Welcome to this session, Triglycerides, Medications and Trials. My name is Jennifer Gilligan, and I will be serving as your moderator today. You'll be hearing a lecture from Dr. Betu Hatipoglu on this very fundamental subject. Dr. Betu Hatipoglu is a professor of medicine at CWRU School of Medicine and vice chair at UH System Clinical Affairs, medical director, Diabetes and Obesity Center, and Mary B. Lee Chair in Adult Endocrinology, University Hospital Cleveland Medical Center, having accepted that appointment in 2020. Prior to that appointment, between 2008 and 20, she was a staff endocrinologist at the Cleveland Clinic and assistant professor of medicine and medical director for pancreas and islet cell transplant program at the University of Illinois at Chicago for nearly eight years prior to that time. Clinically, she's interested in diabetes, thyroid disease in women, and pituitary and adrenal disorders. Her research interests are an autologous islet cell transplant in chronic pancreatitis patients and new treatment modalities in type 1 diabetes and management of diabetes and population health. Dr. Hatipoglu speaks three languages, English, Turkish, and French. Thank you for being here today. I would like to thank the organizing committee for inviting me to talk to you about triglycerides, the medications, and trials. I always like to review for us the basic science of what we will see as clinical practitioners. Just to refresh our minds, I want to remind you that the triglycerides that circulate in our body are resourced from dietary fat as well as internal production of free fatty acids packaged in the liver to triglyceride. This shows you that intestinal dietary fat, that is the breakdown to free fatty acids, are formed into triglycerides and packed with APOB48 with the help of microsomal triglyceride transfer protein and secreted through the lymphatic system as chylomicron. On the other hand, the internal production of free fatty acids, either from the breaking down of what we have inside our bloodstream or formed from the glucose itself, then packaged into the triglycerides with APOB100 in the liver and secreted as a VLDL into our bloodstream. Both triglyceride-rich particles then broken down with lipoprotein lipase near the endothelial wall. Here in that square that you see, the breaking down of triglyceride-rich particles with lipoprotein lipase as an enzyme requires APOC2 activation and will be inhibited with APOC3 or angiopoietin-like protein 3 or 4. These are important small details that I would like to remember as this will help you understand better some of the treatment modalities we have. Elevated triglycerides is not an uncommon clinical disease. Almost 10% of the population suffers from hypertriglyceridemia. Just to remind ourselves that less than 150 is actually normal and high or very high starts becoming an issue as it increases the risk of pancreatitis when it's more than 500 mg LDL. And severe or very severe high triglyceride levels luckily are not very commonly seen but you will see once in a while those patients in the hospital or in your clinical practice. Some of these very high levels of triglycerides and familial form of hypertriglyceridemia such as familial chylomicronemia syndrome helped us to understand better the metabolism and underlying physiology of triglyceride metabolism and helped us perhaps develop some of the newer ways of treating this disease. Lipoprotein lipase deficiency, APOC2 deficiency, for example, seems to be more commonly seen in familial chylomicronemia. Some of the other less common forms of the monogenic is listed here and there are also polygenic forms of chylomicronemia that are more complex in genetic form. We also have mild to moderate hypertriglyceridemia that is multifactorial and polygenic that cannot be necessarily linked to one gene or other and also is influenced by some of the secondary causes of hypertriglyceridemia when it becomes clinically severe forms of presentation. So secondary causes of hypertriglyceridemia are something to remember because when you're dealing with a patient that comes to our practice, our attention, with high levels or very high levels of triglycerides, treating the underlying secondary cause definitely will help you to manage it in addition to the disease-specific treatment of triglyceride increase. Some of those are, for example, really diabetes, right? How many times uncontrolled diabetes will come to our attention with pancreatitis and elevated triglycerides in the hospital setting? Pregnancy, the metabolic syndrome, and drugs. The most common ones that I would like to remind you to remember are the estrogen, such as oral contraceptives. I have seen many young women who would come to me with triglycerides 500, 600 after starting oral contraceptive. Tamoxifen in my breast cancer patients, I have noted that. And, of course, some of the antipsychotic agents that are used that you will notice that might raise the triglycerides level. Also, some of the antiviral agents that some of our infectious disease colleagues would use in HIV patients or others will also affect the triglycerides. So before we go into the complicated and