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Approaching the Treatment of Hypertriglyceridemia ...
Presentation: Approaching the Treatment of Hypertr ...
Presentation: Approaching the Treatment of Hypertriglyceridemia with Confidence
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Welcome everyone to today's webinar. My name is Hannah Andrews and I'm the Director of Digital Learning for the Endocrine Society. We're excited for today's presentation, Approaching the Treatment of Hypertrichlyceridemia with Confidence. Today's presenter is Dr. Maria Bela Pizarro. She's an Associate Professor in the Division of Endocrinology and Metabolism at University of Texas in Galveston. Before I hand the floor over to her to start the presentation, just a few housekeeping rules. You will be asked to complete a post-test after today's presentation before you can complete the evaluation to claim credit. To submit questions for today, and I see someone's already used it, wonderful. To submit questions, you're just going to click the Q&A box and then you should be given the option to submit a question. Note that these questions are public to other attendees. If you want to take a look and notice that your question has actually already been asked, feel free to use the thumbs up icon below it, and that will vote for that question and bring it a little bit higher, so that during the Q&A session later in the presentation, we'll be sure to address those questions. But without further ado, I'm going to hand it over to Dr. Bela Pizarro. Welcome. Thank you so much. Thank you, Hannah. It's a pleasure to be here with you to talk about hypertrichlyceridemia. As Hannah said, my name is Maria Bela Pizarro. I'm an Associate Professor in the Division of Endocrinology at University of Texas Medical Branch in Galveston. I trained in basic and clinical lipidology and ran a lipid clinic for over 10 years. I maintain an interest in cardiovascular disease prevention in diabetes. Why hypertrichlyceridemia? For one thing, it is a very common lipid disorder. We see it all the time in our practice with our patients with obesity and diabetes in particular, and it is quite complex. The role of triglyceride management and the recent trials have challenged our understanding further, with some even reshaping the way we practice. I have no disclosures except that I'm a member of the ABIM Item Writing Task Force, and no exam questions will be shared during my presentation. The objectives for today are to identify key steps in lipoprotein metabolism that explain risk and serve as targets for the treatment of hypertrichlyceridemia, explain the association of high triglycerides with increased cardiovascular risk and pancreatitis, and then select safe and effective treatment approaches that decrease triglyceride levels and prevent the development of acute and chronic complications of hypertrichlyceridemia. Finally, we'll touch very briefly on some emerging treatment options in the management of severe hypertrichlyceridemia in patients with a history of triglyceride-induced pancreatitis. What are triglycerides? Well, triglyceride are molecules that are composed of three fatty acid chains linked to a glycerol backbone. They are found in circulation within these particles called triglyceride-rich lipoproteins. They serve the body as a source of energy and are stored in tissue, mainly adipose. This is how a triglyceride-rich lipoprotein looks like. So the triglyceride content is in the core of the particle, and it is the predominant lipid component. You also have some cholesterol esters. The particle is surrounded by these phospholipids that have a hydrophilic head. The particle also has protein components called apolipoproteins that play a significant role in the regulation of metabolism. The source of triglycerides is dual. We have an exogenous pathway and an endogenous pathway. Let's start with the exogenous pathway. In this pathway, the intestine plays a key role. It takes dietary fat and converts it into these very large triglyceride-rich lipoproteins known as chylomicrons. When released in circulation, the chylomicrons acquire these apoprotein components that, as you'll see later, play an important role in metabolism. Once the chylomicron hits the capillary wall and comes in contact with lipoprotein lipase, the particle is hydrolyzed and releases free fatty acids. The resultant particle is called a chylomicron remnant. This particle of intestinal origin still has triglyceride. It's called a triglyceride-rich lipoprotein, but see how it's become much more cholesterol-enriched compared to the original particle. The marker of triglyceride-rich lipoprotein intestinal origin is this apoprotein called APOB48. In the endogenous pathway, the liver plays a key role. It takes free fatty acids that can come from adipose tissue or can use endogenous lipid synthesis to lead to the production of particles known as very low-density lipoproteins, again, triglyceride-rich lipoproteins that also have distinct apolipoprotein components. Once the VLDL comes in contact with lipoprotein lipase on the capillary wall, it also undergoes hydrolysis, releasing free fatty acids that will go to muscle or adipose tissue, and the particles get smaller. You'll have VLDL remnants and then finally the intermediate-density lipoprotein. And these particles are, again, as they get smaller, more and more