Hello everyone. Welcome. We are grateful that you joined us this this afternoon. Myself and my vice chairs for the Lipid Disease Network will try to give you a sampling of what has been out there in the last 12 months. My first speaker is going to be Dr. Priya Pulipatty. She is a practicing endocrinologist and lipidologist in Tulsa, Oklahoma. She serves as my vice chair for the American Association of Clinical Endocrinology Lipids and Cardiovascular Health Disease State Network. She earned her medical degree in India and graduated with the highest honors as her graduating class. She completed her training first at the University of Connecticut followed by Rush University Medical Center. She is unique in a way that she actually did an additional advanced fellowship in preventive cardiology after her endocrine training at the University of Chicago. She has a passion to advance the field of endocrinology in the cardiometabolic area in patient care education and awareness. My second speaker for this afternoon is going to be Dr. Elliot Brinton. We enjoyed his talk this morning on hypertriglyceridemia as a remnant cardiovascular disease risk. He is a president of Utah Lipid Center. Story Elliot I made you see. Where he operates the only lipoprotein aphrodisiac center between Denver and West Coast. He's a past president of American Board of Clinical Lipidology and of the Pacific Lipid Association. He received his training at Stanford, University of Utah, Duke and University of Washington. He has authored over 160 scientific publications in several prominent journals from New England Journal of Medicine, JAMA, JCM and endocrine practice. He has also served as our expert writer for lipid guidelines and scientific statement for American Association of Clinical Endocrinology and the American Heart Association. He was a founding board member of the National Lipid Association over the last past four decades. He has been an invited scientific and medical presenter at more than 3,000 professional meetings ranging internationally and nationally. He has received several honors and I am myself the chair for our DSN. I'm a professor of medicine at Case Western Reserve. I serve as a vice chair of internal medicine and a center director for diabetes, obesity and metabolism at the University Hospital and Case Western Reserve. I worked at the Cleveland Clinic 10 years in their preventive cardiology hence comes my expertise in lipid. Please enjoy our first speaker. Hi, good afternoon. My name is Dr. Puli Pati. So I'm going to go ahead and do my talk. It was supposed to be brilliantly lined up but whatever. So I picked for you today three articles that I thought would be very interesting to review. The first one is the one you're seeing here that was actually published by European Heart Journal about the prevalence of statin intolerance as a meta-analysis. You might just ask yourself why am I really bringing this topic to your attention but cardiovascular disease is number one killer still for our patients and statin intolerance is the most common reason why we cannot sometimes offer the optimum treatment for our patients or that they stop receiving it. Why this study? This was the first multinational in the worldwide study that looked at statin intolerance. They follow the rules for meta-analysis. They reviewed a large amount of data and they end up choosing 176 articles that they thought would worth to include in the meta-analysis. When we talk about statin intolerance we usually focus on musculoskeletal side effects of the statin even though there are other side effects of the medication. In the world different associations, different groups describes the statin intolerance different ways. So this article asked a question if I would change the description, definition, will I have a different prevalence? Because when you look at the studies some says it's only 1% others say this is 50%. So bottom line 176 studies, 4 million patients and overall what they found was 9%, 1 out of 10 of your patients. Don't be afraid, don't be afraid, the slides will be fearful but it's not that bad. What was interesting that the randomized clinical trials had lower reported side effects than the cohort trials which is more like a real-life experience. Primary prevention versus secondary prevention trials didn't have much difference unless you in one study looked at them together. Don't be afraid, it's simple. What they found no matter what the definition was there was no difference in the prevalence. So you could just put them together and they were the same. Hydrophilic versus lipophilic statins didn't make a difference which was a little bit surprising to me. As you know hydrophilics which is rosucostatin and probastatin are the ones we usually go to our patients with statin intolerance. It wasn't different. So they looked at what made patients more at risk to have statin intolerance. Who were this 10% population? Look beautifully, beautifully they put together if you were on high-dose statin, hey, duh, you had a higher risk to have side effects. We knew that. If you had calcium channel blockers in yours, if you had chronic renal failure, chronic liver disease, if you were women, I don't know why we again have it. If you were older, if you were an Asian race, black race, obese, hypothyroid, diabetes, and alcohol consumption and exercise. So it's possible RCTs shows higher and lower rates than the cohort studies for statin intolerance because you know what they do? They don't enroll renal failure patients, skin liver failure patients. And that's why endocrinologists might be seeing more of these patients because we see all these people with diabetes, hypothyroidism, maybe alcohol consumption patients, obese and so forth. So bottom line is they said based on worldwide data, even if you put all the definition in one pot, overall statin intolerance wasn't 50%, but it was 9 to 10%. And it's important, I think, as physicians, endocrinologists, or caregivers to be aware and to respect when our patients tells us they might have side effects from it. Because if you don't listen, you know what? They're going to lie and they will not take it. They will not. And then what they will do is, like me, ignore the medication because each time you take it, unconsciously you don't feel good. So unconsciously you forget to take your medication. But then, period, it's going to tell you great news about newer medications so we can give the other medications a chance. So statin intolerance, 10%, not that uncommon in my mind. The second study I picked for you, which was I was so excited about it, was published in JCM. It's a Chinese study about intermittent fasting, how it improves cardiometabolic risk