um, and there is. There are three of them. There is Olpasiran, Zerlasiran, uh, and Leopdisiran. Zerlasiran formerly known as SLN 360, being developed by a British company known as Silence Therapeutics. And they all work by essentially the same mechanism, although they're different in how they're structured.
They get into the phytocyte, , they form, what's known as a RISC complex, an RNA induced silencing complex. Where they essentially result in the degradation of messenger RNA for APOA, but they are able to then recycle in such a way that each of those, , short interfering, , RNA segments can then go on and interfere with another messenger RNA.
So the durability is a, is somewhat longer than it is for an antisense nucleotide. Uh, Olpasiran is given, I think, uh, every, uh, um, is it 90 days? Is is that, is that
[00:20:19] Dr Thomas Nero: I believe it's every 90 days.
[00:20:21] Dr Steven Nissen: 90 days? Yeah. , I'm not involved in that trial. , we did studies or Zerlasiran and we saw, you know, 80 plus percent reduction out to 150 days after single doses and Lepodisiracin had a very prolonged duration of action for very specific reasons.
Uh, so that at 48 weeks, nearly one year levels of LP little a, we're still 94 percent below baseline. So a very, very durable response. The duration of the response for each of these drugs is different. And the reasons why are not a hundred percent clear, but, um, Lepodisiran, uh, the nucleotides are extensively modified.
They're fluorinated and methylated, and they have other changes. that make them more resistant to ribonucleases. And so they're not degraded, uh, nearly as quickly. And so that, I think probably is the reason why their duration of action is longer. , but they're all, , look, Pellicarson's once a month.
Um, you know, Passerin every three months, uh, Lepodyserin longer yet. Um, I'd be happy with any of them working. And what I tell people is that, look, we have multiple shots on goal and we hope that one of them ends up in the back of the net. Maybe they all will. Silence.
[00:22:11] Dr Thomas Nero: the mechanism is, as long as they, , decrease LPA.
And as long as that is then associated with decreased, , event rates. We were talking about the possible mechanisms of action of LPA. And one of the things that has been discussed, , was the pro inflammatory effect of LPA and whether it has a direct pro inflammatory effect or whether the pro inflammatory effect really is about the atherosclerotic effect , and what is happening Within that atherothrombotic, , milieu,
[00:22:46] Dr Steven Nissen: , it's a chicken versus egg argument, you know, and, uh, by the way, this has gone on for CRP forever and ever and ever, , you know, I'm very close relationship with Paul Ritker, who really deserves a lot of credit for advancing the inflammatory hypothesis that I think Russell Ross probably started with.
It's effect on atherosclerosis.
[00:23:09] Dr Thomas Nero: yeah,
, Paul is just an amazing guy. . I did a podcast with him, uh, about six months ago. , talking about some of the new stuff that he's doing, which is really exciting. He's just, yeah, fabulous, fabulous
[00:23:19] Dr Steven Nissen: Yeah. He's just a wonderful physician scientist and I work closely with him and have. Publish with him on many occasions. But you know, the argument of course is that, does, does atherosclerosis occur and then that causes an increase in CRP or is CRP somehow independently produced and then it's causal?
Um, I'm with Paul. I think it's causal . I don't think it's secondary. Um, and I think it's important, , now , whether lipoprotein A's effects are mediated by inflammatory responses is really quite unknown, and we'll only find that out when we get these big trials done and we see what happens to inflammatory markers like IL 6 and CRP and CRP.
maybe even IL 1 beta. And then we do a mediation analysis. , we did that for statins. Paul and I each did one, published back to back in the New England Journal of Medicine a long, long time ago in a galaxy far, far away, um, in 2005. Um, and we thought, we thought this was a causal effect on, on atherosclerotic outcomes.
So. We'll find out and we'll hopefully be able to do those kinds of analyses. What you're going to see now when these trials end is a huge amount of secondary analyses, which we have to be careful about because of course they're not the primary endpoint. But we'll look at who benefits, who doesn't, maybe a little bit about how that benefit, if it is there, how it's mediated.
There's a lot to learn here. There's going to be as much as we've seen in the last few years. There's going to be an explosion of knowledge as each of these trials end.
[00:25:23] Dr Thomas Nero: So one of the questions I had is whether or not they're going to be doing, , sub analyses, including CT and geography. , there's a couple that are ongoing right now,, which I think is going to be, , extremely important in looking at, um, plaque progression.
, and also looking at the, um, fat attenuation index or perivascular adipose tissue.
