Chapters Transcript Video A Programmatic Approach to Lipid Management in 2023 Dr. Talreja details the epidemiology and pathophysiology of dyslipidemia. I'm honored to be able to talk to you about this topic. A programmatic approach to lipid management in 2023. And I know it's only 2022, but like a good chess match that has a beginning, middle and end game. I've crafted these slides to sort of tell the story of where we are and where we're heading before I do that. I wanna give a quick moment of recognition to the trainees who gave talks at this year's Heart of Innovation program. They were recognized during the program, but our time schedules were a bit messed up. There were a tremendous series of talks from a number of our trainees. They did a fantastic job and I can't wait to see what next year is gonna bring, calling out our 1st, 2nd and tie for third place winners who are getting cash awards. And uh, and the joy of recognition for success, um, kudos to all those and those of you listening as trainees, pay attention to next year's Heart of Innovation Conference. Another chance again, amy will get together with all you guys afterwards with your certificate book and uh, and the award. So part of Innovation again this coming year, I'll launch right into my topic. And I'm gonna tell you, I'm gonna talk really fast. I have a whole lot of slides and I kept trying to condense them and then add more and condense them. This really should be two grand rounds. But since we're ending the year with this one, I only have space for one. These are my disclosures, they're available on the websites as well. So I started with an interest in lipid ology probably a little over a decade ago, one of my partners in cardiovascular associate steve jones lured me into boarding and lipid ology and as I think of the sort of tale of two cities approach to the world. These are the two differences I see in my clinic I get referrals of patients with severe aortic stenosis for trans catheter based aortic valve replacement. Those patients typically have a lot of information at their fingertips and they come in knowing exactly what they want. They've read everything and they know where they want to go. In fact were often the ones sort of slowing them down and saying, well we have to think about surgical options. You may not actually need a valve replacement at this point. So, good job learning. But maybe we're not there yet. The opposite is the lipid clinic where the typical consult is a patient who has read this among many books and is skeptical of what is again, clearly lifesaving technology. That has a tremendous value proposition. And it's a real tragedy because as a result it limits what we achieve in prevention, which really is the key at the end of the day. So today we're gonna talk about some epidemiology and path of physiology of dis lipid e mia. We'll talk about lifestyle options and specifically the tremendous opportunities that exist in our community for really changing the course of a disease trajectory for atherosclerotic cardiovascular disease. We'll talk about pharma co therapy options and I'm gonna blitz through quick look at data and what's available and what's new integrated throughout this and especially at the end will be guidelines. And then we'll talk about the lipid program where it is and where it's going. So atherosclerotic cardiovascular disease in 2020 is estimated to affect 30 million Americans 19 million. So two thirds roughly are on statin therapy for some form of this disease entity. 15 million receiving statin therapy were not at the A. C. C. H. A. Recommended goal of an L. D. L. Less than 70. So shocking in this era that we really have so much. We're not even at the halfway point in terms of achieving what we set out as our goals. Obviously atherosclerotic cardiovascular disease is a heterogeneous group of diseases. Those of us in cardiology so often think of coronary disease dancing ACUTE. M. I. Semis and so forth. But stroke P. I. A. And P. A. D. Including aortic disease are really a part of this uh different spectrum of disease. Over the last three decades we've seen a tremendous improvement in cardiovascular mortality. Unfortunately over the last most recent decade of those 3 to 4 decades we actually seeing now an increase in deaths attributable to cardiovascular disease independent of definition. Some of this is perhaps catch up you know no one's immortal and so as we make people live a decade longer eventually we're going to run the course on that time. But some of this is a more complex disease process and there's a lot of other factors this slide calls out in diabetics in particular. We've made tremendous inroads with new therapies and the last time I gave a grand rounds on this topic, Elias carriage from the VMS endocrinology department joined me and he talked about management of diabetics after I talked about methodology. Um what we see again and again is even with the newest therapies, you know think of S. G. L. T. Two inhibitors GLP one ras and other therapies. We have insulin pumps. A diabetic patient still has a 1.5 fold increase in the risk of cardiovascular death compared to the general population leaving that as a particularly vulnerable population. The reason is, and we know the molecular level of what's going on in quite some detail. Amazingly enough, I will say of all the boards I've taken the lipid boards were the most nitpicky and hardest to understand. And part of it is the path of physiology we're talking about here is so complicated that even when you sit down and try to draw out everything we know there are huge gaps in the mechanisms that work. But what we do know is a probie bearing lipoproteins. Think of LDL and particles like that are really where the action's at in terms of creating inflammation in the vessel starting the process of plaque accumulation and going on to create ultimate calcification. We know a lot about lipid metabolism. The average american consumes 200 to 400 mg of cholesterol a day. The average american produces between 612 100 mg of cholesterol a day. So bad diet plus good genes or good diet plus bad genes leave us with some variability in how patients respond. We know HDL can be beneficial. We know LDL and the particles like it can ultimately lead to plaque accumulation. And ultimately, If you want to think of this in a fairly simplistic fashion, it's LDL level, circulating LDL times the number of years of exposure to it. That equals your total plaque burden and causes atherosclerotic cardiovascular disease. We can't affect time directly, but we can get patients on good therapy and give them a long run on that good therapy to try to prevent accumulation of plaque and that's really the goal of everything we're talking about in the next 40 minutes. So first and foremost, let's talk about lifestyle modification. This is clearly underutilized, although we've made a lot of inroads in this, calling out the 2022 American Heart Association statement on the comprehensive management of cardiovascular risk factors for adults with type two diabetes. We see that lifestyle modifications are the first thing we think about quitting smoking, exercising, eating right, losing weight. Then we think about social determinants of health. We think of cardiovascular imaging, I think in this era we still massively underutilized, fairly inexpensive tests. Think of coronary calcium scores. Think of cT imaging. We have great stress testing and for those patients that needed cardiac catheterization. But compared to a decade ago, there's there's obviously a lot of ways to pick this process up early in the game. And then we have a great number of