sophisticated ways of treating triglycerides, I want you to remember the simple few points that will make a huge difference in patients especially in mild to moderate elevation. Alcohol is very well known to increase triglycerides and should not be consumed in any form if someone suffers hypertriglyceridemia. Weight loss and restricting carbohydrates, that is a fuel for free fatty acid formation, as well as saturated fat is extremely important to remember as well. Exercise can decrease triglycerides 10 to 20%, which is almost the same as fat in therapy. And, of course, the omega-3s are known with the dietary intake to decrease the triglycerides. So these are, I think, things to remember to help our patients even before you might consider treatment in some mild elevated triglycerides, hypertriglyceridemia cases. Management of hypertriglyceridemia really has two important components. One, we are trying to prevent pancreatitis. And two, we are trying to improve the cardiovascular outcome of these patients and try to prevent the devastating results of a cardiovascular event. So statin treatment, even though it decreases triglycerides only 15% or 20% the most, is still the number one way of treating this disease as we will get the most cardiovascular benefit. And after that, after starting the statin, the additional decrease in triglyceride level is really to try to bring the risk of pancreatitis down. At least that's what we thought until now. And the recent trial, especially the REDUCE-IT trial, really changed the way we are seeing and treating these patients. Let's dive in a little bit and see what we have with this study. Just once more to remind you that the types of fatty acids that we know are beneficial for our patients are the MUFAs that is found in olives, peanuts, avocado, pecan, almonds, and their oils, and PUFAs that are the omega-3 and omega-6 that is found in walnuts, flax seeds, hemp seeds, vegetable oil, fish, and marine oil. So the omega-3 fatty acids that are effective for lowering triglycerides are the seafood N3 PUFAs, and we have icosapentonic acid, docosapentonic acid, and docosahexaconic acid that we are familiar with. So different studies throughout the years looked at the benefits of omega-3 and really had no significant association with fatal or non-fatal coronary heart disease or any major vascular event. These studies used different supplements, different doses, and different enrollment of patient population. One of those studies was really important, I think, to bring to your attention was the JEALOUS trial, which is a Japanese trial that included 18,000 patients with total cholesterol more than 250 before the treatment with statin. And the baseline triglycerides for these patients were around 153, and the statin use wasn't necessarily very robust, but 20 milligrams of provostatin or 10 milligrams of inlet statin. And in this study, there was a decrease of 19% of the cumulative incidence of major coronary events. Here you see the primary endpoints were sudden cardiac death, fatal, non-fatal MI, unstable angina, angioplasty, or coronary artery bypass grafting. And larger decrease in those with triglycerides higher than 150 and HDL lower than 40, which is the metabolic syndrome-specific lipid panel, in a way, benefited the most. So the REDUCED trial was a trial that enrolled around 8,000 patients and randomized them to placebo versus 4 gram, which is much higher than JEALOUS trial, which used 1.8 gram, icosopentanil. The patient population was 45 years or older with established cardiovascular disease, or 50 years or older with diabetes and one additional risk factor. Triglycerides needed to be more than 135, and LDLs more than 40 and less than 100 on a stable statin dose before randomization. When we look at the results, the key medical therapy that could have affected the results in both icosopentanil group and placebo were very similarly distributed. And the primary endpoints of cardiovascular death, MI, stroke, coronary revascularization, unstable angina were decreased almost 30%. The key secondary endpoint in cardiovascular death, MI, and stroke was also significantly lower in the intervention group. What was very interesting to me is that not only the first events were decreased, but second, third, even fourth events were prevented significantly in a better way with the intervention. And then when we look at the different triglyceride levels in these patients, even as low as less than 100 of triglyceride levels benefited from the icosopentanil. To compare with placebo, icosopentanil 4 gram a day significantly reduced total cardiovascular events by 30%. And I think the most exciting part of this study, not only 25% reduction in first event, but 32% in second, 31% in third, and 48% reduction in fourth or more cardiovascular events. And in patients as low as triglyceride of 100 benefited the intervention. The primary prevention group or the subgroup with diabetes was very similar. The icosopentanil and placebo distribution in diabetes subgroup in reduced trial were very similar. And the same way, first, second, and third events were prevented significantly compared to the placebo arm. Safety for the