Welcome, everybody. I'm Dr. Erin Mekos. I'm a professor of medicine and cardiology at Johns Hopkins University, and I want to welcome you to this very special educational session put forward by the American College of Cardiology on lipoprotein, little a it's part of a larger grant activity found on the ACC website for more information about elevating lipoprotein, little a awareness, bridging the cardiovascular risk knowledge gap and on this webinar, we're focusing on what can you do now? Current insights and future directions of cardiovascular health. Next slide. So, for this webinar, I'm very pleased to be joined by 4 expert faculty panelists. We have Dr. Christy Ballantine, who is a professor of medicine and cardiology and the director for the Center of Cardiometabolic Disease Prevention at Baylor College of Medicine. Then we have Dr. Josette Ray Sofer, who is an assistant professor of medicine in the division of preventive medicine at Columbia University. We have Susan Hall Dimitri, who is a doctor of nursing practice at Mayo Clinic, Arizona. And then finally, we have Dr. Steven Nissen, who is the chief academic officer and professor of medicine and cardiology at the Heart and Vascular Institute at the Cleveland Clinic. Next slide. And to start us off, we're going to have Dr. Ballantine give us a brief overview on the background and genetics of lipoprotein, little a. Thank you, Erin. If you go to the next slide, please. These are my disclosures. Go to the next line. So, I'll discuss genetic and observational epidemiological evidence on the role of LPA in cardiovascular disease risk. Next slide. So this is a fascinating lipoprotein. We see the structure of it. It's somewhat like an LDL particle that has ApoB, but bound to ApoB is ApoA. And this is a unique protein. It's structurally somewhat similar to plasminogen. It's on the same genetic location downstream of that. Most of the levels are determined by heredity, about 90%. And there's a huge variation of the levels within a population. It's fascinating in terms of the biology. There's pro-inflammatory, pro-epigenic, potentially pro-thrombotic properties. I mentioned this similarity to plasminogen and maybe inhibiting fibrinolysis. We also have more and more data about fast-progressing and vulnerable plaques, a type of disease. And the exciting part that's come up from a lot of studies using Mendelian randomizations is looking at that this is causal for ASCBD, aortic valve stenosis, cardiovascular, and all-cause mortality. Next slide. So this would be, when you find an individual who has a very high level of LPA, you have also identified a family with high LPA. So this is a really important take-home in terms of cascade screening. This is an example of a proband. And what can happen is if both parents have high LPA, then sometimes one of the kids gets extremely high levels. But it's auto-symptomatic pattern of inheritance. And what you can see is this distribution where there's a right tail, about 20% of people in the population having a high level. We would call that around 50 milligrams. The number we'll mention later on is 125 nanomoles per liter. But let's keep going. Next slide. So it's mostly genetic. However, there are some differences that we see. One of them is kidney disease, particularly proteinuria, nephrotic syndrome can lead to very high levels of LPA. Menopause, the levels go up. Women have higher levels than men. And you can see this. Diet is pretty much not effective. It's actually a little bit in the direction you wouldn't expect. If anything, there's a little bit of a lower levels with a low-carb, high-saturated-fat diet with it. HRT can lower LPA, but has not been shown to reduce events with it. But it's really very hard to change this from diet and exercise. Exercise doesn't do really anything. Next slide. So this has been around for a long time. When I first started in my career, there was a lot of interest in LPA, all kinds of problems with the assays. But what really has focused in on the attention is the genetic studies. Basically, the levels are determined. A lot of it is by the number of crinkle-for repeats. People with a low copy number have higher levels. There's also some other genetic variants that are related to the levels. What we see is that the genetic variants associated with high levels of LPA are associated with cardiovascular disease. Next slide. There's also been some interesting data that's come out of some of the large biobanks like UK Biobank. These are somewhat complicated analyses looking at SNPs associated with levels of ApoB and also with LPA. Basically, if we look at this, for each LPA particle, there is a greater risk, about six-fold more aphrogenic, than LDL on a per-particle basis. However, let's go to the next slide here. It's important to understand what is a high level of LDL. This is showing the hazard ratio here of about 1.24 for LPA per 100 nanomoles versus ApoB. Now, 1.05. However, it's very important to understand what the high levels are. Let's go to the next slide. For example, if someone has a high level of LDL, so if your LDL is 200, you probably have 2,000 at 250 nanomoles. That's your particle concentration. A high level of LPA is 250 nanomoles. There are a lot more LDL particles in your circulation than LPA, certainly for most people. It doesn't take away the focus we have on lowering LDL, still the primary driver for most people. However, there are a number of people who have very high levels of LPA. Usually, they don't know about this. Next slide. There's been more and more studies looking at the progression of atherosclerosis, and also in terms of using both traditional imaging and also newer modalities, CCTA, OCT. What you're seeing is more complex disease, chronic total occlusions, people having diffusely narrow disease. If you look at