medications, especially in the general population and in diabetics that can impact this disease process quitting smoking. I'm just gonna show this slide enough said critical, critical um dietary patterns. This is from an A. H a publication plant based diet will call out specifically as what recognizes one of the healthiest diets out there now. Of course no diet is effective if a patient is not going to follow it. So there are other opportunities available for us. And we've done study work on some of these, I will say, unfortunately, the worst diet out there fits with our geographic location. The southern diet is really the one that is known to increase the risk of cardiovascular disease and heart failure. Physical activity. Any level helps increasing mets, especially up to uh the relatively moderate level has a dramatic impact on all cause mortality. And that's why cardiac rehab programs are so useful. It's tough practicing cardiology in your local community for those of us that want to go out and grab some fast food, you have to hide if you're a cardiologist, I don't get there much. But among the billions and billions served. I try to be not in that pool too much and most of our patients need to do the same. So years ago, almost a decade ago we did a study. Many of the folks in this room were part of this are supported one way or another an investigation of four commonly used diet, plant based mediterranean, paleolithic and dash diets. I showed this in a forum here, but it's been about a decade. This is collaboration between our area and the University of Virginia. We offered 100 patients that self selected their their arm. Four commonly recommended diets and what we saw was interesting just quickly calling out everyone lost weight or every group lost weight anywhere from 4 to 5 up to £12 over a period of 60 days. B. M. I improved blood pressure improved pretty remarkably. This is what you would expect from one or two medications. An average blood pressure drops systolic a between 10 and 15 mm of mercury. For patients that complied and calling out some lipid changes. We saw pretty impressive reductions in everything from triglycerides to LDL, including highly specific markers like L. D. L. P. You see in this, the vegan group really had the most remarkable decrease in LDL. P. 100 and 40 point decline. Diet is extremely effective. Now this was a decade ago. What about since then I'm gonna come back to our rehab programs. I've worked with them to get some of the data from our patients locally over the last quarter for those patients who can't get where they need to be or starting too late in the game for diet to be sufficient pharma co therapy becomes important. There are a lot of trials in this spectrum. These are great trials. We participated in a lot of them and we'll talk about some of the key ones as we look at what's going on. So if we think about lipid lowering agents, our mechanistic understanding of what's going on has allowed the development and testing of specific agents and this is from the journal American College of Cardiology. There are five specific mechanisms called out here. Number two is our H M G. Co a reductase inhibitors statins, very effective, very underutilized patients are very well aware of the potential side effect mechanism. And importantly, even with statins which are the 1st, 2nd and 3rd line therapy, a lot of patients we looked at the numbers earlier cannot get to their target therapy, whether it's related to compliance or insufficient potency. One above the status in the same pathway of production of cholesterol within the parasite is a teepee citrate lies we have a blocker for that which works upstream of statins and can be used with them. That's empathetic acid. Number three. The NPC one. L one receptor is where um I've works and we'll look at that Number four is through interactions with the pcs K nine protein. And that's where we have new injectable agents that can act directly on that. And then today we'll talk about one of the newest editions which actually works on blocking the transcription of M. RNA for pcs canine production and we'll call all those out and the mechanisms to come. So first we always have to think first and foremost in pharma co therapy about statins. There is absolutely no uncertainty whatsoever about the effectiveness of statins in reducing cardiovascular disease. This is the largest meta analysis of almost 100,000 patients showing reduction in every important endpoint all cause mortality, coronary mortality, M. I. C. H. D. Death stroke and major vascular events. Of course there are some patients that have difficulty tolerating these agents but there's absolutely no question that the value proposition, generic, inexpensive costs with tremendous benefit is there. And so it's incumbent on us to try multiple statins at the highest doses patients, patients can ultimately tolerate in all patients. And again, if you look at these trajectory curves, you've all seen many times before whether we're talking about the secondary prevention curve on the top which has a steeper benefit curve or the primary prevention group which has a slightly shallower benefit curve. There is zero questions across all populations as we lower LDL with statins and actually many non statin therapies follow the same curve. But in this slide we call out, lower is better with statins and we really have to be aggressive about it enough. Said I know this is obvious everyone knows it but it's important to call out again. Where that leaves us though is if you look at the major trials of status in every single trial concorde only statins lower event rate, but there's a pretty high residual event rate in each of the trials as well. You see statistically significant benefits. But we see a 25 to 40% residual risk for recurrent events across every trial. Every population we've looked at and that's the group. We have to do more for so many years ago we were in the improvement study that tested the addition of a on top of statin. There's a lot of things you can criticize. But ultimately what that trial showed us is effectiveness of um I've it took about seven years for the curves to reach statistical significance. It takes a while. But the group on combined as a team I've and statin does better with the number needed to treat a 50 that's statistically significant. And that's why again, is another generically available agent. There is a clear utility for this and we'll look at where it falls in the guidelines more recently, the introduction of psychedelic acid has given us another mechanism to affect lipid production within the liver. Some potential benefits of this are it works in a different area than H. M G co a reductase inhibitors, although it's in the same basic pathway, it is a pro drug that has to be converted to its active element. And interestingly in skeletal muscle there's no conversion enzyme. So in theory potentially less skeletal muscle concern with the OIC acid than we see with statins. So gives us one other option and studies have shown us. While outcome studies are still pending, we have clear data that shows about 15-20% reduction in the largest trials trials compared to placebo for the addition of the OIC acid to a satin. And when we look at the combination of a demise and um and and and talk acid together which is one combination pill, we can get up to a 40% additional reduction. So another therapy, again, no hard points yet, those trials are ongoing but this can be effective in patients either statin intolerant or can't get to their max benefit. Everyone here knows about PCSK nine inhibitors. Again, really, a remarkable example of the benefits of