[00:25:42] Dr Steven Nissen: Yeah, , I don't know that there are currently regression, progression studies being done. There may be. I'm just not doing them, , with the, , therapies for lipoprotein A.
I wish that they would be done. Uh, as I think, you know, I did about a dozen of these studies with various therapies, some of which worked and some of them didn't with intravascular ultrasound. And I think we learned a lot from those studies and we've got the extensive array of publications on, you know, all the things that we learned.
And so, you know, disease progression, it would be important to understand the extent to which that is a, is occurring with lipoprotein A and to the extent to which it may be decreasing with therapies for lipoprotein A. We'll get there eventually. Um, but I think we've got to get the, the morbidity mortality trials done first.
[00:26:38] Dr Thomas Nero: , clearly the, , it doesn't matter what the plaque progression is, , the patients being alive or dead at the end of the day, patients having MIs at the end of the day, um, is, is going to be the important piece. And then we can, , sort them out afterwards.
Uh, but , it would be nice to have, , some way of knowing whether or not your therapy is effective, um, and looking at an intermediate level at like 18 months or whatever , and looking at plaque progression or, and, or inflammatory response is going to be.
[00:27:02] Dr Steven Nissen: and that's what we did with IVUS. I mean, we did 18 and 24 month length studies and we saw quite highly significant effects so that it's a way of getting some answers about some things a little bit more quickly. Um, understand now that the reason these outcome trials are being performed is that the regulators, uh, mainly the Food and Drug Administration, which, you know, is obviously rules in the United States, uh, it's very clear that they will not approve any therapy for reducing lipoprotein A without evidence of a morbidity mortality benefit.
And, uh, you know, I think that's wise. I think that's correct, you know, from a scientific and a regulatory point of view, but it means that it's a fairly high bar. We got statins approved because they lowered LDL. That was the reason in 1987 that Lovastatin was approved. We're not there with lipoprotein A and, and that's obviously raised the bar.
[00:28:10] Dr Thomas Nero: question of medical statistics is a , a multi year, , study, or at least a multi week seminar that we could do on, uh, the way that, uh, statistics are running clinical trials. And I'm actually gonna be doing a podcast tomorrow, with , Michael Gibson, , about , statistics in clinical trials and looking at different outcomes and, and outcome levels and how we're, how
[00:28:31] Dr Steven Nissen: well, that's world I live in every single day.
[00:28:35] Dr Thomas Nero: Um, so, um, so, uh, briefly, um, before we get back into the CRISPR question and some of the other things, um, where do you see the association with aortic stenosis and what do you think is the cause of the AS? We know that there seems to be some Homology between aortic stenosis and the development of atherosclerosis, , although that's never really been, , completely elucidated.
, because we do see that there's, uh, clearly an associated risk with elevated LPA and AS.
[00:29:04] Dr Steven Nissen: Well, there's no question that there's an increased risk, and it's not just that there's an increased risk of developing aortic stenosis, but the rate of progression of aortic stenosis has been shown in several pretty well done studies to be about twice the rate of progression. So, if you look at change in velocity or valve area, the change is Is accelerated, uh, in people with high lipoprotein a and someday we really want to do trials to see if we can prevent people with mild to moderate a us from progressing.
to the need for valve replacement. And that's going to happen. I'm certain it's going to happen. Uh, now we did that with LDL. There was a lot of evidence that high LDL was associated with AS and the trials were unsuccessful. Uh, so it's an uncertain pathway. But it is important to know that, uh, because if you measure lipoprotein A in people with severe AS as they are approaching need for TAVR or surgical aortic valve replacement, it's enriched in people with high lipoprotein A.
I mean, multiple studies show this relationship. How exactly it happens, , there is some uncertainty, you know, the role of oxidized phospholipids, uh, you know, all of this is. is speculative. And all we know really now is that there's a very strong association.
[00:30:43] Dr Thomas Nero: , but is there also an association with progression after valve replacement,
[00:30:46] Dr Steven Nissen: you're talking about , after surgery or, or TAVR.
[00:30:49] Dr Thomas Nero: Correct.
[00:30:50] Dr Steven Nissen: Yeah. My recollection is that there are, is some data to suggest that the outcomes. downstream after valve replacement are worse, but that's something I haven't studied. And, you know, I'm not as familiar with that literature as I might probably should
[00:31:08] Dr Thomas Nero: Yeah. I haven't, I haven't come across it, but I also haven't done a deep, deep dive into, into that piece either. Um, but it will be a very interesting one. Do you, when do you believe this trials are going to be initiated? , as are there already phase one or phase two trials that are.
