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Nihar R. Desai, MD, MPH: I'm Dr Nihar Desai from the Yale School of Medicine. Welcome to season one of the Medscape InDiscussion cardiorenal metabolic (CRM) syndrome podcast series. Today, we're discussing low-density lipoprotein (LDL) cholesterol, dyslipidemia, and lipoprotein(a) [Lp(a)]. I'd like to welcome today's expert guest and my very close friend and colleague, Dr Seth Martin. Dr Martin is a professor of medicine in the division of cardiology at Johns Hopkins School of Medicine, specializing in preventive cardiology, lipids, and digital health. He's a core faculty member at the Ciccarone Center for the Prevention of Cardiovascular Disease, where he directs the Advanced Lipid Disorders Program and co-directs the Digital Health Innovations Lab.
In addition, Dr Martin serves as director of the Johns Hopkins Center for Mobile Technologies to achieve equity in cardiovascular health, which is part of the American Heart Association's strategically focused research networks on health technology and innovation. Seth, thank you very much. I want to welcome you to the Medscape InDiscussion podcast.
Seth S. Martin, MD, MHS: It's a pleasure to be here. Thank you so much, Nihar.
Desai: So, Seth, I couldn't have asked for a better person to help us, and the audience think about LDL, dyslipidemia, and Lp(a), in the context of our CRM disease patients. We've already had lots of discussions around the prevalence of CRM, what's going on in terms of social determinants, and all the things that come together for these patients.
Now, we're going to dig into some of the key therapies and some of the key clinical comorbidities that manifest in these patients. We will focus on cholesterol, dyslipidemia, and related topics. I thought we'd start with LDL cholesterol. We've been talking about LDL for a long time. Your work has been instrumental in guiding and shaping the field as we think about the optimal management of LDL cholesterol. Seth, where are we on LDL cholesterol? What's the right LDL cholesterol that we should aim for, and how do you think about LDL in the context of our cardiorenal metabolic patients?
Martin: We have such strong evidence now, and it's an implementation challenge. We have multiple therapies, and combination therapies that are increasingly used. And yet, many patients at risk are not receiving therapies recommended by guidelines and available to them.
The saying for LDL is that "lower for longer is better." We've learned that the risk is tied to the cumulative exposure to LDL. That going to very low levels, there's a monotonic relationship between LDL and cardiovascular risk. So the lower we go, the better. It's the garbage of lipid metabolism that we want to get rid of.
We want to start as soon as possible because that's going to get us to the goal as soon as possible. And then we want to keep the LDL low, as long as possible. We have a rich armamentarium of therapies. Now, if I think back to going to some of our cardiology conferences not that long ago, it was all about statins.
Unfortunately, several lipid therapies failed to improve upon statins.
Then we had the IMPROVE-IT trial come out with the ezetimibe, and we had the proprotein convertase subtilisin/kexin type 9 (PCSK9) trials. We now have bempedoic acid. We have a rich armamentarium. I think we're facing an implementation challenge, but it's a good problem to have. Our patients can benefit from a reduction in heart attacks and strokes. We're seeing about a 25% or so reduction in the relative risk for every 40-mg/dL lowering of LDL. Where do we want to be going with our very high-risk patients or with patients with CRM disease? We know lower is better, but practically speaking, in the secondary prevention space, we want to get at a minimum below 70. In many patients who are very high risk, we want to go below 55. We can talk more about some of the patient profiles where we want to go more aggressive than others.
I think we're in a really exciting time, Nihar, because we have such effective therapies. Now, it's a matter of fine-tuning our approaches on the front lines and scaling up our implementation efforts.
Desai: Yeah, terrific, Seth. Thanks for laying the broad foundation here, and I couldn't agree with you more. It's a very exciting time in terms of LDL cholesterol. There's so much that can be done. We've learned so many things and so many therapies have now come to the forefront.
There is this big question around implementation and how we bridge the evidence-practice gap. Let's think about the CRM patients that we're going to see in our office, tomorrow or next week, when we're kind of in the ambulatory environment, is the distinction kind of between primary prevention and secondary prevention?
Is that still the right framework for us to be thinking around? I know there's been a lot of back and forth about LDL goals, LDL targets, and LDL thresholds. Can you give our audience your best summary on whether there is a number or a range that we should be thinking about for the primary prevention, maybe the CRM patient that has diabetes and obesity, but hasn't yet had a cardiovascular event?
