Welcome to our session for a very important topic. A topic that actually got a lot of attention in the last few years. I cannot think anyone better than Dr. Brinton to cover for us what has been going on in the world of high triglycerides. Dr. Elliott Brinton is a president of the Utah Lipid Center in Salt Lake City, Utah, where he operates the only lipoprotein aphoresis center between Denver and West Coast. He is past president of the American Board of Clinical Lipidology and the Pacific Lipid Association. He is also the founder board member of the National Lipid Association. After his trainings in Stanford, University of Utah, Duke University, and University of Washington, he has served on the faculty of a few universities before he joined as associate president of the Utah Lipid Clinic. He has authored over 160 publications in several very prominent journals like New England Journal of Medicine, JAMA, JCM, and endocrine practice. He has served as an expert writer for lipid guidelines for ACE as well as American Heart Association. Dr. Brinton for the last four decades has taught in scientific and medical as a presenter in more than 3,000 professional meetings and international and nationally, and he has received several honors. Please welcome him. It is a delight to be with you, and there are two there's bad news and good news about this room. One is it's impossible to find, but the good news is that those of you that are here I think are here for a reason. You didn't just kind of wander down the hall and find an open door. You had to come here because this is really where you wanted to be, so this is good. I'm preaching to the choir as it were, and I think I've actually got it wait to see now that's it that's a slide advancer. Hold on what's going on here. Do I have a pointer? Is this a pointer? No. Is that a pointer? This is all slide advancing. Oh wait, there it is. It's the back one. Oh, does it point out? Oh, I see it's pointing at me. There we go. Okay, hang on. That's it. There we go. I think, is that okay with you folks over here? If I point on this one, is that okay? All right, good, because I'll take advantage of the fact that almost everybody's on this side. Okay, so we're going to talk about triglycerides and ASCVD risk. I have some conflicts of interest. As they say, no conflict, no interest, so that's always good. This is very helpful, because I want to give you the 60,000 view of hypertriglyceridemia, and yes, there is such a thing as severe hypertriglyceridemia, but no, it's not very common. In fact, if you do the math, it's actually about 18 to 1. 18 people in the 150 to 500 range for every 1 in the triglycerides greater than 500, and this as you know, is an important cutoff, because that's the cutoff for the FDA, and the cutoff actually makes sense, because if your fasting triglycerides are over 500, then you are at risk for pancreatitis, and you say, how can that happen if somebody comes in with triglyceride of 600, and they're in the hospital with acute pancreatitis, it wasn't the triglycerides. That is true, but if I'm doing a fasting measurement, and I say, come in in three weeks, I'm going to measure your fasting triglyceride, I will bet you that that is the lowest triglyceride you're going to have for the entire year, because you're fasting, and I've said I'm measuring your levels, and so you're going to be on good behavior. So the rest of the year, if you're over 500, under those circumstances, then the rest of the year you're spending a lot of time over a thousand, and a thousand is more or less the magic number above which we say this could be pancreatitis, due to hypertriglyceridemia. So severe hypertriglyceridemia, I know it doesn't sound severe, but it is severe if it's fasting over 500 on good behavior, and this 150 to 500 range, this kind of mild to moderate, a lot of us have thought, well it's 200 to 500, I'm going to drive it down to 150, and maybe even a little below 150, maybe a lot below 150, in terms of where the territory is for ASCVD. Now first of all, I just told you that over 500 is where we worry about pancreatitis, but these are data that actually are coronary heart disease. So even coronary heart disease can be increased, and in some cases rather dramatically, above 500. So if you see a patient who is in that severe, very high or severe triglyceride range we just talked about, think acute pancreatitis, that's a big deal. They're going to spend time in the hospital, they'll be miserable, it's going to cost a lot of money, but they also probably have a risk of atherosclerosis as well. So think about all of this, but our focus is in this group down here, and it's in atherosclerosis. We're not going to talk about pancreatitis after that. Now I told you I'm going to drive that triglyceride level down below where you thought it was supposed to be, because you thought, well, 200 is a pretty safe cutoff. Well, look at this slide over here, and I'm actually going to step over this way, I think. This is, look at that x-axis. That is really astounding to me as a lipidologist, and look at the shape of the curve. Okay, this doesn't even go up to 500, and that right there, that's 200, and that's 100. And look at what's happening to atherosclerosis risk in the range that we thought was just throwaway, you know, flyover territory. Below 200, of course, nothing happens. Well, that's 200 right there. And even below 100, of course, anything below 100, of course, doesn't have anything to do with atherosclerosis. But even below 100, there seems to be some action here. So these are, this is the average of at least two fasting levels. We'll get back to fasting in a minute, but look at how steep that slope may be. Now, this is, these are two large datasets. This is Eric and Framingham offspring, but it's not the universe of all possible fasting triglycerides. But this is a wake-up call to me. When I saw these data, I thought, whoa, this can't be true. But it is true. So well within the range that we think of as normal, don't worry about it, not a big deal. In fact, there can be a lot happening with atherosclerosis risk. So one of my missions today is to convince us all that we can't be so cavalier about triglycerides below 200. Because in fact, most of the action maybe happens below 200. And by the time we get to 200, you know, the horse is out of the barn, as we say. Now, let's look a little bit differently at this. Those are untreated levels. Let's look at people whose LDL is treated to less than 70 on a statin. There's still a lot going on. Now here the cutoff is 150, which is fairly high. But between less than and greater than 150, there's a huge amount of increase, even if you have them on a statin, it's aggressive statin therapy, and the LDL is less than 70. Wow. So a second mission for me today is, yes, do statin therapy, please. That always is first in virtually everything related to lipids. But once you've treated somebody with a statin and with