cholesterol-rich. And as you see in the endogenous pathway, the final product, if you will, is the low-density lipoprotein that we're all very familiar with, which is atherogenic and very cholesterol-rich. The marker of hepatic origin synthesis is APOB-100, and we have one APOB-100 per particle. Let's talk a little bit about medications that reduce triglyceride levels by targeting the formation of triglyceride-rich lipoproteins. So you have omega-3 fatty acids, fibrates of PPAR-alpha agonist, and niacin. They are known to reduce triglyceride levels by approximately 30, and in some cases, over 50%. There are other medications available, some that are used only in limited and limited cases, mainly for LDL cholesterol reduction in the case of familial hypercholesterolemia. This is a molecule that, a medication that inhibits this protein called microsomal triglyceride transfer protein. And this is a protein that's key in lipidating the APO protein B with the triglycerides and lead to the secretion of VLDL. The problem with this medication is that you can see if we block the production of VLDL, the fat is going to accumulate in the liver. And so the problem with the medication is the development of severe hepatic steatosis and transaminitis. Let's go to our case. So we have a 34-year-old woman who comes to you because she wishes to conceive. She was found to have high triglyceride levels and was told that she could be at risk of pancreatitis during pregnancy. She has no other past medical history. Her mom has high cholesterol. She's unsure about her mom's triglycerides. There's no other family history. The BMI is 28. The patient has mild acanthosis nigricans. All her labs were normal except the lipid profile that shows a cholesterol of 220, triglycerides 285, HDL of 43, and an LDL cholesterol of 120. Based on what we have briefly reviewed regarding triglyceride-rich lipoprotein metabolism, is there something she can do to improve her triglyceride levels and reduce her future risk of pancreatitis? So yes, she is at risk of pancreatitis. Her triglycerides are elevated, 285. When she gets pregnant, especially in the third trimester, the increase in estrogen levels, the placental lactogen may significantly increase the triglyceride levels and put her at risk of pancreatitis. But we need more information as targets for treatment are likely present in this patient. So we find that she is a busy accountant. She doesn't exercise. She skips breakfast. She has increased intake of fast foods, and she is using an oral contraceptive. So what can we tell her? We can tell her, based on the physiology that we just reviewed, to modify her dietary intake. If she reduces her intake of dietary fat, she's going to produce less chylomicrons, have less chylomicron remnants, which is going to lead to reduction in triglyceride levels. She can also increase her physical activity and lose weight. These are the changes in her lifestyle will reduce the influx of fatty acids to the liver and result in a decrease in the synthesis of VLDL. But very importantly, in this case, we also have to curb other factors that stimulate liver fat synthesis. And in her case, of course, the estrogens. So yes, it's true, she's getting pregnant. She wants to get pregnant, so she will stop the contraceptive. But the contraceptive is likely a contributor to her hypertriglyceridemia. Also, she didn't provide any history of alcohol intake, and it is very important that we ask her. This is a slide that depicts, gives us some information of the effect of lifestyle changes on triglyceride levels. In people that drink alcohol excessively, it has been shown that alcohol abstinence leads to reduction in triglyceride levels of up to 80%. Weight loss, in our patient, I calculated about a 20% reduction if she loses about 10% of her baseline weight. The reports calculate about an eight milligram per deciliter reduction in triglyceride levels for every one kilogram of weight lost. Aerobic exercise and a diet that is rich in omega-3 fatty acids, fish, flaxseed, can further reduce triglycerides by 10 to 20%. What about triglyceride-rich lipoprotein clearance? I really want to emphasize the key role of lipoprotein lipase. As I showed previously, both the endogenous and the exogenous pathways rely on lipoprotein lipase to clear their particles. You can see that if you have somebody that has increased production of VLDL, either because they have underlying obesity or slightly uncontrolled diabetes, if they are further challenged with a diet that is increased in dietary fat, lipoprotein lipase will be saturated, and triglyceride levels will increase. Lipoprotein lipase activity is highly regulated. As I told you, the lipoprotein particles have this lipoprotein component called APOC2, which stimulates lipoprotein lipase activity. It is a cofactor. They also have APOC3, which actually inhibits lipoprotein lipase activity. But lipoprotein lipase activity is highly regulated, not just by these APOC components. As you can see, there are multiple proteins that are involved in the regulation of lipoprotein lipase activity. You have lipase maturation factor one, for example, that assures that lipoprotein lipase is functional and is secreted. Other proteins that are also involved in the transport across the endothelium that tether the lipoprotein lipase so that it can engage with the triglyceride-rich lipoprotein, stabilizing