Or maybe consider someone who has chronic kidney disease (CKD) and has already had a myocardial infarction (MI) or a stroke? Those are very, very different profiles of patients. How do we think about these patients, within this broad term of CRM? How should we think about the best or appropriate LDL?
Martin: It is a slam dunk when somebody who already is clearly in the secondary prevention space has a CVD event. Having kidney disease is considered one of the additional risk factors that would push you into the very high-risk category in that secondary prevention setting. Many of the patients will qualify strictly based on American Heart Association (AHA)/ American College of Cardiology (ACC) guidelines for going for LDL less than 55. It's trickier in the primary prevention setting. This is where we see some differences between our US guidelines and guidelines from elsewhere in the world because lower is better and many patients with kidney disease have several related risk factors.
Even if they haven't had an event, they are very likely at quite elevated risk for atherosclerotic cardiovascular disease (ASCVD). Generally, I would feel going for an LDL less than 70 is perfectly reasonable as sort of a bare minimum, in terms of what we view as the goal. A more directed strategy to assess risk could take into account subclinical atherosclerosis.
Many patients with kidney disease have already had a non-gated CT scan for whatever reason. Looking at the burden of coronary calcification could be an indicator that this is somebody who already has a moderate or more severe amount of coronary calcification. That would justify being more aggressive with LDL-lowering therapy. If not, you could consider doing a coronary calcium score to further assess cardiovascular risk to justify an even more aggressive strategy. You did mention the terms target vs threshold vs goal. I want to quickly address that. The traditional terms we had talked about LDL is the target: It's the primary target of therapy. Non–high-density lipoprotein (HDL), apolipoprotein B (ApoB) are other targets of therapy but traditionally, we had a goal. We want to get below a certain level. This may seem like semantics, but I believe it does also have some real implications that we've transitioned to this term of using thresholds.
The value in that is that clinical trials were designed so that if you're above a certain level, you qualify for therapy. And so, a threshold acknowledges the design of the trials as well as the importance of engaging in share decision-making with the patient about what their options are. Ultimately, if we get well below that threshold or that number, it's not that we want to get barely below a goal, but the lower the better. That's a starting point for discussion around the intensification of therapy.
Desai: We've spoken in prior episodes in this podcast series about the rising prevalence of CRM conditions and the high risk that many of these patients have for not only adverse cardiovascular events, but renal events, and other metabolic and endocrine effects.
Clearly, optimizing LDL levels has to be an important part of the broad approach that we take for these patients. I might ask you, quickly for the audience, to give us a sense of this. I think everyone's relatively familiar with the statins. They've been around for a long time, but as you think about the PCSK9 inhibitor monoclonal antibodies, then maybe bempedoic acid and inclisiran, can you give the audience your thoughts on where we are in terms of those classes of therapies? What might be particularly relevant in terms of the CRM patient, for the practicing clinician out there?
Martin: We're very fortunate to have an armamentarium of therapies. For the patients with kidney disease, sometimes their LDL is not that bad. It's in a mild to moderate elevated zone. A combination of statin and ezetimibe could be a good way to go.
The SHARP trial was one of the early trials to show the use of ezetimibe in combination with statins and the benefits. Although there was not a placebo control for the ezetimibe arm in that trial, that was still an early indicator. That is a commonly used regimen. Many patients also will require additional LDL-lowering to get well below the thresholds, whether it's a 70 or 55, that they're using as the threshold number.
PCSK9 inhibitors, the monoclonal antibodies evolocumab and alirocumab can provide, at the full dose, 60% LDL-lowering. That is with the single dose of evolocumab or in the full dose of alirocumab. Inclisiran can provide almost that amount of benefit, in the 45%-50% range. The PCSK9 monoclonals are injected every 2 weeks vs every 6 months with inclisiran. Many patients who are highly motivated to reduce cardiovascular risk have been very amenable to injectable monoclonals therapy. For those patients who prefer to stick with an oral strategy, we have bempedoic acid, which can come in a fixed dose combination pill with ezetimibe. Bempedoic acid adds a 20% LDL-lowering on top of the ezetimibe. The fixed-dose combination would give a 40% additional lowering. We have robust options such that virtually everybody, if we are aggressive and use everything at our disposal, could get down to optimal LDL levels.
Now, we do run into some prior authorization access challenges, but, short of that, it is a case where virtually everybody can get to where we want to be.
