Dr. David Cork reviews select non-statin pharmacotherapies and presents recent clinical trial data.
Okay, so uh because we're on a tight schedule, I'm gonna go ahead and move on to our next speaker. I um our next speaker is Dr David Cork, who is my co director for this conference now, Dr Cork has been in practice for many years and it had developed here in SAn Diego and it developed in this incredible reputation for becoming well known for his general cardiology and preventive cardiology prowess. So our cardiology group here, the scripts, therefore, you know, you saw him in the in the community, kind of just crushing it. And so he said man, we gotta recruit this guy. So we were lucky enough to convince them to join our group a couple of years ago. And since arriving here, Dr Cork has single handedly redesigned cardiology management at Scripps Green Hospital. I personally enjoyed working alongside him and it's really gotten to appreciate what he brings the field of preventative cardiology through our work together in designing this conference, Dr Cork is also very well published in multiple areas of general cardiology, including prevention. So it is, with true pleasure that I present. My co director. Dr David Cork is our next speaker who will be speaking on the influence of elevated triglycerides on atherosclerosis and non statin therapies. A review of the data looking at omega threes epidemic acid, nice and easy to me and PCSK nine inhibitors. So dr cork, thank you and welcome. Yeah. Yeah. Thank you very much. Chris I had to meet myself there, appreciate the introduction. Well, he's got the slides back up here. Yeah. Yeah. Yeah. Yeah. Mhm. Yeah, I still don't see the slides and just with that. Sure. Okay, so um let me look here, Not quite sure what happened with our with our slides, we are just going to pause for just a moment as we try to get those back up. Here we go. Okay, Doctor Cork, sorry about that little delay. Thank you very much. The introduction. Thanks again for everyone participating in today's discussions today, I had the privilege to discuss non statin farcical therapies for afro sclerotic risk reduction. I'll highlight some of the um risk that dr trip in eloquently alluded to as well. In the last talk regarding triglycerides and remnant cholesterol and um the havoc that these can wreak on our cardiovascular risk. Mr I have no relevant financial disclosures to this presentation. Today's overview will be to provide uh an overview broadly of the number of non statin agents we have. Um I'll kind of go into detail on some of the historic agents as well as some of the historic data and then I'll talk a little bit about some of the upcoming therapies to anticipate overall. You know, the highlight. I want to highlight all the placebo controlled statin trials that have been published um You know, over the years there has been a large number of large body of evidence detailing the efficacy of statins and reduction of atherosclerotic cardiovascular risk. And then more more recently in the in recent years there's been an interest in non statin therapies and so a number of non statin therapies have been validated as additional add on agents or or single agents to help further reduce patient's risk. As dr griffin just mentioned, you know, it's not always about LDL cholesterol really non HDL cholesterol and other risk factors really play a role in managing of patients appropriately. And so there's a lot of my trials, there's Mehmedovic acid trials, there's PCSK nine trials and so forth. We're going to highlight some of those in today's talk, you know, certainly statin therapy, as I just mentioned, really has been shown to be really the mainstay therapy in general and that that's really founded in the clinical guidelines and the A. C. C. H. Guidelines. We reduced someone's LDL cholesterol By 38 mg per deciliter. You get usually achieve a 22% reduction in atherosclerotic vascular events. And interestingly the benefit is largely irrespective of baseline cholesterol. So we see a risk reduction even when cholesterol is generally very low. And so that's kind of pushing the envelope a little bit on. Maybe lower targets may benefit patients more particularly those who are extremely high risk. However um you know achieving and maintaining an LDL cholesterol has remained an elusive goal. Uh an elusive target. And so part of it is statin intolerance. Part of it is side effects of medications and furthermore if you're able to able to keep the patient on medication and get their cholesterol low, there's still a substantial cardiovascular event rate despite aggressive LDL reduction. And so this is kind of um what I wanted to highlight here in this recent trial uh study that came out in 20. She's a retrospective review that came out in 2020. Looking at LDL calculate LDL cholesterol and adverse events following P. C. I. They looked at about 50,000 patients post Pc. I. And they said, well, how many patients are having an LDL? LDL measured six months following P. C. I. 52% had a lab value evaluated. And of those patients that have actually had a lab evaluated. Uh 57% of those were at target with an LDL less than 70 for these coronary disease