cofactors like APOA5, and then other inhibitory proteins like angiopoietin-like proteins three and four that work by inhibiting lipolysis near the endothelium. The red asterisk depicts proteins that have been shown in genetic studies to be targets for cardiovascular disease prevention. Medications that work on lipoprotein lipase are omega-3 fatty acids work here, fibrates, and the novel therapies that have been developed, we have some targeting APOC3 and angiopoietin-like protein three. What about hepatic clearance? So we all know that the LDL cholesterol is cleared by the LDL receptor. What about remnants? The triglyceride-rich lipoprotein remnants are cleared by the LDL receptor protein one, heparin sulfate glycan. They also very important in their hepatic clearance is the presence of APOE, which allows them to also be recognized by LDL receptor. APOE is also critical in the clearance through these other receptors. Medications that improve remnant clearance include statins, PCSK9 inhibitors, and the novel therapies that target angiopoietin-like protein three. Statins are said to be more effective when the triglycerides are greater than 200. The effect of PCSK9 inhibitors on triglycerides is less marked, it's more modest, and it usually involves the clearance of smaller size remnants at lower triglyceride levels. So these particles of remnants are, like I said previously, cholesterol-rich, and they contain APOE just like LDL does. Note that I don't have in the picture HDL lipoproteins. They do not have APOE-B, they have APOE-1, and are not considered atherogenic. So if you want to have an idea of your atherogenic lipoprotein load, you could look at the lipid profile and calculate the non-HDL cholesterol, which is simply calculated by taking your total cholesterol and subtracting the HDL cholesterol. And with that, we would be measuring the cholesterol in the remnant particles as well as in LDL. Why are triglyceride-rich lipoproteins atherogenic? Well, they may contain up to four times the cholesterol content per particle than LDL, and if metabolism is impaired, they'll be longer in circulation. They are able to penetrate the subendothelial space because they are smaller, they may be taken up by the macrophages, and this leads to cholesterol accumulation and formation of plaque. These triglyceride-rich lipoproteins are also potent enhancers of inflammation. So triglyceride-rich lipoproteins may enhance cardiovascular risk estimate, and this is considered when triglycerides are persistently at or above 175 milligrams per deciliter. Several studies have shown that non-HDL cholesterol and ApoB levels are stronger indicators of atherogenicity than LDL cholesterol alone. Like I said, the non-HDL cholesterol is readily available from the lipid profile and gives you an idea of atherogenicity. ApoB can also be measured, and it is considered a CVD risk-enhancing factor in primary prevention if it is greater than or equal to 130 milligrams per deciliter. So key points so far, triglyceride-rich lipoproteins are synthesized in the intestine and the liver. There are genetic and acquired or secondary determinants of triglyceride levels. Increased production and or decreased clearance may contribute to increased triglyceride levels. Lipoprotein lipase is a key determinant of triglyceride levels, and triglyceride-rich lipoproteins are atherogenic due to their cholesterol content and their pro-inflammatory effects. Let's look at another case. This one is a 42-year-old engineer. He's seeing his primary care physician for a well visit. He doesn't smoke but drinks occasionally. He was diagnosed with hypertension two years ago and is on enalapril five milligrams daily. His family history is non-contributory. He has no complaints. His BMI is 27, blood pressure is controlled. He is African-American, has some mild acanthosis on exam. All his labs are also normal except the lipid profile that shows cholesterol 175, triglycerides 155, HDL is low at 39, LDL cholesterol is 105. So does he have hypertriglyceridemia? And in addition to lifestyle intervention, weight loss, secondary causes of dyslipidemia, what else should be done? Well, what is hypertriglyceridemia? Everybody would agree a triglyceride level over a thousand is hypertriglyceridemia. But the guidelines indicate that triglyceride levels of 150 or greater should be considered hypertriglyceridemia. In fact, the 2009 consensus definition of metabolic syndrome includes triglycerides of 150 or higher as one of its defining components. And in the case of our patient, he's meeting criteria for metabolic syndrome with a history of hypertension, low HDL, and high triglycerides. He may also have central obesity, although the case does not tell us that. But more and more experts are saying that the optimal triglyceride level should be less than 100. And this comes from epidemiological data. Here I am showing data on over non-fasting triglyceride data from over 100,000 individuals that were followed for 26 years in the Copenhagen General Population Study. And it shows absolute risk for the development of myocardial infarction in yellow and ischemic stroke in red. And you can see that people with triglyceride levels of 88 or lower had a lower risk compared to people at higher levels. And you can see that as triglyceride levels increase, so did the risk of these cardiovascular events. Other population