Chapters Transcript Video Updates in the Management of Dyslipidemia: Statins and Beyond Dr. Nishant Shah discusses dyslipidemia and how to manage patient’s risks to decrease cardiac events. Thank you so much, Eric for the very kind introduction and it's an absolute honor to be here today to speak to you guys. Um Thank you so much for the wonderful hospitality, lovely dinner yesterday. Um topic today that I'm gonna talk to you guys about is something I'm very passionate about. Something that I focused a lot on from a clinical trial perspective and an implement implementation science perspective. And that's just uh dyslipidemia. And there's a lot that has gone on over the last several years in terms of uh managing dyslipidemia, you know, with statins of, of course and beyond. So I'd like to discuss all that to kind of catch us up on where the data currently is. These are my disclosures. Um However, this talk is purely meant for educational uh reasons. So why do we need to talk about dyslipidemia? So what, why is this such a big deal? And it's because we want to prevent atherosclerotic cardiovascular disease, we want to optimize our patients risk uh so that they don't have events. Well, what is atherosclerotic cardiovascular disease? Um by definition, in the current guidelines, that is non fatal in line non fatal stroke, tiap ad, non obstructive C ad and any aortopathy, karate disease or arterial revascularization. So it's a loaded, loaded, loaded definition. Um But it's very important to know exactly what we're trying to prevent. But as you guys are probably all aware, there is a calculator that can assume risk that we currently use in the, in the guidelines. But they're very important caveats to remember. Um Which is why uh folks like me in the prevention space really like to focus on some of those gray areas where it's not so clear cut. Um But again, when you're calculating someone's risk for having an event, um it, the calculators currently assume that a patient has not had a prior M I or stroke. They're aged between 40 75 they're ideally not already on statin therapy. Uh They have a total cholesterol less than 3 20. And again, this can, there's underestimate uh underestimation and overestimation based on age. So important caveats. This is what the risk calculator looks like. Now, I know this is a busy slide and the font may be small, difficult to see, but essentially it puts in a patient's demographics and comes up with a 10 year risk and what the 10 year risk puts you into four different buckets. You can have a less than 5% risk of event in 10 years that will put you in a low risk bucket. 5 to 7.5 puts you at borderline risk 7.5 to 20 intermediate and greater than 20 high. Again, very important to note that this is patients between the ages of 40 se 75 without diabetes and don't have an LDL greater than 100 and 90. What do you do with those risks per the guidelines? So, if you're low risk, less than 5% then the guidelines just recommend having a risk discussion and looking at uh lifestyle interventions as your primary target in lowering an LDL cholesterol. However, that risk discussion is such a key piece of this because there may be a family history that is being unaccounted for moving on to borderline risk. Again, same thing. And it's important here to identify the risk enhancers. And we'll talk about exactly what that means when you're in intermediate risk. That's when we start thinking about therapy. Uh that could be statin therapy, that could be nonstatin therapy. It all depends, you know, the key here is a patient centered uh discussion. Um But again, think about those risk enhancers and your goal ideally is to reduce the LDL by 30 to 49% even at intermediate risk patients. And then of course, those at high risk, you want to reduce the LDL by 50% almost exclusively. Uh If you look at the current guidelines and look at where the current data is, uh all of these patients would benefit from being on uh statin therapy at least at moderate intensity, if not high intensity. But there are risk enhancers to keep in mind that can reclassify someone. So for instance, you could have a 30 year old patient. I just saw one in clinic before coming here yesterday. Uh I had a 30 year old patient who had an extremely strong family history of his father passing away at age 32 and he had a lipo protein A level which I'll talk about that was over 200. None of those things. The family history or the lipo protein A level are calculated in these risk calculators for A S CV D. And so the risk enhancers to always think about something I always tell my fellows to talk about um is understanding of premature family history of A S CBD or not. And what that is by definition is a cardiovascular event in a male, less than age 50 or a female, age less than 60. And these have to be first degree relatives. That is by definition, what a premature family history of uh A S CBD is um persistently elevated LDL. Despite interventions, treatment of greater than 1 60 chronic kidney disease oftentimes overlooked, but a very potent risk factor for aroar cardiovascular disease metabolic syndrome. Uh One of the biggest things uh that we cannot miss is thinking about um in our female patients pregnancy history. So, if they've had gestational hypertension, preeclampsia, gestational diabetes, um and then also menopause if they're premature menopause, these are all. So, uh risk factors of coronary disease, inflammatory diseases, uh ethnicity, particularly South Asians, they tend to have a higher risk and then biomarkers, I'll talk a little bit about them later in the talk. But high sensitivity CRP is greater than two and then particular lipid markers, lipo protein, a greater than 50 milligrams per liter and a ob level greater than 1 30 in the elevated triglycerides. And of course, don't forget getting your A bis uh especially in clinics. That's uh especially if you have long term smokers or anyone who's complaining of any sort of leg uh symptoms, even if it doesn't sound like classic claudications. We're really pushing to uh getting people to get a bis because P AD in itself is a very under diagnosed condition. But we've all seen these scenarios um in that someone may come back at us and say, hey, look, I don't know if I want to be on a statin uh or I'm physically active, I'm eating a plant-based diet. I don't even know if this medicine will help me. There's a lot of, you know, things I'm reading online on Twitter nowadays that say I shouldn't take a statin, I need proof. This is the perfect patient of who's like hesitant to be on therapy to do a calcium score. So currently in the guidelines, the calcium score has a two a recommendation. Um uh So, and there's more and more evidence. Now, the guidelines of the cholesterol guidelines have last been updated at least in the US in 2018. I suspect that this is going to get a higher