Jensenian syntax scores, they're higher. Lots of low attenuation plaque, cortical core volume, thin fibrous cap. So a lot of lesions that we would consider to be high risk seem to be associated with high levels of LPA and with more rapid progression of disease. Next slide. So not surprising that that's associated with increased risk for myocardial infarction. What's also interesting is the strong association with aortic valve stenosis, and this is particularly important with an aging population where we are seeing a lot more aortic valve disease. There's some data that, in fact, post-hab or high LPA levels are a bad thing to have in terms of getting restenosis. And there's some associations with heart failure and ischemic stroke, not quite as strong as the associations for ASCVD and aortic valve stenosis. Next slide. One important thing has been that basically, as we've gathered more data in different various populations, we see it's a continuous association. As your levels go up, if you're white or if you're black, your risk goes up. And the shape is fairly similar in different races. Next slide. So in summary, we know this is an inherited, independent, and causal CV risk factor. High LPA levels are associated with increased risk of cardiovascular events in primary prevention and also after a first event. There's increased risk in addition for aortic stenosis. This is the most common monogenic hereditary risk factor for premature ASCVD. So screening for high LPA levels may help to identify vulnerable patients and also vulnerable families. Thank you. I'm on mute. Thank you, Christy for the audience. If you have any questions for Dr. Ballantine or any of the faculty, please put them in the chat box and we'll have some time at the end for some Q and a with the faculty. So, our next speaker will be Dr. who is going to give us an overview of how to do an approach to cardiovascular risk assessment, how to manage care for those patients with elevated lipoprotein. Little a, thank you. Thank you. Dr. for the invitation to this panel and to Dr. Ballantine for that expert introduction to little way. And so, as we saw in the previous slides, these are my disclosures and nothing that is on this slide is related to what I'm going to speak about today. Next slide. So, my learning objectives are to speak a little bit about screening for high plasma levels. And also my 2nd objective is to provide some tools to better assess risk in those with high levels of. And next slide, so Christie did a very nice job of mentioning the significance of high lipoprotein, little a levels in those with high, the significance of high lipoprotein, little levels in those in sort of. Assessing risk for CBD and also increasing risk of mortality and here, I just wanted to have it in a picture that mostly what we've seen is that in those with a greater than 90th percentile of those levels. We have a 2 to 3 full increase in most of these disease and mortality. So, heart attacks, aortic stenosis, PBD strokes, congestive heart failure, and the statistics vary a bit between disease presentation. But what's really, really important to note is that high lipoprotein, little a levels in most individuals are going to be associated with some form is a CBD, but not at all. Next slide. Please. So, who should have an LPA blood test? I. Put it very simply here. Most of the European guidelines are all adults. So once in a lifetime, and then also we should think about children that are at high risk. So those with a family history of age, premature CBD. Those with early strokes, family history of LPA. Next slide. Please. So, recent retrospective studies and publications from large health system, including some from the Mayo Clinic, which was published in the American Journal of preventive cardiology and also a study that was recently published in which included 5 sites from the cardiac health alliance highlights. That low rates of measurements that we have in the population, even in those that have been diagnosed or establish a CBD. So, in the US, it could be due to a lack of updated guidelines, but we do have the NLA statements and the American Heart Association statements that suggest that in all individuals, we should have an LPA measurement. However, let's just remember that statements are not guidelines. So the Europeans and the Canadians are ahead of us in suggesting that probably everyone should have an LPA tested. So, our team at Columbia has also published on these issues. So I presented my data just as a sample of what's been going on and you can clearly see from this data set on. This slide that we're not doing very good on this blue slide. You can see that. The general population and millions of people around our cohort, we have about a 0.3% tested in the general population of our hospital and the bottom line is that when you order the test, actually 73% of patients are compliant with the test. And so it's not a compliance on the part of the patients, but more of the test is not being ordered and this actually increases to about 2.8% of people tested when you have a diagnosis. So, these 52,000 people that you see here on this blue center figure is people that had the diagnosis of either FH, carotid artery disease, high LDL on a statin, coronary artery disease, MI, PAD and stroke. And you can see those diagnosis here on the bottom left of the slide and as you can see FH, carotid artery disease and high LDL on statins, those are the more likely to get. The test order than other individuals and so how does this relate to the other published results? I can tell you that the 2.8 is a little bit higher than the last report that was submitted in, but another report from the UCSF system show very similar about a 3% testing rate in those that are at risk for ASCVD. I also wanted to highlight that there seems to be