[00:31:21] Dr Steven Nissen: Well, there are, there are some pilot studies underway. They're not designed to be definitive. They're looking at things like change in velocity, that sort of thing with treatment. So, you know, we know that there's an acceleration of change with high lipoprotein A. And the question then is, in a randomized trial, do you see evidence that there's less progression when you lower lipoprotein A, if there is some preliminary evidence of that, that would be a gateway to potential initiation of trials that are designed to show that you can change outcome that, you know, people with mild to moderate disease can be prevented from going on to need, uh, aortic valve replacement.
And that's going to be an exciting area in the future that we're going to get to.
[00:32:17] Dr Thomas Nero: It's also very unfortunately, very slow moving, disease state, and so it's a little bit harder to be able to do that analysis.
[00:32:25] Dr Steven Nissen: exactly right. And so there's a paradox here. . The most likely group that you're going to alter progression in are people that have less disease. If you're close to needing aortic valve replacement, it's already a heavily calcified valve. It's You're on a trajectory that may be unalterable, but then if you study people with lesser degree of disease, the time it takes them to get to aortic valve replacement is many years.
And that is a conundrum for designing clinical trials. And we've been, discussing that conundrum in some detail with, , makers of therapies.
[00:33:12] Dr Thomas Nero: Yeah, I clearly it's going to be an important thing in the future. And , given the fact that we are moving towards doing so many TAVRs and TAVR is really trying to replace mechanical aortic valve replacement in younger patients,
how do you decrease morbidity as well as mortality in the long run, um, is clearly going to be a long
[00:33:32] Dr Steven Nissen: The same issue, by the way, comes up, , if you think about it with ASCVD, , the target population currently has been primarily, up until now, been primarily secondary prevention. What should you do with somebody who's 25 or 30 years old and has a lipoprotein little a level of 200 milligrams per deciliter, , 500 nanomoles per liter, is that patient a patient in whom we can prevent the development in their fifties of atherosclerotic vascular disease?
Uh, I think we're going to inch our way toward that population. Perhaps, uh, it would be useful to first study people that are high risk primary prevention, you know, lots and lots of risk factors and including age, but they haven't had an event yet. And then later we'll move to more of a traditional primary prevention population.
If you think about it, that's exactly what we did with statins, you know, we started out studying people. Many people don't remember what the median LDL was in the 4S trial. It was 180 milligrams per deciliter. So, you know, initially, you know, medicine showed that you could help those people. And then eventually, of course, we've come to studying people like we studied and.
in Odyssey and Fourier or already below 100 milligrams per deciliter, that they get an additional benefit. So we're going to have to do that with LIPOR.
[00:35:17] Dr Thomas Nero: And certainly, and that, , another sidebar of which we've had a few of them is part of that question about, , yes, we're, we're showing smaller and smaller benefits, but we're looking at. populations that are smaller and smaller risk overall in comparison to what we had looked at in the past.
Um, and, but as we have these more powerful drugs, we're able to identify that statistical benefit earlier. And it is hard to then continue on with the trial. Once you know that it's going to be statistically significant, just to wait to see how great or grand a benefit it may be.
[00:35:49] Dr Steven Nissen: Something I'd like to get into with you that is an area of controversy, which is how much do you need to lower lipoprotein A to get a benefit that's comparable to a one millimole uh, reduction in LDL cholesterol, 38. 7 milligrams per deciliter.
[00:36:08] Dr Thomas Nero: And if I could interject the similar question is what is going to be the level of LDL at which point LPA may not necessarily be important to lower if you do get the LDLs down to as we can, uh, in many cases down to the 2010 range.
[00:36:27] Dr Steven Nissen: Yeah, I want to circle back with that. So there are several studies that have been done that have tried to estimate this, um, and, uh, the range that has been report is between about 50 milligrams per deciliter, which is that the low end and a hundred milligrams per deciliter reduction at the high end. in order to get the same reduction that is seen in the CTTC meta analysis for LDL C for one millimole, which is 22%.
And we're going to find out, uh, we're going to see that answer at some point, but it is a terribly important question.
[00:37:14] Dr Thomas Nero: , and by the way, do you think that it is going to be just , the absolute reduction, or do you think it's going to be the end LPA level? Now there's some very interesting, uh, sub analyses from Fourier that showed that it's really the end LDL that is really the most predictive of events.
Um, and that if you get drilled and your end LDL down very, very low that you're actually having markedly fewer events that it doesn't, that it actually magnifies the benefit rather than decreasing the
[00:37:41] Dr Steven Nissen: it's, it's very controversial area. Now, the controversy starts when you go back to some of the earlier studies, like the emerging risk factor collaborative study on LP little a, which seem to indicate a curvilinear relationship between LP little a levels and risk so that it's kind of flat at the bottom of the curve and then as you go to higher and higher levels it becomes steeper and steeper.