statin adjuncts to get their LDL where it should be, then you have to look laterally and say, oh, I forgot to look at the triglycerides because that's a factor also. Okay, you see that here, you see that here, these are also statin treated patients. And here we're looking at one less than 135. Okay, there's probably something going on down there too, right. But between 135 and 195 and greater than 195, there's again a big step up in cardiovascular risk, even on statin therapy. So statins first, and then what? Well, and then what is the lecture today? Now, this is non-fasting triglyceride. And this is a big deal too. And that's okay to measure non-fasting. We'll get back to this in just a minute. Because I'll have some things to say about the relative position of fasting and non-fasting. Realize that a lot of what you read about remnants, in fact, is Friedewald calculated remnants, which equals triglyceride divided by five. So when you read the word remnants, don't necessarily think they've done fancy testing. They may have just said, well, let's divide triglycerides by five. And that's a VLDL cholesterol, and that's remnant cholesterol. And that's where we're going. So, and I'll get back to remnants in just a minute. But just realize that a lot of this is driven by total triglycerides simply divided by five. Now, what is it that happens in the artery wall when we have hypertriglyceridemia? Well, the answer is a lot of stuff. So these are the triglyceride-rich lipoproteins, which carry the triglyceride. And here's some other factors. ApoC3 is a very interesting one. Of course, we have cholesterol on these lipoproteins. That drives atherosclerosis. We know that. Saturated fatty acids are really not a player out here in the artery wall, but they're a player in the liver in terms of driving LDL cholesterol levels up. We have various things happening, certainly inflammation, a major player. And we have various players in that. We've got the macrophage. We've got the endothelial cell. We've got leukocytes that have come in from the circulation to become macrophages, although smooth vessel cells can do that as well. We have all sorts of other factors that I'm not going to get into because this is going to be a clinically relevant lecture. But there's a lot going on that is related to hypertriglyceridemia, both as a generic term, which are total plasma cholesterol, but then also these triglyceride-rich lipoproteins that actually carry cholesterol and triglycerides and other factors. These are some of the major players in terms of either what we might measure. Now, none of us is measuring ApoC3 yet, but this is something we may spend a lot more time on. ApoA5 is related to hypertriglyceridemia. It seems to be related to atherosclerosis. These are new acronyms, AngPTL3, AngPTL4. This is one where we actually have a monoclonal antibody that is directed against AngPTL3. And of all things, it does lower triglycerides, but it's actually used for homozygous FH. And folks with familial hyperglycerolemia have little or no triglyceride elevation, and it's used in a very—none of us could have predicted that this factor, which seems to be largely related to triglycerides, if you suppress it enough, you can actually treat homozygous FH. So go figure. That's a lecture for another day, but very interesting little aside. Triglyceride-rich lipoproteins are more plural inflammatory than LDL. So inflammation is the major driver of atherogenesis, and yet triglyceride-rich lipoproteins are even worse than LDL for a variety of reasons. And this now has to do with what we might measure. Now remnants, this is a great concept because we know that remnants are atherogenic, we want to measure them, and the quick answer is we don't really know how. We don't have a very good way of doing it. So let's go back up to the top. Total triglyceride is actually a pretty good metric, as it turns out. Non-HDL is probably a little better. I'll get to that in just a second. APOB probably even a little bit better. We've got a lot of other stuff down here that I'm not going to take the time to go into. So what about fasting versus non-fasting? Most of what we know about triglycerides in particular, and lipids in general, have to do with overnight fasting levels. Non-fasting triglyceride is a player. It gives us very interesting information, but these data are most impressive in aggregate. If you're talking about an epidemiologic study with thousands and tens of thousands and hundreds of thousands of patients, this is really good, but we all see patients one at a time. And triglycerides are noisy. If we measure them, even if we're measuring them fasting, there's a lot of noise. And if we measure them non-fasting, there's even more noise. And so the question is, how much noise do you really want to have? Well, looking carefully at fasting versus non-fasting, non-fasting, you've got on a low-fat meal, you've got a 20% increase. On a higher-fat meal, you've got 50% plus. And of course, our triglyceride-lowering medications, their efficacy is in the 20 to 50 range. So you've got noise here equals signal here. And of course, if signal-to-noise ratio is one, then you're in trouble. So do we really want to go exclusively to non-fasting? I think the answer is no. Now, a non-fasting triglyceride is kind of like a fat tolerance test, but there are problems with that because we usually don't know when the patient ate, how much fat they ate. We don't know what else they ate. We don't know how fast the stomach released it. We don't know how quickly it's absorbed by the small intestine. So there really never has been a good fat tolerance test. That's the bottom line. Glucose tolerance test, yes. You drink glucola on an empty stomach, and it's just glucose. It's emptied immediately. It's absorbed immediately. You can really set your clock by the absorption of glucose in a glucose tolerance test. You can't do that with a fatty meal or just random person who happens to walk in, say, in the middle of a meeting, and they get their triglyceride tested, and they're not fasting. So non-fasting has a role. It's OK in a routine setting. We are endocrinologists, and our job is to do a better job than the primary care docs. I know there are a few primary carers here at the meeting, and you're here for a reason, and that is because you want to be like endocrinology and be a little more deep dive and a little more careful, right? OK. So fasting testing is usually better for lots of reasons, one of which is I love to look at metabolic syndrome. If you think about that, two of the five criteria are fasting, and fasting HDL doesn't matter too much, right? But fasting triglyceride does. What's the third criteria? Fasting glucose. So if I want to look at metabolic syndrome, I need to do an overnight fast, if I'm going to make any sense out of that, because too many of the parameters are fasting tests. And here's another thing. I like to do the testing before