some issues with ordering the test less in blacks and Hispanics, even though they present with higher levels, as we know from the genetics and what Dr. Valentine presented. And in addition to that, people that are at lower socioeconomic status shown here at the top right and also those on Medicaid are less likely to receive the test. So we have a long way to go. The good news is that cardiologists, rightfully so, are the ones ordering the test most of the time and that is shown in the bar graph on the bottom. Next slide, please. So, it's important to note that LPA is not LDL cholesterol. It is an APOV100 containing particle. And if we believe that in those with high LPA, some of the pathology is due to the increase in the APOV content that the particle has, then knowing your APOV100 levels in patients that have high LPA may help you to assess risk better. Because as you lower LDL cholesterol, you're also lowering APOV lipoproteins. And so you would want to know how much of the APOV that you're lowering is bound to LPA. And so that is just something to keep in your mind and something that you should think of. But also, I want to highlight that there is strong literature supporting that APOV is a better marker of atherogenic particles. And so I wanted to write that here and make sure that you know that why not measure an APOV when you are also measuring an LPA level. Next slide, please. So, why should we screen for LPA? First, we can identify individuals with high LPA. It could help us to reclassify borderline intermediate or high risk CVD individuals. We can optimize management and treatment of other CVD factors. And also we can identify familiar risks and sort of cascade screening. Next slide, please. So, there's data on families that highlights the need to measure LPA in family members in those at risk. And in this study by Meta et al, published in the JAC, there are 3 main points that the authors highlight. And I want you to take home and that is that family history and elevated LPA are independently associated with ASCVD. Compare with subjects without a family history and non elevated LPA. Those with either elevated LPA or family history were higher ASCVD risk. And then while those with both had the highest risk. Presence of both LPA and family history resulted in great improvement in ASCVD and CHD risk reclassification. And so this is really important to take into consideration when you're Testing for LPA in your practice. Next slide. So, there are various free tools that could be using your clinical practice to estimate cardiovascular sort of risk of serving those with high LPA. And what I would say about the tool that I'm going to speak up 1st, which is this LPA clinical guidance tool is that you want to do the tool without the LPA levels 1st, and then add the LPA levels after. The current guidelines and statements support lowering all other risk factors that increase ASCVD in those that have high LPA. So, this tool is really cool because once you're lowering all those risks and you're taking all those risks into account, and you can add those to the tool, you can see how the risk is either improving or if they're still at higher risk. So, in the next slide, please, I can show you how you can enter the height, the weight, and then I'll give you sort of with these baseline characteristics, your lipid levels. I'll give you your risk. Next slide. Please. And then you can see here what the risk is once you add LPA and then the next slide please. And then you can see here that it's really nice for showing a visual to your patients of where you think they are and how LPA can increase their cardiometabolic risk. Next slide. Please. And then overall, it even gives you a little paragraph at the end of suggestions and things you may think of. So, I think this is a really cool online tool that you can use with your patient. Next slide. Please. So, another way to incorporate LPA into your practice is by including the 10-year ASCVD risk score. And on the top panel of this figure, I highlight the data published by Patel et al. And so they use the UK Biobank, and in this cohort, the standard right risk for ASCVD was 11% higher for each increment of 15 nanomoles of LPA. And so you can make a calculation sort of independent from traditional risk factors, and you can make, based on this data, you can use a modified 10-year risk estimate calculator. And so we put the calculator in there for you. And recently, a group of us were able to put this in a review. And you can go to the review, get the calculator, and just see how your risk changes. So, it may be that somebody had a risk of 10%, and it could increase up to 16% if you're at the LPA. And that's the example we have on the paper. And then lastly, and importantly, as shown here on this bottom risk-based prevention approach, I just want to highlight that in everyone with high LPA, although diet and exercise have not been shown to lower LPA levels per se, we do want to follow the American Heart Association Heart Healthy Guidelines and the Essential Eights to promote healthier lives. And this whole graphic you can find in this publication that was recent review that we wrote. So, I thank you and hope that this is helpful for your practice. Great. Thank you, Gisette. And now, to kind of put this into application, we're going to hear from Susan Holly Demeter about a primer prevention case, and then the faculty will discuss it. Thank you, Dr. Mikos. Next slide. I have no disclosures. So, I'm going to present a case, a patient named Mimi, who is a 47-year-old Caucasian female who was referred to the Cardiology Lipid Clinic by her primary care provider for elevated lipoprotein A, which, first of all, I just want to commend the primary care provider who was proactive in ordering this test and want to give out a shout out to that