factors and alters gut microbiota in metabolic syndrome patients. China, like India, is seeing an outrageous rise in their diabetes, prediabetes, and metabolic syndrome. So they randomized patients with metabolic syndrome to two groups. One was a control group. They just ate and drank and did whatever they usually were doing the same way. And then intervention group, that they asked intervention group two days in a week to fast, meaning they would decrease their calorie intake 69% to 70%. So it wasn't total fasting, but they just decreased the calorie. Then they looked at different things. They looked at weight, waist circumference, lipid panels, insulin levels, home IR, inflammatory factors, and you know microbiome. To me it was surprising to see their weight. They lost weight and the BMI went down. So they didn't binge eat the rest of the week after two days of fasting. So they were to get, you know, in a way and calorie deficit. Their insulin level, home IR, triglycerides, all improved as expected with the weight loss. When they looked at the macronutrients, when these patients baseline with control were the same, baseline and intermixing fasting days, the macronutrients were the same. There was no difference in the protein intake and fat intake or carbohydrate intake. So overall the calories were lower. The exercise was also the same in the two groups. The inflammatory factors with the weight loss, as you expected with the weight loss, adipokines changed. Leptin actually reduced and adiponectin increased. And here is a horrible little slide here, but I couldn't make them look better. Really not a whole lot with IL-2, TNF-alpha. You see some changes with intermittent fasting with some of the markers, especially I found it interesting that total nitrate actually increased in intermittent fasting patients. They link that to nitric oxide and antioxidant effect. All right, this is the most exciting part. The microbiome. It fascinates me that we live within us. There is a universe, ladies and gentlemen, another world of its own. Microbiome lives with us and what we feed and give them, they produce as a result something different and send to our own system that affects us. This relationship especially has been very much research and still there's tons to do. And there is one amazing researcher in the world. He is one of the top researchers in microbiome. He's an endocrinologist and I think I'm messing up his last name. Max is his first name from Amsterdam. He is coming to give us a talk for our cardio metabolic conference in September. I'm so happy. I expect all of you to come and my slide is advancing. What is happening to my slides? Oh my god. Tech, I need help. All right, I'm so excited that I'm advancing my slide I think. Anyway, let me just tell you quickly what happened at the beginning. Compare intermittent fasting and control. No difference between the microbes in their guts. But when they went in and did the fasting, the fasting group changed their microbiome during this time. 16 species decreased and some others increased. What was interesting here and I'm gonna try to just make it simple. Simple for you and they correlated it with very, very complicated ways to the cardiometabolic markers and the changes that has been seen in different species. But I'm gonna tell you something. For example, you see this acidobacteria bacterium. This acidobacteria has been linked to correlate with people that with diabetes and metabolic syndrome. They have this bacteria in a bigger amount and it's decreased on valeric acid that makes us more metabolically challenged. So with intermittent fasting, this decreased. This rose barrier is like a rosebush you can say. That is also the way it metabolizes the food especially non-absorbable fiber. It produces things that goes to our body inside our blood stream and it has been linked in human studies to have lower rates of metabolic syndrome and that was increased. Now as human beings, we are so prone to say, let me swallow rose barrier and get it over with and eat my bad food, right? That's what we want. We want a quick fix. But let me tell you something. It ain't gonna happen unless you nurture and you respect them the way you would do when you plant a rosebush. You give them to the right soil, to the right air, to the right water. They will not thrive. So we have to change the way we feed them if we want the good bacterias to be there. But this was a very interesting study. It's doable in a way and they concluded that two days intermittent fasting improves the adipokines and has a benefit to the metabolic milieu. And my last article, and I have just one and a half minutes left, my last article is about long COVID. I know you are perhaps sick of COVID, but COVID, even though you might feel it's over, which is not, we have hundreds of millions of individuals in the world living with post-COVID syndrome or long COVID right now. So we have to know a little bit about long COVID. And I picked this article about cardiovascular side effects of long COVID, but as you can see there are actually a lot of other areas that are involved, like memory loss and concentration problems. But the cardiovascular is probably one of the most debilitating because patients have constant breathlessness, exercise intolerance, palpitations, syncope, so they cannot even work. The prevalence that has been reported in the world varies. In Wuhan, China it was 50%, whereas in Norway it was 70%. In other, some of the other, Denmark was 1%. United States is around 25%. So different numbers, depends on who you study and where you looked at your data. But there are some people who are high-risk. Women, again, I'm so sorry my friends. Older age, asthma, cardiometabolic fitness that is not that good. Social demographics that is lower. And some of the, where you live, where you did the data collection, all of them. The only good news, if you are vaccinated, you are in good shape. It decreases the amount of post-COVID syndrome. So COVID, when it infects an acute phase, it does tissue damage to the heart. Then it triggers inflammatory and autoimmune reactions, as well as thrombovasculitic events. The most important things that I think we should remember is myocarditis. Myocarditis, even in young people who are athletes, because they are not supposed to exercise for at least three months, it has been linked to sudden death in our younger population. It causes a lot of psycho-emotional issues. So long COVID is not a psychiatric disease. It causes psychiatric changes. And it's recommended that if you notice, find, diagnose long COVID patients, refer them to a COVID clinic for psychosocial and rehab program. For cardiology purpose, you could do a