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- [00:03]
A
Welcome to this special series of Diabetes Core Update where we will discuss lp, its importance in assessing cardiovascular risk and what to do about it. I'm your host, Dr. Neal Skolnick, professor of Family and Community Medicine at the Sidney Kimmel Medical College of Thomas Jefferson University. This special series of Diabetes Core Update is sponsored by by Lilly. Joining us to discuss this topic is Dr. Michael Wilkinson. Dr. Wilkinson is an Associate Clinical professor of Medicine in the Division of Cardiology. He is also a lipidologist who directs the Advanced Lipid Disorders Treatment Program at UC San Diego Health. His research interests include lifestyle interventions and novel drug therapies, therapy for patients at risk for cardiovascular disease, and that includes those with cardiometabolic diseases, all forms of dyslipidemia, and those with familial hypercholesterolemia and elevated lipoprotein A. He's received grant support from the American College of Cardiology, the NIH and other agencies. He's published many manuscripts and peer reviewed journals, contributed a book chapter, served as co editor for a textbook focused on prevention and treatment of cardiovascular disease through nutrition and diet. He is an Associate Editor of the Journal of Clinical Lipidology and Jack Advances as well as serves on the Executive Council, as Executive Council Chair for the National Lipid association and on the Board of Directors. Don't worry, I'm almost done with his qualifications. Board of Directors of the foundation of the National Lipid association and the American Board of Clinical Lipidology. I could go on, but won't. Mike, welcome to ada's podcast.
- [02:04]
B
Neal, thank you so much for this opportunity. It's really an honor and I'm looking forward to our conversation.
- [02:10]
A
Mike, before we jump into our topic, can I ask you how you got interested in preventive cardiology?
- [02:17]
B
Yeah, this has been a growing interest of mine for many years. I was really fortunate to have mentors in this field early on. So in my internal medicine residency, connecting with people who really encouraged me to take this on, we see this growing need for identifying individuals at risk for cardiovascular disease and intervening earlier. We're really working hard to develop a better way of detecting risk earlier in life and intervening earlier so that we can prevent things like heart attacks and strokes down the road. So that opportunity to really get involved in a space where we're trying to address that unmet need really spoke to me.
- [03:00]
A
Yeah, I understand that. You know, it's one of those areas where there have been amazing advances and a lot of successes over the last 50 years. When I was growing up, we used to hear of men in their 50s, often dying of sudden death of cardiac disease. And you don't hear about that as much anymore. The stats reflect what most people's experience has been. So there's so much that we've done, and yet residual risk, that risk that remains after all that we've done, still remains a critically important topic, which is why we're talking today. So let's jump in. Twenty plus years ago, LP was recognized as an emerging risk factor. It was something that many of us had heard, heard about, but didn't know much about. It's now become a really important topic that we're hearing a lot about. There are recommendations out there about routinely checking lp. We'll talk about that a little later. Let's start, though, with the basics. What is LP and how is it different than regular OL LDL cholesterol that we've known and loved for years?
- [04:18]
B
Yeah, lp, just like you said, is really emerging very quickly as an important and highly prevalent risk factor for cardiovascular disease. And I agree it's important to start with the basics. What is it? How is it different from other lipoprotein particles? So, just like you said, we talk a lot about ldl, and LDL is a particle that, you know, we've, we've understood the cardiovascular risk associated with LDL for many years. But LP is a lipid particle that is similar to LDL in a lot of ways, but has a lot of unique attributes that really contribute to the associated cardiovascular risk. So in many ways, it's a lot like an LDL particle. It is a lipid particle that's synthesized at the liver, so that's where it's assembled. And in its structure, it looks a lot like an ldl. But one of the really important features that distinguishes it from other lipoprotein particles is this apolipoprotein little A. So that little A, that LP nomenclature really comes from this structure that's attached to the LP particle that really gives it a lot of its unique properties. It contributes to the atherogenicity of LP particles. We also think that it contributes to prothrombotic effects, or we say antifibrinolytic effects of lp, pro inflammatory effects of lp. So think of it as a particle that in many ways looks a lot like ldl, but we really have to recognize it as its own independent risk factor for cardiovascular disease. And it's something like I said, it's synthesized by all of us that the liver and the, the levels in our bloodstream really depend mostly on the LP gene. So structurally, it's different. And in the way that blood levels are determined, it is very different from LDL cholesterol in that for all of us, it's really mostly a genetic risk factor. And those levels and how much our liver makes really depend on the LPA gene that we, you know, the two copies we inherited from our parents.