primary care provider today. She has a history of total cholesterol greater than 200. Since as far back as she could remember, she felt she had lipids first assessed close to age 30. Her family history is significant in that her maternal grandmother had a history of three cerebrovascular events, with the first one in her late 60s. Her mother is alive with moderate coronary artery disease, hypertension, and hyperlipidemia, sister with history of Graves' disease, and her father died at age 38 from leukemia. Next slide. Her past medical history was she had a total hysterectomy at age 41 for endometriosis. And then she noted that she had a lumbar laminectomy in 2021 and incidentally developed a venous thromboembolist two weeks post-op. She does not have any children. Her medications include an estradiol patch that she applies twice a week, and then cetirizine for allergies. She's a lifelong nonsmoker, rarely drinks alcohol. She follows a very heart-healthy Mediterranean diet, and she exercises over 150 minutes a week with cardio. She's very active. Her BMI is 24.2. Blood pressure was normal, 110 over 70, and pulse was 60. Her exam was normal. Next slide, please. Next slide, please. So labs, her total cholesterol, 216, HDL, 71. Her LDL is 134, triglyceride 64, non-HDL, 145. Her APOB, 96. HSCRP was 0.8. Her complete metabolic profile was completely normal. Normal renal function, normal liver function. TSH was normal at 2.87. A1C normal at 5.1, and uric acid was 3.8. Her lipoprotein A level came back markedly elevated at 244 nanomoles per liter. And then with using the LPA clinical guidance calculator that Dr. Reyes-Sofer had just mentioned, when looking at her risk for MI or stroke without lipoprotein A, it was 8%, but did get upgraded to 15.2% when adding in her lipoprotein A. So I'd like to open up to the panel for discussion of what you would do next. Great. So I'll bring our panel members back, our faculty members. So I'll start with Christy, because Christy, you and I were on another panel about challenging lipid cases, and we talked about this issue in young adults, particularly young women, and the focus on 10-year risk scores, where they're almost always low risk, and these 10-year risk scores don't include a lot of things like family history or other risk enhancers, and that calculators don't include lipoprotein A. So in this patient, only 47, LDL 134, APOB 96, with that LPA value of 244. Would you put her on a statin? Would you do some other testing, like a coronary calcium score? What are your initial thoughts? Christy, I think you're on mute, too. I did the same thing earlier. Did you use the PREVENT equation, or which equation did you use? We know we have multiple ways for assessing risk, and PREVENT in general may be an advance, but usually you get a lower number. It's substantially lower on the PREVENT. So I'm concerned about that, because she's 47, but her mother had coronary disease. Her grandmother had strokes, and she's looking at probably not just the next 10 years. She's looking at the next 20 to 30 years. So I really think our big focus on 10-year risk is wrong, because I'm concerned that with the new PREVENT, it's going to be lower than what you mentioned here for it. So if she's coming to me, I say, listen, you're, you know, we have a very high level of LPA. Your LDL is elevated. Your ApoB is elevated. These are something that we can do something about right now. We know that in Jupiter, it did help to lower, you know, LDL with a statin and lowered events. We're working on LPA. If she'd like, we could do something. We'd get an ultrasound of the carotid to see if she has plaques, CIMT. Could get a coronary calcium. She's a little young. I wouldn't, I would be, you know, zero wouldn't necessarily mean that she doesn't have problems. So I might just encourage, you know, let's start now to treat, and then we'll see where you respond. And then later on, we could do some imaging if you want to see if you've got disease. Can I just add, we did do a carotid IMT. And what was surprising a bit to us, despite these risk factors is her vascular age was 42, and she had no subclinical atherosclerosis present. Which we found interesting. Yeah, she's 47 though. I think I see Steve with his hand up. Steve, I'd love to hear your thoughts. She comes to you in the lipid clinic. What are you going to tell her? To me, this is a no-brainer. And I don't need a bunch of other tests. You know, we've got drugs that we could treat her with. You know, we could treat her with a very low dose of a statin, five milligrams of rosuvastatin. Get her LDL down to 70 or 80, probably respond very well. And I, like Christy, am worried about her lifelong risk. I do not want, I absolutely do not want to get imaging tests here. Because all they're going to do is convince you not to treat somebody. And we can wait 10 years until her risk is very high, and then find out she's already got the disease. And I think our job is to prevent the disease, not to treat it once it's manifest. So for me, I would say to her, we got very safe, very effective drugs, so let's lower your LDL. And health is on the way. As I'm going to talk about later, we have very good new treatments coming, and she'll potentially be eligible. I agree completely. Because I'm thinking of cholesterol years, like we think of pack years of smoking, or it's not just how many cigarettes a day you smoke, but how many years that you've been exposed. And there's lots of data, including a recent study from the CARDIA cohort that looked at a lipid panel between ages 18 and 30, that even mildly to moderately elevated cholesterol with sufficient years, these individuals still have earlier onset ASCVD compared to those with lifelong low LDL. And I think that we wait too long to treat. I think a calcium score of zero can be very