patients. And again, we see that there was increased major adverse cardiovascular events for those who had an L deal above 70 mg or desk later. So increased rates for those who are not at goal. And so I think really in many ways this tells a story that we've got a lot of work to do. We are not protecting these patients adequately when we get to the secondary prevention uh guidelines in terms of managing patients with clinical A. S. C. V. D. We categorize them in the guidelines to those at not at high risk and then those at very high risk. And when it's basically the guidelines are simple. You know, use a max high intensity or max tolerated statin. And if you have, if you're not at LDL targets, then consider an add on medications such as the enemy or or PCSK nine inhibitor. Yeah. And again, getting your LDL and HDL targets to targets as the goal. What are these very high risk STD patients while patients who had major events or one major event and ready to high risk conditions? Two or greater high risk conditions? Major SCP events include recent acute coronary syndrome in the last 12 months history. By my excluding that A. C. S. Event history of stroke, symptomatic ph D. And the high risk conditions are those that you would expect including ongoing tobacco use. Ckd, diabetes, mellitus, hypertension and LDL greater than 100 despite statin plus his enemy. Uh interestingly and it's heart failure and just age alone aged over 65 as well as a heterosexual mutations. And for FH furthermore, remote history of cabbage or PC. I outside of the recent the recent SCV event. So the challenging issue with atherosclerosis is that we don't always experience a concentric remodeling of the vessel lumen. And uh you know, getting a 70 to 80% stenosis that will cause symptoms then we can react upon. Unfortunately, about two thirds of patients who go on to have acute coronary syndromes Uh do so after having a less than 50% stenosis based on data presented in 2016 in the N. L. A. And you know, so often you have very eccentric plaques and you've got lipid cores that promote untamed inflammation and increased risk for vascular thrombosis events. Um And we don't always have symptoms. So you really gotta rely on these risk calculators to really risk calculators and overall patients risk assessment to really decide how aggressively to treat these patients. And as mentioned earlier, the European guidelines have been a little more aggressive and have recognized that we really should maybe be doing more to identify these very high risk patients. And they have recommended an LDL target of 55 mg per deciliter or less in these patients with a very high risk of cardiovascular disease. Does it really help does reducing LDL cholesterol to very low levels help you look at some of the sub analyses from sub studies from the 48 trial. This is a study in 2019 Jama cardiology. The addition of the velocity of the statin therapy does reduce the initial event. But also these patients are going on to having recurrent cardiovascular events. And you know these events including my stroke need for coronary revascularization, unstable angina admission to the hospital for such as well as cardiovascular death. And we see that the recurrent event rates in these high risk patients also reduced. So these trials again got LDL cholesterols to 30 to 40 on average. So the select patient may benefit from a first event as well as subsequent recurrent events. I want to talk to you about some of the agents. We mentioned that some of the non statin in the details regarding these. So there's the NPC one L one receptor antagonist which is where his enemy works in the small bowel. So basically this medication works to block cholesterol and final sterile absorption of the brush border the small intestine. It's got a long half life of about 22 hours and it really just limits this works by a very simple mechanism. By limiting absorption of dietary and biliary cholesterol. It does not affect the fat soluble vitamin or travel asteroid absorption. But ultimately you have decreased Kyle omicron delivery to deliver from food. You're ingesting from the fans are ingesting and then you get lower hepatic cholesterol stores. Um This promotes more LDL receptor um up to you know, distribution to take up more cholesterol out of your blood stream because you're depleting the liver of cholesterol. There's no sit metabolism. And on average this medication can reduce LDL about 15-22%. There's some inter individual variability. It will minimally increase HDL. The medication is rapidly absorbed in blue color undated in the intestine. So basically it's excreted in the gall bladder and renal system can be dosed AM or PM does not matter with mules but you do need to be cautious about severe hepatic insufficiency. Um And advanced renal, excuse me. Advanced liver failure is a communication, there's really no adjustment required for mild hepatic impairment or even mild to severe renal impairment. But you should be aware that this medication can increase trans AM in aces and they should be being considered for monitoring. There's some clinical data supporting this use and a number of trials they're highlighted here below um as combo