Jaime Burkle, MD, FACC, FNLA, Section Director of the Center for Prevention, Metabolism, and Lipids talks about how to approach treating triglycerides in clinics for patients who are at risk of or currently present with cardiovascular disease.
All right. So we're gonna move on to the first uh talk. Um I'm in charge of that. I'm gonna be talking to you guys about managing triglycerides in 2023. When putting together the program, we thought about talking about something that is really important on an eight day to day for our clinics. And I think that most physicians are very comfortable treating LDL cholesterol, but not so many are comfortable training triglycerides. So let's get an overview of uh uh how do we approach this in clinic? These are my disclosures. So let's start with why are triglyceride is important, right? Uh For many years, we've learned now close to 20 years now that uh elevated triglycerides is directly proportional to the ratio of developing cardiovascular disease. And this is particularly important you can see in the tallest bar in patients with low HDL. So the combination of high triglycerides and low HDL is what we know in, in the lipidology world as atherogenic dyslipidemia. And not only that, but if you take into consideration every aspect of the metabolic syndrome, low HDL, high blood pressure, high BM I etcetera for every subset for every uh component of the metabolic syndrome, having elevated triglycerides directly uh impact the incidence of cardiovascular disease. The higher triglycerides, the higher the risk. But wait a minute, what is the mechanism of atherogenesis? Right. I think that everyone knows how LDL cholesterol clogs up the arteries causes infiltration at. But how about triglycerides? Well, we don't, we're not exactly sure, but there's four postulated mechanisms of AO genesis when it comes to triglycerides, sub endothelial infiltration, endothelial dysfunction, inflammation and activation of coagulation cascade. So let's analyze this when it comes to in infiltration, triglyceride rich lipo proteins are large particles come basically in two forms omicrons and VLDL, right. When exposed to uh lipoprotein lipase, they become triglyceride rich lipoprotein remnants. And these remnants are very atherogenic. This pretty much in a way very similar to LDL can penetrate. The intima are taken up by phages develop into foam cells. And there you go. Yeah, that's the formation of the AOM itself. Not only that but also these remnants can actually activate inflammation. Coagulation, induce endothelial dysfunction, activate playlets. And there's gonna be a monocyte addition. This monocyte will turn into macrophages and then you have a vicious circle of atherogenesis. Now, how about endothelial dysfunction? Well, it turns out that um oxidized LDL glycated LDL dieter lipids in general will cause what we call endoplasm reticulum stress. And this is actually directly related to endothelial dysfunction by increasing basal constriction, oxidative stress, platelet aggregation, vascular leakage inflammation, burden and leucocyte adhesion. So, this is actually a direct effect of, of lipo protein remnants. We also know that oxidized LDL and free fatty acids are direct stimulants for the N LP three inflam om. And they actually catalyze the cleavage of interleukin one beta and interleukin 18, which are two of the most important inflammatory cytokines in the body. And once you have this inflammation going on, then you obviously have accelerated arthrosclerosis. You get uh beta uh cell failure in the pancreas with diabetes metabolic syndrome, you have central leptin and insulin resistance. And leptin is the satiety hormone. Uh you promote STIs and there's a number of other things that uh in general accelerate ao sclerosis. And finally, triglyceride rich lipoprotein remnants can actually activate the intrinsic pathway of coagulation with the subsequent formation of thrombin and clo formation. So, they're actually pro pro coagulant as well. So how and why do we get high triglyceride in the first place? Well, it turns out that um not every obese or diabetic patient has high triglycerides. So what exactly is the mechanism of action? Well, for that, for us to understand what happens, we need to have a basic understanding of Triglycerin metabolism. And I promise you, I'm gonna uh summarize this in two slides. This is the first slide. The first source of um cholesterol and triglycerides in the body is the extrinsic pathway, which is the food that we eat. The other source is the intrinsic pathway. This right here is the extrinsic pathway. So, food that we eat is taken up by the inter site and packaged up in cholesterol and triglycerides. They put an ale protein B 48 as a crown. And there you go, that's a micron. The Callum micro is absorbed in the lymph and then it goes into the circulation is a very large particle anywhere between 306 100 nanometers in size. And they get exposed to lipoprotein lipase in the endothelial surface. And this will turn into a Callum micron remnant. These remnants are taken up by the liver and recycled. But when produced in