full study was the same. It included increases in atrial fibrillation and slaughter, which has been seen in almost all the fish oil studies. And increased bleeding needs to be really kept in mind. Serious bleeding was not significantly different. In conclusion, with reduced trial, compared with placebo, icosopentanil 4 gram significantly reduced both first, total primary endpoint events in patients with diabetes at baseline by 23% and 24% respectively. For the key secondary endpoints of the MACE, reduction for first and total events were 30% and 29% respectively. Reduction were consistent and robust across the pre-specified endpoints among patients with diabetes with or without cardiovascular disease, as well as those with established cardiovascular disease and no diabetes. I think after this, many of our guidelines about triglyceride treatment were updated. For patients with fasting triglyceride level more than 500, we always need to evaluate secondary causes and consider medical therapy to reduce the risk of pancreatitis. And then there is a moderate hypertriglyceridema. The clinicians should address and treat lifestyle factors, which is very important. Secondary factors, which is very much reversible. And medications that raise triglycerides might need to be changed. In patients with atherosclerotic cardiovascular disease or other cardiovascular risk factors on a statin with controlled LDL cholesterol, but elevated triglycerides, the addition of icosapentanil can be considered to reduce cardiovascular risk. And this is really new since after starting statin, we were mainly targeting triglycerides to decrease the risk of pancreatitis. Now, with the information we have, it's not necessarily the only reason we are adding agents as we have seen the reduction in cardiovascular risk. Reduced group researchers also performed additional analysis of the impact of icosapentanil on stroke on the same 8,000 participants. This was recently presented in the International Stroke Conference. The risk of first fatal or non-fatal ischemic stroke was reduced 36% in patients treated with icosapentanil, which I think is a great information. For every 1,000 patients treated with icosapentanil for five years, 14 strokes were averted, and the risk of bleeding stroke was very low. No difference was found among those taking icosapentanil and placebo. So another study that we were waiting recently is published in JAMA as the STRENGTH trial that looked at the omega-3 fatty acids versus corn oil on major adverse cardiovascular events in patients at high cardiovascular risk. So this was a large trial that used a different formulation of omega-3 fatty acids. It wasn't just icosapentanil, but it was a combination of icosapentanil and DHA, and it was a carboxylate acid formulation. And the placebo was corn oil. This study did not show any effect on the primary MACE. As you can see in this graph, as a result was stopped in a way earlier. So what we learned from STRENGTH trial is that atrial fibrillation was increased, so it seems to be the side effects of omega-3 for sure. The primary endpoint of cardiovascular death, MI, stroke, or vascularization were not different in this study with the formulation it was used and the placebo that was used. The trial was terminated early due to the analysis revealing really not much benefit. So the STRENGTH and the OMIMI trials that I'm not gonna go over, which is similar to STRENGTH trial, yielded neutral results. The efficacy of high-dose EPA, which is the only prescription for ACVD risk reduction, I think should not be extrapolated to agents with a mixture of EPA plus DHA at this time. There appears to be also a signal for nuanced atrial fibrillation associated with high-dose of omega-3 supplements that needs to be kept in mind, and more studies are needed to explore why the results were so different between reduced STRENGTH and OMIMI. And one can really only today guess some of the possibilities from using different maybe the population that was in the study to different formulation of omega-3 to different formulation of placebo. I think it will be only a speculation at this time. So omega-3s, we have them available in the market. You really need to monitor the LDL. Sometimes it can be increased, especially if triglycerides are higher than 500. Omega-3s definitely prolong bleeding time. I think it's important if someone is warfarin or they are using other over-the-counter agents that can also increase bleeding time. They need to be aware of this. ALT and ASD needs to be periodically checked in this patient. And of course, if someone has a sensitivity or anaphylaxis with fish and shellfish, one should be very careful. Atrial fibrillation and atrial flutter are definitely side effects of these formulations. One has to be really very careful about it and closely follow these patients with maybe previous history the first three months. Most common side effects are more like a GI side effects of dyspepsia, taste change, and so forth. And definitely not for nursing mother or pregnant women. So we are gonna enjoy a small movie here. I was hoping to bring a little bit of fun for you. This is a YouTube movie that I love as