therapies as well as mono therapy uh in one of the one of the combo therapy trials to improve it. Uh is it Tommy was added to simvastatin post acute coronary syndrome. And this was founded reduce major after school cardiovascular events here it is here. The trial came out in 2015. About 18,000 patients hospitalized with acute coronary center within 10 days. And we look at the baseline enrollment criteria. LDL 50 to 100 on statin therapy or 50 to 1 25 non staten. Uh huh. They looked at seven and 14 other pluses and my 10 versus Simba 40 plus placebo. Use a composite primary endpoint. Let me see it. Seven years. There was 2% absolute risk reduction. So it seemed to be statistically significant in the combination drug therapy in these high risk patients. But no, The patients in the monotherapy arm already had an LDL of less than 70 mg for escalators. These are traditionally well treated patients. Also note that we found still despite a well controlled patient population in a randomized trial. Again, these patients had an elevated event rate despite well controlled cholesterol and LDL cholesterol 53 in the combination arm And they still had a current event rate of 33%. So this many authors have editorialized that this may be due to these other untapped, other uncontrolled risk factors including for Lyssarides, LP little a and other factors including non HDL Pcs Canada division has really been a game changer and the management of high risk patients. The role of the PCSK nine molecule has been found to be an important one. After genetic mutations found this was essentially Jenna mutations in PCSK nine founded the cardio protective when very low and so investigators went on and developed in monoclonal antibody against this PCS canine molecule. PCS canine as a as an enzyme really is one that takes the LDL receptor and chaperones it to its degradation. When Monica and antibody is present, the LDL receptor is not degraded and instead is recycled back to the cell surface for more uptake of LDL while the LDL particle is degraded in the license. Um so the the landmark clinical trial that showed initial benefit was the 48 trial, nearly 28,000 patients high risk patient cohort, SCB known SCP and LDL greater than 70 already on statin therapy in general, 81% headed history of my 19% history of stroke, 13% of the peripheral vascular disease In the trial used about 36% diabetics, randomized block versus placebo, composite primary endpoint and kind of hard secondary endpoints. Short clinical trials, 2.2 years on average and the medication was found to robustly reduce LDL cholesterol from an average of 92 in the placebo arm versus 30 In the Ebola combat arm, which was sustained throughout the trial. And they found that they met both primary and secondary Kiev eventually end points at the end of the trial 36 months. So really uh nice data for this for this drug class. And um as you go on and look further into the timeframe from 12 months to 36 months, the benefit was continued to improve and furthermore, as dr griffin alluded earlier when you have really, the patients who benefited most, however, were the really high risk patients. So, the patients with multi vessel coronary disease benefited more than those without multi vessel disease and patients with peripheral vascular benefited more. So, patients who are really high risk of multiple after histological lesions in multiple vascular beds were benefiting more from this drug class. The second trial briefly with the odyssey outcomes trial similar uh slightly higher risk group patients who had an A. C. S. Event within 12 months, baseline lipid panel enrollment criteria documented here and already had a run in period for high intensity statin therapy that again used composite primary endpoints and again Four years. They had a about 1.6% absolute risk reduction showing benefit of this therapy and again high risk cohort. The next agents that were excited to see will be the a small interfering RNA therapeutic agents that have been shown to have nice efficacy in a couple of published trials so far. Orion 10 and brian Levin and this medication include Iran will be is theoretically a sub Q injection that will offer twice monthly um administer twice monthly clinic administrations and we'll offer robust LDL reduction with the need to take a medication twice per year. And so this has been uh this is expected to have FDA approval sometime in the near term. So I think that will be exciting to see another novel medication class has come out as an ATP citrate lioce inhibitor. This is called Mehmedovic acid. It's a pro drug that's rapidly absorbed in the small intestine informs Coetzee thio ester and liver but basically it's converted to another enzyme sl co a synthesis converted by a co a synthesis which is found to be high levels in the liver was undetectable in skeletal muscle. So theoretically uh fewer muscular side effects of this medication suppose stands the medication competitively inhibits um 80 P citrate lies which is an enzyme upstream from GMg koa reductase where statins are working in the liver to reduce cholesterol production. This medication has no set for 50 metabolism. It's been showing a couple of couple