the visit. You all know the concept of shared decision making, yes? Shared decision making is critical to our ability to take care of patients as providers. We've got to talk to the patient, right? So if I do what is routine in most clinics, which is I see the patient, and then I say on the way out the door, yeah, let's get your tests, we're going to do these tests, and then we'll, you know, you'll get a phone call in a couple days with the results. OK. That's not shared decision making. That is a voicemail or a text. Here are your numbers. So I'm sitting there as a patient. What do these numbers mean? Well, six months from now I'm going to see my doctor, and we'll talk about six months ago tests. I want to have the test done the week before they see me so that in hand I've got fresh fasting test results, and I say, OK, we're going to talk. We're going to talk about your levels now, what's happening in your life, not we'll let you know in three days with a voicemail what your tests are today. And we're measuring them non-fasting, so they're not that good anyway. So some of us already do this, but I'm actually asking for a paradigm shift in how we test, at least if you're testing in my world, which is metabolic syndrome and lipids, test ahead of time, overnight fast, and then have it available as we talk to the patient. Why do we want to make suboptimal testing routine? OK. I just don't, I get that we can do non-fasting and do it if you want to, but understand that you're taking a step backwards in most cases. OK. So the remnants I've talked about a little bit already. That's the same slide I showed you. RLPC may not add anything to triglycerides, and this is a direct measured RLPC. So there are kits. You can measure one from the lab. You can order remnant tests, and it's a pretty good test, but it doesn't necessarily give you anything more than just a total triglyceride, which we just talked about. And here's some recent statements. There have been a couple of really nice reviews on remnants, and one of them specifically in diabetes by Alan Chait and one more generic, not only in diabetes, but the bottom line is that we're just not ready to talk a whole lot in depth about remnants, at least not clinically, because we don't know, we don't have one consensus test, and it's a great concept. The remnant particles are really important, but we're just not there yet. So APOB is a very interesting test, and there are a lot of data that show that it is incrementally better than non-HTL, which can be better than total triglyceride. There's evidence for that, although there's some evidence where some data sets where it's really no different. So what do we do? Well, one very interesting concept is APOB is kind of the junction between LDL and triglycerides. A total plasma APOB will give you cardiovascular risk in a patient with high triglycerides, it'll give it in a patient with high LDL. So that's the good news, but here's the problem with APOB. We're kind of stuck in a catch-22. We do not order this test because it's expensive. So why is it expensive? Because we don't order it. How are we going to solve that? I don't know. It's a really cheap test, and you can do it very accurately, but it'll never be cheap because we never order enough APOBs. For the moment, I actually am in favor of total triglyceride, fasting preferably, and non-HTL because those are cheap, easy, and it's just part of the lipid panel. APOB is not going to become a part of the lipid panel ever, I don't think, and it's an extra test. It's just a little too much trouble. So non-HTLs are very good. If you want to do research, do APOB. So here's a question. How should we reduce triglyceride in patients with ASCVD risk? That seems like the question of this lecture, and guess what? It's the wrong question. The better question is, how do we reduce ASCVD in patients who happen to have high triglyceride? Now why am I saying that's a better question? I'm going to tell you why, okay? So we've gotta reorient our brains here. We're used to thinking LDL, right? LDL, what you see is what you get. High is bad, middle is better, lower is better, lowest is best. Get the LDL down to less than 10 if you can. I mean, really, truly, the risk is lower and there's no harm. If we could take everybody on the planet and put their LDL less than 10, that'd be great. That's totally impractical, so we've got some higher goals than that. But with triglycerides, that doesn't seem to be the case. And this is kind of a newsflash. I'm a lipidologist, I'm used to thinking linearly and numerically and I get to triglycerides and I have just in the last month concluded that that's wrong. So I'm letting you in on some new news. We're gonna get there in just a minute, okay? So here's the reduced trial, had the good fortune of being involved on the steering committee of this trial. And with pure EPA, that's psychosepidethyl, on top of appropriate statins, so we always start with statins, right? We see a huge drop in mace, so major adverse cardiovascular events in either hard mace or broader mace, it doesn't matter. Okay, so that's an omega-3, so let's take the next omega-3. Very nicely thought through, very high quality prescription product, which was approved by the FDA but actually never sold in the US, that's another story, called epinolva. And where's that 25% risk reduction? Whoops. So what happened? What happened? So here are the two trials, and I'll spare you the agony of looking through all the data. They're basically identical, or virtually identical, as close as two trials could be, except for the result is like, how does that happen? Something is very strange. So, was strength neutral? Why was strength neutral while reduced was favorable, why? Well, the folks who presented strength had some ideas, and the one that they threw away is actually one I'm gonna pick up out of the recycling bin and we're gonna reuse this one. I think this is our best one, actually, that there's something wrong with DHA. They talked about mineral oil, we'll get to that in a second. They talked about EPA levels. In fact, none of that explains it. So, was it bad mineral oil? Well, light liquid paraffin, which is a prescription-grade product, is probably not the answer, okay? Let's look at this, let's see. I can't remember why I've got this here, but anyway, oh. Okay, so this just shows that if you take randomly selected, mostly mix of EPA and DHA, then there's no benefit. But if you look at the one trial that was pure EPA before Reduce-It, that's the one that worked. So, this one worked and all the mixes don't. Okay, so here's Jealous, a Japanese trial a few years ago, where you see very similar pattern with Reduce-It, and the reason that I'm showing you this right now is because there was no mineral oil placebo. So, if the benefit of Reduce-It was driven by a bad placebo, then how could Jealous give you the same result? Because there was no placebo in Jealous. So, the