Desai: That's great, Seth. I think your point is so well taken. I love the pragmatic approach that was outlined for our listeners around the use of statins as the cornerstone of therapy. And then between ezetimibe, the PCSK9 inhibitor monoclonal antibodies, inclisiran and bempedoic acid, it's really finding that right combination, if you will, that's going to get that patient to the appropriate LDL.
I think developing and designing a pharmacologic regimen for LDL is important. This is in addition to lifestyle and all the other things that we advocate for. Given the different options that we have available now, it's a really exciting time because I think we can find the right pharmacologic combo that's going to work for most of our patients and get them to the appropriate LDL.
Oftentimes, our CRM patients, especially maybe the reno-metabolic patients who have an important contributor in terms of chronic kidney disease, albuminuria, and then metabolic diseases like diabetes and others, it's often not just LDL, but it's just as much maybe the triglycerides.
Could you give us your thoughts and your sense of where we are on triglycerides? What have we learned thus far? How do you manage triglycerides? And then, what are you excited about in terms of the future when you think about triglyceride lowering?
Martin: Yeah, absolutely. We often see the elevated triglycerides as a mixed picture in these patients. It's often in the more moderate zone, but sometimes severely elevated. I define severe hypertriglyceridemia as 500 mg/dL or more. Anything below that, I put in the more mild to moderate zone. But it's very commonly seen, certainly in the population of patients with kidney disease with metabolic conditions like prediabetes and diabetes. When it's in the severe zone, I would say this is something that clearly needs pharmacologic intervention right away. Typically, a combination approach, including fibrates, omega-3 fatty acid therapy, along with the statin therapy. I rarely use niacin. That is also another option, but certainly, the fibrates and omega-3 fatty acid therapy on top of statin are key options.
Generally, I find that these patients need very close attention — if they have diabetes — to their diabetes management. Often, the patients who are having the most trouble with triglycerides, their diabetes is not under adequate control. Certainly, lifestyle modifications are the foundation of therapy and can help lower LDL, sometimes substantially, often more modestly. But with triglycerides, it can make an enormous difference for some patients, particularly those starting at the high end of the spectrum. If they're drinking lots of sugary beverages, or they've become very sedentary, there can be big room for change, and that change then can be a key part of their triglyceride management.
With patients that have triglycerides below 500, those lifestyle strategies are even more important. That is the zone where the REDUCE-IT trial was with icosapent ethyl. For those with persistent hypertriglyceridemia, we added icosapent ethyl for ASCVD risk reduction in the secondary prevention setting or in other patients that are at risk in this CRM group with diabetes and so forth.
To briefly address your last point around exciting emerging evidence, we've just now seen multiple exciting trials presented using APOC3 inhibitors, and we're seeing strong triglyceride reductions as well as a reduction in the risk for pancreatitis. I wanted to mention that that is part of their need for aggressive treatment in those with triglycerides above 500 is the prevention of pancreatitis.
Frankly, we still have a lot to learn about how lowering triglycerides translates into cardiovascular risk reduction. Although the REDUCE-IT trial saw a cardiovascular risk reduction, it didn't look like that was strongly tied to the TG lowering in that trial. That's where this emerging evidence around APOC3 inhibitors could be part of what we learned from that story. We have such a clean and beautiful story with LDL. We don't have that with triglycerides when it comes to ASCVD risk reduction. That is what I am anticipating we will learn more about in the years to come.
Desai: I think there are so many clinical pearls in what you just spoke about. It sounds like if the triglycerides are above 500, that deserves to be almost a primary focus for intervention. We have to do what we have to do because again, the risk for pancreatitis and other complications come from that. Outside of what we're thinking about for our CRM patients, we've got some evidence for the omega-3 fatty acids, like icosapent ethyl. And then there are a lot of emerging therapies, which again, highlight how prevalent hypertriglyceridemia or mixed hyperlipidemia is in our CRM patients.
This is an unmet need that continues to persist. We haven't had the kinds of improvements in cardiovascular outcomes if for many of those therapies that we might've otherwise expected. It's nice to see that that continues to be an area for therapeutic development because we certainly see that clinically for so many of our CRM patients.
We've talked a lot about LDL, and we've had a great discussion on triglycerides. I'm going to take us maybe to an area that is just emerging but likely will be one that we spend a lot more time talking about. At least, you know, I think we all hope that, and that has to do with Lp(a).
I was hoping that you might be able to give the audience a very brief primer. What is Lp(a), what do they need to know about it now, and what's on the horizon?