- [06:37]
A
And so it doesn't necessarily go up or down then. And even though it looks a lot like ldl, it doesn't go up and it's not associated level wise with lp, I. E. If someone has a low ldl, they can have a high lp, is that correct?
- [06:55]
B
That's exactly right, yes. Those two things are going to be independent from each other.
- [06:59]
A
Okay, and can you now go over the evidence linking independently LP to cardiovascular risk?
- [07:10]
B
So that's a really important part of the story that has led us to this moment where we now have expanded recommendations for universal LP screening and a lot of LP targeted therapies that are in development. What it took was many years of both epidemiologic studies and genetic studies, so Mendelian randomization and GWAS studies that established over and over again this causal relationship between elevated LP and cardiovascular risk, namely risk for things like atherosclerotic cardiovascular disease as well as calcific aortic valve disease. So we saw when you look at populations of patients with high lp, a clear link between the degree of LP elevation and increased risk for those cardiovascular events and forms of cardiovascular disease. And then because as I mentioned, LP is almost entirely determined by the LP gene, we can use those genetic studies like Mendelian randomization and genome wide association studies to draw a tight relationship between the inheritance of LP genes or copies of the LP gene that increase blood levels and downstream risk of cardiovascular disease. So it's been many years in the making of all forms of these lines of evidence leading us to really recognizing the importance of lp.
- [08:38]
A
So it has a very separate and independent effect on risk. And therefore the recommendations, as we've learned more, have evolved over time. I know back in 2001, the National Cholesterol Education Program, ATP 3 classified LP and I'm going to quote here, as an emerging risk factor. Obviously, we've learned a lot since then. Can you go over a little bit of the evolution of guidelines in this regard, bringing us to the current and recently released cholesterol American Heart association cholesterol guidelines.
- [09:17]
B
Yeah. So just as you pointed out, our older guideline recommendations really classified LP as more of an emerging risk factor or something to measure especially in individuals at increased risk for cardiovascular events, people with a strong family history of heart disease, people with premature cardiovascular disease. But as we've really grown to understand the importance of LP as an independent risk factor, through those lines of evidence that we were discussing, the guideline recommendations have expanded. So over the past four years now, we have seen a steady increase in recommendations for universal LP testing in adults. And in the US that was recently recommended through the National Lipid association statement on LP. That was from 2024. And just a couple months ago we had the ACC AHA multi society dyslipidemia Management guideline that recommended universal screening of adults for lp. So we have come a long way and a lot of that very quickly over the past four years with this expansion into universal screening recommendations.
- [10:28]
A
And when they say universal screening, at what age should that start? How often does it need to be done?
- [10:37]
B
So we recommend one time testing for everybody, 18 and up. Yeah, there are some nuances to that. We need to think a little bit about what to do for people less than 18. We need some more evidence to guide us around pediatric screening, for example. However, we know that a good starting place is going to be test every adult one time for lp. Great.
- [10:58]
A
So that level doesn't change substantially. And we'll talk about things that may affect it a little bit later. But on the average it doesn't change substantially over time, is that right?
- [11:11]
B
Correct. People reach their LP level by about age 5 and then it tends to be pretty stable from that point on.
- [11:18]
A
So let's now talk about how to interpret those results. And we're going to test for lp. That result is going to come back. It'll sometimes come back in someone who's had their lipids tested for the first time, they're 18 or 20. Many patients haven't ever had it checked. They're 50, 60 years old. That number comes back. How do we interpret it?
- [11:42]
B
So I just want to emphasize the number one thing is to test for lp. And we just need to do a better job of testing patients for LP then what we do with the results. Of course, that's the important next step. And how do we interpret those? It does become a little more challenging with LP because we report LP in two different units of measurement. So if you send your patient for LP testing right now, you might get that test back in either a milligram per deciliter or a nanomole per liter unit. And this is evolving very quickly. We are moving toward a preference to use that nanomole per liter assay. It's overall, the more accurate way of measuring lp. But again, we just want to get people tested. We know that risk associated with LP increases fairly linearly as LP levels go up. But we used cutoffs to really start worrying about cardiovascular risk associated with LP of greater than 50 milligrams per deciliter or 125 nanomoles per liter. Okay.
- [12:51]
A
And it really does get confusing because in the ACCAHA guidelines, they do list both. They list the 125 first. And it really emphasizes how careful we need to be to look at the units that are being reported when it comes back to us. So, Mike, can you give us a sense in terms of the degree of elevated risk? Because it's not just a line in the sand, right?