recommendation in guidelines in the future. Um Other societies have started increasing the or lowering the threshold rather for getting coronary calcium score. But this is a great example of being more precise in your risk assessment. So uh you for all of us here, probably know how these coronary calcium work. They're noncontrasted CT scans. People can just walk into uh the scanner get scanned, oftentimes in some protocols, the radiation given by a coronary artery calcium uh test is the similar to a chest x-ray or even a mammogram. Um But different protocols can be different. Uh However, it's, it's nice because um you can pull up this in your clinic visit and if show the patient their arteries and say, look, you have evidence of calcification, you have evidence of plaque development and oftentimes that changes people's um thought about starting treatment. Um This is one of my favorite studies ever to show the impact of coronary, arty calcium and all cause mortality reduction. So, these are two independent cohorts. Um One has a five year follow up. I don't know if y'all can see my mouse here. Uh look like it, but the one on the left has a five year follow up and the one on the right has a 12 year follow up And from the top, the top line, uh on these curves, the calum curves is uh calcium score is zero. And in a graded fat, you go from 0 to uh 1 to 100 to 100 to 400 to 400 to 1000 and greater than 1000. And as you see, there is a graded increase in all cause mortality over time. Assuming you did nothing, assuming you left that patient alone, both at five year follow up and at uh a 12 year follow up. Moving forward, this was a nice study led by uh Mike Blaha and Kareem Nazir and colleagues, again, sort of landmark in the coronary artery calcium space that compared the interplay of traditional risk factors. So, diabetes, smoking, hypertension, uh and coronary artery calcium score. And if you look uh at the color coding, um assuming you have uh and I hope people online can see my mouse, but if you look all the way to the right, um if you have greater than equal to three traditional risk factors, but a cordinate artery calcium score of zero. So this yellow box all the way on the right, your risk of mortality is lower than, let's say if you had no traditional risk factors. But a coronary artery calcium score of over 400 the top left over there. So it goes to show how potent of a prognostic factor. Uh A coronary artery calcium can be especially in patients who are hesitant, uh uh one of being on therapy but also want to better understand their risk and aren't really satisfied by the ac cah a risk calculator. And then we also have a way if you want to plug this in to reclassify the risk in their overall risk calculator there. If you uh based on uh MESA, which is a large, large, large, large registry, multiethnic, um very diverse um where a lot of um with a lot of data for coronary calcium score, they've created a way for you to be able to plug in someone's total calcium score, putting that into um the risk calculator to reclassify someone's 10 year risk for an event. Um So it's, if you're interested, just Google mesa uh risk calculator and it'll, it'll show up. So some of the things to consider about calcium score. I, as I mentioned earlier, the pros the radiation dose is low uh in, in several protocols now, um can easily be done uh just by walking into a clinic. Um You don't have to really prepare, there's no contrast, there's no IV and it can really be precise, it can individualize one's risk. However, there's also cons as well. Uh There is radiation even though it's low dose radiation, uh the cost can vary by center. So like I often times um uh take that into account and we've partnered a lot with some of our surrounding sort of private radiology groups that will just do this out of pocket for anywhere between 80 to $100 versus some pay lists where you have to actually go through insurance. And let's say the insurance approves it. The copay is still higher than that 80 to $100 that they could get some uh very nicely vetted private radiology vendors. And so, um you can work with the patient uh to figure out how the best to lower the cost. But then also incidental findings. What are you gonna do with like uh you know that nodule, for instance, that'll pop up, you know, you have to be able to follow up on it. So keep that in mind and that incidental findings oftentimes leads to downstream testing. I've also uh with a lot of calcium swing that I do found a lot of dilated aortas, which I'm glad I did. But um that's something to just keep in mind. Um and then future questions, you know, when do I worry about stress testing? Do I let like a high calcium score dictate? Um if I stress the patient or not, and there are studies now that are looking at that. Um And if there's any benefit in outcomes, um is there a role for serial calcium scoring? So, uh there is data um on that and typically what we recommend for serial calcium scoring is un we really only do that in patients who have a baseline calcium score of zero and who are not on any therapy because of that and then doing it every five years or so to see if they have developed calcium because statins in general can influence coronary artery calcium. And so if someone's already on a statin, I tend to not seriously check because um I know that some of it might be confounded. Um And then in the elderly patients or renal disease and things like that, that can also influence um calcification. So, so what is the benefit of a calcium score in, in an elderly patient? So, all right. So we talked about risk, we talked about uh all the things that we can do to assess risk from the risk, calculators to the risk enhancers to the calcium scoring for more precise risk assessment. Well, how do you manage it? So, the foundation of management is statins and this is probably a table that we've all seen at various points in our lives. But um there's low intensity, moderate intensity and high intensity statins by the textbook, uh LDL reduction for low intensity standards can be less than about less than 30% up to 30% moderate, 30 to 50 high intensity, greater than 50. However, in anecdotally speaking, I've seen variable response. So I could start someone, let's say on a moderate intensity of rosuvastatin at 5 mg. Um and they can have an over 50% LDL reduction. People tend to absorb these medications metabolize these medications very differently. So, um by textbook, on average, these are kind of the percentages but um everyone just be mindful that everybody can have variable responses um in my practice and this may just be me. Um, but I know me and a lot of my colleagues, we tend to not do anything more than Reba and a Tova statin anymore. Um mainly because one, we have a way to get up to high intensity dosing if we need it to. Um, and two, both of those tend to be