Why is that important? Well, if you're flat at the bottom, if there's not much difference between a level of, you know, 40 and 20 milligrams per deciliter, then if you start out really high and you get down below that threshold, you're on the flat portion of the curve and you're not going to have very many events.
And along comes the UK biobank, which is the very, very best data that we have. And it looks like the risk level is linear, almost down to zero. And so what it suggests is that, and just like we've seen, frankly, with LDL, if you lower LP little a by say 50 milligrams per deciliter and you get down to 10 you start at 60 and you go to 10 the benefits likely to be the same as if you start at 100 and go down to 50 and that would suggest that lower is better and you know we'll have to see.
Um, and we're going to have different levels in these different studies, and we'll be able to do secondary analyses and try to tease out what that relationship looks like. But what's the target? Uh, we have some people that have levels that are exceedingly high. I mean, 300 milligrams per deciliter. So if you get a 75 percent reduction , those people still have a pretty high level.
, and so I just think we don't know the answer.
[00:39:46] Dr Thomas Nero: And then, , circling back to the LDL question. , one of the things in getting our patients involved in, , Oceans A, we're trying to get their LDLs down to, , 40 because they are our secondary prevention, um, and I'd love to be able to say, yes, this is an issue that is going to be about LPA lowering and not to be involved
[00:40:05] Dr Steven Nissen: Okay. There's something I want to jump in here with, and that is you raised this question earlier. So what do you do? With somebody, , the argument I get from some primary care physicians is, I measured this. We can't do anything about it yet. But the answer is we can. And so I'll see people in families where, you know, a parent, let's say, or maybe a sibling has had an event and we check the level on another person within the family.
And it's very, very high. So what do you do? I say, look, we can't yet treat your lipoprotein A. But we can take every other risk factor off the table and get your blood pressure really low.
We can get you off the couch, get you exercising. We make sure your body mass index is within the normal range, including your waist to hip ratio, which is maybe even a better predictor. Uh, we can do all of the things that we know are beneficial to people at risk for atherosclerotic vascular disease. And we can, at the very least, very likely delay when you may get this disease, and we can delay it long enough until we have effective therapies.
And so, you know, my view of this nihilistic thought, whether you can't do anything is just wrong. It's just plain wrong. The aggressiveness. of preventive therapy in people that are in families with elevated levels is an important initiative that we need to do a better job of taking on.
, . And, , just to give a plug, we will also do a short podcast for patients more of a, , a clinical podcast.
[00:41:51] Dr Thomas Nero: one last question, , on this research front , you were talking about CRISPR initiatives, , , , where are they with that? Because that's obviously going to be, you know, a very interesting, mode of research for both LDL as well as LPA
[00:42:04] Dr Steven Nissen: There are several companies that , are developing, , therapies that will edit the gene responsible for elevated levels of lipoprotein A. , they involve a lipid nanoparticle, uh, typically with Gal Nac, but not necessarily. There may be other ways of directing the therapy that are basically designed to alter the gene so that the messenger RNA.
the codes for APOA is not produced or not produced in any significant amounts. , these, uh, therapies are going to be entering clinical trials in the United States soon. And they're one and done therapies. You basically, you get one injection, the gene gets edited, your lipoprotein A level will go down and stay down.
And, you know, now how many years we are away from getting regulatory approval for these therapies? remains to be seen, but they're being developed and it's pretty exciting. There is one other topic we probably ought to just circle back on for one minute, which is I hear I get getting a lot of patients and I hear a lot from patients about taking a PCSK9 inhibitor to lower their lipoprotein A level.
And my own view is that that's very speculative. Uh, that I recognize that these post hoc analyses of Odyssey and Fourier showed an apparent relationship between lowering of lipoprotein A with the PCSK9 inhibitors. Uh, and benefit. But like all postdoc analyses, there are a lot of limitations. Uh, the evidence is not so overwhelmingly strong.
And so I'm not doing it. And I know many people are. but I'm simply not prescribing PCSK9 inhibitors because of an elevated lipoprotein. Now, if I have another reason to give them, I'm going to certainly do that. But in the absence of another reason, I'm not giving them simply because they lower lipoprotein A 25 percent or so.
, the add-on question to that is, are you changing your LDL goals based on their LPA levels? And, and if so, then sometimes PCSK nine inhibitors are very reasonable. Add-on, on top of statin therapy for those patients because it, it dramatically lowers LDL levels.