BNP, CRP, an echocardiography, and an EKG. Now, you might think, well, why do I do that, Dr. Hatipola? Well, I'll tell you. My cardiology friends in my institution are so busy treating diabetes that I decided someone has to take care of cardiac disease. So we are stepping in. That's what we are doing. So then you can send it to them. Studies about rehab, different treatments like steroids and some of the immunomodulatory drugs, antifibrotic treatments and anticoagulants continues. They are in progress. We don't have too much information yet in these other studies. So I thank you for your attention. This was not supposed to be this way, but that's okay. We will have, I think, Priya, you're next, hopefully, this time, unless someone removed your slides. All right. So technically, it's me, yes. Good afternoon, everyone. I'm Dr. Vishnupriya Pallipati. I do not have any financial disclosures, but I do have a personal disclosure. I am an early career member, so I have been in clinical practice for less than a year. While my other distinguished colleagues have a lot of years of experience, I promise I come with a lot of enthusiasm, so much that I convince them to give me the cooler topics to discuss today. So my objectives are to discuss significant therapeutic advances within the last year in clinical lipidology, discuss the impact of these findings on clinical practice, and the applicability of the recent developments to improve patient care. So the first medication I'm gonna talk about is evinacumab. In February 2021, FDA has approved this for use in patients with homozygous familial hypercholesterolemia through a trial called ELIPS homozygous FH trial. Now, just a small introduction to what is heterozygous FH and homozygous FH. Homozygous FH is more relatively rarer health condition. There are two defective genes, which is causing a significantly elevated hypercholesterolemia of more than 400 milligram per deciliter. There's a very, very early heart disease in this population with very poor response to medications, and the chance is one in 300,000. On the right side, I understand it's a busy slide, but on the right side on the upper half is what is considered as normal. The liver gives VLDL, which gets digested by lipoprotein, and endothelial lipase into VLDL remanence, which further gets lipolyzed into LDL, and both of them are being uptake by the liver. As you can see above the LPL and endothelial lipase, there is AngPTL3, that's how I call it. I know different people call it different ways. That's kind of the villain of the story, right? It's not letting those enzymes digest the VLDL. So as a result, VLDL accumulates and is heterogenic. On the bottom half, you can see what happens with iminacumab, which is a monoclonal antibody of AngPTL3, which inhibits this. So as a result, the VLDL is getting digested to VLDL remanence, and these remanence are taken up by the liver through an LDL receptor-independent pathway. So the study which we are talking about today is a double-blind placebo-controlled phase three trial conducted at 30 sites in 11 countries. The inclusion criteria were men and male or female more than 12 years of age with a diagnosis of homozygous familial hypercholesterolemia either by genotyping or by clinical phenotype, which is significantly elevated cholesterol in the patient or both of their parents or cutaneous or tendinous xanthomas before the age of 10. The LDL apheresis, majority of these patients are on LDL apheresis since childhood, but for this study, if they are on it, then they had to be on stable settings for at least eight weeks. And the other criteria such as willing to compile by a diet, clinic visits, and giving an informed consent. The eligible patients were randomly assigned into two is to one ratio to receive intravenous infusion of evinacumab with a dose of 15 milligram per kg every four weeks or matching placebo. This trial went on for 24 weeks and they were continuing their other lipid-lowering medications. And after the completion of 24 weeks, they had a choice of entering into a 24-week open-label study or a follow-up period. So this is the baseline characteristics. So the mean age was 41. Around 50% were women, 70% were Caucasians. The mean BMI was 25 and majority of these patients had cardiovascular disease. Approximately 90% of them have cardiovascular disease. And genotype testing was confirmed in at least 68% of these patients. And the mean LDL, as you can see, is 255 milligram per deciliter. And the other heterogenic factor, which is apolipoprotein B, was a mean of 171 milligram per deciliter. So the result is as follows. At the end of 24 weeks, let's first talk about percentage change in these heterogenic factors. With LDL, there was approximately a 50% change, which was statistically significant. And with apolipoprotein B, which is another heterogenic particle, there was at least a 30% decrease, which was statistically significant. Now let's talk about absolute change in LDL. There was at least 132 milligram per deciliter absolute decrease in LDL, which is very significant. And in other factors, there was a 50% decrease in triglyceride, maybe 2% decrease in lipoprotein little a, and apolipoprotein C3, which is similar to AngPTL3, there was at least a 90% decrease in that. So the adverse events were similar in both the groups. The most common were noted to be nasopharyngitis or influenza-like illness. Serious adverse effects are very, very few, if any, and both patients, which were kind of the two patients who had adverse effects, recovered. None of the effects had discontinuation of medications and there were no deaths in either of the population. And this is what the FDA has approved. It has approved as an orphan drug designation, breakthrough therapy, or priority review designation. It is in evanacumab is indicated as an adjunct to LDL-lowering therapies for the treatment of adult and pediatric patients age 12 and older with homozygous familial hypercholesterolemia only. Contraindication is if they have any hypersensitive reactions the limitations is they do not know the safety or efficacy of this medication in heterozygous FH and the effects on cardiovascular morbidity and mortality have not been determined. The recommended dose is 15 milligram per kg administered by intravenous infusion every four weeks. And the warning and precautions are serious hypersensitive reactions and embryo-fetal toxicity. So patients should be made sure that they're not pregnant and using contraception during treatment and at least five months following the last dose they should continue their contraception. Adverse reactions were nasopharyngitis, influenza-like illness, dizziness, rhinorrhea, and nausea. The next