studies, this one's showing results in over 300,000 participants across 68 studies, looking at the hazard of coronary artery disease, and triglyceride levels. And you can see the higher the triglycerides, the higher the coronary artery disease risk. But when triglyceride levels and risk, but when risk is adjusted for other covariates, adding to sex and age, systolic blood pressure, smoking, diabetes, BMI, HDL, and non-HDL cholesterol, the association of triglycerides with cardiovascular risk disappears. However, this is considered not appropriate by most experts, the adjustment for non-HDL due to the very high correlation between variables. Remember how I told you how non-HDL cholesterol includes triglyceride-rich lipoproteins. There is also evidence linking triglyceride through genetic studies with cardiovascular risk. Genetic polymorphisms associated with high triglycerides include variants in lipoprotein lipase, APOC3, angiopoietin-like protein 3, APOA5, with increased cardiovascular risk. Let's go back to our case. So if we go ahead and calculate his 10-year risk for a cardiovascular event, we find that it is 5.2% at 10 years. Guidelines show that this would be considered borderline risk, and that we should have a discussion and look at risk enhancers to decide about statin therapy. When we look at the list of risk enhancers, we find metabolic syndrome there. So we have to discuss with the patient the benefits of starting moderate intensity statin. Guidelines say that even triglyceride alone, a high triglyceride that persists at 175 or higher should be considered a risk enhancer and should lead to intervention of lifestyle and consideration of initiation or intensification of statin therapy. Well, going back to our patient, he decided against statin therapy. He got lost to follow-up, returns a year later, and his repeat lipid profile shows a cholesterol of 215, triglycerides of 300, HDL remains low at 38, and the LDL cholesterol is 117. What now? Remember our triglyceride-rich lipoprotein basics. So we wanna make sure that we don't have any secondary causes of hypertriglyceridemia at play right now. He might've gained weight. He might have diabetes now. His alcohol intake may have increased, all which could contribute to this finding of worsening triglyceride levels. We have to get serious about lifestyle with him and remind him of the benefits. But what about a fibrate or the use of fish oils? His triglycerides are quite elevated. Let's go and review the case for fibrates. So this is a table that is summarizing key findings of fibrate trials. They include medications as gemfibrozil, phenofibrate, and the more current one, pimafibrate, which is a selective PPAR-alpha modulator. The earlier study the VA hit was a secondary prevention study, and they used gemfibrozil in patients with high triglycerides. They did see a benefit, a significant reduction of 22% in the primary outcome. This was in predominantly or a full population of males, so no women were included here, and none of the patients were on statin. So no statin, 22% reduction, secondary prevention. With more contemporary trials, the use of statins increased. You can see in phenofibrate how 8% to 17% of participants started taking statins during the trial. In the ACCORD trial, everyone had to be on simvastatin. The average dose was 22 milligrams, whereas in the most current trial that was reported at the end of last year and that was ended early due to futility, almost 100% of people, 96% of people were on any statin, and 69% were on high-intensity statin. So with the concomitant use of statins, there was no reduction of the composite cardiovascular outcomes. Of interest is the finding of PROMINENT, which was, as I said, published the end of last year, that compared pimafibrate versus placebo. It is a very potent fibrate, second-generation fibrate, and we all thought that it was gonna show a beneficial effect on cardiovascular disease reduction, mainly based on subgroup analysis of ACCORD that suggested that in men with high triglycerides and low HDL, the fibrate did have a benefit. Well, this study was done in a predominantly male population with high triglycerides, medium of 271. A quarter of participants had triglyceride levels over 340. A secondary prevention in over two-thirds of people, but there was no reduction of the composite cardiovascular outcome. Other outcomes of interest, aside from cardiovascular, is that with phenofibrate, we've seen less progression of albuminuria and need of laser therapy, retinopathy needing laser therapy. In the PROMINENT trial with pimafibrate, there was a decrease in the diagnosis of fatty liver disease, and although rare, there seems to be an increased, a small increased risk of pulmonary embolism. So the take-home message is that in patients with hypertriglyceridemia, use statins. What about fish oils? Well, when we talk about fish oils, we have to look at omega-3 fatty acids given as supplements, and then studies that look at omega-3 fatty acids in pharmacological doses. So you can see that when used as supplements, it's a combination of EPA, a cosapentaenoic acid, and DHA, the cosahexaenoic acid, at doses of less than one gram a day, whereas the pharmacological doses are two to four times higher. Here, I show the two primary prevention trials using omega-3 fatty acids as supplements, and they showed no reduction of the composite