understanding molecular level pathways from initial identification of the relevant genetics and populations out there to FDA approval and outcome studies, we're looking at a period of under 15 years to get this therapy available to us. The idea is P C S K nine is an enzyme our body produces on the left. It's the things that looks like cheetos and orange color and what they do is when they couple together with an LDL particle and an LDL receptor, the PCSK nine results in degradation of that LDL receptor, you destroy your own LDL receptors. They finessed over time. Each LDL receptor recycles about 100 and 50 to 200 times. And this is the natural sin essence mechanism. There are people who genetically don't make pcs K nine and they have a lot of extra LDL receptors because they stay in circulation and they work longer. They tend to have low LDL. And so we've replicated this with available mechanisms based on current molecular biology. Um this is lucca mob one of the available ones monthly or every two week injectable agents available multiple trials in the Oslo program that show us very effective reduction in LDL cholesterol. The LDL has dropped by about 50 to 60% across studies and it's a durable effect with potentially a monthly injection for this. Initial costs were high. Those costs have come down as coverage has improved. And now, in addition to proving that we can get a much larger number of patients to their LDL goals, we see outcomes. This is the LDL cholesterol goals. If you look at the LDL goal on the left of an LDL less than 100 we see that in the standard care therapy which includes statins, diet nutrition and the Hamid, about a quarter of patients are getting to that LDL target of less than 100. If you're looking for the LDL target of less than 70 it's under 5% of patients with traditional therapy in that high risk group that get there when you add PCS canine inhibition onto that, it's not 100% but we're getting 90% now to the target of less than 100 and three quarters of patients to that target of less than 70. So tremendous impact on LDL cholesterol and LDL concentration. For a long time. I think many providers wanted to see the outcomes data. We do have multiple trials showing us that correlates with what we would expect an improvement in cardiovascular outcomes. Hard outcomes including death, M. I. And unstable angina and outcomes including coronary vascular ization, stroke tia and even heart failure. You see standard of care alone is effective compared to the general population, but when you add in the PCSK nine inhibitor on top of that, you have a very significant improvement in overall outcomes. I have talked fast. I've gone through a lot of the things that I think have been with us through the last iteration of the guidelines. The 2018 american Heart Association and american College of Cardiology guidelines. So I'm gonna slow down a tiny bit as I go into newer therapies because I think this is the area where folks are a little bit less familiar, just recapping, we've talked about the disease process the burden of disease and deficits in our treatment strategies. We've talked about why lifestyle modification is critically important as the first step and we have to keep coming back to it. It's a battle that's never won. It's like keeping my house clean just after I get it all clean, it seems like it's starting to get dirty again and I got to start from scratch. And then we've talked about a lot of the the conventional therapies we've had available from statins to and there's older ones that are available to the data points are a little weaker for some of those but they are in the guidelines in the interest of time. I've left them aside and then we've culminated with the PCSK nine inhibitors. So now where science has taken us next is the RNA based therapies and I'll give a light dusting of the surface of this topic. There's a lot more to come. And the world of lipid ology is where there's a huge amount coming in this arena as we think on the far right of the slide about M. RNA back to our our days of uh of biology and biochemistry. So M. R. N. A. Is what's transcribed or transcribed from D. N. A. And translated into protein. M. R. N. A. Is sort of the working blueprints that allow our bodies to produce the proteins that actually cause things to happen. And so when that M RNA is translated, we make things like for example PCS canine. We talked about where PCS canine sort of works against us by degrading our own LDL receptors. There are two types now of commonly used RNA therapy. Moving to the left side of the slide here. Anti sense RNA are double are single stranded RNA that are a complement to the other side, making a double stranded um um molecule. So remember DNA double stranded, we transcribed one of the strands and make a single stranded messenger RNA. Back thinking back to A T. G. C. And all those things. If we make a compliment to that we'll now use that complement in circulation if you can get it into the cytoplasm to bind with the matching M. R. N. A. So you can target a specific blueprint specific M. R. N. A. And gum up the works so that you're not going to produce that protein. So you can imagine how that can be used to stop the body from making something like C. C. S. K. Nine. There are also small interfering RNA. These are actually double stranded RNA. Again you have to get them to where they have to go but they're going to ultimately gum up that process of translating the M. RNA into the protein. And so these are techniques we're gonna see more and more, the durability is longer than with the traditional oral agent but these agents can be consumed orally currently although there's interesting work going on in that realm. So now we're gonna talk about in clustering and so PCSK nine inhibitors let's focus on the left side of the slide in a traditional human body. What's happening is our body is translating messenger RNA A making the enzyme PCS canine, releasing it to the cell surface. The pCS canine is coupling with an LDL particle and with an LDL receptor as that endorse it, toast the LDL receptor is destroyed and we lose a valuable tool for getting rid of cholesterol in our circulation. So PCSK nine inhibitors, the traditional ones we've thought about our monoclonal antibodies that once that PCS canine enzyme is released into circulation, destroy it, they bind to it and use our immune system to clear it. We're kind of getting to it after it's gone out into circulation. And obviously uh if you think about it we're never gonna catch 100% of them. So another effective technique which is where in clustering works is to use this M RNA technology to stop the synthesis of PCS K nine in the first place. Now again you're not going to stop 100% of it but you're gonna have less circulating PCSK A nine and as a result you're going to have more circulating LDL receptors. So the mechanism is very similar to what we're already familiar with with monoclonal antibodies to attack this. Some interesting differences are that this therapy is given typically after its initial loading as accused six month therapy which which opens up the opportunity especially in patients that are potentially less compliant to have every six month therapy that could be given potentially in the office on top of that it can be used in addition to the other therapies, including monoclonal antibodies to PCS canine we talked about in the Orion series of trials. This is one of the trials we see again a sustained and highly potent reduction in LDL cholesterol of about 50 to 60% once again. So yet another tool in our armamentarium here accused six monthly injections trying to keep an eye on my