- [13:23]
B
That's right. It's a continuum of risk. So at any LP level that's elevated above the normal range, there's going to be some increase in risk for cardiovascular events. If you look specifically at atherosclerotic cardiovascular disease risk, ascvd, when you get up to that cutoff that we're now using to really pay attention to LP related risk, 125 nanomoles per liter or 50 milligrams per deciliter, we see a 1.4 fold increase in risk, or about a 40% increase in risk. And if you get to really high levels of elevated LP, 180mg per deciliter or 430 nanomoles per liter, we're seeing four fold increases in risk, similar to other patients with inherited forms of very high LDL cholesterol, familial hypercholesterolemia. So a really important inherited risk for heart disease.
- [14:18]
A
Yeah, so it really is an important increase. The other question that comes to mind is how common is elevated LP? If we look at people with levels above that 125 cutoff, are we going to see that often or is it infrequent?
- [14:35]
B
We're going to see it often. That's the thing about lp, is that this is really, I think, a lot more common than people realize. We estimate that about 30% of people will have some elevation in their LP above that 30 milligram per deciliter or 75 nanomole per liter cut off. And then for LP associated risk, those higher risk patients with LP levels above 50 milligrams per deciliter or 125 nanomoles per liter, we think about 1 in 5 or 20% of people will be in that group. So if you think about the current population of a country like the us, if we're, you know, if we're considering a risk factor like that, you know, 267 million adults in the U.S. 1 in 5 have high L.P. above 50 milligrams per deciliter. That's 53 million people, 53 million adults living in the U.S. with high L.P. yet we are testing less than 1% of patients. It's a big gap you need to fill with increased testing.
- [15:44]
A
That sure is. And that's where education is so important. Because when we have new things emerge that we ought to be paying attention to, we can't pay attention to things we're not aware of. That's why I'm so glad you're joining us on this podcast. Let me ask you a few practical, clarifying questions before we get to what to do about it. And one, does LP need to be measured on a fasting specimen?
- [16:09]
B
No, it does not.
- [16:11]
A
Okay. We talked about the fact that it's a once in a lifetime test. You don't have to keep repeating it. But are there any other things that affect it? Things like menopause, chronic kidney disease, or anything else that we should be aware of?
- [16:30]
B
There are. That's some of the nuance around LP that we're going to need to appreciate more and more, especially as we're looking for it more often, testing more of our patients. Most of the level is genetic, but you're static. There are things that can influence lp and we're even learning that for individuals, if you repeat their LP level, there's going to be some variation. But like you alluded to, there are certain situations or other medical conditions that can impact LP levels. So just like you said, with worsening renal function, we see increases in lp. With liver and thyroid dysfunction, pregnancy is associated with mild increases in lp. The menopausal transition, loss of estrogen effect increases LP inflammation, and certain medications, including in some cases statin therapy. These are things that can cause modest increases in lp.
- [17:29]
A
Interesting. So we've established lplidated risk marker. We ought to be checking it. The next obvious question, what do you do with that information you've ordered? It comes back elevated. What then?
- [17:46]
B
The most important thing that we can do right now with LP is to incorporate it into our individualized assessment of patient risk and use that information to really provide our patients with a better understanding of their risk for cardiovascular disease, to encourage them to take steps to optimize their overall cardiovascular health. So we look for other modifiable risk factors. When we identify a patient with high lp, blood pressure is high, we treat it. If LDL cholesterol or apob isn't at an optimal level. We treat it, we use LDL and APOB lowering therapies. So that's the current approach to the patient with high lp. But as we've alluded to already, there are a lot of targeted therapies for LP in development.
- [18:35]
A
So we'll talk about them in a couple of minutes. I just want to throw out a case for you. Let's say we're seeing a 52 year old woman, no past medical history. Total cholesterol is mildly elevated,210, HDL of 50 and LDL of 136. If we put those numbers into the prevent calculator, her tenure risk comes back at 2.5. Her 30 year risk is calculated at 18% so it puts her in the 57th percentile. These calculators are amazing. We need to get used to using the prevent calculator. She's categorically though below the level where statin would be routinely recommended. She isn't in the group of people who automatically had an LP done in the past. Should we think about getting an LP on her and how would it help our decision making for her?