medication of interest is inclicinib. In December 2021, FDA approved inclicinib for use in patients in high-risk adults. And I'm going to be talking about the pooled patient analysis of the inclicinib trials. Inclicinib, so remember in medical school we learned DNA becomes messenger RNA, which becomes a protein like transcription and translation processes. So what the inclicinib does, it is a small interfering RNA which affects the mRNA of the PCSK9 protein. So as a result, the PCSK9 protein is not created. Now in this story, PCSK9 is the villain of the story. The reason is it kills the LDL receptor. So when the PCSK9 protein is less, what is happening? There are more LDL receptors available to pick up the LDL. As a result, there's a significant decrease in LDL. Now the pooled analysis came from three phase three studies, Orion 9, Orion 10, and Orion 11. Orion 9 included subjects with heterozygous FH. Orion 10 included atherosclerotic cardiovascular disease and elevated LDL, and Orion 11 included subjects with ASCVD or ASCVD risk enhancers and elevated LDL-C. Participants on maximally tolerated statins with or without other LDL lowering agents were randomly assigned to one is to one ratio to receive either inclicinib or placebo administered as a subcutaneous injection on day one, day 90, and every six months thereafter for at least 540 days. So the demographic population, the mean age was 64. Majority, that is 66%, were men. 90% of them were Caucasian. Statins were used in at least 90% of this cohort. And cardiovascular disease was present in 85% of the patients. Familial hypercholesterolemia were represented by at least 20% in the populations. The mean baseline LDL was around 110 mg per deciliter, and the upper B was around 99 mg per deciliter. Now, the results was the placebo-corrected percentage change in LDL with inclicinib at day 510, which was a core primary endpoint, was 50.7%. That's a significant decrease. And the absolute change in LDL with inclicinib at day 510 was 55 mg per deciliter. Now, if you're looking at the percentage of participants achieving the specific LDL targets by day 510, inclicinib has shown a significantly higher. For example, in high-risk patients, we want the LDL to be less than 70. Inclicinib achieved 68% of that, while the placebo achieved only 12% of that. And percentage of participants reaching LDL levels more than 50%, that is a maximal intensity statin equivalent from baseline at day 510, was at least 62% with inclicinib and only 2% with placebo. The treatment, the adverse effects overall, the safety was really good. The injection side, there was mild to moderate reactions. Bronchitis was the other reaction which was noted with this medication. So from the FDA approval, it is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous FH or clinical atherosclerotic cardiovascular disease who require additional lowering of LDL-C. Limitations of use as cardiovascular morbidity and mortality have not been determined. Recommended dose is 284 milligram, administered as a single subcutaneous injection into the abdomen, upper arm, or thigh, initially on day one, third month, and thereafter every six months. There are no contraindications, and the adverse effects include injection site reactions, joint aches, urinary tract infections, diarrhea, bronchitis, pain in extremity, and dyspnea. Let's go to the next exciting topic, which is statin use in pregnancy. In July 2021, FDA came with a request to remove the strongest warning against use of cholesterol-lowering medications in pregnancy, and I picked one of the systemic review and meta-analysis which addressed this topic. So statins, just as a background, were previously strongly contraindicated with category X, which is the strongest one in pregnant women and preconception period with possible teratogenic effects. These suggestions were made purely based on observational studies, case reports, and animal studies, and these are examples of two of the studies which kind of made them have this category X. However, recent studies could not find this association of increased risk of congenital abnormalities in pregnancy, and that is why they have addressed this topic right now. Now, this particular meta-analysis we're gonna discuss has included five different studies, and the effects of statins, they looked at three major outcomes. First one is abortion, which is pregnancy interruption before 20th week, stillbirth, death of a fetus after 20th week of pregnancy or during delivery, preterm delivery, labor before 37th week of pregnancy. So the first outcome was statin exposure in pregnancy on overall abortion. Now, as you can see, the hazard ratio is more than one, so the statin exposure is associated with an increased risk of abortion. I'm not really making my point that well, right? But let's look at this a little more clearly. If you see the types of abortion, induced abortion, spontaneous abortion, elective abortion, the spontaneous abortion was what drove this to be statistically significant. Now, we need to identify some caution in interpreting this information. It's because most of these studies which are giving this data are observational studies. Majority of these participants had underlying medical conditions which were affecting their outcomes, like APLS syndrome or hypercholesterolemia, preeclampsia. And also there are other clinical conditions like advanced age in the women who were pregnant, cardiovascular risk factors. So they were all contributing and we need to understand that in that context. And the next one is statin exposure in pregnancy on the rate of stillbirth. Statin exposure was not associated with an increased rate of stillbirth. And the next outcome was preterm delivery. And statin exposure was not associated with an increased rate of preterm delivery. So the US FDA requested revision of the information about use of statin in pregnancy for the entire class of statins, not just one medication. And these recommendations were removing the contraindications in all pregnant women because the benefits of statins may include prevention of serious and fatal events in a small group of high-risk pregnant patients. Contraindication is not appropriate for that reason. And it doesn't mean that in all pregnant women we can continue statin. What it means is like in the right population, at least this removal of contraindication allows the clinician to make individualized decision, especially in patients with homozygous FH and those with the previous atherosclerotic cardiovascular event. In conclusion, evinacumab, fully monoclonal antibody and a specific inhibitor of AngPTL3. It's an orphan drug breakthrough therapy and prior to review designation. It's used as an adjunct with lipid-lowering therapy for patients older than 12 years with homozygous familial hypercholesterolemia. The adverse events were really not different than placebo, but were noted as nasopharyngitis, influenza-like illness, diarrhea, rhinorrhea, nausea. Inclisirin is a small interfering RNA which down-regulates the PCSK9 mRNA and decreases the PCSK9 protein. And this is used for patients who are on maximally tolerated statins with heterozygous familial hypercholesterolemia or a clinical ASCVD. The adverse effects were injection site reaction, joint aches, urine infections, diarrhea, bronchitis, extremity pain, and dyspnea. Statin use in pregnancy, the US FDA removed its strongest contraindication against the entire statin class in pregnant women. And it advised individualized discussions based on benefits and risks, especially for those with an underlying homozygous FH or a high risk of ASCVD or a previous ASCVD event already. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Well, those are my conflicts. Don't need to talk about them. We're gonna talk about Reduce-It. Now, some of you were in the group in that one room that nobody can get to, the Baycat room. I'm gonna do a brief review of the same topic and then we'll get on to something else. So, we're gonna talk about Reduce-It. Reduce-It is in the news because we keep publishing new aspects of it even though it was first published a while back. The design is actually very straightforward. We collected patients who had, first of all, a high risk for ASCVD either with a prior event or with diabetes mellitus plus at least two other risk factors. And then they had to have their LDL controlled on a statin. So, they were taking a statin. Their LDL was less than 100. And then they had to have a triglyceride that was between 135 and 500. So, those are the people in the trial. And we followed them for five years on either four grams a day of icosapent ethyl, pure EPA or a matching light liquid paraffin placebo. So, these were patients that were well treated. They were on antiplatelet agents. They were on anticoagulants if they needed them but most not, of course. Many using RAS, R-A-S inhibitors for their hypertension, a beta blocker and basically everybody on a statin. And these are the results. Huge drops in a five point mace and a three point mace and highly statistically significant. Took about a year or two for the curves to separate. Maybe a little bit slower than some of the statin therapies but rapid enough and very dramatic. And notice the numbers needed to treat very, very low. This is actually a record for a statin adjunct. Any lipid drug added to a statin, no other drug has done this well. And here we are looking at individual or composite endpoints and this was the pre-specified hierarchy of analysis and we got all the way down to a total mortality which was close but not quite statistically significant. And these are really very impressive ones including cardiovascular death. You know, a single cardiovascular death will ruin your whole day. So, some very, very striking reductions in basically everything we looked at in cardiovascular events Now, this was an analysis of first event. Of course, patients over a five year period of time may have more than one event and many of these patients did. So, the first event, the data I just showed you here in green and then looking at second, third, and then fourth or more events. Every one of these was statistically reduced by about the same number. And so, really very, very dramatic cardiovascular benefit especially given the fact that these were patients adequately treated with statins at baseline. Well, what about the bad news? The bad news is there was a little bit of a trend towards bleeding events. This is a feature and not a bug. Omega-3 agents are anti-platelet and so we expected some bleeding and it was actually fairly modest. You see here just a very small increase and you see the types of bleeding. Notably, no increase in intracranial bleeding or hemorrhagic stroke. No fatal bleeding events in the entire trial so that's all good news. So yes, a little bit of bleeding but fairly mild and not really of particular note. Another thing and this is something you may not have known but Omega-3s have tended to show an increase in atrial fibrillation and other agents have shown this and we found this again, that the increase is modest. This is total events, this is hospitalized events and I'm not a cardiologist but as I talk to cardiologists, they really are not concerned about this. This is a modest increase and it's something that is easily managed by them and there's another type of fibrillation which is ventricular fibrillation which is death and we actually had a decrease in sudden cardiac death and of course, that's where you wanna see the decrease. So a little bit of an increase in atrial fibrillation especially in patients with a prior history but note that this prior history of AFib is not a contraindication to icosabenethyl. There's just a very modest increase that you can be aware of and the more serious arrhythmias are actually decreased. So let's look at diabetes, a topic near and dear to our hearts as endocrinologists. 60% of the patients had diabetes either as a standalone without any prior cardiovascular event or along with a prior cardiovascular event and here they are according to the randomization scheme and these are very representative of the entire study population. Really not much of anything was different except glucose of course a little bit higher and A1C but these are well-controlled diabetics with an average A1C of 7% and the lipids very similar to that in the entire trial. Triglycerides just a little bit above 200 and the LDL controlled very near 70 milligram per deciliter and of course, everybody has statin and a reasonable number of folks on ezetimibe. This was an international trial so we had a pretty good representation across populations and races. Nine out of 10 were on an anti-diabetic medication, the others were just on diet and lifestyle and you see a distribution here of the number of diabetes drugs. So let's now look at the same Kaplan-Meier plots but we're now looking at just the patients with diabetes and the primary composite which is five-point maze, this key secondary which is hard maze or the three end points and you see a first event here in the slightly fainter curves and then in the stronger curves you see the total events and you see very much the same pattern and very much the same relative risk reduction of right around 25%. So similar risk reduction in the patients with diabetes versus total population or obviously those without. And again, the breakdown according to