The Evolving Role of Nonstatin Medication in the Management of Hypercholesterolemia

Hello, my name is Joseph Saseen. I’m Professor and Vice Chair at the University of Colorado Department of Clinical Pharmacy and Family Medicine. I’m happy to be here presenting Nonstatin Medications: Their Role in the Evidence-Based Treatment of Dyslipidemia. Treatment of dyslipidemia has been a particular passion of mine. In my current role as President of the National Lipid Association, I’m very engaged in educational programs that discuss lipid management and we do have some new innovations in nonstatin medications that are the focus of today’s presentation. I have no financial disclosures. The three objectives that I have for today are first to describe guidelines and other expert recommendations that talk to the use of nonstatin therapy for the management of dyslipidemia. We’ll also examine results from cardiovascular outcome trials, evaluating nonstatin therapies, and lastly, review the mechanisms of action efficacy, safety profiles for new and novel LDL-cholesterol lowering medications. Let’s talk about our guidelines. So in 2018, the American Heart Association, in collaboration with the American College of Cardiology, teamed up with ten different partner organizations, of which the National Lipid Association, the American Pharmacists Association are one of these. I was fortunate enough to be the representative from the American Pharmacists Association on this guideline writing committee, and we published guidelines in 2018. They were actually officially in press in 2019 about management of blood cholesterol. Typical evidence-based guidelines should have a rating scale for recommendations, and those used by AHA/ACC have a class of recommendation which is either a class I, IIa or IIb, and then some class III, which are things not to do. And class I is the strongest, meaning that there’s the highest confident that benefits outweighs risk in contrast to a class IIa which is moderate, and then a class IIb which is weak, then they’re also coupled with the level of evidence which really is A, B or C, which implies A being the highest level of evidence and C being sometimes expert opinion. It’s important to know the recommendations, but also know how they’re classified and what the level of evidence is supporting that. The first concept I want to actually share with you, though, is the concept that lower is better, related to LDL cholesterol. Now, even though we do have other lipoproteins which have a strong relationship where we reduce them, they reduce or are associated with fewer cardiovascular events. What we have a large amount of data with is the relationship between LDL cholesterol lowering and cardiovascular event lowering from a major outcome trials that used statin therapies. We see these in statin versus placebo, and even in clinical trials that looked at high intensity statin versus moderate or lower intensity statin therapy. And based on all these trials together from the cholesterol treatment trials meta-analyses, we see this very strong relationship that for every mmol reduction we have in LDL cholesterol, there’s about a 22% risk reduction in cardiovascular events. So that concept is the further we treat LDL, or lower it with drug therapy in at-risk patients, the more benefit we get from a cardiovascular event reduction perspective. The guidelines have ten messages right in the beginning of the guideline. They start off with lifestyle modifications as the anchor or the cornerstone to treatment go all the way down to assessing therapy. This is sort of a summary slide for you to appreciate and to take home, but I want to dive into some of the most salient points of this guideline and other recommendations We have to start off with lifestyle modifications, and I do need to emphasize that nutrition and diet coupled with exercise and physical activity and then weight loss for those who are overweight or obese, is an important cornerstone for both prevention and treatment of cardiovascular disease and in particular, lipid disorders. There are specific recommendations here, such as avoiding trans fats and reducing saturated fats and increasing physical activity. This is something that we should never forget and always emphasize in our patient populations. But when we dive into the guidelines, I want to clarify some terminology. The overarching goal is to reduce cardiovascular events, but if we’re looking at surrogate goals in this guideline, it really we don’t have that exact number, we have this concept that there’s a percent reduction, that when we have a recommendation, use high intensity statin therapy, that the coupled goal is to reduce LDL cholesterol by at least 50% because that is the potency that is associated with high intensity. We do also have thresholds which are specific LDL values. They’re not necessarily treatment goals, but there are thresholds at which a clinician should consider intensifying LDL lowering therapy. Starting off with statins, and then if that is maximized to go to the nonstatin therapies in certain situations. Let’s talk about the four statin benefit groups. These were introduced in the 2013 ACC/AHA Cholesterol guidelines and they still are present in the 2018 guidelines. We have secondary prevention patients and primary prevention patients where are considered proven benefit groups, where evidence supports statin based therapy. If we first talk about clinical ASCVD which defines secondary prevention patients, those with coronary disease, ischemic carotid disease such as ischemic stroke or TIAs or even peripheral arterial disease, that is the population that we call secondary prevention with clinical ASCVD, and the treatment algorithm is listed here. For secondary prevention patients, after lifestyle modifications, the question for the clinicians should be, is this person considered very high risk or not? And this is really getting recommendations that are backed by specific clinical trials evidence. If the answer is no, that they’re not very high risk, but they do have clinical ASCVD, follow the left of the algorithm here, which really is promoting statin based therapy, high intensity statin therapy, maximized to achieve at least a 50% reduction, and then if LDL cholesterol is not less than 70 milligrams per deciliter, to consider either maximizing that statin or adding ezetimibe. On the right are for patients who are very high risk, which I’ll share with you what that is on the next slide, but we still start off with high intensity statin therapy. We still maximize to achieve a 50% reduction and an LDL of less than 70. If not, we’re not at that threshold, then