time as I go to. Alright, I'm making a good pace. I know I'm going fast. Um It is interesting as we think about this technology. There are a number of RNA based drugs in development in testing and we've already seen the first ones come available to us more coming. We've seen the effect on the far left for PCS canine antagonism and now we're looking at trials coming out which will be my next grand rounds in a year on a pOSI three on a po A And also on and P. T. L. three. We'll talk a little about that in the in the time to come so we can impact multiple different lipoproteins and hopefully further affect this disease process where we still have residual risk left behind. It is interesting one question that often comes up is so what about triglycerides? What about HDL HDL therapies to date besides exercise, low doses of alcohol and uh cessation of tobacco use have been largely ineffective in improving mortality outcomes. So HDL is very difficult to figure out right now. Triglycerides. We know that if you look at epidemiologic data, high triglycerides correlate to increased disease risk. It's unclear whether that's causal or whether it's related to an other underlying disease process. But we'll come back to triglycerides. I could give a whole other grand rounds on that. I've included just a little bit because again looking at trials, there is some benefit there I mentioned briefly and PTL three. I also want to talk about um this uh this group of patients with homocide. FH those patients are rarer so if you think about it we have patients with familial hypercholesterolemia. That's a disease where the genes for the LDL receptor don't work well. Um Homocide FH is when a patient has two broken genes um There are five patients I follow in the lipid clinic in this region with homos. I guess FH it's rare. Heterocyclic FH is much more common. This disease process results in early mortality, catastrophic levels of disease. And there are many different criteria. We can do genetic testing for it. And what's complicated is there are a lot of genes involved. Some of them are the LDL receptors. Some of them are other things like a po B. And P. C. S. K. Nine. We can't identify them. All genetic testing is useful but can be expensive. There's a lot of stuff we have to test and the genetics are pretty interesting because you can have um double heterocyclic compounds. Heterocyclic or identical um home they can have two of the same broken gene or two different types of genes. Um Family members have to be screened. There has to be some form of genetic counseling and typically they have very high LDL. I'm not talking about their total cholesterol. Their LDL can be 400 to 600. And frankly any time you see someone on therapy who has an LDL greater than 300 you should think of this disease condition. These patients need the kitchen sink thrown at them. They need aggressive diet change. They typically need to be on 34 or five therapies. We often did L. D. L. A. For reasons for these patients which is inconvenient and difficult to arrange and not widely available. But recently a different mechanistic pathway. Different mechanistic pathway has been employed to treat these patients. And if we look at another injectable therapy avenue ca mob. This is a therapy that utilizes a different pathway. Now this is an oversimplified pathway. But let me explain what's happening on the far left. You see the liver is producing V. L. D. L. The LDL particles. Very low density lipoproteins are metabolized through like phases the lipoprotein lips. The red LPL and cecilia like paces the red E. L. Into the LDL remnants, intermediate density lipoproteins and then ultimately go on to form LDL. Which is what we typically think of in some genetic disorders, patients can have excessive levels of just the LDL itself. But typically if you think of the average patient in this pathway, it's the lie paises that push the particles along and there's this enzyme and PTL three and important like protein three that inhibits the life. Now if you now follow the circuit around so you go down to the bottom through the LDL LDL particles and you see those are taken up in the liver by the LDL receptors which are those spaceship shaped purple things on the bottom of the liver. So in a typical patient we secrete the LDL metabolize it, take the LDL back up into the liver and get rid of it. And that's where for example are PCSK nine inhibitors are so useful. Uh Right because they increase the number of LDL receptors. But now you imagine the poor patient who has nonfunctional LDL receptors, we can give them more of those receptors but they're not working in the first place. And so we're gonna have limited efficacy to just ramping up LDL receptors which is ultimately what statins zita, my psychedelic acid and all our forms of PCSK nine inhibition do. It turns out there's another way to get cholesterol out of circulation. We have V. L. D. L. Remnant receptors which are the green space ships on the side of the liver there and so there's a secondary mechanism completely independent of LDL receptors to get rid of these particles. And that's what does is it up regulates that the LDL receptor receptor receptor remnant uptake. What it does is it blocks the ndp TL three and through a complicated mechanism that's not entirely uh you know clearly laid out in this slide because it's super complicated. What happens is you get more V. LDL remnants taken up by those remnant receptors which are largely functional in these patients who have non functional LDL receptors. And what happens when you give patients this therapy This therapy is a once monthly therapy now it's not a sub Q injection, it's an infusion that's given. But what it does is it reduces LDL in these homocide FH patients another again around 50%. It seems like every time I show you a therapy I say it reduces LDL by 50%. That is kind of what the data shows. So with these newer generation of therapies this is approved for Homo ZegaS F. H. This is not for your hetero zygotes or other patients. Yet interesting trials will be ongoing but for that group of patients the unique mechanism makes absolute sense. And this can be again a really impressive add on therapy we still like to use the other therapies and those patients. And in fact this 50% reduction is on top of in the trials, I don't have enough time to go into all the data. But those patients who are largely on three or more therapies, including Pcs canine therapies um on a crisis on limited pied, which is an older therapy really isolated for those patients. And so now we've looked at a bunch of different, newer injectable therapies from PCS canine therapies to imply sarin now to even upthe map. And so the world moved ever forward with this. As with so many things, I think many times it's overwhelming to the average clinician out there who has, you know, 15 or 20 minutes to see a patient. Our staff does tremendous work to help us get preauthorizations and so forth. This is why in the slides to show you, I'll go over, we have the lipid clinic available for those patients who identify that needs some of these more aggressive therapies. Please do not hesitate to reach out to me or anyone on our team that can help and try to make this happen for patients. Last thing in terms of pharma co therapies I think has to be called out because it's been an area of controversy over the last decade is E. P. A. And D. H. A. Therapy. So we're talking about omega three fatty acids. We're talking about fish oil here. There are some plant based versions recent trials have made us suspect that there really is a difference between E. P A. And D. H. A. Both of which are