it brings in a better understanding of the lipoprotein metabolism. And I'm hoping this will make the next part of my talk more fun for you. So let's watch a little bit of this movie now. ♪♪♪ A key to effective treatment of cardiovascular disease is understanding the body's complex lipoprotein transport system. At the operational helm are apolipoproteins, which through their various functions, such as enzyme activation and receptor binding, choreograph the transport of lipids from sites of absorption or synthesis to sites of utilization. This system cycles triglycerides for distribution to muscle for energy use or to adipose tissue for storage. And it cycles cholesterol for distribution throughout the body for cell membrane, bile acid, and steroid hormone synthesis. A complementary cycle called reverse cholesterol transport completes the system. APO-B-containing lipoproteins, also called non-HDL, comprise the lipid delivery pathway, while APO-A1-containing lipoproteins, or HDL, participate in reverse cholesterol transport. APO-B-containing lipoproteins originate from two sources, an intestinal APO-B48 lineage and a hepatic APO-B100 lineage. Traveling along similar pathways, APO-B particles are remodeled into smaller and smaller cholesterol-rich remnants as triglycerides are released in the form of fatty acids to peripheral tissue. Let's take a closer look at this process. The newly assembled APO-B-containing lipoproteins are secreted from the intestine or liver into the lymph or plasma, respectively. Secreted with them are APO-Lipoproteins E, C2, and C3. These APO-Lipoproteins may also be acquired from HDL. With attachment to proteoglycans on capillary endothelium, the lipoprotein remodeling process begins. Here, APO-C2 activates lipoprotein lipase, LPL, which hydrolyzes the lipoprotein's core triglycerides into free fatty acids, which diffuse through the capillary to muscle or adipose cells. As fatty acids exit, the lipoproteins become smaller and smaller remnants. In remodeling of the APO-B100 lineage, a further step by hepatic lipase, HL, transforms remnant IDL particles to LDL. During remodeling, remnants of both APO-B48 and APO-B100 pathways shed APO-Lipoproteins E, C2, and C3, which then reassociate with HDL. Eventually, most APO-B remnants are recycled to the liver through the LDL receptor-related protein LRP or LDL receptors. However, APO-B remnants can have other metabolic fates. For example, LDL may be taken up by peripheral cells for its cholesterol content or of more clinical concern, chylomicron remnants and LDL may become targets for uptake by the arterial wall macrophage. Excess APO-B-containing particles can invade the arterial wall, become oxidized, and be taken up by macrophage scavenger receptors, creating the foam cells that lead to atheroma. Now let's examine the complementary APO-A1 or HDL pathway that protects from atherogenesis. HDL's two major atheroprotective roles are reverse cholesterol transport and properties which prevent LDL oxidation, a key trigger for atherogenesis. Let's look at reverse cholesterol transport. To begin, poorly lipidated APO-A1 is secreted from the liver and intestine and released into the plasma for circulation to peripheral cells where it removes excess cholesterol, forming nascent HDL. HDL's removal of cholesterol from cells is of utmost importance when those cells are cholesterol-laden arterial wall macrophages. Let's examine several of HDL's cholesterol-removing mechanisms. Excess cholesterol in the macrophage triggers upregulation of the ABCA1 transporter and a hydrolase which converts cholesterol ester in the lipid pool to free cholesterol. The ABCA1 transporter operates to harvest this free cholesterol and deliver it to the cell membrane where it is acquired by poorly lipidated APO-A1 to create nascent HDL. The transporter shuttles back and forth, transferring cholesterol from the macrophage to HDL. Next, the free cholesterol on HDL's surface is esterified by lecithin-cholesterol acyltransferase, or LCAT. The cholesterol ester then moves to the lipoprotein's core, forming the more spherical, mature HDL3. Further cholesterol removal by HDL3 occurs through SRB1 receptors in membrane cholesterol pools. As HDL3 collects more cholesterol and is acted on by LCAT, it expands to HDL2. As we've seen, ABCA1 and SRB1 are key devices for cholesterol efflux. However, HDL also collects cholesterol from both lipid rafts and cavioli within the cell membrane. In these ways, HDL facilitates cholesterol efflux from the macrophage. Now rich in cholesterol esters, HDL2 engages in an exchange with triglyceride-rich lipoproteins mediated by cholesterol ester transfer protein, CETP. Cholesterol ester from HDL2 is transferred to APO-B-containing lipoproteins in a one-to-one exchange for triglycerides. The result, further cholesterol enrichment of APO-B lipoproteins and triglyceride enrichment of HDL. HDL may now have one of three fates. HDL's triglycerides may be hydrolyzed by hepatic lipase, converting it back to HDL3. Or, HDL2 can return to the liver, interacting with scavenger receptor SRB1, which removes cholesterol, converting it back to HDL3. Or, finally, HDL2 may be catabolized by the