first, second, third, and in this case, we didn't have the fourth or more events, but again, dramatic reduction across the board as you would expect. And this again is the hierarchical analyses, very similar to what we found in the overall population, just as you would expect and hope. So the bottom line is that icosabeneth works very, very well for patients with diabetes, whether they have that alone or whether they've had a prior cardiovascular event. And these are now data, this is very interesting because now you see patients who just have diabetes, plus at least two other risk factors, or who just have established CVD without diabetes or who have both. And of course, it is much worse to have both, we all know this, but here you see the curves. And notice, by the way, that this actually has an expanded vertical axis. So the risk is actually even a little bit less in a patient without a prior history of cardiovascular disease, but this is still plenty high. I mean, this is 18% over five years. So double that, it's going to be, what does that work out to be? That's going to be 37% 10-year risk. So that is sky-high risk, even though it looks shorter. But you see that there's very comparable relative risk reduction in first and total events in all three cases. And of course, the patients with both prior event and diabetes have the very highest risk and the greatest relative risk reduction. And you'll notice here, this is a 10% drop, meaning the number needed to treat is 10, which is really a record for a low number needed to treat in patients already well-controlled on a statin. So if your patient has diabetes at a prior event, then, and their triglycerides are over 135, then it is incredibly helpful to give them icosapent ethyl. So, safety and conclusions in the diabetics subgroup. Basically, it's the same as it was in the entire group. So excellent safety, a little bit of increase in AFib and in total bleeding, but not really in any degree serious. And no adverse glycemic effect. This is good news. Of course, statins tend to have a modest adverse effect. Niacin, a very bad adverse effect. Nothing here to notice. And icosapent ethyl prevents ASCVD in patients who have diabetes, and especially if they have both diabetes and a prior event. Briefly, reduce it BMI. We're looking at body mass index. So we're looking at obesity. We've had some great presentations at this meeting, heavily on obesity. And so here we have three categories, normal weight, overweight, and then obese over a body mass index of 30. And you can see that across the board, there is a decrease and it's very similar for first event and for all events. And really nothing to say, except that the risk is good across the board. So you don't have to be fat to get a benefit from icosapent ethyl. If you're totally slender, you get the same benefit. That, of course, is good news. We don't have to think about that. Now, let's talk about cost effectiveness. This is kind of an expensive thing to make. You take a giant barrel full of anchovies and you do all sorts of things to purify it and get it down to nothing but icosapent ethyl. It's not oxidized, it's just as pristine as you can get it. And it costs a lot of money to make one of those capsules because you start with a barrel and end up with one little capsule, right? But what is the cost effectiveness? Well, this was looked at very carefully by two groups. First of all, with the so-called ICER group independently, but they were using a much higher actual price. This study that I was involved in, we did the actual price that payers pay for the drug, which ends up being right around $4 a day, $3 to $4 a day. So if you look at this, here is $4 a day. It's actually a little bit less than that. But $4 a day, if that's what the payer pays, then you look at the price, or at the cost, rather, per QALY reduced. So per quality adjusted, year of life saved, how much does it cost? And the answer is almost nothing. In fact, in the highest risk patients that reduce it, you actually save money and save events and save lives. Wow, that almost never happens with a branded product. So this is really a major finding in terms of cost effectiveness. And if you have a lower risk patient, then you're gonna get up a little bit higher here into the 25, 50, maybe even $75,000 per year of life saved. But this is well under our usual threshold of $100,000. So it is always cost effective, and in some cases, actually cost saving to put patients on icosabenethyl. Now, unfortunately, the payer that covers our patients doesn't know this, and so they will fight us. If we try to prescribe this drug, it just drives me crazy because they're not supposed to, and we need to tell them that this is a cost effective drug, and that has been well shown. Now, let's talk briefly about EPA alone versus DHA. These are very similar molecules. They're just a little bit, the DHA's just a little bit longer, one more double bond. How much difference could there possibly be between EPA and DHA, right? Similar structure, should be the same outcome. Well, let's look at a couple of compounds that we know a little bit more about, and that's estradiol and testosterone. They're actually even more similar, as it turns out, as you may know, and yet there's quite a difference between testosterone and estradiol. So, could there be a difference between EPA and DHA? And the quick answer is yes. Here we have a cell membrane. It's a phospholipid bilayer, and you'll see the cholesterol in red, and what you see is under oxidative stress, which is dyslipidemia, cigarette smoking, hypertension, diabetes. You end up with stress, you get peroxidation, which mainly runs through the middle of the membrane, and what that does is that tends to cause aggregation of the cholesterol, the red molecules, and that causes trouble. So, what can we do about it? Well, we could give somebody pure EPA, and that gets into the membranes, and it changes the signal. This is an NMR signal of what you see inside this membrane. Here is DHA. DHA is gonna cause some trouble, and it causes a very different signal, and if you add back some EPA to the DHA, you can't actually get back to this pattern. So, if you add a certain amount of DHA to the membrane, it will foul up that membrane and cause trouble. It'll negate whatever good may happen from EPA. So, here we are back to EPA and DHA. DHA, what it does is it drives the cholesterol together, just like we saw under oxidative stress. The DHA and the presence of DHA, this tends to happen with any oxidative stress whatsoever. It's very sensitive to that, whereas the EPA, because it doesn't expand the membrane, and it doesn't cause membrane trouble, the cholesterol stays where it's supposed