quick answer is, this is powerful evidence that it was not the mineral oil placebo, and this is a long list of all sorts of things, but the bottom line is, super low dose of mineral oil, I mean, the typical dose is 15 to 30 mLs, and in Reduce-It, we gave a total of four mLs. So, low dose, and it's probably not that. I mean, there's some funkiness about mineral oil, but we had to use something that was odorless and totally clear, and you can't find vegetable oils that meet those criteria. Second key point is that there appears to be a dose-dependent benefit with EPA. These are on-treatment EPA levels, and these are all of our endpoints. So, if higher ELP EPA levels predict greater event reduction, that suggests very strong evidence for mechanistic benefit. It is EPA that is driving that. Now, exactly how EPA drives that, we don't know. But was, so maybe, so in Strength, they didn't give as much EPA. So, was it just not enough EPA? Well, that's a great question. Let's look at that. Here is Reduce-It. Start low, go high with four grams of pure EPA. Here is Jealous. You're Japanese, so you're eating fish three times a day, not three times a month. So, your EPA levels are much higher, and a 1.8 gram dose gets you the same level as a four gram dose if you're non-Japanese. Here is Strength. Again, non-Japanese trial, but they're giving quite a bit less EPA, and so their average is less. So, maybe it's just not enough EPA. Let's go back and look at this. Here are the Medians, and yeah, there's a difference. So, maybe Strength just wasn't enough, but let's look a little different. Let's look deeper here. Let's take the top tertile of EPA in Strength, and their Median is 151, actually a little better than the Median in Reduce-It, and they had no benefit at all. So, now what? Well, there was a big increase in DHA levels in Strength, and no increase in Reduce-It. So, you go, ooh. So, maybe it has to do with the EPA-DHA ratio. Now, we have no good data on the EPA-DHA ratio yet, but that's where we're headed. And then the question is, well, so if it looks like the DHA just went up at the same time as the EPA, and that's what blocked the benefit that we should have seen here, what's wrong with DHA? Well, DHA looks very similar to EPA, okay? That's good. But could that little tiny difference make a difference? Well, we're endocrinologists. Let's look at something near and dear to us. Testosterone and Estradiol, and they're very similar. That's really, that's a negligible difference. But it turns out there's a huge difference in what happens with Testosterone versus Estradiol. I mean, really, truly. So, little differences in structure can make big difference in function. So, check this out. Here we're looking at membrane oxidation, and here's EPA, drops the bottom out of the oxidation. Here's DHA, whoops, no effect, okay. Let's look at EPA on hemoxygenase. This is something you want to promote, and this is actually promoted by EPA, and apparently DHA doesn't do that. Here's one where DHA is okay, but it kind of waters down the EPA. It's less effective than EPA. So, in some cases, it has no effect. In other cases, less effect. Well, what would, oh, this is interesting. This is a proteomics, and each line here is a different protein. And here is bad news. This is inflammation, IL-6. So, this is the bad news pattern. And this is DHA, and DHA changes a few things, a little bit, but not really very much. Here's EPA, and it kind of turns this on its head. So, all the down regulation becomes up regulation. All the up regulation becomes down regulation. So, here you see a very clear contrast in proteomic downstream effects of EPA versus DHA in terms of inflammation. Now, here's a membrane, and here's, this is your, this is how a membrane is, a cell membrane with a phospholipid bilayer, right? And you've got oxidative stress. Here's our dear friend, diabetes, and our dear enemy, cigarette smoking and hypertension. Okay, so, you get a lot of peroxidation going through the middle of the membrane. Why is that important? Well, I'll tell you in just one second. This shows now, you're looking at the width of the membrane with pure EPA, and that has a certain effect. It keeps the membranes pretty tight. You have pure DHA, it expands the membrane. And if you add DHA and EPA at the same time, this pattern is a lot more like this one than it is this one. So, DHA, in modest amounts, in moderate amounts, fouls up what EPA's trying to do. And the way that happens is that DHA is too tall. It's like me in a regional jet, and my legs are too tall for that regional jet seat, right? So, DHA is too tall, and what it does is it spreads the membrane out, and it kinda kicks around like I may do in that regional jet flight, and when it kicks around, it pushes cholesterol together. See those red guys? Those red guys are cholesterol. They're supposed to be spread out, but DHA makes such a fuss that the cholesterol, like adults at a kid's party, the adults are gonna hang out in the next room because they can't hear anything, right? So, they're gonna hang out together, and the kids are gonna do whatever they're gonna do in the next room. That's what DHA does, but it also splits the membrane wide enough that the oxidative factors, the proxidative factors can just travel right through unimpeded. So, it's not as good an antioxidant, and it's gonna push the cholesterol together. So, then what's gonna happen? If you push the cholesterol together enough, it says, okay, we're gonna form cholesterol crystalline domain, and then if we have these big enough, then we get cholesterol crystals, and what do they do? Well, they skewer holes. They poke holes in macrophages, and they poke holes in plaques, and a hole in a plaque means you've got a plaque rupture, and then you're dead from a heart attack. So, not a good idea to let the DHA be too much because it's gonna cause havoc, and what you're gonna see in terms of plaque volume, not just plaque rupture, but plaque volume, EPA works, and you add just a moderate amount of DHA to the EPA, and you've lost the benefit. So, adding DHA to EPA may actually be harmful because at best it's neutral or kind of watered down version of EPA, but it can actually block the anti-atherogenic effects of EPA. Now, DHA is not a toxin. If you happen to be pregnant, God bless you, you need to take a lot of DHA because what? A quarter of the dry weight of the brain is DHA. You gotta have a lot of DHA to make a brain, and the DHA's gonna get there, and then when we're adults, we need about this much DHA. It is an essential fatty acid, but only that much because this half-life is 90 days, whereas the half-life of EPA is 90 hours. So, taking large doses of DHA in your standard fish oil or your prescription fish oil, probably not a good idea. So, should we use IPE, pure EPA, icosabenethyl, to lower TG? Well, that's a great question. I'm a lipidologist, let's talk about that. First of all, baseline triglyceride doesn't