liver. As we have seen, these complementary systems work in elegant harmony to choreograph the body's lipid needs. And as science continues to unravel these intricacies of normal lipid metabolism, our ability to understand, diagnose, and manage various dyslipidemias continues to improve. I hope you enjoyed the movie. I love this movie, and it helps me to understand the metabolism of the lipids better. So it was a break for you to looking at the screen and the tables, and hopefully it was successful, and you got a break. Testatins, as I said, is always the first line, and the goal is not necessarily to decrease the triglyceride levels to prevent pancreatitis, but rather to help with cardiovascular risk. And we have studies that helps us to really back this concept. But the other group of medications we will review briefly are the fibrates. The fibrates are really, really great group of medications to decrease triglyceride. Their benefit, in many different studies, and you see here the HHS-VA-HIT-BIB2 field and ACORD lipid trial, test in gym fibrozil, there's a fibrate and centrifibrate, has not provided necessarily this robust information that we have been looking for when it comes to preventing death, cardiovascular death, or even cardiovascular outcomes. You know, one could really go back and forth about these studies and discuss in detail what might have gotten into our way of understanding the benefits of fibrates in the specific groups of patients that these studies looked at. But I think it's important to understand that fibrates, first of all, are great medications to decrease triglycerides. Yes, their effect on cardiovascular reduction of these agents could be only seen perhaps when the patient has dyslipidemia that one expects them to be effective. Not in everybody. Not like the omega-3 in reduced trial when your triglycerides was even as low as 100. No, but if you have patients who have triglycerides higher than 200, HDL low, lower than 40, this seems like in each of these trials benefited the patients who were already on statins. So this is, for example, just showing you the data from Accord Lipid Trial where the high triglycerides, low HDL group had a 31% lower event rate when fenofibrate was added to simvastatin in this. So I think it's important to remember that these medications are great addition and a tool for us to really treat the high triglycerides. And we might have a better information with an ongoing study called PROMINENT Study that is using pemifibrate to reduce cardiovascular outcome by reducing triglycerides. But this study is really looking into the patients that we have seen in the others that received the benefit of fibrate, the moderate to high-intensity statin therapy or LDL control in patients with triglycerides that are higher than 200 and HDL lower than 40. So we will see what this shows. We have fenofibrate and gemfibrozil. As you can see, they decrease robustly the triglycerides, increase HDL. They decrease some LDLs, especially the stenofibrate. Just to keep in mind a few important side effects, choleric acid is important to remember. It's important also to remember that both of them may potentiate the effect of anticoagulants if someone is on coumadin, for example. Myopathy and rhabdomyolysis, when used with statin, can be increased, especially with gymfibrozole, and they can increase serum creatinine, which is not really a reflection of renal dysfunction. Those needs to be adjusted in renal failure patients. This is just the understanding of different agents we have. Omega-3 we reviewed, fibrase we reviewed, and niacin very briefly we will review. The niacin actually was a drug that was probably first approved for triglycerides and lipid management around 1955. It's a nice agent that increases HDL, decreases LDL, decreases triglycerides, but unfortunately, none of the trials that we have been looking forward to, to really seeing any significant effect in MI, stroke, or cardiovascular death was successful. Aim high, and HBS to thrive. Really brought in a little bit of disappointment about this agent, and I think we don't as much use it anymore, especially as we have additional agents today to use for LDL reduction as well. It has a side effect for skin flushing if it's to issue the immediate release is used, which is not much available, but extended releases that are tolerated. So nevertheless, though, even though we have these amazing agents and tools, we still have some of these patients that come to our office with more tough, tough to treat, and puzzling, and challenging. For example, this is a patient I use a lot as an example, when I teach, that has a triglyceride of 4,000, comes with abdominal pain, nausea, vomiting, and the skin findings that are significantly small, popular, eruptive, exonotomas. So these kinds of patients are rare, but nevertheless, you can see, this is an example of familial chylomicronemia, where lipoprotein lipase deficiency, or upper C2 deficiency, causes lipemic serum. You can see it in the little tubes, and of course, in the back of the retina as well, we can see that as a lipemia retinalis. So what do we do about these challenging patient population? And