more tolerable. Avastatin is, uh, kind of a little bit more lipophilic, which tends to be more intolerable rather than resin, which is more hydrophilic, which people tend to tolerate better. And so, uh, and now as we'll, we'll get to later in my talk, there's so many other options for patients that, um, uh, you know, if you are intolerant to either one or both, we have more things in the toolbox. Um, but there are people that have been on pravastatin for a very long time. There are people that have been on simvastatin for a very long time and it's working and they've not had an event, let's say their primary prevention. Um Then I, you know, if it's working for them, I tend to leave them alone. I don't make that switch. But if I were to initiate a statin, I tend to do that. Um, again, the high intensity statin that those dosing are re suva 20 to 40 A tova 40 to 80. Those are high intensity cents, anything less than that for Reuven A Torah would be moderate intensity. And uh I put here that, you know, moderate intensity statins are again class one recommendation for intermediate risk patients or borderline risk is two B and then high intensity uh class one recommendation for those higher risk, greater than 20% event risk in a year. Um how to use coronary artery calcium score to dictate statin treatment. So if you have zero, usually it favors no need for treatment, but be careful with that. It's not just zero calcium score means no treatment. You could also have things like an elevated LP A or you could just be 28 years old and have not developed any plaque yet. And therefore you have no calcium. And also remember, zero calcium doesn't mean zero plaque. You could still have soft plaque development. So, again, patient centered discussion um to really be sure that we're OK, not treating at this point point, but any anything from one to like on favor statin therapy, especially if you're greater than 100. How do we reassess lipids? So this is a uh a thing that I always tell, you know, my, you know, colleagues around um our health system as well as our fellows and everything is like every time you start a treatment, you gotta make sure it's working. So reassessing the LDL is actually recommended in the guidelines as well. So there's, you have backup there. So every 4 to 12 weeks after in initiating a stent or adjusting a stand dose, we recommend rechecking an LDL just to make sure you're hitting their target goals. And I'll talk about what those are. But, uh, a routine measurement every 3 to 12 months is also very reasonable, particularly in a patient who, who has aros cardiovascular disease. And fasting is typically not recommended unless you're looking for a genetic dyslipidemia or uh triglycerides. If you're trying to assess triglyceride, then we typically recommend fasting. I personally don't recommend fasting for LDL alone as well just because I want to see what their LDL is like in their everyday life. And so, uh it, it gives me a good, good um assessment. Uh and for primary prevention, the goal that we're trying to reach is less than 100 in general. Now, if you have somebody that has an elevated calcium score, however, then we treat those patients as if they've already had an event. So then those are the patients that we try to move less than 70 mg per deciliter. Um But we may encounter stat intolerance and just two weeks ago at AC C stand intolerance got headlined on every media source. Um uh Thanks to uh Steve Nissen's trial on clear outcomes which we'll talk about. But um stand intolerance is, is, is uh is interesting. So, um the there's a lot of definitions for stat intolerance. Most of us use the National Lipid Association definition, which is the inability to tolerate at least two statins uh at the lowest starting dose due to objectionable symptoms. So, symptoms that start after the onset of the drug and abnormal laboratory values that also are abnormal after the onset of drug that both resolve with discontinuation. So it's a loaded definition. Um but it, it seems to be the most uh consistent definition um uh out there and also one that we adopt a lot in our studies in clinical trials and, and so forth and so in terms of adverse reactions. So, myalgia um are a thing with statins and anywhere between 3 to 5% stiffness, soreness uh at arthros aching, those are probably what you commonly hear about. Again, if we look at the actual statistical numbers, they're not that common, but there is a pretty profound nocebo effect, uh myopathies, which is where you really start worrying, especially when you start seeing CK levels trend upward, uh greater than five times the upper limit of normal er CK levels that uh you need to be concerned about nuance. That diabetes is a thing that we, we're actually just publishing some data uh in the journal of the American Heart Association, actually defining this subgroup. And this is usually a patient that already is insulin resistant. And so they have metabolic syndrome or they're prone to get diabetes, they're overweight. These are the patients you want to worry about their A one C going up. But there's been several, several, several studies showing that the benefit that that patient would achieve by being on a statin far outweighs the risk of the hemoglobin A one C going over the threshold of diabetes. Um, and then hepatotoxic when your uh, liver enzymes go up three times the upper limit in normal. So those are the things to look for um how to manage that intolerance. So it's much easier in the secondary prevention realm. In the primary prevention realm, it gets a little bit harder. So secondary prevention if you are intolerant and depends on the state that you're in. But if you are intolerant to at least two statins, that is enough to have most commercial insurances approve lipid lowering therapies beyond statins. And we'll talk about what those are but like P CS K nine inhibitors, uh monoclonal antibody or SI RN A type. Um and others. Um and so uh also don't forget about ezetimide that can be your friend, especially in ST tolerate uh intolerant patients. Let's say you have a patient that can only tolerate five of recoin. Don't forget to throw on a Zam because Zam can also give you an additional 30% reduction. That may all be all you need to get that patient to go um in the primary prevention setting. However, if you've not had an event that's where it gets a little bit harder. So historically, this is where people have done the, the art of deescalating the dose. Uh trying every statin known to man alternating, you know, daily dosing once a week. Statin. I mean, people have done all sorts of stuff is that I can be your friend here too. But I think that now uh what, what we've been doing in the prevention circles and, and now even more so because we have data behind it is we've actually been looking for disease in these patients. So we've been risk