seem to predict benefit and reduce it. Even below 150, that's 135 to 150, they get the same benefit. So, remember how we're stretching down into the lower range of the triglycerides. We used to think it was 200 and higher. Well, these folks are, they're all below 200, and a lot of these people are below 200. They're still getting the same benefit, baseline, okay? So, baseline doesn't seem to matter, and maybe even below 135. What about on treatment? Now, that has to matter, right? How much triglyceride lowering you get with icosabenethyl has to determine the risk reduction. Well, unfortunately, our patients did not get that memo, so they had the same triglyceride, they had the same event reduction, whether their on treatment triglycerides were above or below 150. So, do we need to measure on treatment triglyceride to tell how low it is, to tell if we're getting benefit from icosabenethyl? Well, the quick answer is no. So, the message from REDUCE-IT is that triglycerides are very different than LDL, and icosabenethyl is for CVD prevention, not really for triglyceride lowering. It lowers triglycerides, and I'm a lipidologist, and I should want to lower triglycerides, but I have to let go of that concept because REDUCE-IT tells me it doesn't matter what your triglycerides do on icosabenethyl. Ouch, that hurts me, because now I'm just kind of part of the wallpaper, I guess. So, should we use IPE to lower triglyceride? No, we use it to lower ASCVD in patients who have high triglyceride. That's a different orientation, yes? So, we're back to REDUCE-IT. The number needed to treat, very, very low. The cost effectiveness is incredible. I don't have this drawn right, but this is the cost right here. It's about $4 a day is actually what icosabenethyl costs, and check out the cost per QALY. It's either less than zero or above zero. So, this is one of the rare cases where a branded product, an expensive branded product, saves money and saves lives at the same time. If you're lower risk, it's well within this threshold. $100,000, right? You're well under the $100,000 threshold, even in the lower risk patients. So, if you're a REDUCE-IT patient, low risk, it's cost effective, and if you're a REDUCE-IT patient, high risk, it's cost saving. Wow. So, here's our paradigm. Lowering LDL with statins, with ezetimibe, with PCSK9s. We've got other drugs that are coming along where they're gonna give us data, you know, bempanoic acid and inclisiran or whatever. We've gotta think laterally to triglycerides, and icosabenethyl, maybe instead of going all the way to the right, I mean, if somebody's LDL's really high, keep going this direction, get it lower. But if the LDL's pretty good, which it was in REDUCE-IT, then take a turn here and look at icosabenethyl in the high triglyceride patient. And guess what? Here's ACE, ha ha. On the cutting edge, thank you, along with lots of other good company for writing guidelines about REDUCE-IT and what I just told you to do. So, let's use over-the-counter fish oil, right? Because that's cheap and that's easy. Just so happens there are no over-the-counter fish oil. Not in the US. It's all dietary supplement, which is trouble because that means the FDA's not watching. And then we've got prescription EPA and DHA. Let's talk briefly about those. So here's dietary supplement. A fair amount of EPA, that's the good guy there. A lot of saturated fat. A lot of these have more saturated fat than EPA, plus a lot of DHA, which isn't so helpful. There's the DHA. And it can actually be solid at room temperature. I mean, we don't look at the fish oil necessarily at room temperature, but in fact it can be solid like coconut oil, which is, of course, not a good thing. And lots and lots of oxidation, huge amounts of oxidation in these fish oils. So fish oil dietary supplement, not a good idea. Here is now, this, I put Omicor, because this was for an international talk. It's actually Lovesa in the US, generic Lovesa, which is cheap and it's a prescription product, but it's got a ton of DHA. It's got more DHA than the drug they used in strength. So that's probably way too much. So we've got supplements, we've got prescription. We really just have one EPA-only prescription product, and that's really where we need to go, okay? Now, let's talk about fibrates. What's the story with fibrates? I mean, this is triglycerides and ASCVD. Well, here's some data from a little mini meta-analysis, and I think, I hope you have this picture in your brain somewhere, but if not, I'll put it there right now. So this is if you take lots of fibrate studies, and these fibrate studies were kind of yes and no in terms of CVD reduction, right? Okay, so we're not doing too well over here. Let's go over here. Let's pick patients with high triglyceride and low HDL. Makes sense. Those are the people who need to fibrate, right? So if you do that and you look at the subgroups, wow, there's the benefit. So that means fibrates work, and phenofibrate is the one that works well with a statin, so we're gonna use phenofibrate to lower ASCVD, right? Okay, well, that's okay. What this does, these are actually subgroups, so we have to label this hypothesis generating. We do. This didn't prove anything, but it generates a hypothesis that in the right patients, high triglyceride, low HDL, fibrates lower ASCVD. Okay, let's test it with a trial called PROMINENT. Here's PROMINENT, and uh-oh, PROMINENT stopped a month ago for futility, stopped early. Now, they're not, oh, not, anything more than that is public at the moment, but that one right there goes, oh, dear. So we've tested the hypothesis that all we had to do is select for high triglyceride, low HDL. That's what PROMINENT did, right? Very, very rigorously. They selected for these people, and this fancy new, better than phenofibrate, fibrate called pemifibrate did what? It ran right into the brick wall. So I'm gonna tell you, and you don't have to take my word for it. You don't have to follow what I'm saying, but I'm just thinking, you know, I used to use a lot of phenofibrate in folks with high triglyceride, low HDL, because that's cheap and easy, and it's gotta work, right? Except when we tested the hypothesis, it didn't. Ah, darn it. So, phenofibrate's still probably first line for triglycerides over 500, although remember, they're at risk for ASCVD, so we probably wanna throw a statin pretty quickly, because statins and fibrates are super cheap, but once we've done that, then we've gotta realize that using phenofibrate to try to treat triglycerides to goal and get that ASCVD down is probably no longer tenable as of a month ago. And that's top line, but the top line isn't gonna change. It just didn't work in these carefully selected people. Ouch. So, I'm not using phenofibrate. I've gotta use icosapenethyl, and icosapenethyl is way more expensive to make. You've gotta take, I don't know, a massive barrel of anchovies to get one little capsule, that puripia, I mean, it's