here, we are gonna review for the next five to 10 minutes, our newer agents that are being developed and used, in some cases, in other countries. Just to, reminding you about the angioprotein, lipoprotein 3 and 4, and upper C3. From the genetic knockdown, or loss of function of the genes for these proteins, there has been clinical findings that when you have a, you don't have the angioprotein 3 or 4 and upper C3, you do have a better function of lipoprotein lipase. And decreased level of triglycerides, and protection from cardiovascular disease, in patients who has been diagnosed with that mutation. So with that in mind, some drugs have been produced, and we are gonna review briefly those. The first one I would like to just bring to your attention, is the buprenorphine, which is a drug that inhibits the translation of the NGPTL3 messenger RNA. This was tested to see if it lowers triglycerides, and is effective in patients with diabetes, hepatitis steatosis, or hypertriglyceridemia. This is a study that was published in 2020. And the intervention, which was a phase two trial, in patients with 100, around 100 patients, with high triglycerides and diabetes or hepatic steatosis. This intervention was provided for six months, in different doses and intervals, compared to placebo. And one could actually see, that buprenorphine resulted favorably, in changes of the lipid profile, and possibly a potential intervention, in challenging cases for us to use. Another agent was ebinacumab, which is actually used in homozygous familial hypercholesterolemia, but also known to be effective, decreasing hypertriglycerides. This was a study that was published in the New York Journal of Medicine. Testing the ebinacumab, which is a monoclonal antibody, against the NGPTL3, it resulted in decrease of LDL in these patients, but also triglycerides. Polonethorcin, in another study that was published in the New York Journal of Medicine, was used in familial chylomicronemia. It was a phase three trial, that really showed the effect of the same agent, in changes of the triglycerides were very significant, and it lowered to less than 750, especially in patients with familial chylomicronemia, which they go really very high. Thrombocytopenia was one of the side effects. And we also just recently seen the results of the COMPAS trial, another phase three trial with polonethorcin, and I'm hoping that we are gonna see perhaps the approval for at least a subset of hypertriglyceridemia. A gene therapy that was used with a viral vector intramuscularly to help familial lipoprotein lipase deficiency was developed and used in Europe for a while, but the efficacy didn't last as much, and the cost was too high. I believe it's not available anymore. It was marketed under the name of Glyzora. So last two slides for us. I would like to just remind you there is exciting new advances in triglyceride world that we are gonna see coming up. But in the meantime, when you see your hypertriglyceridemia patients with acute pancreatitis in the hospital, remembering to give them the fluids, especially non-glucose-containing fluids as glucose will turn into fatty acids and further might complicate the picture. Insulin, as insulin blocks the release of free fatty acids, this might be potentially important to use, especially in patients with diabetes. Heparin sometimes is provided to help to release of lipoprotein lipase. And of course, the fibrase, omega-3, statin, ezetimibe, PCSK9 inhibition. In acute setting, we try to avoid them until the patients are more stable. Plasma therapists has been described as case reports. It's not routinely recommended, but can be used, especially in patients who suffers high levels of triglycerides and acute pancreatitis or risk of acute pancreatitis impending acute pancreatitis during pregnancy. This is just remind you our ACE algorithm for the management of hypertriglyceridemia. And if you need more information, feel free to come to our website and review the Lipid and Cardiovascular Health Resource Center. Thank you for joining me. I hope you enjoyed my lecture. Thank you, Dr. Hatipoglu for informing us on this very informative topic. We will now go ahead and open up the floor for questions. Please type your questions into the chat and we'll try to address all that we see. I'm gonna get started with the first one we have, which is, if you have a young female in reproductive age trying to get pregnant who also has hypertriglyceridemia and a history of pancreatitis, what would you recommend for treatment? Thank you. First of all, I wanna thank everyone who put up with my talk. It was a long talk, a lot of things we tried to cover. I salute you that you really stayed with me and listened to me. Thank you. So that was an amazing question because luckily it's not common. It's rare, but we do see once in a while these challenges cases, right? The pregnancy is not just one life. You are responsible for two, if not more. And we have to be very careful and gentle with the way we treat patients. I will tell you that diet actually can be extremely, extremely potent in pulling down the triglycerides. I have seen with my own eyes, the triglycerides of 2000, 