misleading. Calcified plaque is late stage plaque. And we want to sort of prevent the disease in the first place, rather than wait till somebody already has advanced disease before we retreat. And as Steve said, I probably also would do, Fibromazuba can give you a 35, 39% LDL lowering. You can get pretty robust lowering. And if you start treating earlier, because they have more life years at risk, you actually have more to gain than greater reductions later in life. So I would also skip imaging and probably put her on Fibromazuba 5 and talked about lifetime risk. Does that, I don't know if you have more, any comments here too? No, I would just say that it's great to see a low CRP and it's great to see a low TG. And it would have been nice to see the BMI to make sure that this is not a person- 24. It was 24. Oh, so it's a great BMI. And I think that the one thing I would follow up on is the calculator for ApoB. So if you calculate how much of the ApoB is on LPA, plasma ApoB will go down to about 83 milligrams per deciliter, just taking away how much of that ApoB is on LPA. So what it is right now, it's about 83 milligrams per deciliter. And if you put it on a stat and just to look for any elevations in LPA that you may see, those aren't my only comments, but I agree, someone that should be treated. And addressing a comment in the chat asked about aspirin. So I'll see what the other panelists say, but I would do aspirin if this patient's at low risk for bleeding. Now, we don't have any direct trials that assess this, but secondary analysis from the Women's Health Study and the ESPRI study that looked at those with genetically predicted high LPA, there did seem to be a net benefit for aspirin because their bleeding risk was the same as everybody else, but because their vascular risk is higher, they're anticipated to derive more benefit from aspirin. So I probably would consider low dose aspirin in this patient as well as a statin. I don't know if any of my other panelists have any other thoughts about the aspirin question that was in the chat. Well, Erin, I rarely disagree with you, but in this case I do. Okay. I would hold off on the aspirin for now. Yeah, yeah. So Christy and I both think we should hold off on the aspirin. There are downsides to aspirin. The data don't look very good. And looking at the data on aspirin and LPA, the data are weak. And so I think the evidence is just, in my view, not strong enough for this patient to give her aspirin. Maybe different profile, different patient, older, different gender, maybe yes, but not here. So I did pre-vent on her and her pre-vent score is, I don't have an EGFR, but I put it in 100 and she's like 2% 10-year risk. And so I think it's just one of the things where you really don't end up treating younger people when you do these things. Her 30-year risk is pretty high with it. So, but I do think it's someone that, this is also the thing of the family history. She's worried about her family history and she'd like to know, can she do something about it? And the answer is clearly yes. There is something you can do about it. We can reduce it. She's doing the lifestyle. She's doing a nice job on lifestyle, but we could lower her ApoB and her LDL. Yeah, so clearly we need more data in terms of aspirin and some better trials. And I think we all agree on a statin. And if a calcium score was done, it might only guide my intensity of treatment. Certainly if there was evidence of disease, I would aim for even lower LDL targets. But I worry about imaging, giving false reassurance. A certainly a zero score wouldn't mean not to treat in this patient who kind of has a high lifetime risk. Well, I wanna make sure we can move on to the next section, which is exciting, to talk about Lipoprotein A Emerging Treatment. So next slide. So to present this next section, we'll have Steve Nissen kick it off. Well, thank you, Erin. Thank you to the other panelists. This has really given an enjoyable discussion so far. I am gonna talk with you about emerging treatments. I'm gonna compress a lot of information into 10 minutes, but I'd like to at least touch on all of the, most of the treatments that are currently in development. Next slide, please. I'm gonna skip the learning objectives. Certainly there are lots of things we need to talk about here. Next slide, please. My disclosures are shown here. I do work with many companies. However, I do not accept any honorary or speaking or consulting fees so that I can be completely independent. Next slide, please. So as pointed out by others, Lipoprotein A levels are mostly determined genetically. We can't fix this problem with diet, lifestyle, or aesthetics. We can't fix this problem with diet, lifestyle, or statins. Although we do give advice on lifestyle, diet, and statins to these patients, they're not gonna affect the Lipoprotein A levels. Apheresis is approved in some countries, but it's time-consuming, expensive, costs up to $4,000 per session, and it's really not widely available. Next slide, please. So what we have on the way is help. The help on the way includes at least four injectable therapies, an oral LPA lowering therapy, and coming soon, CRISPR-based gene editing, which is already in research, but not in the United States, but coming soon to the US. Next slide, please. Now, to understand how to approach treatment, it's important to understand the structure of Lipoprotein A. As pointed out earlier, it is an apolipoprotein A associated with a disulfide bond to an LDL-like particle that contains apolipoprotein B. Next slide, please. And there are several approaches to treatment. I'm gonna talk about the top two. At the top is an antisense oligonucleotide. That is a single-stranded DNA. And in the middle is a small interfering RNA, which is a double-stranded RNA. In both cases, there is an