the traditional omega three fatty acids, E. P. A. And D. H. A. Combined trials generally haven't shown a hard endpoint benefits. But to really important trials, the jealous trial and we'll look at reduce it shows specific reductions in cardiovascular endpoints on E. P. A specific formulations and there's some mechanistic reasons why that might work. But reduce it. Just to call out this trial looked at 8000 patients with pretty well controlled LDL and triglycerides of 1 35 to basically 500 with risk factors like diabetes for cardiovascular disease And what they showed that was impressive and consistent with the previous jealous trial is reduction in both the softer primary endpoints of CV death. My stroke and also unstable engine and revascularization. Those latter two make it softer but also of the harder cd det M. I. And stroke. You see statistically significant reductions. You see the p values are much much less than 0.5 and you see numbers needed to treat of 20 to 30 in this situation. So kind of a breath of life back into thinking really about the appropriate patient with that moderate elevation of triglycerides for using E. P. A specific formulation. So the guidelines, there's a lot of them. The last time I gave this talk in full version and we looked at guidelines was when the 2018 A. C. C. H. A guidelines came out. I didn't love those guidelines because I thought they left more to clinician judgment than they specified. But first let me take a second and pause and talk about this because at the end of me showing you a bunch of guidelines really quickly. This is where we're headed 2018 H. A. C c 2019 european Society of Cardiology. To the right of it. To the right of that is the 201988 guidelines. And to the right of that is the 2017 American Association of Clinical Endocrinology Guidelines. You see what's changed from the old days when many of us trained is there's been the addition on top of low medium and high risk of very high risk and even extreme risk patients. What gets you into. I know I'm not sure how to get that. Even super fantabulous risk will be like the next one I think after that. But but these patients are out there and the idea is we really have to be aggressive with these patients it's not enough to quit and say yeah they're kind of high risk. Those patients that continue to have events continue to smoke, have diabetes and even a lot of simpler stuff. I'll be honest with you in the average clinic one of us sees a cardiologist sees there's no one left that's not in that very high or extreme risk group because now that includes anyone with an event within the last year or multiple events who has hypertension or diabetes or is a smoker or chronic kidney disease with an E. G. F. R. Of nothing up to 59. I don't think there's anyone I'm seeing that doesn't fit one of those categories quite honestly anymore. So pretty much everyone now is very high risk of extremists in our clinics. And you see the numbers we're looking for SDL less than 70. Less than 55 based on really excellent data sets that show hard endpoint benefits. I'll go into where these guidelines come from in a really brief sort of pass through the guidelines over the last for the last five years worth of guidelines. But this is where we're headed. LDL is less than 70 and even less than 55 I think it's really easy to pat ourselves on the back to in our guideline order sets, there's hard stopped items for starting patients on statins. You can get out, you can say they're intolerant but often we don't get them onto max tolerated doses. We have a really hard time in this era where clinicians are unavailable. Many of us are booked out for months if not close to a year, titrate has become really difficult and we're gonna we have some solutions for this. I'm just pointing out the problem first. So the 2018 H. A guidelines, these are now out of date and yet still we're not even at this level yet, these guidelines say that for secondary prevention you've got to get the LDL hopefully below 70. And if they started out with an LDL of 71 it's not enough to get them down by one point and claim victory. You need a 50% reduction from where they were when they started. So that patient that comes in with an acute M. I. And has an L. D. L. 71. If you read the guidelines really, what they're saying is you got to get them down further. So we got to set the target lower and lower. Um aggressive risk scoring is important. And I called out earlier that really I think the future of this field is aggressive imaging early on in these patients, calcium scoring has become very affordable and with the with the current generation of CT scans of chemo in the audience. You know the quality of reads we have locally that there's a lot of room for the diagnosis. Well in advance of that acute stem E actually got a page as I was driving in that there's a stem e headed from Sam see the beach and I wish I could be there doing it right now. But I said I'm on the way to Norfolk already and it's always a tragedy when someone comes in with that notice that back in 2018 the A. C. C. H. A. Kinda really took a very heavily evidence based, they wanted multiple trials with endpoints. They called out Staten Staten Staten Staten Staten and if you couldn't tolerate it then Zetia and a week call out to PCSK nine inhibitors. But they didn't really give us a lot of guidance on newer therapies that fortunately has changed the 2019 guidelines from the european society of Cardiology which tends to run a little bit ahead of us called out that LDL reduction to a goal of less than 55 which now has been called out by a number of other societies. A really thorough and great set of guidelines is the A. C. E. American Association of Clinical Endocrinology guidelines from 2020. The reason I love these guidelines is they are robust. They call out every detail, they talk about all the risk categories. They talk about all the particles. I'm not gonna read through all this, I'm calling it out. So those of you who want to look at a really well written set of guidelines can look at this set. They really call out lifestyle recommendations that we've talked about a little bit. They talk about the targets where you need to get patients what therapies they use. They use both older and newer therapies and they readily call out for instance look at the far left for extreme risk, it's high intensity statin. If they don't get to an L. D. L. Of less than 55 at either Pcs canine Hmeid cole Sullivan epidemic acid. Now remember this is 2020 so we didn't have some of the therapies we talked about today and then they talk about really pushing LDL down, we'll update these in a second. In fact right now, this is the newest set of guidelines. Just fresh hot off the press from the american College of Cardiology and the american heart association. These are expert consensus decision pathway guidelines on newer therapies available. I've cut it short so I can uh just show you basically all the high risk groups. If you can't get the LDL down by 50% or more and get the LDL to less than 70 on max intent intensity statin they specifically call out addition of and again this doesn't have to be sequential but um I'd consider attacking Pcs canine directly. First step is probably your your monoclonal antibodies. Next step is epidemic acid glycerin. And again, we're waiting on hard endpoint trials from those latter two but clearly very effective agents in in our therapeutic armamentarium. And notice how the curve keep cycling cycling you back up. If you don't get the LDL, less than 70 and down by at least 50% then add more, add more, add more. And I think at any point you can either go back and