stratifying. So we get a calcium score to see. Do they actually have atherosclerotic cardiovascular disease? You get a bis, um you can get carotid doctors, you can get studies to really assess this person's overall risk because now the FDA has loosened their guidelines a little bit that if you have even non obstructive aros to cardiovascular disease, you can, you can get approved for a P CS K nine inhibitor or so on to really help that patient's LDL come down. Um And of course, don't forget about familial hyper cholesterol Leia. Well, if you have an LDL greater than 1 90 make sure you think about that because familial hyper cholesterol Leia alone is an indication for A P CS K nine inhibitor um or Beidou acid and uh you know, advanced lipid lowering agents. The other things I always tell people about too is look at the patient as well. So, hypothyroid patients, they tend to be more intolerant. So, seeing if their thyroid levels are um at, at a good level, what other drugs are on fibrates or common drugs that can cause statin uh interactions with statin drugs and lead to statin intolerant symptoms, aols, a Odone uh diver apa sorry eric, uh these uh agents can also lead to um uh statin intolerance as well and then heavy alcohol use. So um just keep those things in mind. Uh but I mentioned familial hyper cholesterol Leia. Um and, and what is that exactly? So it is a gen genetic condition. There's where there's a problem in the LDL receptor. So your LDR receptor is essentially not functional and there's four or four mutations, but three that are much more prevalent. The most common mutation is where you actually have a issue on the LDL receptor. The LDL receptor is defective. So, if you think about your hepatocyte, where LDL is metabolized, you have receptors that can't suck in LDL coming from the bloodstream, um they just, they just can't. So, hence, you have a lot of LDL in your blood, you can have a AOB dysfunction. So, a OB is a, a lipo protein that is on top of LDL that binds to a receptor. So if you have a functioning LDL receptor, but you have whatever binds to the receptor to suck that molecule in that's not working. Hence, you're gonna have a lot of circulating LDL and last a gain in function of A P CS K nine. So P CS K nine is a uh a molecule that usually degrades um LDL receptor. And so, so essentially, if you have a gain in function, you have a lot of P CS K nine around, you're going to recycle, you're going to degrade all the receptors. So your surface is gonna be naked. You won't have any LDL receptor to suck in LDL. So again, you're gonna have a lot of circulating LDL. Hence, we inhibit P CS K nine to allow for more LDL receptor on the surface of the pacy to uh bring down on cholesterol. But those are like the, the most common mutations, you can be heterozygote or you can be homozygous heterozygote essentially for those that remember, you have one bad uh mutated gene from one parent and a good one from the other parent. And this is uh and this is an important distinction because uh homozygous where we have two bad genes in homozygous patients, all the therapies you try may not work at all. So like you could try, you could give somebody a statin. Um but they have two dysfunctional LDL muta uh receptors. There's, there's no way you because it's the way the statin works is that it increases the expression of LDL receptor on the pedo site. So if, but if all those receptors are dysfunctional because you have two bad mutations then no, it's not gonna work stands will be ineffective. And we, you guys may have all seen patients where you start lipid lowering agents and nothing is working to bring down the LDL uh versus heterozygote half the receptors may be working. And so they'll have a response to treatment and that and, and that's a more common uh phenotype that we see in clinic is the heterozygous FH patients. So how do you manage these? Like, what are our goals here? So typically, if you have an LDL greater than 1 90 in a patient, start thinking of FH that should be like your red flag. Is there is this, does this patient have FH what is their family history like? Is cholesterol run very rampant in the family? Um High intensity stands to reduce the goal of LDL by 50% is ideally or 100 or less. So, whichever is lower. Um That's what you wanna do in primary prevention. If unsuccessful add a zine to your stem, if that's not helpful, then go and add a P CS K nine inhibitor. That's just the, the algorithm in the guidelines. Um And then of course, Duodote Acid as well, whatever, whatever the patient um is comfortable and you're comfortable with. And I can, I, I can talk about my approach and how I pick. But uh for secondary prevention, just like anyone who's had an event, less than 70 lower, the better. So you really really, really want to put, push it down. And now if they're homozygous, we have some advanced therapies um, that are currently out there and FDA approved. Um, but oftentimes these patients end up also getting a, a first. And so, um, just keep that in mind essentially dialysis for lipids. Um, but, um, some of these patients need it. Um, the guidelines for secondary prevention are pretty clear cut. Um, I think that, uh, looking here, they, they, I try to just um divide the groups into high risk secondary prevention and just regular risk, secondary prevention. But the end goal is the same, you want the LDL to be less than 70 as best as possible for those that are above 79 at least in the 2018 of the guidelines. They say uh they don't necessarily target a goal but there's been a lot of um they wanted you to get low but, you know, if you're under 70 that's fine. But there's newer, it, there's newer guidelines and newer consensus statements that are trying to push it lower even despite um elderly, especially their functional elderly patients. And we've all seen that too in clinic and that you'll have patients who are 80 but they are robust like they are functioning as if they're 65. Um You know, and so you definitely don't want to just use age as a limitation in treating them. You want to treat them as if you would treat them if they were five years younger at 75. So I, I, they, they, they use this age cut off. But I think the biggest thing to take away from that is, you know, risk benefit and, and, and seeing, you know, it is these preventive therapies, are they going to, are they gonna live long enough to, to have a benefit from these preventative therapies? So, more recently, um uh a group of uh uh folks uh came together and they came up with this expert consensus decision pathway. I know this is hard to see here. It's long, but essentially the summary of it is that in high risk A S CV D patients, what that means by definition, someone with multiple events, someone who's young, who's already had an event, someone who has very difficult control LDL or have diabetes, you wanna