- [19:34]
B
Well, we absolutely should measure her LP now we've got that in our major society guidelines for identifying patients at increased risk for cardiovascular disease and incorporating LP into our prevention strategy. So I think in this case, I think it's really the perfect case to think through what additional information we could use to provide this patient with a more individualized assessment of her risk. That's really where LP comes in. Even before the recent guideline update that recommended use of universal screening of adults for lp, LP was acknowledged as a risk enhancing factor. We have to find some way of incorporating it into our overall risk assessment for a patient. And there's a list of other risk enhancing factors. Kidney disease, for example, disorders of pregnancy like preeclampsia, gestational hypertension, that can increase risk for cardiovascular disease that aren't incorporated into something like the prevent calculator. So in her case, I'm thinking through all those things and I'm adding LP to recalibrate that risk estimate, the prevent equation, it's a good starting place, but we've got to use things like lpa, other risk enhancing factors and other tools like imaging, coronary calcium scoring to give us a more refined risk estimate.
- [21:01]
A
So as we get that our LP back for her, her prevent score was 2.8% tenure risk, let's say her LP came back at 225 millimoles. Per liter. How does that. What would, would it change what we do for her?
- [21:22]
B
It would. I think one of the challenges, one of the unmet needs in this space is how to quantify that change in risk for a patient like this when you add that into the equation. So if we go back to our discussion about Lp levels influencing ASCVD relative risk, 250 nanomoles per liter, that's a twofold increase in risk. We're starting out with estimating her risk as low by prevent, 2.8% over 10 years. We've got to at least qualitatively throw in LP and that roughly twofold increase in increased risk for ASCVD. So it does really change the discussion that I'll have with a patient like this, because one of the other things that we always need to be thinking about is not just shorter term risk or 10 year risk, but 30 year risk, lifetime risk. And if we find high L.P. again, it's mostly genetic. This patient has had high L.P. her whole life. So I think without acknowledging that, we're likely to underestimate her risk.
- [22:33]
A
Yeah, I've heard some of my primary care colleagues say, well, if there's not a medicine to bring it down, why even check it? And I've often responded to them saying, well, it's kind of like family history. It is what it is. But we still ask about family history because it influences our assessment of risk and therefore how avidly we approach our other modifiable risk factors. And, you know, I think one way to think that I think about LP now is in a way similar to family history, that it is important information with regard to decision making about other modifiable areas. Does that make sense to you? Is that a reasonable thing for our listeners to incorporate as an approach?
- [23:30]
B
100%. I completely agree with you. I think that's part of why we need to be testing all adults for LP now. It is actionable. We don't need an LP targeted therapy to make knowing a patient's LP actionable. But of course, that's the future. We'll get there.
- [23:51]
A
We're getting to the future and the future of this podcast in about five minutes. So first, let's just go through pretty quickly, if we can, the effect of currently available treatments that are targeted to LDL. And we have statins, we have ezetimibe, we have PCSK9s and glycerin and bempedoic acid. How do they affect LP?
- [24:18]
B
So, great question. And these are our tools that we're currently using for lowering Cardiovascular risk. And I think that's one really important point, is that we're really not using something like a statin to lower lp. They don't lower LP in some patients, as I mentioned, they may even contribute to some modest elevation or a modest change in lp. Um, but they're very, very good at lowering LDL cholesterol and lowering cardiovascular risk. And so in those patients at increased risk who would benefit from a statin to lower their risk for heart attack and stroke, we should be using them, including in those patients with high LP. Ezetimibe has really little to no effect on LP and PCSK9 inhibitors. They have a variable effect on LP, but they really are one of the few things currently available that can produce some LP lowering. So it's variable and the effects are relatively modest. We see at best about 20 to 25% reductions in LP with PCSK9 inhibitors. But the recent guidelines do suggest that we reach for LP. Excuse me, reach for PCSK9 inhibitors. When LP is elevated in patients with cardiovascular disease who need add on therapies, who need to intensify their LDL cholesterol lowering with non statin therapies.
- [25:43]
A
Excellent. And then inclisiran and bempedoic acid. Do they have any effect?
- [25:49]
B
Bempedoic acid? No. Again, that's going to be helpful for LDL cholesterol lowering as part of the overall strategy to lower cardiovascular risk. Inclisiran is a PCSK9 inhibitor, SIRNA, and also lowers LP. The effects are similar to what we see with the monoclonal antibodies. And again, it's a variable effect. But we have Data from the PCSK9 inhibitor monoclonal antibody outcomes trials that suggested in those patients with the highest Lp levels there could be benefit to even more modest Lp lowering with PCSK9 inhibitors. So that's why those monoclonal antibodies that inhibit PCSK9 have that place in the current guidelines is something again to consider reaching for in patients with cardiovascular disease, high LP who need more LDL lowering.