Martin: Lp(a) is an inherited atherogenic lipoprotein that is quite prevalent around the globe. Depending on where you draw the cut point, about one in five people have elevated lipoprotein A levels, and those levels are largely genetically determined. There is some biologic variability over time in Lp(a), maybe upwards of around 25% over time in Lp(a), but largely the levels are genetically determined. What's been documented very clearly now in the epidemiologic literature is that the higher your Lp(a) goes, the higher your ASCVD risk is. As well as your risk for aortic valve disease. That's also been shown to be a causal connection through Mendelian randomization analysis. The levels of Lp(a) vary across race and ethnicity. However, in each racial and ethnic group, as the levels go up, there's a similar monotonic increase in cardiovascular risk. So Lp(a) clearly is an important biomarker and risk factor that is inherited, and so it can explain familial clustering of cardiovascular risk. In families that have had excessive amounts of premature cardiovascular disease and aggressive courses of coronary artery disease, Lp(a) may be part of the explanation for that.
It may have particularly strong interactions with other cardiovascular risk factors like smoking, for example. And so, we're learning a lot around its risk. The evidence and the story have built to the point that we now have very effective interventions at lowering Lp(a) in development.
What we know now is that Lp(a) can be robustly lowered using new pharmaceutical agents, and there's multiple agents from different companies at various stages of development. The two that are furthest along and are in clinical outcome trials are the HORIZON trial and the OCEAN[a]-DOSE trial.
When we get the readout from those trials, we're going to know for sure whether this will be an established target for prevention of cardiovascular disease. We're all kind of keeping our fingers crossed that it's going to work out and we'll have a new effective option that would be applicable for many people around the globe.
Desai: There's been some very interesting discussions about how we should be screening for Lp(a), and I think different professional societies and different groups have advocated for different things. The European-based groups have advocated for universal screening, even going back a couple of years. I think the American professional societies are still working through that, and I think we're all eagerly awaiting that. The National Lipid Association recently put out an updated scientific statement that also advocated for at least one-time universal screening, if you will. What's been your approach for that? Have you integrated that into your prevention practice, and your clinical decision-making? What might you say to the audience about testing?
Martin: I've personally checked my own Lp(a). My wife's checked her Lp(a) and in my clinic, I routinely check it for our lipid program. It's just part of the intake labs that we do on patients as they come into our program. We routinely check it. I realize though, that although there are calls for universal testing, we're far away as a health system and as a country, to being able to implement it. Right now, we're in the single-digit percentages in terms of patients getting tested. Although I respect the calls for universal testing, it does seem that we need to also take some prioritized approaches.
I think for the CRM population patients with kidney disease and metabolic disease who are already at elevated cardiovascular risk, Lp(a) could compound that risk, I think would be a high-priority population to test in. I would point back to cases where there's a family history and that may be partly unexplained. That would be another group that it makes a lot of sense to check an Lp(a). I think we're going to see a lot of testing in the years to come, particularly if these trials pan out the way that we hope, but we're still just past the starting line when it comes to getting going on the race for Lp(a) testing. I wanted to certainly advocate for it and say that I've done it in my clinic, and we find it to be a useful part of the care we provide.
Desai: Well, thank you so much, Seth. This was an incredible discussion. We covered LDL cholesterol, dyslipidemia, triglycerides, Lp(a). I couldn't have asked for a better guest, to join us. Please take a moment to download the Medscape app to listen and subscribe to this podcast series. Thank you again for joining us. This is Nihar Desai for the Medscape InDiscussion cardiorenal metabolic syndrome podcast series.
Resources
Evolocumab and Clinical Outcomes in Patients With Cardiovascular Disease
Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients
Two Phase 3 Trials of Inclisiran in Patients With Elevated LDL Cholesterol
Cardiovascular Risk Reduction With Icosapent Ethyl for Hypertriglyceridemia
Effect of Pelacarsen on Lipoprotein(a) Cholesterol and Corrected Low-Density Lipoprotein Cholesterol
Small Interfering RNA to Reduce Lipoprotein(a) in Cardiovascular Disease
A Focused Update to the 2019 NLA Scientific Statement on Use of Lipoprotein(a) in Clinical Practice
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Cite this: Cardiorenal Metabolic Syndrome: LDL Cholesterol, Dyslipidemia, and Lipoprotein(a) - Medscape - Oct 17, 2024.
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