of clinical trials to have efficacy and safety. Um Clear harmony was about 2200 patients with a baseline cholesterol. About 103. It was a short 12 week trial showing them phenolic acid reduce the mean cholesterol by about 2019 mg for desolate er and it was found to have safe, safe it did so safely. This was done regardless of background statin therapy. So it could be it could be used as an add on to statin therapy. The adverse event rates. Um There was most most notably I think is the the increased rate of gout. There was also some increased rates of muscular intended to open these and so that is one key feature to be aware of when prescribing this medication. Um there was a small, I think about .5% rate of increase achilles. Uh achilles and other Tendon apathy issues in the shoulder and the joint. So if you have a patient with achilles tendon apathy issues you might want to avoid this medication. Um Uric acid level did increase as well. Um And that's a consequence of the competitive competition with the uric acid renal tubular co transporter. So this is a has been recommended that periodic observation of uric acid and treatment of elevated uric acid have indicated. But basically those patients who had a history of gout went on to have more gout in the clinical trials. Other details regarding prescribing information here is that you can you can use the medication as an add on as I mentioned to Staten. And or is it I mean there's also a combination medication Mehmedovic acid with his job. and there's some contraindications and cautions regarding other drugs including simvastatin, 20 mg or more and pravastatin. 40 mg should be avoided in co administration with Mehmedovic acid. Also you need to use caution with with the use of cyclosporin particularly the combination of epidemic acid is my similarly fiber co administration with phenolic acid combinations that in mind should be avoided. There is clear outcomes trial which we anxiously anticipate to see well what would effect beyond a CVD risk reduction. Next I want to mention just kind of some of some of the historic therapies including vibrate therapies and how we came to use them and how they're working. So the they work as agonists. The nuclear transcription factor at the base of the people are alpha, which is responsible for stimulating synthesis of the enzymes of fatty acid oxidation, including up up regulation of lipoprotein like pace, which ultimately will reduce the LDL. It also increases hepatic synthesis of a pro A one and A two, thereby raising HDL or the key proteins in HDL. And it will help increase lipoprotein like paste just mentioned. Um increase like policies, lipoprotein, excuse me. Like protein paste like policies and that are therefore reduces regulatory level. In general. These medications medication class can help reduce triglyceride levels by up to 50%. It can raise HDL 5-15%. Furthermore, there's been data that it shifts the component as dr traffic was mentioning small dense LDL and the risk there. Um similarly with HDL, it can shift small dense LDL two more larger buoyant particles and may be less susceptible to oxidation and therefore less pathogenic, less dangerous. As a rule, these medications do not reduce cholesterol as robustly as statins or nicotine IQ acid. However There's been studied and we'll briefly go through these uh some some studies here. The V. A. Hit trial came out in 1999. It was basically men, 2500 men with coronary heart disease and they really didn't have significantly elevated triglyceride level based on triglycerides were 1 60 in this trial, but they did have low HDL less than 40 and LDL less than 1/40 at enrollment. They looked at a primary endpoint of nonfatal MI or death from coronary causes and they found a 22% reduction in this primary endpoint. However, those effects were hard to replicate and follow up trials in 2005. A large trial of the field trial, about 10,000 diabetic patients with a median a one c 6.9% patients were not taking statin therapy and had a based on triggers, right? About 200 mg per deciliter. They looked at it again, primary endpoint of coronary events, specifically corn heart coronary heart disease, death or nonfatal. My and they did not meet the significance in this primary endpoint. However, they did meet uh they did say that total cardiovascular events including carrot and coronary vascular vascular ization was reduced Um that included a 21% relative risk reduction of coronary revascularization. But they also saw a nonsense of an increase in total mortal. Now, there's been some some trial design. Many have argued that the fiber arm may have been the risk reduction in the final fiber arm was potentially attenuated by the two fold greater use of statin therapy in that arm compared to placebo and female. And also interestingly enough, fiber, it did show some reduction in microvascular disease, including less treatment for retinopathy required and less eldon, honoria progression. So, kind of a mixed study and then the accord lipid trial came out, evaluated Final fibroid again is an add on to statin therapy. Overall improved lipids nicely but did not show clinical benefit. Um for patients with fennel fiber added