add another agent, there's a clear titrate, an algorithm that exists in this pathway or refer onto lipid specialists. Either one, whatever is gonna get the patient there. And so that leads me to the last topic which is our Sentara cardiology lipid program. So if I look at what's going on, what needs to happen at a health care systems level, There's clearly an urgent need to bridge implementation gaps in health care systems to improve population outcomes. We need to better assess the most important modifiable barriers, whether it's tobacco use, whether it's diet and nutrition, whether it's access to pharmacologic therapy, we need to apply what we've learned from trials and really do what our guidelines are telling us to do and we need to keep on these until we successfully implement these interventions. If the obstacles getting the patient on diet, we have tremendous rehab programs. I'm gonna discuss in a minute if it's for example, getting a patient on therapy either it's their noncompliance, we have to hammer them with that. If it's access to therapies, there's a great partnerships we have with industry to help get patients on therapy when they can and sometimes you tried everything you can. You can't get them on therapy this year. Don't give up try again next six months or a year later. And then we have to get the sustained improvement and focus our patients attention on this. How many times have you seen someone that's had an M. I they're terrified. They're willing to do everything right. And one or two years later they're right back to where they started. We have to keep on these patients. So I mentioned 2023, this is now the end game. This is where we're gonna talk about what we're trying to do in 2023. This is a slide from the central cardiology. 2023 co management metrics on care delivery metric one is ambulatory access. We're trying to get providers available for patients more every system and every subspecialty in the country right now is facing significant shortages in providers and nursing staff and technicians and office front desk staff and everything that makes it possible for our patients to see us and get the care they need. There's tremendous needs right now we have to leverage what staff we have and we have to figure out more effective ways to deliver care. And part of that is getting every provider to work at their highest level of certification. We have tremendous nurses and one of our metrics is develop and implement our end protocols for Hyperloop anemia RN visits beginning by third quarter. We're already doing some of this work and the idea is tight rations instead of getting back into dr McKechnie scheduled to increase the Crestor from 10 to 20 or potentially to add the next drug or the next drug or the next drug on R. R. S. Can help us with that. And so we're gonna start this program and be tracking it and that's one of our key co management metrics Rehab programs. We have a lot of fantastic rehab programs here. They're all tremendous many of you like me here are patient experiences and one of the fun things I think I get to do with post my patients nowadays is every single time my experiences when I talk to a patient about rehab, pretty much 90% of patients. You can see their lack of enthusiasm when I describe the idea that we're gonna put them in cardiac rehab and it's so much fun to see them come back the vast majority after they've done whichever program they chose throughout our community say that's fantastic. Many say I'd like to stick with this forever. And with maintenance programs they often can, although remember we have a shortfall in staff Sharon, Henry and uh and and Dr Penny have done a tremendous job developing the Ornish program at Princess Anne. And there are two main things I want to share, sharing was kind enough to um share with me slides. This is from Q two of 2022. Looking at baseline and nine week measures of dietary fat dietary cholesterol and exercise. And you see changes of 50 to 1000% in stress management techniques and exercise in improvement and diet. A very intensive rehab program. We have a series of standard cardiac rehab programs and then I'm showing you now some of the results from the intensive rehab programs because they're tracked If you look at the princess and specific results, weight loss of 5%, which again fits with the data. I showed you from our independent small little trial earlier cholesterol reductions independent of pharmacologic therapy of almost 20%. LDL went down 25% in these patients, triglycerides down a little over 10% and improvements in blood pressure of 5 to 6% both diastolic and systolic with improvements in depression 10% drop in a one C and up to a 50% improvement in exercise capacity with almost a 50% reduction in reported angina. Many patients get off medications. Um I think it's a tremendous program for those patients that are interested. I think too often we take as an out that this patient probably wouldn't be interested in a vegetarian diet and in fairness many aren't. But one thing I've become increasingly aware of is we should at least give them the choice. We should mention it. We should put the opportunity in front of them and let them think about what they want to that end. Many of us don't have a lot of familiarity with the Ornish program and with what's really involved, Santora's run three separate conferences talking about this program in specific and they've been widely attended in the community. Last time we had to cap it at 1000 people and offer virtual options because there's so much of the community that actually is interested in this. Um What we're working on right now is generating probably in february, what will be a four day program for cardiology providers to participate in the goal is not just to do those four days. We're going to spread it out over a couple of weeks and we're targeting february 2023. We're looking at doing it monday and Wednesday from 4 to 9 p.m. This will be open to the initial program, will be 10 providers will pay out of pocket those of us who want to do it. I'm actually excited to do it and I'm saving a spot for me. And uh, so if any of you want to come join, please email me. There'll be more detail coming. I think if we need to try it for a little bit and see and really commit to a couple of weeks and see what it's all about. Maybe maybe sounds sick with it. Maybe some won't. But I think we all owe it to ourselves to at least think about this option for our patients on top of Ornish. We actually started something new this year. So center is a large system. We have hospitals up and down the state of Virginia and north Carolina. A second intensive cardiac rehab program has just opened that the critic in program critic in is very much like Ornish a little bit less heavy in the meditation side. And this program again is versus traditional cardiac rehab, which is 36 sessions. Mostly exercise with some dietary counseling. This is 72 sessions with exercise and education. It has the potential to offer a different option potentially less expensive because there's a little bit more video work shopping. Again, some of the benefits of an orange type program but maybe uh with a little bit less of the cost, a little bit less and less of the focus. So Ornish is probably still the, you know, the most intense version of this. Uh Sentara Martha jefferson hospital went live with this november 28th and it'll be extremely exciting to see the results and Sentara care plex will go live and anticipated in january of 2023. So what I love about our rehab programs in this area are we're offering the latest, the greatest the cutting edge and multiple options for patients. Why