to be. So, here you have these increases in these cholesterol-rich domains, and you actually end up with cholesterol crystals, and the question may be, so what? And the answer is, turns out the cholesterol crystals play havoc with macrophages. Those macrophages try to eat the cholesterol crystal, and that's like trying to swallow a javelin. It doesn't work. It's gonna kill you, and that little javelin, that cholesterol crystal, is long enough and sharp enough, it can actually poke holes in the fibrous cap, causing plaque rupture, causing heart attack and death. So, not a good outcome. So, unfortunately, DHA drives this, and EPA prevents against it, and if you had too much DHA, you actually block the ability of the EPA to keep things where they're supposed to be. Here is another look at the same sort of story, but now we're looking at EPA versus DHA. In this case, just in terms of inflammation. So, if you give cells IL-6, there's a pro-inflammatory state, and there's an up-regulation of these proteins, and a down-regulation of these proteins. So, if we add EPA plus IL-6, we switch that around. This down-regulation becomes up-regulation, and the up-regulation becomes down-regulation. Well, what if we added DHA to IL-6? It doesn't do a whole lot. There's a little change here and here, but not much. So, DHA does very little to block the inflammatory effects of IL-6, and EPA does a whole lot. So, there's a really night-and-day difference between these two very similar-looking molecules. And does this basic science translate into clinical science? The answer is yes. Here we're looking at plaque volume by CT angiogram, and you can see that EPA alone gives you a big decrease, and if you happen to add enough DHA to the EPA, so you're doing a mix of EPA and DHA, then you have blocked that benefit. Ouch. So, pure EPA is better than EPA plus DHA mix, and adding DHA to EPA may actually be of net harm. It at least dilutes the EPA benefits and may actually block them. That's very surprising, but true. Now, you need DHA if you happen to be a pregnant woman, if you happen to be a little baby, and of course, nobody can get infant formulas, so there's a DHA shortage out there. I don't know what to do about that, but if your brain is growing, you need to have DHA, and if not, you've got enough DHA, you can stop. So, should we continue? Here's a totally different question. Okay, we talked about omega-3. Let's talk about fibrates for a minute, and here's where we get to some very, very recent data. Should we use fibrates for ASCVD prevention? Well, let's look at patients with high triglyceride, low HDL. You are familiar with the fact that fibrate trials have been a mixed bag in terms of ASCVD prevention. Some have shown benefits, some have not. The more recent ones that everybody gets a statin and then you add a fibrate have not worked, except if you select for patients with high triglyceride and low HDL, then you see benefit, and you see this benefit across five different trials with three different statins, and here's the aggregate. So, very convincing benefit in this subgroup. However, it's a subgroup analysis. So, what are subgroup analyses by definition? They are hypothesis generating. So, great hypothesis. Should we test it? Yes, let's test this hypothesis. Let's do something called PROMINENT, and PROMINENT is a CV outcomes trial using a fancy new fibrate, better than phenofibrate. It's called Pemafibrate. We don't have it yet in this country. It's available in Japan. So, I had the good fortune of being involved in the PROMINENT trial. So, what did PROMINENT show? Well, unfortunately, PROMINENT showed the same thing that STRENGTH did. So, here's REDUCE-IT, the very positive trial. We've gone into that in great detail and some recent data. STRENGTH, using a mix of EPA and DHA, did not show a 25% benefit. It showed no benefit, even though, if you look back and forth here, there's really very little difference between these two trials. So, same population, very similar drug, you would think, just add some DHA, and yet you've blocked the benefit clinically. Ouch. Well, let's go to PROMINENT. Remember, PROMINENT is testing the hypothesis that if we simply use a fibrate in a patient selected for high triglyceride, low HTL, we'll see that benefit that was seen in the subgroups. What did PROMINENT show? We don't have a whole lot of detail yet. We just have a press release with the top line, but the top line was stopped early for futility. No benefit, stopped the trial at about 80% or so of the events. So, we've tested the hypothesis and we found that it's not true. So, question. Should we continue to treat patients with mild to moderate hypertriglyceridemia for ASCVD prevention and with a fibrate? And the answer is, unfortunately, no, because that was a very cheap workaround. Fibrates are cheap, they're easy, we've used them forever, and it just doesn't look like we should because of this futility result. Now, we'll get a lot more detail about this trial, but I think we know enough about PROMINENT to know that we can no longer rely on that as cover for our use of phenofibrate for ASCVD prevention. So, icosapent ethyl, pure EPA, is the only proven agent to lower ASCVD on top of statin therapy in patients with high triglycerides and low HDL. And that is bad news, except it's good news. I mean, we have one agent, we don't have the other agents that we were hoping for, but at least we've got something to go with. Thank you very much. Okay, we're coming up here with the panel, and let's do questions. Yes, we are happy to answer any of your questions. We have six minutes. Oh, Dr. Beringholz, my mentor. Please give her a big applause. Thank you. Thank you. Elena Beringholz, previously from Chicago, it was Betul, and now in Los Angeles. You can't hear. They can't hear you. Step up. Now? Yes. I was from Chicago, Elena Beringholz, and that's how I know Betul. Now I am in Los Angeles. Very happy. So, wonderful talks. Thank you, thank you. The question for the last speaker, if I understood it correctly, and please correct me if I'm wrong, the only benefit that VASEPA was shown for was patients with diabetes with established disease. And if they coronary cardiovascular disease, if they do not have established cardiovascular disease, there was no benefit. And it was, again, subgroup analysis, and if you doubt other subgroup analysis, you can say it the same for this study. So it's a little bit of bias. Yeah, thank you for that question. I'm sorry I didn't make that clear. So we had three groups of patients. We had 30% of the patients diabetes alone, 30% diabetes plus a CVD event, and 40% who had a CVD event and no diabetes. In the overall population, that's where you start