cardiovascular outcomes. One was done in a fully diabetic population, and another one that only had about 14% of people with type 2 diabetes, very large studies with 15 to 25,000 people. No reduction of cardiovascular composite outcomes, although there was a signal, this was not a pre-specified secondary outcome, of a component outcome of a vascular death, and here of total myocardial infarction where there was a reduction in the risk of that was quite marked. When we looked at pharmacological doses, so we're talking about doses of 1.8 to four grams of fish oils a day, we're talking about EPA or a combination of EPA and DHA in the strength trial. We're talking about participants that had cardiovascular disease and some that did not. Again, participants in the study had high triglyceride levels. In the more modern trials, well above 200. Again, in these trials, all of our participants are on statins. The JEALOUS trial, which was a Japanese trial, mostly primary prevention, had everybody on very low dose Pravastatin or Simvastatin. In REDUCE-IT, more than 99% of participants were on statin, about a third were on high-intensity statin. In the strength trial, 100% of them were on statin, 50% or so on high-intensity statin. Triglyceride levels, again, above 200 in these recent trials. So what did we see? We saw a reduction in the composite cardiovascular outcome in the JEALOUS and REDUCE-IT trials, 19% in JEALOUS, 25% in REDUCE-IT. But no difference in outcome in the strength trial. In fact, this trial was ended early because of futility. In the case of REDUCE-IT, there was also a significant reduction in key secondary outcome of non-fatal MI stroke or cardiovascular death of 26%, and cardiovascular death was reduced by 20%. So what these trials show us is that the cardiovascular benefit is not a function of triglyceride reduction. Look at the reduction in triglyceride levels in REDUCE-IT and STRENGTH. They're very similar. In JEALOUS, this was a trial done in very hypercholesterolemic patients. So they had an LDL cholesterol of 182, which started on a statin at the same time that the EPA was started, and the triglyceride lowering was very, very modest at 5%. So not a function of triglyceride reduction. Some have said that the difference between REDUCE-IT and STRENGTH has been the formulation of the omega-3 fatty acid. Note that the two trials that showed a benefit had only used EPA, whereas in STRENGTH, it was a combination of EPA and DHA. So there may be a deleterious effect brought about by DHA. Others argue that maybe the difference, particularly between REDUCE-IT and STRENGTH, lies in the placebo, because placebo capsules for REDUCE-IT included mineral oil, whereas the ones in the STRENGTH used corn oil. So some argue that maybe the mineral oil increased the risk in the placebo arm, and they say that they think this may be true because the placebo arm had a significant increase in CRP and in LDL cholesterol. However, this has been reviewed extensively. The FDA itself does not think that the mineral oil explained the outcomes of the REDUCE-IT trial. Other issues worth mentioning are the risk of atrial fibrillation and flutter that was seen in these two trials at higher doses of omega-3 fatty acids, particularly in people that had a history of previous atrial fibrillation. So what is the consensus? ACE, ADA, several, the National Lipid Association, the European Society of Cardiology, the European Atherosclerosis Society, they all endorse the use of ecusapent ethyl in patients with cardiovascular disease, diabetes, or other high-risk condition that are on statin and that have controlled LDL cholesterol and elevated triglyceride. What about pancreatitis? Well, we all know that as triglyceride levels increase, so does the risk of pancreatitis. Severe hypertriglyceridemia is defined as a triglyceride level of 500 or higher, and some also include extreme or very severe hypertriglyceridemia in the classification, and define it as triglyceride levels over 880 or over 1,000. Population studies have shown that the risk of pancreatitis increases quite significantly when triglycerides reach 500, over threefold. In lipid clinic cohorts, people with severe hypertriglyceridemia have a risk of pancreatitis or have been observed to have acute pancreatitis in up to three to 19% of cases. So the risk of pancreatitis increases as chylomicron remnants and chylomicron particles increase in circulation. The mechanism is not clearly known. We know that hypertriglyceridemia does account for up to 10% of the cases of acute pancreatitis, but the mechanism is still unclear. So some of the explanations are that these triglyceride-rich lipoproteins increase viscosity, and this impairs blood flow in the pancreas, which leads to ischemia and acidosis. There have also been experiments demonstrating increased endoplasmic reticulum stress. What can we do? Dietary fat restriction. It is critical in the treatment of chylomicronemia. And it is, when you have chylomicrons present, the rule is to have a diet that has less than 20 grams of fat per day. You also have to make sure in these patients with chylomicronemia that you address secondary causes, such as alcohol, which is common. Guidelines in fact say that whenever patients have triglycerides at 500 or higher, we have to address lifestyle factors, consider the initiation or intensification of statin therapy, and this