do we need to do all the stuff we talked about it today. This is from the asteroid trial. This is old data. This is 2006. This is when I had all all dark hair and no gray and many of you in the audience that I know and love were in the same category for those of us who start at the same time. Right. This is an actual intra cardiac intravascular ultrasound from a patient enrolled in asteroid. After six months of therapy at baseline. The lumen area of this led was 7.7 millimeter squared and the aroma was almost twice that 13 millimeters squared with aggressive diet, lifestyle exercise and Crestor 40 mg. Six months later, the patient's luminaria had increased from basically seven to basically 10 millimeters squared. And the as Roma was cut basically in half from 13 millimeters squared to seven millimeters squared. And that doesn't even call out the plaque stabilization. We believe that occurs and the reduction in hard endpoints. Am I death and stroke? So summarizing a lot at once and then I'll open up the floor for any comments or thoughts or questions. What we talked about today is we talked about the extreme disease burden that exists, which is tragic in a first world nation where we have great therapies and yet we see an increasing incidence in cardiovascular deaths in the last decade. We talked about a lot of guideline sets and saw how they're very largely concordant. 50% reduction in LDL and LDL targets in the highest risk patients now of less than 55. We talked about conventional therapies. We talk about statins And statins and statins and then we talk about all the newer therapies. What's available, what's approved? What's coming? We talked about in line hard endpoint benefits and then we've talked about guidelines rehab programs and what we expect to see in 2023 is for those that want to refer patients into the lipid program. We're increasing bandwidth. But this is something that's within the purview of every provider here cardiology. Non cardiology. And so we all have to really just jump in and engage and take care of patients. Thank you guys for your attention during a lot. I know I went really really fast. I'd love to hear any comments or thoughts or questions and amy ology relay any from from the audience. And if I don't hear questions I actually have something I'm gonna throw at you guys. Okay doctor uh like secondary endpoint um used in trials and also like yesterday for example 23 patients came in with carrot I. M. T. Yeah. Are you are you discounting that using that at all or? What a really great question. So you and I both worked in an era where credit I? M. T. Sort of became exciting was used in some trials we implemented in our practice and there are still some doing it in the area. Um I'll be honest with you. So I'm not doing much now when I order it is when it's hard to find a normal C. I. M. T. In someone. We see some of them right? But you don't see them much. So to me it's a strategically deployed testing. That patient. I absolutely want to just convince them that I see plaque there and I want to scare them into doing what I want I think. And to your point I was gonna put you on the spot with a question about calcium scoring and cardiac C. T. A. Which I'm still gonna ask you in a second. But in this era with coronary calcium scores costing $75. It's hard not to be excited about sending patients for that now. Is that useful in a 30 year old? Probably not so much. That's where gosh, if I really needed something in a 30 year old, maybe I'd get a C. I. M. T. And there's folks that do it locally. But my enthusiasm has dropped off a fair amount for those to be honest with you. I'd love to hear your thoughts as an imaging. I mean you've spent a lot of time thinking about this. What would you answer that question I can't use because it's just too variable. Yeah. I've gotten on the same patient at eight a.m. Got it at noon and five PM. Get different answers which is you pick the highest level one and that's the only one you report out, you destroy all the other. And and and and uh again I think it's been a great boon to our area to have calcium scores available now, $75. It's interesting. I just had a patient recently who came to me wanting a study. It had been um and again you have to be careful any single story is a single story. But to me it's one that this is an example. You see not infrequently a patient came into the lipid clinic self referred. They had asked the primary care provider who is absolutely fantastic to get a calcium score on that day for whatever reason the answer they got was no, it's not really worth it. It's radiation exposure and that's all true. But at $75 the value proposition is pretty high. He happened to be one who had a calcium score in a, he was 48 if I remember his age correctly, who um had a calcium score of 1200 which for his age, sex race put him in the 99th percentile. And he's largely asymptomatic. But really if you ask a lot, he's not doing the stuff he used to do. He's not going up the stairs anymore. He uses the elevator everywhere he goes. So the warning signs are there. He ended up with bypass after a calf showing three vessel disease. And it's interesting because he credits himself for thinking of getting the test and he's he's right. I mean at some level now, I'm not saying he would he was taking time, I'm waiting to have a heart attack, but I will say We need to be aggressive about thinking about early screening. So if 10 years ago we put him on statins, maybe he wouldn't be there now. Maybe another 10 years. Great great comment there. Other comments, thoughts or questions is real, really great question here. How to how to um tackle statin intolerance. I'm going back to my first slide where I talk about structural heart clinic versus um ah the lipid clinic. And you know, my daughter keeps informing me on on books that are banned in the school system. I think we're banning the wrong books. I think those book banner people need to go after things that are misinforming the population around us. But in all seriousness statin intolerance is probably real. There probably are some patients that are truly statin intolerant. Now when we say statin intolerant, what do we mean? Well they didn't die from the statin but they might have had some muscle complaints. Um Maybe their hemoglobin a one c went up an average of 0.1 but with a reduction in mortality a lot of those things patients will tolerate. I think of one physician patient I have who has a true statin um My site as he gets irritation of muscles, he gets uncomfortable but he wants to live for a long time and so he sucks it up and he takes a statin, we take it a lower dose coenzyme Q 10 many people believe helps. The data's not, not 100% clean but if it if it works and gets them on it, that's great. Remember that in the four s trial status in the statin intolerant group 8% of patients reported side effects in the placebo, group 6% of patients reported side effects. And so some of it is really that whole um placebo effect of patients thinking they're on something. And as a result expecting to see side effects, they've been educated about. There are strategies. One is switch the type of statin patients on and you can never predict which they'll tolerate. You know, Zukor was traditionally simvastatin was traditionally the mo most likely to produce side effects. I've had patients who have not tolerated Crestor which is uh a statin, but they've tolerated simvastatin and so switch around the statins. Think about co Q 10, think about using alternative therapies and for those that are statin intolerant or at least believe they are at the end of the day. You do have to listen