to simvastatin, 20 to 40 mg and diabetics that are poorly controlled. But when you look at the subgroup analyses later on the, you know, there's been some data that, well those patients with the highest triglyceride cohort really benefited from these medication classes as add on therapies. Field trial and court trial showed this. So, you know, many have argued that maybe we haven't looked at the right patient population here in general. There's, you know, some summaries of fibroids and E. S. C. And H. A. Guidelines have been commented on when to use these therapies. Um Overall the benefit of uh these medication class seems to be correspond with the level of non HDL reduction you can achieve. Um There are some side effects listed here, particularly gi side effects of this medication class. Um But the guidelines would suggest consideration for use as an add on therapy. The particularly high risk patients. Um niacin is been a long you know agent that's been around for a long time really, vitamin D. Three. It works on the liver and adipose tissue and essentially reduces mobilization of free fatty acids periphery to help reduce um V. L. D. L. Secretion. And so it also can increase HDL by reducing april a one hepatic uptake and then maybe stimulating more april a one production. So again basic effect is that reduction of mobilization of free fatty acids from at a post leads to less substrate for the liver to taking these lipoprotein lipids. It could lower LDL fairly robust in 10 to 20% but it's been limited by side effects. Interestingly, in a coronary drug project study back in 1986 did not show initial benefit early on and then later, when the trial was discontinued, patients may have come off the drug. They showed benefit in the late years and so many have argued, well, maybe this is because we had controlled LDL and other and other factors early on and then, you know, patients were seeing benefit much later, but one of the first drugs to show some significant benefit there. However, the more landmark trials game high trial 3400 patients with cardiovascular disease and LDL, less than 70 already managed on simvastatin plus or minus is M. I. A randomized niacin plus versus placebo composite primary endpoint, well controlled patient population in general and does not show any incremental benefit from Dyson with these patients in this with this uh, with these olympic profiles. Again, more trial criticisms, trials doctoral e lack of diverse patient population exclusion of A CS so forth and a lot of nice and drop out. There was interestingly also a little bit trend towards ischemic stroke of the nice enormously which was concerning. So a subsequent study was done much larger trial 26,000 patients nearly with vascular disease. Again, two g niacin plus a medication that the prostate gland and receptor antagonist versus placebo. And again, they did not really reveal reduction in major events and there was some risk of increased adverse events, including diabetes, mellitus infection, bleeding muscular and G. I symptoms. So this um, I'll comment in a bid, but again, may unfortunately not a robust data supporting that medication class. I think in a way the medication's fallen out of favor. As a result, bile acids. Your questions is very briefly are medications that binds the bile acids that generally are synthesized in the liver from cholesterol and released into the intestinal lumen. So these medications will bind bile acids, they're not absorbed, they deplete the bile acid pool, the increase your LDL receptor expression. There are limited by very poor tolerance in many cases, But they can be something in your back pocket if you really are struggling to manage the patient's LDL cholesterol. Um there are some significant side effects, most notably constipation and they also notably may increase serum triglycerides, particularly a very high triglyceride levels above 300. You may want to avoid this class of medications. There's no major HDL effect of this medication class. Um so you need to be careful about drug drug interactions. Um and specific drugs are listed here. You got to avoid, you know, hours of time between doses. Or they may bind these Medicaid, mm hmm. The conclusions the show shown here may reduce cholesterol, LDL cholesterol about 20%. So overall the anyways viewpoint is that is specifically that we have limited randomized control data existing to evaluate the statin therapies. Um excuse me, the add on therapies of statin um, patients with significant residual after hygienic cholesterol. I mean the average in the medians uh LDL cholesterol were very fairly well controlled in these clinical trials. So maybe we didn't look at the right patient cohorts to really understand how well these medications may work. And then these sub analyses have suggested there is some benefit. So the international lipid association would suggest until further randomized controlled data is available. It's reasonable to consider these add on therapies to mac tolerate statin therapy is if you have persistent pathogenic cholesterol and you may consider a second and or third agent um to help manage the very high risk patients. And so I think that overall the