is to decrease cardiovascular risk. There is also some effect, as I showed you, on triglyceride reduction with statins. And in the case of severe hypertriglyceridemia, as we are talking about now, there should be consideration of adding a triglyceride-lowering agent to prevent the onset of pancreatitis. How do we manage pancreatitis, hypertriglyceridemia pancreatitis, acutely? Well, we offer supportive management, ICU care if severe. We keep the patient NPO until intake is tolerated. When diet is started, we have to be very careful that we do less than 20 grams of fat per day. It is very important you involve the dietitian. And with this conservative management, triglyceride levels usually improve within 48 hours and may reach 500 milligrams per deciliter by the fourth or fifth day, and this is well documented in the literature. What about insulin? So we know insulin decreases triglyceride levels by blocking the release of free fatty acids, may improve lipoprotein lipase activity. There's no randomized controlled trials, and there's unclear benefit versus conservative management. So most experts agree that the use of insulin infusion in hypertriglyceridemia-induced pancreatitis should be limited to individuals with uncontrolled diabetes. What about heparin? So heparin releases lipoprotein lipase from the endothelium. So it's not going to work if you have a patient, say, with familial chylomicronemia syndrome where there's no lipoprotein lipase or where there's severe malfunction of the enzyme. There are no randomized controlled trials showing that heparin has a benefit versus conservative management. And the concern is that the effect of heparin may actually be transient because it depletes lipoprotein lipase stores. There is also a concern of risk of hemorrhage in the case of necrotizing pancreatitis. What about plasmapheresis? So plasma exchange effectively removes triglyceride-rich lipoproteins and lowers triglyceride levels quickly, up to 80%. Unfortunately, we don't have any randomized controlled trials, and there's no clear benefit versus conservative management. Most people would consider use of plasmapheresis in the case of severe pancreatitis, and others even support its use in pregnancy if there is risk of impending pancreatitis. The American Society of Epipharesis considers hypertriglyceridemia-induced pancreatitis a Category 3 indication. There's an optimum role not established, and individual decision is necessary. Prevention of acute pancreatitis and familial chylomicronemia syndrome, the mainstay is very low-fat diet, less than 20 grams. You need to replace essential fatty acids, limit simple and refined carbohydrates, supplement fat-soluble vitamins. So you recommend a diet that's rich in vegetable, legumes, whole grains, and lean protein. And very aggressively, manage secondary causes of hypertriglyceridemia. So uncontrolled diabetes, obesity, alcohol. Emerging therapies for severe hypertriglyceridemia. We have quite a bit of information on agents that block ApoC-3. Remember ApoC-3 inhibits lipoprotein lipase activity. So we have volane-sorcin, which was a first-generation antisense oligonucleotide. And then a second-generation formulation that is being tested right now. This is the approach trial that looked at volane-sorcin. In 66 patients with familial chylomicronemia syndrome, they had to have genetic confirmation or a lipoprotein lipase activity measured to be less than 20%. Note that almost 80% of these people had pancreatitis and had triglyceride levels of a mean of 2,000 or higher. So the people were randomized to either 300 milligrams of volane-sorcin once weekly, sub-q versus placebo for a year. The doses were decreased to every other week and later on even reduced to 150 milligrams if adverse effects were noted. But the primary outcome was to look at the change in fasting triglyceride at three months. And you can see in these patients with familial chylomicronemia syndrome, a 77% reduction in triglyceride levels with the treatment, whereas in the placebo arm, there was an increase of 18%. This is a picture depicting the change in triglyceride levels over time. The medication is in red, the placebo in gray. Exploratory analysis looking at acute pancreatitis showed that in the placebo arm, there were three patients that had acute pancreatitis, four episodes total. In the treatment arm, there was only one patient that had acute pancreatitis, and that was nine days after the final dose of volane-sorcin was given. The main problem with this medication was the thrombocytopenia. Two of the patients had platelets drop to less than 25,000. The good news is that with the newer generation of the antisense oligonucleotide that has less systemic effects, they haven't seen yet in the pilot trial thrombocytopenia. Other therapies, like I said, in development, we have some that are targeting angiopoietin-like proteins, three. These are focused more, though, on patients with familial hypercholesterolemia. So in conclusion, hypertriglyceridemia is a marker of increased cardiovascular disease. Triglyceride-rich lipoprotein remnants are likely associated with cardiovascular disease due to their increased cholesterol content and pro-inflammatory effects when they reach the subendothelial space. Statins are the mainstay of therapy in patients with hypertriglyceridemia to reduce cardiovascular risk. Lifestyle interventions with