excess, obviously, they're gonna produce atherogenesis. Like I showed you in the first light. This is the intrinsic pathway. This is what the liver makes. So the liver takes up cholesterol triglycerides, packet it up together into a lipo protein and puts a crown and a protein B 100. That's how you know, it's LDL. This BLDL particle is released to the circulation and once exposed to lipoprotein lipase again, lipoprotein IPAs will take all triglycerides out, will give it to muscle and heart for energy adipose tissue for storage. And it will turn this this particle into an intermediate density lipo protein or ID L. These ID LS are again taken up by the liver and recycled. But if produced in excess, they're gonna turn into LDL and cause atherogenesis. So, as you can see here in both instances the extrinsic and the intrinsic pathway. The key step in live in trigly metabolism is lipoprotein lipase LP L. And there's one thing that I want you to take out of this talk is that word lipoprotein lipase. The key the enzyme in trigly metabolism. Why? Because it is the the enzyme responsible for breaking down Triglycerin into smaller particles that are easier to take up by the liver and recycle. But when, when the lipoprotein, light pace is actually decreased in activity uh in a way similar to lactase deficiency. For those who are lactose intolerant. If you are lipo protein, light deficient, your Triglycerin will go up. And how do we get lipoprotein lighters in the circulation way is genetically driven and is produced uh in the, in the uh endothelial cells. And very importantly, there's three factors that inhibit lipoprotein lipase. A OC three coming from most lipoprotein circulating lipo proteins and like three and four coming from the liver. Uh A OC three is overproduced in patients with diabetes, metabolic syndrome and obesity. So, in summary, what are the key elements for physiologic tri scary levels? Well, you need to have low blood glucose because high blood glucose will actually increase A OC three, which gene lipo protein like a low calum microns and low VLDL. On the other hand, you wanna have high LP L activity because that's gonna break down the triglycerides down. And you wanna have low levels of A OC three and the two AINS like three and four. And obviously, you wanna have a good number of epa uh remnant receptors. So, what are the take home points, lipoprotein lipase again, is the most important enzyme in Triglycerin metabolism. High levels of lipoprotein lipase, clear Callum microns and VLDL very effectively. So that's what you wanna have. A OC three and HPTL three are the most important inhibitors of lipoprotein lipase, obesity, hyperglycemia and insulin resistance induce a OC three production and inhibitors of this inhibitors A OC three and HPTO three will result in greater LP L activity and therefore decrease triglycerides. So how do we classify hypertriglyceridemia in clinic, we have two major classifications. The AC C and A H A classification which classify normal triglycerides. Less than 1 50 hy triglycerides, 1 50 to 4 99 and severe hypertriglyceridemia greater than 500. We like the endocrine society of America classification better because this one, this, this one gives us a better picture of the patient's risk. We call it my hypertriglyceridemia patients with triglyceride between 1 50 to 1 99 moderate 200 to 9 99 severe hypertriglyceridemia. 1000 to 2000 and very severe hypertriglyceridemia greater than 2000. These are patients that are at the highest risk for pancreatitis. Ok. So now we have a patient coming to our clinic with hyperglycemia. How do we approach this? Well, first and foremost, we want to make sure the patient doesn't have secondary hypertriglyceridemia. These factors listed here in the slide are common causes of hypertriglyceridemia. So, rather than just chasing a number and trying to lower it with statins, fibrates and everything that you can find. Let's try to find reasons why the patient has elevated triglycerides. Alcohol is a very important one. The cellular disease, chronic kidney disease, pregnancy, of course, diabetes and metabolic syndrome. For the reason I mentioned increase a oc three production, poor diet, obesity and certain medications. Sorry, going forward what medications can cause hypertriglyceridemia. We have a typical antipsychotic anti retroviral therapy is actually a common cause of hyer some beta blockers, acid equestrian steroids, estrogen, etcetera. But also think of other reasons for the patient uh to have hypertriglyceridemia like hypothyroidism, chronic kidney disease, chronic liver disease, fatty liver, et cetera. What are the goals of treatment in our patients with hypertriglyceridemia? We have two major goals for those patients that have high triglycerides in the thousands. They have micro, very large particles. We don't worry about aosis. Those patients are gonna develop pancreatitis. So that's the first goal, lower the risk of pancreatitis for those patients that have moderate hypertriglyceridemia. Less than 500. Those patients have increased number of remnants. The risk is in uh cardiovascular