- [26:42]
A
That is all very helpful, and that's what we have now. But Wayne Gretzky, the great hockey player, was once asked by a reporter from the New York Times what made him such a great hockey player. And he said that he never cared where the puck was. He spent obsessed, he spent his life obsessed with where the puck was going. Let's now talk about where things are going. There are some medicines in the pipeline for LP lowering. Can you tell us a little bit about those?
- [27:17]
B
I'd be happy to. We're discussing how prevalent LP is, we're just scratching the surface of identifying patients at risk due to elevated lp. But thankfully, as we're ramping things up with our testing and identification of patients, there are targeted therapies that are in development. And the genetic basis of LP actually lends itself to the use of these targeted therapies that are in development. These are, for the most part gene silencing therapies. They are RNA based therapies directed at at lp, directed at the product of the LP gene I mentioned. One of the really important structural features of LP is that apolipoprotein, that's what the LPA gene encodes for. And if you can go after the MRNA that is required to make that apoa, you can put a big dent in the liver's ability to assemble LP particles. So pelacarson, opacirin, zorlacerin, lepidycerin, these are all RNA based therapies that go after that LPA mRNA. And we've seen in the trials that have occurred to date pretty dramatic reductions in LP levels with these therapies. So there's a dose dependent effect, but if you give subcutaneous injections of these drugs, we can get up to 85 to 95% reductions in LP.
- [28:57]
A
Wow.
- [28:59]
B
There are other therapies currently in development. There's an oral therapy called mobile Applin, which is a inhibitor of LP assembly. So that actually gets in the way of the LP particle's ability to be assembled for that APOA to bind to the rest of the particle. We see placebo adjusted LP reductions up to about 85% with that therapy. So with very few exceptions, these drugs that I just mentioned are now in phase three cardiovascular outcomes trials. So the really exciting thing right now in the development of these LP lowering therapies is that we are really on the cusp of learning to what extent, to what degree does lowering LP prevent cardiovascular events like heart attacks, strokes, peripheral arterial events? These are all the focus of these outcomes trials. And we're going to know very soon how effective these drugs are at lowering risk by reducing LP really dramatically.
- [30:12]
A
That's amazing. So if they're currently in phase three trials, there is a reasonable chance, chance that at least one of them may, if things go right, be approved by the time our current group of interns, who just started in the last couple of weeks, graduates in three years, right?
- [30:37]
B
Yeah, that's exactly right.
- [30:39]
A
It is amazing how quickly things move and the rate of innovation in pharmacologic therapies. They say the right the days move slowly, the years move quickly, and it sure is that way with regard to innovation and new therapies. We're about out of time. Do you have any final thoughts for our listeners?
- [31:08]
B
Well, Neil, I just want to thank you again for the opportunity to join you for this. It is a really exciting time in preventive cardiology and in lp. And, you know, our understanding of LP has just expanded so quickly. The therapies that we have in development are giving us a lot of hope for a future where as we expand testing, as we identify patients with high lp, we'll have more and more things to offer them. And I think for now, it really is. Yeah, it's. It's the time. The time is now. We should test. We really need to start moving the needle on the identification of patients who are impacted by this very prevalent risk factor for cardiovascular disease. So my final message to everyone listening would be to get your LP checked. Encourage your patients to have their LP checked. For those who have had their LP checked, talk with your family about it. Give family members, test it again. This is inherited. This is mostly a genetic risk factor for heart disease. So cascade screening, identifying affected family members is really important. We need to be having these conversations in the clinic and with our families.
- [32:26]
A
Fantastic. Dr. Michael Wilkinson, thank you so much for joining us.
- [32:30]
B
Thanks again, Neal.
- [32:32]
A
And most of all, of course, as always, thanks to our listeners. Thank you for joining us on this special edition of Diabetes Core Update, discussing lp, its effect on cardiovascular risk prediction and treatment. We heard a lot of information from Dr. Wilkinson, an expert in the field, how LP is distinctly different from ldl, how it tracks at a given level throughout one's lifetime. So that the current guidelines, the ACCAH guidelines, recommend checking LP for all adults at least once during their lifetime. And that knowing that both affects our current risk assessment and in the not too distant future, there may be therapies to help us directly address LP and further chip away at residual cardiovascular risk. This special edition of Diabetes Core Update is sponsored by Lilly. We thank you for listening. For the American diabetes association, I'm Dr. Neal Skolnick. Till next time, stay safe and keep learning.