push these people to an LDL less than 55. And that is actually consistent with the European cholesterol guidelines that are also pushing patients at high risk for A S CBD to less than 55. So it's not 70 anymore. It's try to push these people as low as you can and you may not get there alone with a statin. So keep that in mind and that's why it's important for us to understand these other therapies. Another angle in lipemia management is hypertriglyceridemia. Uh Oftentimes we see uh this as a bigger issue than the LDL. Now, the way you know why hypertriglyceridemia is important to us. You know, the, the actual, the, yes, it's a risk enhancer when you're above 100 and 75 for aroar of cardiovascular disease. But more important you want to avoid pancreatitis, you know, that that is the biggest thing. And so uh the redo the reduction in hyper Triglycerin is really, really to get you to a point where you want to keep them under 500 ideally to avoid pancreat complications. And almost the exclusively hypertriglyceridemia in many cases is is secondary. So, lifestyle modifications is important and identifying secondary causes is also extremely important. Common culprits, obesity, uh diabetes, um hypothyroidism, liver disease, renal disease and medications as well, which I've listed. Um and for us in cardiovascular disease, diaz sides beta blockers um uh on our transplant patients like to inhibitors. Those can certainly lead to uh elevated triglyceride. Um Now, what do we do to manage triglycerides? So, historically, um people have been using fibrates, uh fibrates uh work because they definitely bring down the number in terms of absolute reduction of triglycerides. However, to date, there's not been a fibri that has actually shown us any cardiovascular outcome benefit. Uh at A H A. Uh in 2022 you guys probably may have heard of the prominent trial that looked at um Penna fibrate again, looking at a high risk A S CV D cohort to see if Penna fibrate on top of statin therapies will reduce outcomes and they did not um there was a signal towards some improvement in the fatty liver disease space, but they need to study that more. Uh And it's interesting, you know, I was talking to a lot of uh folks at A H A and in the US right now after statin, the next most common lipid lowering therapy that has been that is being prescribed are fibers, but we have no cardiovascular outcomes as so a reduction with fibers that we know of. And so it goes to show, you know, are, you know, do we need to continue these therapies and patients who don't, aren't really on them for high triglycerides or their triglyceride control with other methods. Um but I say it, it is an interesting conversation. So, Niacin is another therapy for hyper trigly ria again also associated with no cardiovascular outcome benefits in large clinical trials. Um Niacin uh tends to also have a lot of side effects. So to keep that in mind where we have seen some signal of improvement uh in outcomes and and it's a highly debated topic right now in the prevention circles for sure, is in the omega three fatty acid phase. Um in prescription strength, omega three fatty acids like icosapent, for instance, or vasa is the name of the brand name um that is a purified uh epa fish oil um uh with icosapent acid. Um The the other types of prescription strength fish will have a combination of icosapent toto acid or EPA and DH A. Um And then there's other plant based fish oils that we haven't really studied that well. But I mentioned, uh icosapent ethyl is because this was uh studied in the reduce it trial, which was a multi centered double blinded placebo controlled trial patients with established cardiovascular disease, uh, or have diabetes and they're on a statin therapy with the triglycerides that were technically elevated. Um And with the primary end point of uh of um five point may CB death, my fail stroke, cordate rivas and unstable angina. And they had a significant reduction in the composite primary end point. Um There was uh an association with atrial fibrillation and flutter in the fish oil arm. But otherwise, um there wasn't any sort of adverse events that were reported. But the interesting thing here was that there was a reduction in cardiovascular outcomes like whoa, this is the first fish oil trial we've ever seen that showed reduction in cardiovascular outcomes. That's very interesting. And you can see here uh compared to the placebo, which we can talk about what that placebo was. But um the there's a huge divergence of the curves uh over uh starting at year. Uh One even so, it's very interesting. So the FDA approved this in 2019 as an adjunct um to uh uh patients to reduce cardiovascular events in patients with triglycerides over 100 and 50 ok, fast forward a year and a half later, you had the strength trial. This looked at a prescription of screen fish oil, but it didn't just look at a purified epa study. It looked at a EPA and DH, a combination molecule at the Nova was the name of it. Um And that actually had a very similar study population, maybe a little less riskier than uh the uh reduce it trial had a little bit more primary prevention. Folks looked at the same composite primary end point. Um Again, 45% were without established CV D and they found no difference in the primary outcome. There was no difference in mace using um uh the DH A EPA combo compared to placebo. Well, why is this? You know, and these are the questions that are out there, is it because ICOSAPENT ethyl produces higher EPA levels and is epa protective uh against coronary plaque formation. There have been cer certain studies since reduce it. The evaporate uh study which looked at coronary CT A and looked at plaque regression in patients on a high dose EPA. Um So that's mechanistically was suggestive. Oh, well, it is reducing plaque. Maybe that's why EPA is what is making the difference. Um uh Recently, uh there was the respect EPA trial that looked at a Japanese population only. Um that didn't really show uh statistical significance, but there was a trend towards benefit in the EPA arm in terms of reducing uh the primary uh composite of mace. Um The other question is, is DH a harmful? Well, that's hard to know because, um, DH A is also in a lot of uh prenatal vitamins. It's in uh over the counter, readily available. So something need to be studied more, um, reduce it at a higher secondary prevention population. Maybe they draw a higher risk population. Maybe that's why there was a benefit. Um, was it a placebo effect? Uh the reduce it used mineral oil versus a strength trial? Used corn oil, mineral oil can add more inflammation. And so, um could that, could that be what it is? I think that's been studied after. Um And people have seen in smaller studies that mineral oil didn't really significantly increase HSCRP by too much. But um uh a topic of debate and you know, what's