risk, aosis. This is taken directly from the uh 2018 AC cah A guidelines on management of patients with high cholesterol. So when a patient comes to your clinic, the first thing you wanna do always is calculate the 10 year A S CV D risk by the pool cohort equation. Initiate lifestyle, assess secondary factors, etcetera. And the first stop. The first hard stop is what is my patients A S CV D risk? What my patients LDL cholesterol does my patient has a established A S CV D. If the answer is yes, that patient has to be started immediately on a statin. If the answer is no, then you're gonna take the time and say, OK, so where do I classify? My patient? Does the patient has low A S CV D risk and triglyceride level? That is less than 1 50 continue lifestyle. The other side of the spectrum is, does my patient have a triglyceride level over 500? That's the patient, you need to start fibroids because fibroids would lower the risk of pancreatitis. How about patients in the middle borderline A S CV D risk or intermediate A S CV D risk? If the patient has high A S CV D risk, greater than 20% 10 year risk or established A S CBD, you immediately initiate life time modifications with the statin and you're going to add a for those patients who have triglycerides over 1 50. So what are the take home points? Moderate hypertriglyceridemia, 1 50 to 500 causes increased triglyceride remnants which are atherogenic, therefore, increase aortic cardiovascular risk, severe hypertriglyceridemia. On the other hand, triglycerides greater than 500 to 1000 means Callum Mym. And like I said earlier, Callum microns are very large particles. They're not aro, but they increase the risk of pancreatitis. And that's not a S CV D but pancre. So, diet and exercise does. It really work? Yes, it does. And this table actually shows you that weight loss can reduce triglyceride up to 70%. And it does, it doesn't require a lot of weight loss to start with 10 £15. That's gonna be significant to reduce triglyceride. Dietary modifications, uh, including alcohol restriction, greater than 70% reduction in triglycerides, physical activity and exercise up to 30% reduction. And this is what we recommend to our patients. Right. That's why when they come to our prevention center, they meet with our dietician and our wellness coach and the two things that we focus on is your diet. You wanna make sure if your triglycerides are less than 500 you consume less than uh, 6% of added sugars, 30 to 35% total fat and restrict alcohol. But if you're on the other side of the spectrum, if your triglycerides are over 1000 you definitely want to eliminate added sugars. You want to restrict total fat to 10 to 15% and abstain completely from alcohol and all my pay, all our patients get an exercise prescription and a particular diet. Ok. Finally, what are the drugs that we use for hyperglycemia? This is that we have in our Armamentarium fibrates, lower trigli rates anywhere between 25 to 50%. Omega three, the same thing EPA. But a 20 to 50% reduction particularly, we obviously have statins. Statins are not very powerful in lowering trigli rights. Obviously, they lower mostly LDL but you use it in addition to standards. And finally, although there's not a whole lot of data on safety and efficacy in the long run, why do we like? Um A this is the result of the reduced trial that was presented in 2019 at the AC C by and the collaborators, they took patients uh with established A S CBD or diabetics with multiple risk factors. They were all on statins. Their L DS were less than 100 but they have elevated trigli rights. Over 1, 35 patients were random mice to receive a placebo with the primary end point of cardiovascular death, non fatal in mind, non fatal stroke, coronary vascularization and hospitalization for unstable angina. And these are the results. After five years, there was a statistically significant 30% reduction in the primary end point when adding A to statins. So what are the take home points, diet, exercise, weight loss alone can decrease dig levels up to 70%. Statins are first line drugs to reduce cardiovascular mortality in patients with hypertriglyceridemia and A S CV D. No questions about that and is indicated to reduce cardiovascular mortality in patients with established A S CBD on statins. But who have residual hypertriglyceridemia, pheno fibrate decreases the risk of pancreatitis in patients with severe hypertriglyceridemia. But they do not decrease cardiovascular mortality. And finally, although niacin can reduce triglyceride levels, large scale clinical trials have failed to demonstrate cardiovascular mortality reduction. How about off label drugs? We are, you get asked all the time, what can, what else can we use when the patients have persistent hypertriglyceridemia in spite of statins, in spite of fibroids, in spite of ICO and ethyl. Well, we use all these drugs, they are off label drugs, but they're actually very effective in Triglycerin. In fact, many people don't know that itself can lower Triglycerin by about 15 to 17%. The early trials with Euka uh for uh LDR reduction also showed a significant