antisense strand designed to degrade messenger RNA for Lipoprotein A. Next slide, please. Now, all of these therapies now, fortunately, are conjugated with something known as N-acetylgalactosamine, or GalNAC, which has a receptor in the liver. And if you attach the therapy to GalNAC, then it gets taken up within hours by the liver after injection, and it makes the oligonucleotide or small interfering RNA 30 to 100 times more effective, leading to lower doses, improved safety, and improved efficacy. Next slide, please. The first of these drugs to be developed is known as pelicarsin. It is an ASO, or antisense oligonucleotide. When studied in phase two, doses of up to 60 milligrams every four weeks or 40 milligrams or 20 milligrams, you can see a dose-dependent reduction in Lipoprotein A levels reaching about 80% within 24 weeks. Next slide, please. And in that phase two trial published in 2020 in the New England Journal, 20 milligrams a week yielded an 80% reduction. This is now in phase three, using a dose equivalent to 20 milligrams a week or 80 milligrams given once a month. And that trial has been going on for several years. I'm the study chair, and results will be available within the next couple of years. Next slide, please. Now, the alternative to an ASO is a small interfering RNA. And without walking you through this entirely, I would just point out that it's a Galanac conjugated, double-stranded RNA. It cleaves to produce an antisense strand that degrades the messenger RNA for Lipoprotein A that's responsible for formation of Apolipoprotein A. That's the rate-limiting step in assembly of Lipoprotein A. If you don't make ApoA, you don't make Lipoprotein literally. This shows the basic structure of a small interfering RNA therapeutic. Double-stranded RNA, the Galanac moiety is shown at the right in gold. Once it gets into the hepatocyte, it's cleaved into an antisense strand. And that antisense strand has been chemically modified to resist degradation by ribonucleases. Next slide, please. So the first of the siRNAs was olpacurin. In a phase two dose finding study published in 2022, and you can see very profound reductions in Lipoprotein A in doses of 10 to 225 milligrams. The drug was given every 12 or 24 weeks and did in fact produce nearly a complete elimination of Lipoprotein A from the circulation. Next slide, please. This shows waterfall plots showing that particularly at the higher doses, there was a very consistent reduction that very few people failed to respond. So here's a therapy and development that can lower Lipoprotein A in virtually everyone. Next slide, please. Now they did do recently a long-term extension study and quite remarkably drugs like the small interfering RNA olpacurin have a long tail of activity. And you can see out to 96 weeks, there is still at the highest doses, some modest reduction in Lipoprotein A. So quite an extraordinarily long duration of action. Next slide, please. Zerlacerin was studied in phase one. This is something I published in JAMA in 2024, showing in a multiple ascending dose trial going out to a year that this drug given in a single dose could reduce Lipoprotein A for about 150 days. And again, you see a slow rise with still some significant reductions out to a year after initial administration. Next slide, please. Here's the multiple ascending dose portion of the trial. And you can see after two doses out to 201 days, nearly 100% reduction, in excess of 90% reduction in Lipoprotein A. Next slide, please. And then finally, Lepodicerin. This also has been, is in developments in phase three. This drug had a profound effect on Lipoprotein A. It lowered levels at a 608 milligram dose below the lower limit of quantitation for 9.4 months and still showed a 94% reduction, 337 days after a single dose was administered when given at the highest dose. Next slide, please. And finally, we have an oral drug in development. This Steve Nichols published in 2023 in JAMA. And what this drug does is it blocks the association of apolipoprotein A to the APO-B particle, APO-B containing particle. And again, if you don't assemble the APO-A and APO-B components, you don't make lipoprotein A and this drug is available orally. Next slide, please. Now in the initial study, which was quite limited, it only went out to 15 days. Doses were given up to 800 milligrams. You can see that there was about a 60% reduction in lipoprotein A, but there are some concerns that the assay used here underestimates the actual effect of the drug for reasons related to how measurements are made. We will hear more about that soon. Muvalapin, certainly a promising oral therapy. Next slide, please. And then finally, how much do we have to lower lipoprotein A? The estimates are anywhere from a 50 to 100 milligram per deciliter reduction should be approximately equivalent to a one millimole reduction in LDL cholesterol, which is a 22% relative risk reduction. We certainly hope these estimates are right. Now with at least five drugs in development, we are going to find out very soon from phase three trials whether in fact these estimates are right. I'm very encouraged. I think there's a high likelihood the drugs will work and will bring hope to the millions of patients that suffer from this disorder. Next slide, please. Let me then turn it back to Susan, who's gonna tell you more about secondary prevention with a secondary prevention case. Thank you, Dr. Nissen. So we will now discuss a secondary prevention case. Next slide, please. I'm going to present Diana. She is a 61-year-old black female being seen in the cardiology clinic following PCI with a drug-eluting stent to the LAD. Her history is significant that she had a previous PCI with a drug-eluting stent to the RCA at age 57. Her past medical history also includes three uncomplicated pregnancies with no