consistent is that there is a signal towards more a fib for both of them. But um uh lot lots to still uh think about. However, this uh I sen is still a tool in our toolbox um if needed for um uh optimizing cardiovascular um events now, um or risk the the thing to think about though is, is finding the right patient, right? We have a lot of tools in our toolbox. So it's a very patient selected approach that you want to take when you want to use the. Um OK. So in terms of other novel lipid lowering agents, I mentioned these sort of a little bit in my slides earlier, but there's vado acid. Um this is a pill. It's a once a day medication that you take it. It is a nonstatin medication. It works upstream of the HMG A reductase pathway which is how the statins work. And the why, why that's important that it works upstream is that it doesn't have metabolites that are created that will concentrate in the skeletal muscle and lead to intolerance. That's mechanistically why vampiric acid was kind of um uh studied is because it, it's supposed to cause less statin intolerance um compared uh compared to other therapies. Um And it's been studied in adjunct to statin up up until recently uh with the clear outcomes trial. And then you have in which is an SI RN A based therapy targeting P CS K nine. So it is a P CS K nine inhibitor, but it works differently than Alaa or Ayro. It actually works at the RN A level. Um And it, it, it, the whole thing about in glycerine uh is that it can be used on maintenance once every six months. So you get an injection at day zero, you get an injection at three months and then after that, you get an injection every six months. So you have a shot twice a year to lower your LDL up to 60%. Um So another pretty II I, you know, novel and its uh breakthrough uh in the lipid space. So a little bit about bedok acid, I said that it works upstream. And so the idea of the statin pathways. So the idea is it doesn't concentrate metabolites in the skeletal muscle that leads to intolerance first studied in the Clear Wisdom trial and has a modest LDL reduction, bedok acid alone anywhere between in this, in the clear wisdom trial that looked at the LDL reduction in about uh small again for a cardiovascular trial, but about less than about 15% reduction in LDL compared to placebo. Um If you uh be do acid also comes in a combination pill with eam and so that together will give you an additional 15% somewhere in the 30 to 40% LDL reduction range. So modest. Um I I mentioned this because this is just some of the adverse effects. And one of the things that you want to just make sure uh to think about is that gout uh in patients who have gout gout was seen to be a little bit higher in the beed acid arm in the clear wisdom trial. So here, the clear outcomes uh trial um that was just recently published um at uh the AC C or presented at the AC C and published in the New England Journal. Um So this was a randomized placebo control trial in involving patients who were unable or unwilling to take statin therapy. They signed a waiver actually, that said I am not taking a therapy that I know is good for me. Essentially, they signed it. And so that's how they were able to randomize to either be acid or placebo. Uh 13,000, about 14,000 patients underwent randomization. And uh about about 7000 of them were in Beano acid arm and then equally the other in the placebo. And they were followed for me in duration of 40 months, 30% of these patients were primary prevention, meaning they did not have an event yet, but they were high risk. They had diabetes and other things. Um and 70% had a history of an event. They found across the board, a statistical significant reduction in major adverse cardiovascular events. So four point mace this is includes CV death, nonfatal M I non fatal stroke and coronary vascularization. And then, so then three point mace. So going just from like panel ABC and D three point mace and then fatal and non fatal, am I alone? And then Coronary re vask. In fact, the curves uh in for panels A B and C have diverged and they appear to continue to diverge versus there may be some crossover in the Coronary Rivas Arms card to know we'll see what the long term um follow up is. But that, that was kind of thought provoking because now you have an um you have in outcomes data for a therapy that is uh more novel uh in a subgroup of patients that we all see a lot in clinic. Now, one could argue, well, are they really stat intolerant or not? Because there have been so many studies showing that the people's perception of stand intolerance and truly stand intolerance, huge discourse, huge discourse. But regardless in a patient's mind, they're stand intolerant. So like if they think they're stand intolerant, they're not the chance of them adhering to a statin are very low. And so, um this was nice because it actually added an additional option for providers with outcomes data to use in patients with statin intolerance, especially because 30% were in the primary prevention arm a area that's not been tapped by other more novel advanced lipid lowering uh agents. Uh So you can see the LDL reduction that Bedok acid had was about 26% and also reduced uh CRP pretty significantly as well. Um Now the couple of things to keep in mind, um they didn't uh they controlled for it as best as they could. But, you know, these, a lot of these patients could have been on other therapies as well, the US as they could have been on P CS K nine inhibitors, you know, in addition to beed do acid and things like that. So just keep that in mind but still very uh important study for the field. Um In cly, I mentioned that again, it's an SI RN A uh therapy that blocks P CS K nine, um we have great LDL reduction data in two separate cohorts. This is both Orion 10 and Orion 11. Um up to 60% LDL reduction. I mean, this is pretty remarkable. And if we believe that LDL reduction is how we reduce cardiovascular, this is very promising data. And in fact, in cerin is FDA approved, uh we are implementing a lot um as are other institutions as well. Um In addition to, of course, the monoclonal antibodies, we're also implementing those a lot um A as well. And so um just another tool again for our toolbox, something that's investigational. But in the works are the oral P CS K nine inhibitors. Um These currently have gone through phase two clinical trials. Um but essentially it's a pill. Uh you take it every day. So far, the early data has shown that the adverse effects are very little. Um there is um some uh absorption um uh component that needs to be considered. So uh there is a negative food effect. So you want to make sure that uh that the investigators for this molecule are working to figure out how best to absorb it through the, the um through the G I system. But uh it has an LDL reduction of up to 65% and it's another pill option. Um And