decrease in triglyceride anywhere between 16 to 25%. The G LP one receptor agonist are now obviously very popular. Nowadays, patient want to lose weight, patient wanna have their glucose under control. Well, in two clinical trials, the sustained six and the pioneer six trials, they showed a 20 to 25% reduction in triglycerides. So we do use percent of patients as off label, but mostly in patients who have obesity, hyper uh uh metabolic syndrome and diabetes. Of course. So you're going to be training all those um um um entities with a G LP one receptor agonist and as a secondary gain, you're gonna get lower triglycerides. Same thing with the G LP one G IP dual receptor agonist. There's a lot of clinical trial uh uh data going on. Now that is showing that not only they lower uh glucose, they lower weight, but also they can lower uh triglycerides in a dose dependent fashion up to 50% in 12 weeks. SGLT two inhibitors. Not as strong triglyceride lowering drugs as G LP one receptor agonist. Why? Because you don't get as much weight loss and glucose control with SGLT two inhibitors compared to G LP one receptor agonist. But SGLT two inhibitors, particularly lysin is associated with a 12% reduction in triglyceride. Let's finalize now with future therapies. What's uh in the future for lower in trigly rights? Remember, I told you a protein C three is the most important inhibitor of lipoprotein lipase. Well, there are a OC three inhibitors in development. There's HPTO three monoclonal antibodies development and of course, there's li li replacement gene therapy for those patients who have familial and total absence of LP L activity. In this graphic, you can see there's a molecule of lipoprotein lipase and the three major negative um um factors for lipoprotein lipase A OC three HPTL three and HPTL four. So this drug called A is an A OC three inhibitor is an antisense oligonucleotide. As many of you are familiar with these technologies now that are used in many entities in cardiovascular medicine. These are injectable drugs is injected as a single stranded RN A that gets into the cytoplasm into the nucleus, it binds to the messenger RN A and it prevents the formation of the protein in the first place. This drug was given fast track designation by the FDA on February 8 2023. And results sorry about that results in a significant reduction in both A OC three, but about 80 to 90% and a significant reduction in triglycerides by about 45 to 50. uh but about 65%. So, um we are participating on this phase three clinical trial called the core two in patients uh who have significant hypertriglyceridemia with or without a history of pancreatitis. This is a phase three clinical trial where the primary end point is gonna be percentage change in triglycerides from baseline to six months with some other secondary end point. So, we're really excited to participate in this clinical trial at Georgia Heart Institute and provide this additional benefit to our patients. And finally, the lipoprotein lipase inhibitor HPTL three, which is produced by the liver. There's an HPTO three antibody called AAB. This is a monoclonal antibody that is actually administered intravenously once a month uh to our patients is currently approved by the FDA for patients with homozygous FH. But this is the data we presented at the AC C 2021 Robinson presented on behalf of um the investigators of our trial on severe hypertriglyceridemia. We took patients with severe hypertriglyceridemia prior history of panis, they were randomized 2 to 1 to intravenously every month um to uh compared to placebo. And these are the results I want you to focus on cohort three. The drug was associated with an 80% reduction in trigly is very impressive, very well tolerated, virtually no side effects because it's a monoclonal antibody. So it's directed therapy and the patients come to our clinics basically once a month to receive a one hour infusion of this drug. Finally, this is gene therapy and this is the future. So for patients who are born with complete absence of lipoprotein lipase, they have what we call familial Omm syndrome. These are kids that have Triglycerin in the 5000 to 10,000 range and they develop severe pancreatitis. Well, now we have gene therapy available as replacement therapy and this drug is called a Lipogen typo and actually, it is administered um intravenously and you're providing the gene for the liver to make this uh li li base and it works very effectively. So, in conclusion, hypertriglyceridemia remains one of the most important independent risk factors for A S CBD and acute pancreatitis. When approaching patients with hypertriglyceridemia, always rule out secondary causes first diet exercise and lifestyle modification should always be the first step and that alone can lower trigly rate up to 77%. Don't forget statins for a S CBD risk reduction always. But if a patient has trigly over 1 50 you add eic acid or A and if greater than 500 add fibrates to prevent pancreatitis. Early data on GOP one receptor agonist and G IP agonist look very promising. And finally, we're awaiting a OC three inhibitors HP 203 