3000, 4000, even more to come down within a week of very restricted carbohydrate and fat diet. But one of my patients once told me that he just eats lettuce all day and that's not life. Well, they eat lettuce all day. They will do very well with the triglycerides. You could, if it's very severe during pregnancy, that's one of the very rare cases you do use plasmapheresis. And there was a question, I will just address that. Can we use something like Vesepa, omega-3 during pregnancy? You could, if it's really, really the only choice you have and you have to use it, otherwise I would not routinely use it. So that's a tough case. Yeah, absolutely. I'm gonna, another question that I think is a really good one. What's the proposed mechanism of action for development of AFib in the EPA patients? That is an excellent question. I think one could just say that there has been studies that showed the effect of Vesepa or omega-3s because it's seen in other ones too. They seem to actually have an effect on the membrane stabilization and their effect on sodium and calcium channels seems to make the heart a little bit more irritable. And if the patient is prone, they can trigger arrhythmias. Okay. The next question is, what about saroglitazar available, which is available in India, it reduces triglycerides and is a dual PPAR alpha and gamma agent, works on both diabetes and NASH. And it's been available there for more than six years. Apparently it's under study in the U.S. phase two trials. Do you- Yes, yeah, I didn't, I should have probably included. Yes, I know that there are dual effective drugs that are currently in the studies and we will perhaps have them available ourselves as well soon. Okay. Looks like we have time for a few more. I'm sorry, go ahead. No, there was something that came here that I see. When do you choose Vesepa versus Fibrate? Does it add on to a statin? When do you use Vesepa and a fibrating combination? Yeah, that's a good one. Yeah, it's a great one because that's absolutely right. So we started to go, at least in my group, our practice to go to Vesepa next after statin, especially because we see a lot of diabetics as well, right? The effect and the cardiovascular protection. If I have to pull the triglyceride lower, especially if they seem to linger higher than 250s after I add Vesepa, you add the fibrates to it. Yes, I do. I do use them all three combined if I have to. There was another one too. I just saw Jennifer. Yeah. Oh, that was the one you just read about. Okay. What about, please speculate on the use of non-EPA agents in lowering CV risk, e.g. fibrates. Is this CV lowering effect of EPA directly a result of triglyceride lowering, in which case fibrates should also be effective or could the reagenic effects of EPA be important as well? Yeah, that was an excellent question as well. I mean, when the audience is live, I get so excited to see the individuals who ask the questions and we celebrate together. I think those are all amazing questions, everybody who is sending us questions. Yes, absolutely. You can see from the reduced trial that even, I mean, below 100, the people benefited from cardiovascular outcomes. So you know there's more into this group than just lowering triglycerides. Yes, definitely they do have, you know, it has been shown effect on endothelial function. They do have effect on decreasing some of the atrogenic components of even LDL, oxidization of LDL. They do have anti-inflammatory effects. So they really, we will probably find out even more in the coming years that it's just not about triglycerides, right? It's just not about triglycerides. There themselves has the benefit to the atrogenicity of the specific population. Yeah. I think we have another question here. You, here it goes. You mentioned about avoiding dextrose fluids for acute hypertriglyceridemia. What about the concept of giving dextrose fluids to enable higher rates of intravenous insulin to reduce triglyceride levels? Yes, yes. I knew I'm gonna get dinged on that. They were listening. They were listening, paying attention. Yes, yes. So we say that if someone needs hydration and you're not using insulin, try to avoid glucose load because glucose will just feed free fatty acid production in the body. So, but if you're gonna use insulin and give them a higher doses of insulin because you're trying to bring triglycerides, hey, we have to do what we have to do. Yes, you're gonna have to use glucose. Glucose to balance so that we don't harm the patient from hypoglycemia. Yes, excellent, excellent question. Good catch. Okay. I think that's all the questions we have. Oh, someone did wanna know how long from initiation of VASEPTA do you see the decrease in the triglycerides? Yeah. So, you know, we usually don't repeat them very soon. We would do it within four weeks or six weeks. You can even do it in two weeks. You can see the decline very fast. Okay. I think this is, I think that's all the time we have to today's session. Thank you everybody for participating. Thank you for joining us.

triglycerides

medications

clinical trials

pancreatitis

hypertriglyceridemia

lifestyle factors

weight loss

statins

omega-3 fatty acids