overarching theme is that this is a systemic process. We need to get LDL and non HDL at target. And so one of the other major risk factors we want to talk about today is you know, hyper triglyceride anemia. And all the fanfare is getting more recently as maybe a very under recognized and under treated risk factor. And we go through some of the data and some of the trials. But specifically looking at this condition of metabolic syndrome is enlightening this syndrome is your recall. You gotta have three of the five following criteria blood pressure greater than 1 30/85 fasting sugar over 100 Waist circumference greater than 40 in men or 35 and women HDL under 40 for men or under 50 for women and triglycerides over 150. This increases risk of cardiovascular disease by twice and increases risk of diabetes by about five times. But the display academia this syndrome is such that we increase F. F. A. Free fatty acid production. Which increases the LDL. We turn on the C. Tech activity. We decreased HDL. We've increased small dense LDL and really created very much more pathogenic um milieu for cholesterol. There's more small dense LDL comes out occurs as a result and you get to feel invasion increased susceptibility to oxidation. Again this this pattern of insulin resistance free fatty acid production is pro probiotic, pro inflammatory related to endothelial damage and really an aggressive form of atherosclerosis in the vasculature. Yeah. And so those rights have been shown, if you look at the proving 22 trial, um, sub analyses persistent elevated triglycerides are, has been shown to increase overall risk similarly to elevated LDL. So the Omega threes and specifically to have some purported mechanism in terms of benefit people alpha again regulates the gene expression we talked about in the polyunsaturated fatty acids. The Lagan for people are alpha on deficits and inflammatory cells and ultimately work to decrease april be they lower triglycerides, increase insulin sensitivity. They also been shown to decrease inflammatory mediators. Really important ones that seem to be really wreaking havoc on this end of helium and so forth. So it's been shown that this has been helpful. And so the graphic shown here that maybe it's not just LDL, it's also inflammation and ophelia was function and other oxidants oxidative strategies to reduce someone's risk. And so they reduced at trial 2019 was a very landmark clinical trial. Over 8000 patients, mostly for secondary prevention, were enrolled With the following enrollment criteria. Um and basically you have to have a fasting triglyceride over 150 or less than 500 enrollment and age over 45 with established cardiovascular disease or age over 50 with diabetes. At least one risk factor. Overall, the patient population was fairly well treated. I mean over 90% were on moderate to high intensity statin therapies based on LDL about 70 74 at baseline. And at one year we had about 20% reduction in triglycerides and E. P. A. Level that went up about 360% of this trial. This is a purified E. P. A. Consequent ethel's that purified E. P. A. And the study dose was two g twice a day. And when we look at the primary endpoint, as well as the key secondary endpoint with hard endpoints of cardiovascular death and mind stroke, very robust clinical improvement in this patient cohort. So this was an exciting trial when he looked at the data. Well the benefit was seen across all all the levels of triplets or I didn't really matter for triglycerides were relatively normal or similarly elevated. Everyone seemed to benefit. And if you look at all the all the composite endpoints and detailed primary endpoints really kind of benefit across the board in general. And so um there was a slight increased risk of atrial fibrillation which was statistically significant. Um There was a non statistically significant increased risk of serious bleeding. The study um uh sorry uh there's been some data on why this might be prior combination E. P. A. D. H. A. Trials were uh less favorable. And so when you look at some study that's come out of various labs we see the E. P. A. Has a slightly shorter to carbon shorter chain than D. H. A. And that maybe uh responsible for something to benefit basically. It may fit between the fossil lipid legs and the lipoprotein and cells and create a little more stability and a little less uh fluidity more stability of the fossil lipid violator. The D. H. A. Has been shown to increase cholesterol crystals. It may because it's interacting more with the head group we may get more shifting within the fossil lipid membrane. And so there's been maybe a better anti inflammatory properties E. P. A. In general. And the EPA has been shown to significantly reduce the crp and so forth. There's also been some really nice data regarding oxidation levels related to E. P. A. As opposed to other vehicles shown here. And this has been a dose dependent manner. Has you increase E. P. A concentration the ability to oxidize small dense LDL significantly reduced. So this trial and all this data kind of um has been hotly debated recently. And after the publication of this trial at the end of 2020. The strength trial large trial looking at