history of gestational diabetes or preeclampsia. Menopause was at age 45. She has a history of stage one to two hypertension and a history of cholecystectomy. Next slide. As far as her family history, it's pretty striking because her father died from a myocardial infarction at age 70. Mother died from a stroke at age 68. Her oldest son is 39 years old and had a recent drug-eluting stent to the LAD. All three of her children have hyperlipidemia and she has three younger sisters who also have hyperlipidemia. She is a lifelong non-smoker, no alcohol use. She follows a relatively low-fat diet and she doesn't engage in any formal exercise regimen, but she tries to stay active. Her medications include Metoprolol XL, 25 milligrams a day, Losartan, 50 milligrams a day, Clopidogrel, 75 milligrams a day, aspirin, 81 milligrams a day, atorvastatin, 40 milligrams daily, noting that she had myalgias at the 80 milligram dose and therefore was treated with 40 milligrams and ezetimibe, 10 milligrams daily. Her blood pressure in follow-up was 120 over 80 with a pulse of 70. Her BMI was 24.9 kilograms per meter squared and her exam, unremarkable. Next slide, please. So her labs, I just wanted to note before she went on treatment with atorvastatin and ezetimibe, looking back at her chart, at baseline, her cholesterol was as high as 283, triglycerides, 203, HDL, 55, LDL was 187, her ApoB was 132, her non-HDL was 228 and her liver function, normal, renal function also, just to note, was normal. And with the current treatment that was studied when she was in the hospital for her second event, with the atorvastatin on board and the ezetimibe, her cholesterol was 160, triglycerides, 87, HDL, 74, her LDL, 70, non-HDL, 86, and then there was a lab that was LDL corrected for lipoprotein A that was 68. Her LFTs were normal and the lipoprotein A was assessed at that time and was found to be elevated at 225 nanomoles per liter. So I will now open it up to the panel discussion of how we would further treat this patient. Okay, great, I'll bring our faculty back and maybe this time I'll start with Steve. So, you know, she comes to see you in your lipid clinic and she hasn't tolerated escalation of her statin beyond her current doses. You know, what are you going to recommend for her now and, you know, potentially for her family members? Well, obviously this is a, you know, a cluster. This is where cascade screening is critical. I don't correct LDL for lipoprotein A. I do not think there's a reliable formula for doing that. So that's something I generally would not attempt to do. This is a patient that needs maximal treatment of every other risk factor. We've got to take every risk factor we can off the table. And that means she's got to exercise. We got to get her LDL down to very low levels, as low as we possibly can. I would certainly target less than 55 milligrams per deciliter and try to keep her safe until we can bring these new therapies forward and get them available for her. But she's certainly very high risk and we've really got to treat her maximally. She's not on maximal LDL lowering therapy. If we can't get there with the most effective statin, 40 milligrams and the zetamide, we have to consider a PCSK9 inhibitor. But I would caution that any suggestion that PCSK9 inhibitors actually are effective in lowering lipoprotein A enough to make a difference is probably not correct. Yeah, so I certainly would target an LDL less than 55 and she has ASCVD at very high risk and not having tolerated higher doses of statins, I think she would be a great candidate for PCSK9 inhibitors. They have some modest effect on LPA, but as you mentioned, that's not nearly enough and we really want to target her LDL down. I'll ask Christy about your thoughts and about genetic testing in this patient. Do you think she has FH? I mean, her LDL untreated was close to 187 in this family history. I mean, her son had an event at age 39. Certainly all family members need an LPA testing, but would you actually do genetic testing? What are some of your thoughts, Christy? Yep, I think you might be on mute again too. I'm concerned about FH when I heard about the son, age 39. I don't know his lipids. Now he also could have a extremely high LPA. We don't know what the father's LPA was. So I think it would be important to try to get that data on the son. It would be reasonable to get genetic testing on this patient to rule out the FH. And I would agree. The issue ends up right now is, Steve, although we do know that the PCSK9 inhibitors for individuals who had high LPA levels was beneficial. And now it may have been because on average it would bring their LDL to 30 here, right? I mean, so the issue ends up is that there was a benefit in those patients. You really can't tease out how much was LDL versus LPA because there was some LPA reduction. There was a lot of LDL reduction in those patients here. And I would favor that. Now, some people might say, well, her triglycerides are high but they're not after treatment. She's 87. So she's gone down tremendously afterwards here. So I think the most obvious thing would be a PCSK9 inhibitor. I don't use also the correction for LPA on LDL. That's out of favor now because you really can't tell how much cholesterol per particle there is with it. And it would be reasonable to get genetic testing. I certainly want to find out about the son and make sure if the son has kids that his kids find out early on about getting their LPAs checked. Okay, Josette, did you have any comments on the case? I think the cascade screening within the family, I think it's very important in this patient. All right, well, this patient's very high risk. He's a very aggressive approach and cascade screening of family members. We only have a few minutes left. So I want to make sure we have time to get to some of