with a clinical trial, there was a huge benefit, highly statistically significant across all the endpoints. Very convincing. Now, we are allowed to do subgroup analyses in positive trials, and so we did. And basically what we saw was the same benefit, very similar benefit in all three subgroups. So, the bottom line is that icosaben ethylpurea PA works if you have diabetes alone, if you have diabetes plus a CVD event, and if you have CVD event alone and no diabetes. It really works the same. I can show you the data later. This slide did not show that. Okay, so, yeah. No, the way you do this is you look for differences and there were no differences. Sometimes when you get to a subgroup that has lower events, you may fail to see a statistically significant benefit. And so, statistically, I think in the group with diabetes without a prior event, it might not have reached statistical significance. However, clinical trial rules are that you look for any statistical difference, and there was no difference. So, there was no difference. And I can say with confidence as a trialist that there is evidence that it works in people with diabetes and no prior disease. So, if you have primary prevention for a diabetic, don't tell them, sorry, Mr. Jones, you have to wait until you have your heart attack and then I can put you on eicosapenethyl. That's not a good dialogue with your patient, and we don't have to say that. The evidence is considered sufficiently robust to say that we have proven a benefit in patients with diabetes without a prior event. So, please treat before they have any event because, of course, their heart attack may be fatal and it's a little hard to go back and treat the patient at that point. So, please treat with confidence across the range of what we did in Reduce-It. And that's what all the societies say, including our own ACE, right? The ACE guidelines say, please treat according to Reduce-It criteria. So, either one or both, it's totally fine. And we can talk about more, but just trust me, this is all good. And if the risk is lower, then the benefit is a little less secure, right? So, focus on your high-risk patients. Focus on the high-risk ones. Yes? We have two more questions. Let's do it quick, quick, quick. We are getting more and more questions. There we go. I'll try to make it quick. I'll do it rapid fire. Sorry about that. Three excellent talks. This talk is for Dr. Burton. I'm Greg Holland from UVA. Just looking at the data, would you argue that we shouldn't even use a triglyceride concentration of greater than 135 as criteria? I mean, it seems like the whole theory of triglyceride lowering has been disproven by the last trial that you've shown. So, would you argue that we should just consider icosapent ethylene, anyone, regardless of triglyceride? Quick answer. Quick answer, please. In the best of all possible worlds, we treat everybody with a triglyceride over, I'd say, 80 or 90. Okay. In the real world, the payers are gonna go with the FDA indication and all of it, and it's around 150. So, if you're above 150, non-fasting, go ahead. If you're below that, see if the payer will pay. They should. It will work. If you cheat and do it non-fasting, it will be above 150. So, here's the thing. The FDA didn't say it had to be fasting. So, if somebody's close, draw them non-fasting. I like fasting, but take them non-fasting. Try to get it over the 150. If it's over 150, then you're on label, and the payer should pay. Don't quote me on that, though. I've been to McDonald's before. So, yes, it should work, but we can't afford to. Yes. Yes, sir. Hi, Romeo, Jocelyn. Just a quick question regarding those, maybe thresholds for the dose of the SIPA. Do you feel, is there any study in the pipeline to look for a dose dependence, or we're just gonna be stuck with the four grams that sometimes is hard to tolerate? The amount of EPA in the plasma seems to be important, and I mentioned that in the other talk. So, the higher the EPA level, the better the benefit. That said, could we underdose somebody who's more responsive, and overdose somebody who's less responsive? Probably, but we won't have a trial. Unless you happen to have a half a billion dollars, we can't go back and do another study to prove that. So, probably, yes, but practically, probably not. Just four grams a day. Thank you, and this is gonna be our last question. I wish we had more time. We just don't have it. Great talks. So, my questions are for the second and third speaker. So, when should one withdraw a statin in advance of a woman attempting to conceive? Typically, two months before conception, we have the discussion about trying to stop the statin, and after they complete all their pregnancy and breastfeeding and they're back to their baseline is when we kind of go back on the statin, if needed. If a woman has homozygous FH, since childhood, she has been on a statin, or they have a premature heart disease already, then those are the patients where the FDA has relaxed that so we can do at least a small dose statin to prevent that atherosclerotic event recurrence. During the pregnancy? Yes, because what happened is many of those women did not even know they were pregnant when they were on statin in some of the studies, and nothing bad happened to the babies. So, that is where the accumulation of data kind of consistently showed the same thing. It's just that some of the pregnant women were scared that something bad was going to happen to the babies, so they were induced abortions too. So, the data of abortion looked like, oh, there was abortions, but it was by choice sometimes because they were on a medication which was category X, or sometimes because they were spontaneous because of their pre-existing comorbidities. So, as of now, the relaxation is like, use it appropriately for the patient who you really need to give it, not as a common theme for everyone who's pregnant. So, the choice would be homozygous FH and patients with already existing heart disease. One other quick note, apheresis is safe and effective during pregnancy. If you have somebody with really severe hypercholesterolemia, you are welcome, you're invited to actually put the patient on apheresis temporarily through the pregnancy, and there is basically no adverse effect on the fetus, and you get marvelous reduction in LDL. So, that's something to keep in mind in the severe cases. Gotcha. We will be available for more questions if you want to. Thank you so much for coming. We really appreciate your attention. Thank you.

lipid disease

cardiovascular health

statin intolerance

intermittent fasting

metabolic syndrome

ReduceIt trial

icosapent ethyl

EPA medication

high triglycerides

cardiovascular events