just, it's a long and drawn out process. It's not a small molecule. This is not five cents a capsule to make, no. So, to summarize, folks with high triglyceride have high ASCVD risk. Please don't forget that. They do, and we can assess it by total triglycerides and non-HDL, that's where I generally stop. If you wanna measure ApoB, go for it. It's a little bit better, and if it's worth your time and effort, do it. Advanced lipid parameters, you know, I hope nobody's here from Quest or any of the other labs that are out there paying for our meeting, but I just don't do these very often, really, truly. I mean, they're interesting, but it's just, you can spend a lot of time here and not get very far, because you can infer an awful lot by that number right there and that number right there, and especially if you're measuring at fasting. So, we're gonna treat these patients, cal, statins, always first. Please, do your best. Not everybody will take a statin, but do your best. Put them on as high a dose of statin as you can get away with, and then you can do other LDL lowering if you want to and need to, and there's nothing wrong with that. This is all good. I'm just giving you the rest of the story, which is down here. If the triglyceride is still high, once you're happy with the LDL, then please realize that that triglyceride is high enough to put the patient at risk, even as low as 135 and probably lower. We did not look below 135, so we don't know. I can't give you data, but it's probably true below 135, and I would add icosabenethyl, and let me just make a little plea here. This is gonna sound very weird. I'm totally pro-generic. I am. Except in this case, and the reason is, and you know, I don't really think that I'm this flaming social justice warrior, but I'll tell you something. A literally crazy federal court judge decided to steal the patent that Amarin had on icosabenethyl for no reason. She looked at it and she said, it is obvious. It was obvious to any school child back in mid-teens, 2015. It was so obvious that icosapentaethyl was the only way to prevent atherosclerosis if you're using an omega-3. And I thought, okay, well, I don't know how she knew that, but we just figured this out a month or two ago, right? But she said, no, that's obvious, so you can't have a patent. So they had another 15 years to go on their patent, and she took it away from them. It's like, ouch. So I'm normally totally in favor of the company gets to have its patent and they get to charge $5 for a pill that costs them five cents to make. That's fine. Let them get their investment back. Let them have money to pay for the endocrine ACE meeting. That's all good. I have no problem with that. But once their patent's over, then it's over, and then we can turn to the five cent generic. Okay, this is not that. Somebody stole their patent. And secondly, you can't make icosapentaethyl for five cents a capsule. It's probably pretty darn close to a dollar, probably a little less than a dollar. And so there are generic icosapentaethyls out there. But first of all, they're so darn expensive to make that the generic, in fact, the price difference between the generic and the branded is not this. It's, watch my fingers, that. Oh, it's actually that. It's very close. But actually, the branded product costs less than the generic. It's like, whoa, how does that happen? Well, Ameren just says, hey, guys, we're just gonna cut our profits to the bare bones because we don't want these generic folks out there selling a lot of drug. So they actually have made their branded product cheaper than the generic, which is like, how do they do that? I don't know. So your PBM, your payer is gonna say, we've gotta do generic. Knee jerk reflex, hit the knee, and it says generic, right? Okay, except for this case. Don't let them do this. And there's one thing we have in our favor, and that is that the generic folks, although they stole the patent, well, the judge stole the patent and handed it to the generics, they don't have a label for what? ASCVD prevention with triglycerides under 500. Their label is only for triglycerides over 500. And I have to tell you, I almost never use icosapent ethyl for triglycerides over 500. Why? I don't need to. I start with phenofibrate and a statin, and then if I really want an omega-3, I'll go with generic Lovesa because that's cheaper. It's easier to make, right? It's got a bunch of stuff in there in addition to DHA and EPA that they didn't bother to purify out, so that's what I do for triglycerides over 500. I basically never bother with icosapent ethyl, so I never write generic IPE. I just don't. I do DAW, and I never do that except this is a special case, and you've listened very politely to my long, drawn-out diatribe about this, but this is an exception to the rule that you just always do generics, okay? And there are some other exceptions in endocrinology, but that's my bottom line, so sorry to, oh, and by the way, here's my ace in the hole, BlinkRx, and I'm not supposed to be pushing one pharmacy, but it turns out they made a deal with Amarin. Amarin made a deal with them, and so they will, first of all, this is so cool. Amarin basically will give, and drug companies do this, but I think Amarin's being very kind. They will give your patient the first month free while you're arm wrestling the payer to do what's actually in their favor, which is to give the patient branded IP instead of generic. I mean, they actually tend to pay less, but they don't wanna do it because it's not generic and branded they don't wanna do. So Blink through Amarin will give you the first, will give your patient the first month free, and then after that, if the payer does not pay, if the payer pays, then it doesn't matter, right, because it'll be cheap to the patient, but if they will not pay, then the patient can pay $99 cash, and that sounds like a lot, but this, I mean, each little capsule represents who knows how many anchovies, and it's hard to make. So if your patient could possibly afford it, and the payer won't pay, first of all, shame on the payer, and arm wrestle the payer, and tell them that you're not gonna write off label, because the payer sometimes will listen to that, actually. Don't make me write this off label. This is branded, and they should do it, but if they don't, then you can actually get it cheap. So that's kind of a weird twist at the end of this talk, but that's my little social justice diatribe. So thank you for your attention, and let's do Q and A. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. So generic Lovesa is like $70 a month-ish. Okay. And your payer may pay for it, but it's not quite as effective as the Fibrate for sure. Right. Start Fibrate first. And the statin is about the same in terms of triglyceride lowering. The quick rule of thumb, by the way, with statins is that the triglyceride reduction is half what it is for LDL. So you know what the LDL is roughly. It's half that much for triglyceride, except if the triglyceride's over 500. Okay. And then it's the same. So the LDL goes down a little and the triglyceride goes up a little, but it's kind of in that 25, 30% range, which is what you'd get with generic Lovesa. So statins are cheaper and they're way better for event reduction, ASCVD, right, because we have a ton of data for ASCVD. Generic Lovesa, branded Lovesa, has never been tested for ASCVD. Based on strength, I think it wouldn't work. It's got way too much DHA. So I'll use it to lower triglyceride, get them out of the pancreatitis range, but that's a distant third after phenofibrate and a statin. Statin. And of course, my goal is to lower the triglyceride level. For atherosclerotic cardiovascular disease risk, I don't care so much what the triglyceride number is, and I would use Bacepa. Instead of, let's say, I mean, this patient has high triglycerides, I'm worried about pancreatitis, but I'm also worried about their cardiovascular risk, phenofibrate, statin, and then Bacepa. So if the triglycerides are still above 500, and there is a triglyceride goal for those patients, it's below 500, okay, then sure, you could add whatever omega-3 you want to, really, but understand that only one of those would lower risk, but then back up a step and say, wait a minute, I'm an endocrinologist, this patient almost surely has either diabetes or prediabetes, so what am I gonna do? I'm gonna treat their diabetes, and I'm gonna get their A1C down, and then their triglyceride comes down, and if they've got prediabetes, I really love Ken Kusey, and one of the things I love the most about him is that he loves pioglitazone. Pioglitazone is the best drug for prevention of diabetes, I think. I mean, there are some caveats, yes, but it's better, it's more powerful than metformin, it costs only a little bit more, it's a cheap generic. So I use a ton of pioglitazone in these prediabetics, and guess what that does? It lowers triglycerides again. So I end up treating the heck out of their diabetes or their prediabetes. I look at metabolic syndrome, I do the diet and lifestyle, and over and over, and you know, diet. So if you're doing all that stuff. And let me just say this. Diet does this much for LDL, so why do we do diet for LDL? Because it does this much for things that we cannot prevent, and what can we not prevent? Diabetes and cancer. Or not diabetes, diabetes we can prevent. Dementia and cancer. The healthy diet for LDL does this much for LDL and this much for athero, and this much for the things we cannot prevent. Now diet and lifestyle for triglycerides is much more effective. So, back to the question. So diabetes, prediabetes, diet and lifestyle, secondary medications, you know, oral estrogen. If you have a workaround for a woman, get her off the oral, because that'll oftentimes raise the triglyceride. Anyway, back to your question. Sorry. All right. I mean, so there's plenty to do before like just jumping to the SEPA, I guess. For a triglyceride, over 500. I can't remember the last time I used a SEPA for somebody with a triglyceride over 500. There's just no reason to, because you've got all these other things, and if you've run out of those, go back over them, because they've forgotten to do whatever it was you asked them to do. Okay, all right. So the SEPA's more like maybe triglycerides of 150 with high cardiovascular risk, assuming I've taken care of all these other things. That's right. So if somebody has a triglyceride in the 150 or 135 to 500 range, and they've got low ASCVD risk, don't bother. Right. Because, I mean, eventually they may die from heart attack, but that's like 60 years from now. So don't go there unless they're at high risk, and I didn't emphasize that. The people in Reduce-It either had a prior cardiovascular event or diabetes plus at least two other risk factors. So don't treat low-risk people with a SEPA. Bad idea. Okay. Yeah. Because it's expensive. Because it's just too expensive. I mean, this is a lot of work, and we've got other things. I mean, statins are dirt cheap, and we know they work, and ezetimibe is dirt cheap. Nobody ever uses ezetimibe. It's a tragedy. You do, Seth. See, I'm preaching to the choir here, but you know how many, the percentage of folks who needed ezetimibe in the PCS-K9 trials, 100% of them needed it. You know how many were actually taking it? 5%. And the reason? Okay. Most people think ezetimibe doesn't work. They think it's not worthwhile. It's not very dramatic and it's LDL-lowering, but it's worth three statin doublings. Do you know that 10 plus 10 equals 80, math? 10 plus 10 equals 80 is 10 of atorva plus 10 of ezetimibe equals 80 of atorva. And back in the day, when we had to pay an arm and a leg for statins, that was a big deal. But in fact, it's true. So lower doses of statins plus throwing ezetimibe is oftentimes a really good workaround. And guess which population ezetimibe works the best in? Probably diabetes. Ooh. Okay. So if we're endocrinologists, and our patients either have diabetes or are gonna get it because they're pre-diabetic, use ezetimibe freely. Yes. Okay. Thank you so much. Thank you. Thank you for the talk. You know, I have a different kind of question. So I'm a vegetarian and I don't get any EPA in my diet. So actually I had my EPA omega-3 level checked. I put myself on Visepa, so because I, you know, for down the road for primary prevention. I know there's no trials, but is this a reasonable thought for vegetarian patients that don't get any omega-3 in their diet? So I think, first of all, a vegan is out of luck in the sense that, well, no, no, no, they're not. I guess what you'd have to do is you'd have to do, what is it, seaweed or algae? I guess their algae is what actually makes the EPA that are in fish. So there is a vegan source, but you'd have to look on the web to see where that is. I don't know even where it is. Because 99% of all the EPA and DHA that we consume is from fish and not from the things that fish eat. So that's one caveat. Second thing is, branded icosapenethyl is expensive stuff. And if you want to take it and you're low risk, go ahead. I mean, it's not going to hurt you, but I do try to focus on the higher risk people because it's costly enough that I don't want to give it to somebody for 50 years before I prevent their first MI. I want to give it in a shorter range. And statins we can give for 50 years, and that's cheap and easy. So your next question, oh, so how to get it? I mean, there are supplements that have it. I actually hesitate to have you take a dietary supplement fish oil because they've got, they're mainly oxidized. And oxidized fatty acids are probably harmful. So I don't know, that's a very interesting question. I like it. Go ahead. Fantastic presentation. Chris, Chris. Yeah, you didn't recognize me. I didn't? I got a beard. This, by the way, is a true lipid guru. Yes. Fantastic, my goodness. And I love the analogy, when you