the questions here. One of the questions was, and I guess we can defer it to Christy. Maybe it's related to your talk. Given that this is autosomal dominant, what is the recommended age for screening for Lipoprotein A? So the levels, you know, when we put in the NLA scientific statement was anyone over the age of 18 with it, because that's an adult when you're over 18 with it. You get actually levels are stable after puberty. So you can measure that. And even before puberty, you can get some percentiles and have an idea where they are. I like to get the levels checked in people when the kids are still at home for it. It's a little easier to get the information on that. So that's gonna be probably, you know, 13, 14, 15, 16, sometime when they're in high school for that. And one of the things that is important, you know, is the lifestyle aspects, particularly for younger people. You know, smoking is a vasoconstrictor, premature anaphylaxis, one has a high LPA. I like to tell them, it's as if you would be allergic to cigarettes. Vaping is a big problem for young people. You know, and the other one is, unfortunately, the person with a really high LPA, might the person, you know, when they're at the party and they're doing cocaine, they get, unfortunately, a cocaine EMI because they've got plaque there and, you know, they're at a higher risk. So these warnings coming from a physician to a patient have a little more impact than the parents telling them it, just because it makes them realize, I've got something hereditary that could put me at risk in terms of a lifestyle issue. And it's just not a smart decision to be smoking, vaping, or doing cocaine if you've got an LPA of 225 nanomoles. Why put yourself in that situation? You know, Christy, I do exactly what you do. And I have uncovered a number of adolescents with some of them with 400, 500 nanomoles per liter. And I sit down with them and with their families and I say, look, we've got to manage your risk factors from a very early age. You need to exercise, you need to keep your body weight down, you need to do all those other things. And hopefully before you're, you know, 30, we're gonna have a lot of therapeutic options available for you and that's good. But in the meantime, let's get your lifestyle habits to be as healthy as they can possibly be. I think, Gisette, you mentioned about, you know, Life's Simple 8 being beneficial in people with high LPA. Yeah. Next goes along, there's a couple of questions in the chat about what do you do about patients that have normal LDL? Somebody even said 70 to 80, but their LPA is high. And so sounds like lifestyle is what everybody's sort of recommending. Anybody have any additional comments about an isolated elevated LPA, but normal-ish LDL, would you still do a statin? Would you do anything else besides- This is one where if somebody is, for example, at the age where it's more appropriate. So if you have a 55 year old man who's got an LPA that's 300 nanomoles with an LDL that's normal, I'd like to get a calcium score in that patient. Let me know where do we stand. So I do think there is the issue if someone has atherosclerosis and then if they had a really high tax score, then I might be thinking about aspirin and also a statin anyway, even though their LDL is there. And it also be the awareness that we have a lot in the pipeline. I mean, if they had some risk factors, I might be able to put them into a trial. I think Steve, I think Steve, you're doing a trial where I get it with a high tax score. Yeah, I got a few things going on and just add this to this partner with something in that trial. So, and this trial is including both primary and secondary prevention patients, which I'm very excited about. Okay, great. And talking about imaging, somebody asked about aortic stenosis. And what is your approach about elevated lipoprotein A in a patient with aortic stenosis? Is there any trials going on to see whether lowering LPA can prevent or slow the progression of calcific aortic valve disease? Do you wanna comment? There are some pilot studies underway. They're not the large outcome trials yet, but there is something everybody needs to know. The rate of progression of AS, if you have a high lipoprotein A, is about 50% higher. And so the frequency with which I do repeat echoes will be different in patients with a high lipoprotein A. And you'd be surprised. If you wait two years to get an echo, their aortic valve area has gone down a lot and you may have missed a better opportunity to intervene. So for lots of reasons, you need to know that progression is gonna be faster. And there is another thing that's maybe it's old school. It's called a stethoscope and listen to the heart. But if someone has a high LPA, please listen and to see if they have a murmur. And if they do have a murmur, get an echocardiogram and then follow them sequentially like Steve is saying. I know it's kind of, people feel you don't need to do that anymore, but it can be quite helpful. Can it Steve? I saw one of those stethoscopes in a museum once. All right. Well, although there's more questions in the chat, I think we're at time. So I know we could talk about this topic all day. I want to thank all of our faculty panelists for your expert talks and contributions and thank our engaged audience. I wanna let everybody know that the slides will be available on the ACC website. There's a grant page at the ACC online called Elevating LPA Awareness, Bridging the Cardiovascular Risk Knowledge Gap, where you can find the slides there and as well as more activities. And so thank you again for everybody for participating.

Lipoprotein(a)

Cardiovascular risk

Genetic screening

Antisense oligonucleotides

Small interfering RNA

PCSK9 inhibitors

Aortic valve stenosis

Risk assessment tools

Lifestyle modifications