inhibitors and gene therapy clinical trials. Thank you for your attention. That that was a great talk. Um really comprehensive, look at trigli rights. So I know from the prominent trial that was presented at A H A about pe fibrates showed a real decrease in trigly rights, but didn't really turn into cardiovascular mortality benefit. And you highlighted that about pheno fibrates. But here's the practical question. You have a patient in front of you that you started on a fibrate years ago thinking you're benefiting them from a cardiovascular standpoint, they don't have triglycerides over 500. Are you gonna stop their pheno fibrate? Yeah, that's a great question and something that we see regularly a clinical practice, right? So first thing we wanna do is want to make sure we cover the basis of a S CBD reduction with the statin. Make sure their L DS are go, make sure the particle numbers are go and then we address trigly and try to get a little history. Why were you started on trigly was the reason you had severe hyperglycemia over 500 they gave it to you to reduce the risk of pancreatitis. If that's the case, we're gonna try to go back and say, OK, were you overweight, then were you diabetic where you are, are out of control diabetic. And if all the answers are in the right direction, in many instances, we stop fibrates because like you said, they haven't shown any, any reduction in, in cardiovascular mortality. Uh And we follow them very closely. If you see the trigly jump back up in the 500 to 1000 range, that patient by definition has lipoprotein I deficiency. So you have to put him back on the fibroid just to prevent the risk of pancreatitis. Thank you. I I know we don't have a lot of time, but I think there's a question out in the audience. Is there a question? No, anybody on the pan, any questions in the back? One question or one last question, Anita, it's remarkable that Tri Lister is the data that you showed is reduced by 70% with diet and exercise. Yet our society is set up to allow patients to fail on that end. Meaning it is a public health issue where, you know, a salad costs three times as much as a burger or French fries. So, and we have no idea what's a lot in the processing of the foods. Um And a lot of neighborhoods are set up so that you can't really walk around even if you wanted to, for fear of getting run over by cars along the way. Um 70% is a remarkable number and, and I, I it just sounds, this is more of a comment. It just sounds like we need to do more in terms of advocating for these changes on a, on a public health uh level. You're absolutely right. And that's uh the reason why when patients come to our center, they have a dedicated time with our dietician and our wellness coach, who's an exercise trainer, because that component of diet and exercise has to be critical is you're basically set for failure. Like you said, if you just tell a patient to take your pills, you're gonna be fine. If they don't do the lifestyle modification part, they're not gonna get to go. We have a question from the audience. That's yes. Let's go ahead from the audience first. Ok. Thank you. I'm the dietician on Doctor Bekele's team. Um, and just a quick note about what you are talking about with the lack of access to cost-effective um, nutrition. That is one of the biggest things that I talk about with my patients and I also encourage them. It's OK to eat frozen fruits and frozen vegetables. These are the things that we wanna look for. I actually created a handout with, um, you know, kind of dietician approved foods from the Dollar store that they could go get. And so some of these options, you know, we do have to take quite a bit of time and background to look into them, but that's kind of the job of the dietician is to help make it possible for that patient to work with what they have so very good point. And I agree with everything that you said. Um, my question for Doctor Berkel. So I know in our clinic, we've recognized that the lower LDL cholesterol, the better benefit. Is there any extra benefit of going below 100 50 for triglycerides? Yes. Thank you, Anna. That's a great question. Um And the answer is yes. Um very similar to LDL, the lower, the better. And when it comes to triglycerides, I think that that can apply as well. Um In these patients that have even mild hypertriglyceridemia, they have a lot of triglyceride rich lipo protein remnants, which are atherogenic and we don't pay a whole lot of attention to those we're focused on LDL so much because obviously it's the, it's a much greater risk factor, right? But our patient is truly not at low risk until you can get all those numbers at goal. Not only your LDL, but also your uh triglyceride levels, your particle number, your HSCRP. Very important data from Paul Riker has shown us that you have to not only look at lipids, but you have to look at inflammation as well. And it's only when you have down lipids, down inflammation when your patient is truly at low cardiovascular risk. So, yes, when it comes to Triglycerin lower is better as well.
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