so, er this just recently at AC C Christie Valentine presented the phase two B uh trial results which showed a 61% reduction in LDL. No significant difference uh in adverse uh events as well as medication adherence. Again, this is a clinical trial population so very different than real world. Um But they, I thought was interesting about the inclusion of the phase two B is that it included not only patients with A S CV D, but it included patients at intermediate and borderline risk too. Again, tapping into that primary prevention arm, which is great. I mean, we don't want patients to have an event, you know what I mean? So we're tapping into the area where people haven't had an event yet is very interesting and that's what clear outcomes did. And so uh Homozygous FH therapy, we have um a therapy called Ivan Aab. It's an angle like three protein, three inhibitor. Essentially, it works uh upstream to uh LDL um uh uh metabolism as well. And it's another, it's a targeted therapy in Homozygous FH patients currently to, to help them um respond to treatment and avoid ayres. Very, very uh it, it's FDA approved but uh still, you know, homozygous FH is not very prevalent and so not used as often, but a therapy out there for homozygous FH patients, I wanna talk about this molecule a little bit because we're gonna be hearing more and more about lipoprotein A. Um So for those that don't know, lipoprotein A is a what I've described to patients as a very sticky, sticky cholesterol molecule uh that causes early onset coronary artery disease and has been linked to calcific aortic stenosis um lipo protein A uh the way it works is that it's got a lipid core. Uh it was yellow ball that you see here, 45% of that lipid core includes LDL and then it's bound to these protein molecules called cringle um which uh is the A O A component of lipo protein A, hence the name lipo protein A. And so it is completely genetic. It's uh you can't eat your way into a lot of lipoprotein. A several iso forms exist because that protein, these cringle, they can come in different shapes and sizes. So the smaller the particle or the smaller number of cringle, the worse the lipo protein molecule is or more agentic, it is uh levels don't typically vary over time. Um 45% almost can be LDL and then standard essays like your regular lipid panels. They don't distinguish the LDL that's bound to the lipoprotein A or the LDL that's free. And so we have ways of kind of distinguishing them. But if you have a patient that may have a very high LDL, think about that patient having a high lipoprotein A and maybe that's why the LDL level is very high. Um and the pathogenic mechanisms can include uh aro aroma development, thrombosis and inflammation. I mean, those are kind of how these events are occurring. Um There's two ways of measuring lipoprotein. A there is a mass dependent uh assay. So that, that is looking at the entire molecule. So milligrams per deciliter is the units for that. And it, it's, it's these assays are um they're good and we use 50 as our cut-off for ev risk. But remember, it doesn't, it won't, it won't actually look at the individual uh particle number. It just looks at the overall mass. So you might underestimate how much uh small particles of lipoprotein A you have. That means that you have higher risk. So the isoform independent assays is typically what a lot of people prefer in this uh clinical trials tend to like if possible because it looks at the individual particle, it'll bind to the cringle no matter if you have 50 cringes, no matter if you have two cringes, it'll bind to it. So you have an accurate particle number and that's, that's um reported back in animals per liter. Um And to do a conversion pack, if you guys get transfers of patients that have elevated lipo protein A levels, but the numbers reading in animals per liter, just think of the number 2.5 against the poor man's conversion. It's not perfect, but it'll give you a sense. So like if you have someone in milligrams per deciliter, and you wanna know how much they are in animals per liter, multiply it by 2.5 and vice versa, divide by 2.5. You want to know what an animal per liter assay means in milligrams per deciliter in terms of distribution by gender. Um We know that across the board, 20% have elevated lipo protein, a elevated being defined as greater than 50 mg per deciliter uh by ethnicity. Um There is a higher proportion of lipoprotein a in folks of, of African American uh descent uh with a mean that is higher than other races. However, prognostically, we don't know what that means yet if uh but they tend to have, have higher levels um in terms of screening uh guidelines. So, right now, in the US guidelines, we recommend screening for lipo protein A uh for patients who are at least at borderline or intermediate risk as a risk enhancer to really make sure that they don't have elevated levels. That class reclassifies their risk to high. The European guidelines actually recommend screening everybody once in a lifetime to make sure that people don't have extremely high levels. Um And, and I, and that you don't need to certainly aggressively treat them early on. So what can we do for elevated lipo protein A right now? So I will be clear there are no current direct treatments or elevated lipoprotein A, they're all indirect. Um Typically what we are doing now is if you have an elevated lipoprotein A, we aggressively treat their cholesterol. So we lower their LDL as much as we can, we modify all the other risk factors that we can. So if they have diabetes, we really are aggressive with that. They have hypertension, we're really aggressive with that. So what, you know, a lot of people will argue that well, if I have elevated lipo protein, a, it doesn't mean anything to me because I can't do anything about it. But I would say yes, you can, I, I think that you can, you have other risk factors you can modify, you can they have screening implications. So all your first degree relatives can be screened to see who in the family has elevated lipo protein A. And why does that matter is because we have clinical trials currently going for treatments for lipoprotein A that can drop lipoprotein a by up to 80 to 90%. And so you can send a patient potentially to a clinical trial if they meet inclusion criteria. But also to know that in three, in 4 to 5 years, there might be a therapy available for that uh for them. So I think there's a lot you can do knowing an elevated li per day. And you're see, I almost exclusively screen my patients for it and we're seeing that practice more and more be adopted across institutions. But um in terms of uh what's out there that can reduce it currently. So the anti Senso nucleotides, um Pearson that is out in uh clinical trials right now, uh one of them just finished enrolling for phase three, which is great. Um You have si RN A molecules