combination E. P. A. D. H. A. In a carbon oxalic acid formulation and the you know theoretically has increased by availability. Does not require hydrologist by pancreatic like place with this Um with this formulation they also studied high risk cardiovascular disease patients. And just to briefly go through baseline demographics about 56% with established cardiovascular disease at baseline and about 69% 70% with diabetes at baseline were randomized and really the end points were very um negative. I mean really not a lot of benefit here again. We saw increased rates of atrial fibrillation in the omega three arm some of what we saw and reduce a trial. And they look at the first incident to any of the primary primary composite endpoint. And really uh un remarkable in terms of outcomes and benefit. So um there's been um some discussion as to why this might be kind of surprisingly negative trial compared to reduce the trial with your husband ethel. Um We saw that the strength increase to reduce the reduce the trial ePA increased E. P. A. Interest by uh 393%. Whereas in the strength trial the E. P. A. Level was increased by 269%. So slightly lower E. P. A. Levels question about by availability. However both trials reduce triglycerides by about 18% of 12 months. But there was a slightly different patient population and again this is a different compound. And so we got to keep that in mind further. There's been a lot of debate about their comparative differences. The placebo differences and minimal oil did show worsened patterns of this leukemia, particularly crp um as well as the LDL and april be. However whether or not this was really enough to to change the outcome here as debated. Um There's been some sub analyses published as well by the same authors that looked at. Well if you those patients in the strength trial who had the top turtle of E. P. A. Level, they saw no benefit and likewise did D. H. A. Counter the affected E. P. A. While they looked at the top turtle of D. H. A. And they saw no really risk of harm there. So um kind of still being debated in the literature currently but reviewing the prior Omega three data, there's been a number of priory ph trials that have been quite positive. Um and so um it kind of remains to be seen. We think I think maybe need more data. There's been some negative trials in the combination Omega arms. Uh just briefly there's some um the comment on the future therapeutic targets, I think that we've all recognized that um there's you know, patients are still having residual events despite just the LDL target reduction. And we've got to tamp down the non HDL and triglycerides and other risk factors. And so there's been some novel therapies including and PTL three and four. Um anti sense therapies coming along. We heard from dr Sinica's earlier about LP Little a reduction and that's that exciting space as well as small interfering RNA therapies coming along there, we talked about the small interfering RNA therapy for pCS canines is expected to be approved. There's also some interest in a pOSI three uh for hyper triglyceride evening management. And then probably we'll see some directed anti inflammatory agents. Um Just briefly, the anti no uh medication that really F. P. T. 03 inherently works as an inhibitor of lipoprotein like peace and and ophelia like pace and thus converts LD LDL, LDL. And so blocking this has shown to really robustly reduce LDL cholesterol. And and this is uh this is actually currently approved for Hamas, FH patients and maybe we'll get a broadening of that approval the future. We thought we heard about LP Little A and the reductions there, here's some ongoing cardiovascular outcome trials that were expecting anxiously anticipating data from the various agents we discussed today, including another fibroid summary of the non statin therapies. Is that, well, you know, we need to maybe more aggressively treat the residual atherosclerotic disease in those particular patients with metabolic syndrome, diabetes and obesity add on therapies seem to benefit the benefits commensurate with the amount of HDL reduction we can achieve. And they're also maybe these play a tropic effects and selective agents we discussed. And so I think we have significant interest in pharmaceutical delivery to resist to combat this residual at risk. And as you saw earlier on the slides, we need to do more to risk stratify our patients and particularly manage those high risk patients. Thank you very much for your attention. All right, well thank you dr cork. Uh you know, we're gonna go ahead and click your your slides over. But as we're pulling up dr Gonzalez, I do have a minute to give me one minute to ask you a question in between. We have had some questions coming in, but first of all, thank you, I think you're talk was spot on, as far as giving us opening our toolbox up to uh you know, non statin therapies, you know, there are patients that really struggle tolerating statins or you know, have interesting in trying to avoid the statins. It looks like they already got a slides up, so I don't know if I have time for that question, I may not. So uh we're gonna hold it um and uh again save it for the for the end.