brought testosterone yesterday on, and she literally peed. Oh my God, that is like mind blowing, amazing. So I have three questions, but I'll quickly ask those and I'll sit. Nobody else is behind me. Niacin, I've been a believer all these years, 43 years of clinical practice, and I've had fantastic results. And then Aim High comes, and then HPS Thrive comes, and then suddenly we throw the baby out along with the bath water, and then suddenly gone. And then here is triglyceride. So your comment, because I know that you've been a believer in niacin, niacin, long-acting, whatever, so that's one. The second is the diet that he talks about. So if meat eaters and egg yolk eaters get a lot of DHA, perhaps we should throw that out and then bring fish and salmon and those kinds of stuff in the dietary portion, because triglyceride, I still want to believe that it gets modified by diet. And the genetic basis with ApoC3 and lipoprotein lipase and many other are impacting the triglyceride level, but diet plays a major role as well, so maybe perhaps an alteration into a pescatarian, so to speak, rather than a meat and the egg yolks and throw it out. Third, if DHA is so powerful in really bringing up the brain power, so are you suggesting that the super intelligent people are at risk for cardiovascular disease? Okay, now these are all good questions. Okay, so yeah, so DHA is structural and it's metabolized very slowly, and if we eat fish anywhere near as often as we think we should, which would be Mediterranean diet, then we're probably fine. And so, yeah, DHA in pharmaceuticals and pharmacologic doses is probably not helpful, and I probably would take trouble to steer away from that. You know, if I'm gonna take a dietary supplement, fish oil, just to get enough DHA and EAPA to meet my essential fatty acid needs, it's like one capsule a week. The half-life of these things is forever. This drug, by the way, is given two twice a day, and you know why? Because they just never have tested four once a day. And it's supposed to be given with food, because it's absorbed better, it's an ethyl ester, so it's absorbed better if it's with food. But in fact, the half-life is so long that twice a day is just an artifact, and I'd way rather have somebody take four capsules once a day, every day, than have them take two capsules once a day, every day, because they always forget to take that second dose. So that's just a little practical matter. I mean, the second dose is there for a reason, but it's not really a good reason. Niacin. Oh, yeah, now, you know, I thought about that this morning. I thought, you know, I didn't say anything about niacin in this talk. My definition, by the way, of a true lipidologist, which you don't have to be, you're an endocrinologist, is somebody who's prescribed niacin within the last year. We just don't use niacin. It's not that niacin got any worse, it's just that we have so many other things that are better, but niacin is still our utility infielder, and utility outfielder. It does everything you could ask a drug to do. It's got a long list of side effects and potential problems, and it causes flushing. I mean, you can take this drug for five, 10, 15 years, and then the next time you take it, you've got a flush, and that was totally unexpected, and we just don't know why. Niacin probably works for atherosclerosis, even on top of a statin, probably. But the people who did those trials didn't do them correctly, and so we don't know. So we don't have good data, but if you look carefully at the data, you'll see, first of all, they stopped aim high right when you'd expect the curves to separate. Secondly, HPS2 Thrive, which was the big trial of niacin plus loroproprant, which was a flush blocker, we think that there may be some adverse effects of loroproprant that aren't just flush blocking, but pro-atherogenic, maybe. But the other thing, if you look carefully at HPS2 Thrive, you'll see that this very rare group of patients that we never see in our clinic called Caucasians actually had benefit. The folks who didn't have benefit in HPS2 Thrive were East Asians. Now, we see a lot of East Asians. That's very common, and I will not give niacin to somebody from China, Japan, the Philippines, Southeast Asia, none of those places. They don't get Korea, they do not get niacin from me, because HPS2 Thrive seemed to show that they were harmed, and it was that harm that counterbalanced the benefit, and therefore, the trial was neutral. Also, the folks with LDLs over 67, of course, we never see LDL over 67, but if they were over 67 on their statin, they had benefit. It's like, okay, so this was a very odd trial that supposedly proved once and for all that niacin was no good, and in fact, it was a very poorly designed trial, and it didn't really show anything except in this very odd group of patients that were overtreated with the statin and happened to be almost half East Asian, it didn't work, so I don't know. I use it when I run out of other things to use, because we have so many other things that do so well in so many other settings, but niacin remains on the list, and niacin, in many ways, is the ideal drug for South Asia, not necessarily for South Asians in the US, because we don't need cheap niacin. We've got cheap statins and whatever, but I'll tell you, if you wanted to go to the Indian subcontinent, and you and I have talked about the possibility of doing this, and doing a big trial with dirt-cheap, small-molecule niacin, that would be the place to do it, because niacin fixes all the things that go wrong in South Asians, but also, turns out, East Asians, and also Native Americans, and also Middle Eastern folks. Those are the four races that tend to have the central visceral adiposity thing, and that's what niacin seems to fix. But the other thing that fixes that is pyoglitazone, because pyoglitazone is another cheap generic, and it gets rid of your visceral fat, and lowers triglycerides, raises HDL, prevents heart attack and stroke. So niacin's a fascinating drug, and I would have included it if I'd had a second hour, but niacin remains a good drug, and if you want to use it, just be careful, because it can cause atrial fibrillation, which, by the way, icosapenethyl does. All the omega-3s do. Not much, and the cardiologists tell me no big deal, but there's a little increase in AFib with icosapenethyl, and with a mix of EPA and DHA, and with niacin. There's also peptic ulcer disease, not a good thing. Gout, not a good thing. The flushing, not a convenient thing. But it's one heck of a drug that just is like, it's kind of like Dilantin, you know? Back in the day, you'd treat 12 different diseases with Dilantin, and we just don't use it anymore, so. Thank you very much, Dr. Nunes. Thank you. Thank you. Thank you. Thank you. Thank you.

high triglycerides

cardiovascular disease

pancreatitis

atherosclerosis

LDL cholesterol levels

icosapent ethyl

REDUCE-IT trial

fibrates

niacin