[00:44:38] Dr Steven Nissen: Yeah, absolutely. And that's what I meant when I said, unless I have another reason to do it, you know, I want to get people's LDL down below 55, you know, and if they have a high lipoprotein A, and you may be able to get there with a potent statin and zetamib and whatever else. Uh, but if you can't, then you have PCSK9 inhibitors and, and they're, you know, they're good.
You got the monoclonal antibodies, you have Inclisiran, you got lots of, lots of opportunities to lower LDL further.
[00:45:09] Dr Thomas Nero: And, , finally, , are you utilizing, , antiplatelet agents in these, primary prevention patients? , and have you ever used, vascular dose Xarelto in secondary prevention patients?
[00:45:20] Dr Steven Nissen: Well, the DOACs are less certain, , but, for sure. In these patients, uh, administration of aspirin in primary prevention patients in general. We just don't do it. Uh, but if they have a high lipoprotein a, we do, and it's the 1 exception, or at least 1 of a few exceptions to the, the advice not to use aspirin and primary prevention.
And, , no, I can't prove beyond a reasonable doubt, but there are a couple of analyses that, uh, strongly suggest that it makes a difference. Um, the Women's Health, uh, study and the ESPRI trial, you know, both seem to indicate that aspirin conferred benefits in people with high lipoprotein A. It's good enough data and the risks are low enough that I do it.
, .
[00:46:15] Dr Thomas Nero: And, , circling back to one of the conversations, one of the bits of conversation we had before is there may be a time when we're going to have to redefine what atherosclerotic heart disease is. And I'm really, I'm in the camp of Matt Budoff saying, you know, atherosclerotic heart disease really happens when the atherosclerosis occurs.
And when we're starting to see coronary calcification rather than. just when we're waiting for a clinical event like a stent placement , or an MI.
[00:46:39] Dr Steven Nissen: Yeah, I'm a little more skeptical, you know, um, and part of the reason is that, once calcification has occurred, you're later in the disease process, and You know, I'm sort of thinking about primordial prevention, , we did a study many years ago where we took transplant donors and we did intravascular ultrasound on the transplanted heart after it was implanted and about half of these donors at age 30 had evidence of coronary plaques.
They weren't calcified. They were, they were early plaques and, , Matt's been such , an advocate for CT calcium scoring that I think it's not what we really are want to be looking at what we really care about is the more soft, vulnerable plaque in the, in the coronary.
[00:47:35] Dr Thomas Nero: Well, you know, that may be a semantic question , and I agree with you. I think that the soft plaque is the issue, the hard plaque, the calcified plaque is what you can see easily. And so there may be a different in difference in how we, um, identify that population, once we're using CTAs to the level of which they are using them in Europe.
We'll be seeing, certainly getting a much better idea, and so we'll, in younger patients, we do tend to use CTAs here in order to identify those at higher risk, um, rather than waiting for calcium to be, to deposit because it's not, it may not be there. I want to be respectful of your time and I, .
I hope that I can, uh, um, nudge you into doing another, , discussion, , at some other point, because this has just been absolutely wonderful. , do you have any. Last parting words of wisdom,
[00:48:25] Dr Steven Nissen: You know, we we've covered a lot of territory. There is so much to talk about, you know, and I've been living in this world now for for long enough that, uh, you know, uh, there's the scientific questions just never, never seem to end. And the controversies, uh, are, are there. So there's a lot more we don't know than what we do know.
And, uh, we know a lot. And if you actually go to PubMed and you look at the number of publications on lipoprotein A by year. It's unbelievable. The acceleration of interest in this, in this end point, you know, we'll have to see. I will be, you know, I, I was one of the people that were thinking that raising HDL would be beneficial.
We were wrong and we think lowering lipoprotein A will be beneficial. I hope we're right because I want to treat these patients. But I can't tell you yet that we're right
[00:49:29] Dr Thomas Nero: you know, the CTP and hypothesis, I think, is still alive, uh, with, uh, with the, with the current trials that are going on. But we'll, we'll see. And so I don't want to necessarily put the
[00:49:39] Dr Steven Nissen: and I am
[00:49:40] Dr Thomas Nero: on that coffin yet.
[00:49:41] Dr Steven Nissen: I'm, I'm very much involved in those trials. So, you know, I, I'm, I'm with you.
[00:49:46] Dr Thomas Nero: All right. Well, thank you again, Dr Nissen. This has been an absolutely wonderful discussion and I look forward to talking to you again.
[00:49:54] Dr Steven Nissen: Good.