strict dietary management and treatment of secondary causes are fundamental to the prevention of hypertriglyceridemia-induced pancreatitis. And novel therapies are bringing hope of an improved quality of life for those with the most severe forms of hypertriglyceridemia. With this, I think we've covered our objectives, and I will be glad to take some questions. Thank you so much, Dr. Velikazar, for today's presentation. We did receive a few questions throughout the presentation. So to kick a few off, are the definitions for hypertriglyceridemia based on fasting levels? So that is a good question. The definitions are based on fasting levels, but that doesn't mean that we have to, you know, basically you can do non-fasting lipid profiles on your patients. If you see that the triglyceride levels are elevated, you may want to get a fasting level to confirm that hypertriglyceridemia is present. It doesn't really affect the non-HDL, and you can still estimate the etherogenic load. Great. Now, can you describe the mechanism of TPN-induced hypertriglyceridemia and the management of it? So TPN-induced hypertriglyceridemia. So the way I would see it would be that you would have a high influx of carbohydrates in the TPN formulation, and then in people that are predisposed, they would develop hypertriglyceridemia. You have to be careful when you're using TPN that you do not use the lipid supplement. And this is something that is forgotten many times. So you'll have the, you know, the regular TPN, and on several days in the week, they'll get the additional fat supplementation, so that can worsen hypertriglyceridemia. How would I treat it? I would probably, you know, avoid. And we had a patient like this in the hospital with pancreatitis. We told them to avoid the fat emulsion, so no fats. And we also reduced the dextrose component in the TPN. That patient ended up actually needing plasmapheresis. His triglycerides were horrible, and he was very ill. Now could you comment on the use of insulin sensitizers, particularly pyoglitazone, in metabolic syndrome patients with moderate hypertriglyceridemia? So that is a very good point. Some of the guidelines, I've seen it in the ACE, are actually recommending the use of pyoglitazone, even in patients with prediabetes. And the effects of this Ppar gamma agonist on triglyceride levels are favorable. In addition, pyoglitazone has been shown to have a cardiovascular benefit. It is cheap, so it should be used more often. Now going back to your previous presentation point on statin therapy, what is the rationale for using moderate dose statins in moderate risk patients versus using intensive statins in all patients that are already treated with statins, knowing that cost isn't really an issue now that generics are available and side effects are more easily detected and managed at this time? I guess we try to use medications to minimize the risk of adverse events. Yes, they are low, but you want to balance the benefits, the pros, and the cons. I would say that is something that you could individualize and discuss with patients, but overall, that is what the guidelines recommend. If you have a patient that is on moderate dose of statins and their LDL cholesterol is, I don't know, 70, 72, you may want to consider, look at those additional risk factors and consider intensifying therapy. There is also the role of measuring, like we said, ApoB, and maybe you could look at that to determine if you need to be more aggressive. This is really important in the intermediate risk category where these factors can end up leading to more intense statin therapy. Now on the same, in the area of statin therapy, can you discuss the recommended monitoring strategy for combination statin and fibrate therapy? So I don't think, you know, after the prominent trial, I don't think we have an indication for the combination of statin and fibrates anymore. I mean, this is something that really has reshaped the way we practice. So the only time that I would see using this is in a patient that would have severe hypertriglyceridemia, so we're talking about people that have triglyceride levels over 500, and in those patients, because of the risk of pancreatitis, you would add a fibrate to a statin. So how would you monitor that? I guess one of the things that you want to look at is liver function. You want to look at renal function. Usually you want to use, you know, you don't want to use gemfibrozil in combination with a statin because you have a higher risk of rhabdo. So if you are going to do a combination, I would not recommend using gemfibrozil. Now we've had several questions about some alternative pharmacotherapy, specifically, I hope I'm pronouncing it correctly, niacin and vesipa, if you could speak a little bit to those as therapy options. So niacin, so niacin used to be a poster medication. It made the lipid profile look ideal. So it lowers LDL, it lowers triglyceride, it increases HDL. However, when the trials were done, when the niacin trials were done, they showed that there was no cardiovascular benefit from adding niacin to statin therapy. And in one of the trials, the aim high, it appeared there was a concern of an increase in ischemic stroke with the use of niacin. In that and another trial, the HPS2 Thrive that was done with niacin, they also saw, and we know this, it increases insulin resistance, it makes diabetes control