which I don't have here that are currently undergoing phase three clinical trials. AIS niacin can reduce it by 30%. But again, remember the side effects and we don't know if there's outcomes tagged to it. Monoclonal antibody P CS K nine inhibitors like Ripa, the PLO or AAB and aroma can reduce it by 20 to 30%. Uh CTE inhibitors and meers and those aren't really available anymore, but they were able to reduce it. And the statins can maybe increase by 10 to 20%. However, the benefit you get from it lowering the LDL compared to this marginal increase in the LP A far favors the benefit that's been studied over and over. Um So as I mentioned, the nucleic acid based therapies are the future for lipo protein A, these are the two molecules that have uh come the greatest uh distance. There's OPPA which is a SI RN A molecule targeting lipoprotein A this just completed phase two clinical trials. Uh and you can see up to a 95% reduction, absolute reduction in LP A. And then you have Pelo car San uh which is currently just finished. Uh one of the phase three clinical trials also up to 80% lipoprotein a reduction. So very exciting areas here. Um But I talked, you know, a lot about different lipid lowering therapies, right? I talked about all these tools in the toolbox, but there's a much, much, much bigger problem here. So, this was a study from our group, um that looked at uh statin use across 600,000 patients uh over just a year on uh who all had um commercial health plans and what's striking here. Right. Uh If you don't look at anything at all, these are all A S CV D patients, only 22% were on high intensity statins, up to 50% were not any statins at all. And then other, any statin at all, like any, like not necessarily high intensity, only 30% were on that. So that is a problem that, I mean, that's the bigger problem. We have a lot of tools, right? We have a lot of um clinical trial data showing us that these therapies work, they reduce events, but our patients aren't on even the foundational therapies. And I think this is a huge problem that we definitely need to uh think about and we need to raise awareness. We need to work both at the patient level, community level, health system level. Um It's, it's a multipronged approach. I think that's gonna fix this. Um And what's more striking to me is that there are clear health care disparities in this space. Women tend to not get LDLs check or tend to have uh cholesterols that are uncontrolled more often than men, underrepresented minorities. Same issue. People with a lot of comorbidities tend to not have their cholesterol as well controlled as others. And so there are a lot of disparities here that we need to think about. So some of the things that we're doing at Duke, um but one of the things that we created was a lipid dashboard to really track how we are at the health system level are doing. This is a screenshot of our dashboard. But what we have here, we have basic demographics. We have number of people with no LDL. And I'm, I know I'm throwing my health system out under the bus, but like I'll tell you, I've talked to multiple other health systems and our numbers are very similar across the board. Um This is uh and then a number of people, uh we, I tiered people based on their risks. So tier one being our highest risk patients who have had an event in the last year and they have an LDL still over 100 and 30. So we're tracking that we're tracking um what their other risk factors are with blood pressure. BM. I like how many of them have a BP greater than 1 30/80. How many BM I over 35 A one C over eight, what therapies that they're on and their event rates? What are the event rates? And we update this dashboard by month, every month we have and we look to see, are we trending any differently? Are we not? So, we can test interventions that we make are things getting better or worse. This is a busy slide, but we created a remote lipid monitoring program. Um Where through our E hr we have uh who I call lipid champions. So these are um uh nurse practitioners or pas or clinical pharmacists that can screen patients across our EMR that need to be on uh a statin or need escalation of lipid lowering therapy. And we have a whole algorithm that we've created to work with that patient remotely as an adjunct to their primary care provider or their cardiologist who are seeing five patients an hour and are just way too busy to, you know, focus on this on one particular visit and like all health systems, getting patients back in to follow up is very difficult. So people are waiting months and months and months before their lipids are even addressed. And as we know, that's a months too long. And so that is something we're doing to help. I'm not saying these are the answers, but some things that we're doing at Duke that I just wanted to share um uh that we're hoping will help. And then of course, we have a cardiometabolic clinic. So a dedicated clinic just in this space. These are my best friends and colleagues uh in prevention and one of the things that we created, this is not just all cardiology as you can see, um it's multidisciplinary. So we have the cardiologist, of course, but we also have endocrinologists in our cardiometabolic clinic who help us with the diabetes and more advanced um uh genetic dyslipidemia or rare diseases. Um We have hepatologists that help with uh non alcoholic fatty liver disease. And then of course, nephrology in the chronic kidney dis uh space uh resistant hypertension. And so, cardiometabolic disease isn't just dyslipidemia. I know that was my talk, but we kind of try to go down the renal route, the liver route as well and the diabetes route, obesity as well. And so, uh this multidisciplinary clinic really helps us put the heads together and come up with the best possible plans we can for not only folks in our health system but our surrounding health systems. So I'll end there in conclusion, I just want to end with letting you guys know that there's many different strategies and options that exist for lipid management. A lot of new therapies are on the horizon. We have several diagnostic tools, biomarkers and therapies to help optimize and understand risk. Um And but despite all of this, it's important to remember that it's, we need to have a personalized strategy through shared decision making because every patient can be different and not one tool may be appropriate for one patient, we can do the same thing in multiple different ways. And so uh the key to that is gonna be collaboration, whether it's across colleagues across health systems. Um uh a across communities, you name it. But I think the best way we're gonna get better is by doing it together. So I'll stop there. Thank you so much for this talk. I really appreciate it. Published June 15, 2023 Created by Related Presenters Nishant Shah, MD Cardiology Duke University Hospital