to your patients if they tell you, I just get reasons I can't take it. Ultimately try, try try again and at some point move on and try something else too. Oh, john's question is uh how do you manage third party influence that limits appropriate therapy. And that, that is traditionally a problem for us across the spectrum. Right, john, reading into your question, 30 party influences our, our insurance companies, write our insurance companies sometimes they're really frustrating to work with and in this era to me it's gotten a lot worse. I don't know you guys, I'm doing a ton more pre ops and I don't mind preauthorize anything cause I'm ready to defend any decision I make, It was interesting the other day, in the middle of a super busy over big clinic that day, a patient who I actually hadn't ordered a stress test on, but I agreed with the stress test, I was asked to do an urgent call to um to get um to get um to get a patient approved for a stress test at 11 a.m. That day. So at nine I started calling and my A. P. P. Was out of the office. So we switched two of her patients over a double over books for me in that time period. And I burned 20 minutes talking to a super low level person on the phone. Um It's funny they're asking me to call and she wants all this information like the D. E. A. Or the N. P. I. Number for the A. P. P. Who prescribed the stress test. And I'm thinking you guys have all that stuff. I mean I don't know they're N. P. I. Numbers I barely know my N. P. I. Number and after 20 minutes I couldn't get the physician on the phone and they said it would be another 15 minutes. And I had three patients stacked waiting. So I told him have him call me. So guess what didn't happen even with my cell phone they didn't call. We had to reschedule that test to another day. And I called them at the end of friday and tortured them. Um Once I was done seeing patients but insurance companies sometimes are making our lives somewhat difficult now. Again they have to be cost conscious and so forth. I think the best we can do is work together to get to the right place. Some of these are expensive therapies. We should start with generic therapies that step one step two is we do have industry partners that often make copay assistance programs available. Getting our staff doesn't have time a lot of times to do that. But getting the patient to help and make phone calls, doing things like that whenever we can, utilizing resources available to us often gets a patient there and then if you do get frustrated you have two other options. One is use resources like the lipid clinic. Um We're trying to staff up to try to get help on this. There's a lot of work that still has to be done because we don't live in an era where there's an hour someone can spend to try to get patients on therapy but also remember this Coverage continually is a changing phenomenon, patients change insurance plans like we change outfits sometimes right every year it's a different plan. And so if in 2021 you had difficulty getting someone on therapy, try again in 2022 and then in 2023 and eventually we'll get patients there john brushes asking can you comment on the reducing controversy? Some people say the placebo was actually actively harmful. This is really interesting and I probably don't have time to do this topic justice john you've obviously read into the data really really well. Um So let me just take a half step back and talk about. Um just E. P. A. And D. H. A. Therapies in general those of you that that have patients bring you in a news article. There are like two topics that are the most common articles patient brings patients bring Us right. One is um well 331 is class or other anticoagulants and why they maybe shouldn't be on aspirin Plavix or anything else. And it's always the patient that has 11 stents that brings in the article saying you know they can stop Plavix early or don't need aspirin anymore. So patients don't have good insight into which category they fall in when like a primary prevention group is called out. The second one is eggs and chocolate and coffee. Those ones every other month there's an article that says helpful, harmful, helpful harmful and then the same thing with fish oil. Uh Many of you remember probably two years ago the pilot, the virginian pilot and a bunch of groups were carrying a slight misinterpretation of a new England Journal article that was a poorly done article suggesting an increase in the diagnosis of prostate cancer in patients on fish oil. First of all it wasn't patients on fish oil it was patients with higher blood levels of fish oil. And it was a retrospective claims analysis looking at patients diagnosed with prostate cancer which is very different from causing prostate cancer but all that gets lost in the study in the you know in the in the one line headline. So many of you, there are 30 studies that have looked at prostate cancer and fish oil. Only five studies have actually looked at death from prostate cancer which is hard endpoint. That actually matters. All five of those studies found if anything neutral or reduced endpoints. But if you look at the totality of data, it's very confusing and in the same way in the reduce the trials are with a lot of controversy. Now the thing that gives me a little bit of um a little bit of I guess comfort with that study is that it mirrors the earlier jealous trial J. E. L. I. S. Which also showed with E. P. A specific therapies and benefit. Um the comparator arm in the reduce it trial and again, it was a pretty broad trial platform um that that that comparator arm performed at a different level than we we traditionally see. So that's kind of my short version of that answer, john I know it's hard for you to add anything, but if you have any other thoughts, I'd love to hear what you thought after hearing that. It is always disturbing though, when you see the placebo group actually does worse than normal comparator because that does make you wonder what's going on. Hopefully both arms would mirror that if it's a truly well randomized trial, but that's why the fish oil arena remains a difficult arena to completely understand that being said the most recent H. A. A. C. C. Guidelines 2021 22 that specifically have an algorithm that I didn't include on triglycerides. If their triglycerides are about 500 it's unequivocal you have to treat with aggressive therapies and use everything in the spectrum. What's messy about triglycerides is we had therapies including niacin and we have therapies including fiber rates. And ultimately when we did trials comparing on statin treated patients with both those therapies we failed to find reductions in hard end points. And so that started casting the whole triglyceride mechanism of action for reducing cardiovascular events into some doubt. And then official controversies on all the studies If you look at the totality of data has made that difficult. I've gone on and on and and and the guidelines do suggest that if a patient has triglycerides especially a diabetic or patient with atherosclerotic cardiovascular disease with triglyceride levels of 1 35 to 4 99 that group that were less certain of among your therapy's definitely get them on a statin definitely think about LDL reduction and then potentially think about E. P. A heavy Omega three john if you're if you if you want to type in any additional comments or thoughts you have. Please do so and if anyone else has questions we're approaching the end of the hour Published January 23, 2023 Created by Related Presenters Deepak Talreja, M.D. Sentara Cardiology Specialists View full profile
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