worse. So if you have people that are not on insulin, they end up having to start using insulin or it worsens glucose control. So we generally do not want to use niacin. Some people use it in cases of very severe hypertriglyceridemia when they have tried fish oils, fibrates, and lifestyle interventions, and the triglycerides still remain elevated, but it is not a medication of choice. What was the other medication? I believe it was Vasepa, Vasepa. So Vasepa is, we talked a lot about Vasepa. So that's the eicosapent ethyl. That was the medication that I showed you from the REDUCE-IT trial that definitely had a benefit in cardiovascular risk reduction. We saw a 25% reduction in the composite outcome, and it effectively reduces triglycerides. So if you wanted to use an omega-3 formulation to lower triglycerides, ideally it would be that one. So I want to try and fit in two more questions, specifically in the vein of safe use of medication. So we've had a couple of people ask specifically about GLP-1 agonists, one with triglyceride levels of 500 or above, who might be at risk of pancreatitis. Wow, that's a hard one. That is a hard one. So you know that we shouldn't be using GLP-1 receptor agonist because of the risk of pancreatitis. That is where I think you have to talk to your patient and review the benefits and risks. I would definitely stay away from using them in patients with severe hypertriglyceridemia. What you could do is maybe control the triglyceride levels with lifestyle, with fibrates, with fish oils, and then after discussion with the patient, if the patient is obese and other measures have failed, you may consider using it. But again, I don't know if it would be something that I could recommend overall as safe. It would have the benefit of the weight loss, and with weight loss, you would have significant reduction in triglyceride levels and thereby reduce the risk of pancreatitis. But unfortunately, we don't have enough data to say that it is safe in that particular group of people. And my final question is, still in the space of therapy safety, what medications would be safe for patients who are pregnant with hypertriglyceridemia? That's an interesting question, and we sometimes get consults like that. So patients with hypertriglyceridemia at risk of pancreatitis, what medications to use? So again, the paradigm is you have to start with lifestyle. Diet plays a key role. Think of it. People that don't have lipoprotein, lipase, the way they control their triglycerides is with diet. So diet will work in anyone, and there are published cases in the literature. I remember reading one where the patient with familial hypokalomyconemia syndrome was pregnant, and they managed the hypertriglyceridemia just with diet, very strict starting on the third trimester. The consensus is that you start omega-3 fatty acids as first-line therapy in pregnant patients if a diet has failed. The addition of fibrates, so there's the concern of effects on the fetus. I've seen some reports on the use of fibrates in the fetus. The use of fibrates in the third trimester of pregnancy, but again, that is something you'll have to discuss with your patient versus the use of plasmapheresis. So plasma exchange in patients in pregnancy is said to be recommended in people that are in impending risk of pancreatitis while they're pregnant because of the very high mortality risk and the effects of fetal loss. And so we use it usually when triglycerides are above 700 with symptoms or when the triglycerides are above 1,000. So start with fish oils. Work with lifestyle. Diet is key. I remember having a patient with severe chylomicronemia syndrome that was pregnant, and on the last trimester, right before delivery, we had her in the hospital for two weeks just for her to have the low-fat diet, and she was able to deliver safely without onset of pancreatitis. So diet is key, and then you add your fish oils, and then you go to the extreme of either considering the fibrate or the plasmapheresis.
Video Summary
The video is a webinar on the treatment of hypertriglyceridemia. The presenter, Dr. Maria Bela Pizarro, discusses the importance of managing hypertriglyceridemia, which is a common lipid disorder, and its association with increased cardiovascular risk and pancreatitis. She explains the key steps in lipoprotein metabolism related to hypertriglyceridemia and discusses the role of triglyceride-lowering medications such as omega-3 fatty acids, fibrates, and niacin. Dr. Pizarro also highlights the use of statins as the mainstay of therapy to reduce cardiovascular risk. She emphasizes the significance of lifestyle changes, including dietary modifications and weight loss, in managing hypertriglyceridemia and preventing complications. Dr. Pizarro also touches on emerging treatment options for severe hypertriglyceridemia, such as medications that target ApoC3 and angiopoietin-like protein 3. Throughout the presentation, the importance of individualizing treatment approaches based on patient characteristics and risk factors is emphasized. The video provides a comprehensive overview of the treatment of hypertriglyceridemia and its complications.
Keywords
hypertriglyceridemia
lipid disorder
cardiovascular risk
pancreatitis
lipoprotein metabolism
triglyceride-lowering medications
omega-3 fatty acids
fibrates
niacin
statins
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