we intensify and the nonstatins that are recommended here is ezetimibe, and then we see a recommendation for PCSK9 inhibitors based on clinical judgment and the evidence supporting their use. So what is very high risk ASCVD? It’s patients who present with more than one form of major ASCVD events in their past, such as a recent coronary artery disease, acute coronary syndrome in the past 12 months, a history of prior myocardial infarction, ischemic stroke or symptomatic PAD. So any two of these would be considered very high risk. Then we have patients that just have had one major ASCVD event, maybe just a myocardial infarction. If they have multiple high risk conditions, everything from being age 65 or older, a history of diabetes or hypertension or smoking. There’s other ones listed here like CKD, multiple high risk conditions coupled with just one major vascular event would be considered a very high risk patient, where we would still start with statin therapy, but we would have an option to, with nonstatins, to use ezetimibe and then even a PCSK9 inhibitor. Statins are the cornerstone of a pharmacologic therapy for lipid lowering. The way that statins work, their mechanism of action is very simple. They inhibit HMG-CoA reductase, which is the pathway in our in vivo where we produce cholesterol and statins being HMG-CoA reductase inhibitors are competitive inhibitors of this rate limiting step in cholesterol production, but they also have a secondary mechanism where they increase expression of LDL clearance receptors, which is sort of the second reason why they’re so effective in lowering LDL cholesterol. Not only are we making less cholesterol, but we’re increasing clearance receptors, which further lower LDL in our circulation. Statin intensity is defined by how much LDL lowering is expected with an average patient who is adherent with therapy. High intensity would be a 50% or more reduction in which we only get that with two statins, atorvastatin and rosuvastatin, at the two highest doses. Every other statin at their normal starting dose approved by the FDA is considered moderate intensity, which gives 30 to 49% LDL lowering on average, and this includes all seven of our statins at their normal lowest starting doses. Then we do have low intensity statin therapy, which is lower than recommended starting doses. Perhaps this may be needed for a drug-drug interaction, or for patients that can’t tolerate higher doses. But most of the evidence, nearly all of the evidence, supports high intensity statin therapy or moderate intensity statin therapy, especially in clinical ASCVD. When we look beyond statin therapy, statins are right there in red. Anything in red is primarily an LDL lowering therapy, and anything in yellow is primarily a triglyceride lowering therapy. We see statins are right at the top giving up to 55% reduction depending on which statin we use, and at which dose. But we do have bile acid sequestrants, ezetimibe, and PCSK9 inhibitors currently on the market for treatment. Now what was recently approved was also bempedoic acid, an oral agent which does provide additional LDL cholesterol lowering. And right around the corner is a newer medication called Inclisiran, which is likely to be approved by the FDA at the end of 2020. So let’s talk about some of these nonstatins. First, we have ezetimibe, and ezetimibe really works on a niemann C1-like receptor in the intestine. Ezetimibe simply blocks intestinal absorption of dietary cholesterol. By blocking absorption of dietary cholesterol, we absorb less, so we have lower LDL cholesterol in the circulation, but there also is an increase in LDL clearance receptors which further enhances LDL lowering. With ezetimibe, we typically see a 15 to 20% LDL cholesterol reduction. We do have outcomes data demonstrating that the addition of ezetimibe to statin therapy reduces cardiovascular events in very high risk clinical ASCVD patients. This comes from the IMPROVE-IT trial was a randomized double blind trial in over 18,000 patients, all with a recent ACS and other high cardiovascular risk features, so multiple high risk conditions. These patients were treated with the baseline of simvastatin, but half were randomized to ezetimibe, and half to the addition of placebo. And after 4.9 years, the primary endpoint of cardiovascular events was assessed. Now, of note if we look to the right of results, those treated with simvastatin alone, only 40 milligrams, which is moderate intensity, had an LDL cholesterol of approximately 70. But those with the addition of ezetimibe had LDL cholesterols of about 53 milligrams per deciliter. But the outcome that was demonstrated was cardiovascular event lowering. We see that there was statistically fewer cardiovascular events in an average event rate projected out to seven years in those treated with ezetimibe and simvastatin versus simvastatin alone. This is a small difference. There was a 6% relative risk reduction, though it was statistically significant with a P value .016, not less than 0.01, but .016. And it was a small reduction, but at least it was in a positive direction with this particular trial demonstrating the first nonstatin on top of statin therapy really did provide that evidence. We also have PCSK9 inhibitors and what our PCSK9 inhibitors are proprotein convertase subtilisin/Kexin type 9 inhibitors. And to understand how these drugs work, we need to understand what the role of PCSK9 is in cholesterol regulation. So if you look to the left, what is depicted here is the process. Red is blood and the light blue on the bottom is hepatocyte. So we know that all of our blood goes through our liver, and here we have purple LDL receptors which capture LDL particles from circulation, and pull them into the liver cell. When this is pulled into liver cell by the receptor complex, there’s a clathrin-coated vesicle that’s formed. And this actually eventually gets transformed into an endosomes where the LDL particles broken down and the receptor is released unhithered, where it can go back to the cell surface and repeat this cycle. This actually is our body’s way of regulating LDL cholesterol in the circulation. But what we have on the right here is influence of PCSK9 inhibitors, our PCSK9, I should say, the protein. So what does that protein PCSK9 do? Well, it actually gets in the way with the LDL particle in the receptor that both of them get engulfed and pulled into the hepatocyte. There still is a clathrin-coated vesicle that’s formed, but instead of an endosome, a lysosome is formed, which means not only is the LDL particle broken down, but also the receptor is too. So if you see there’s fewer LDL receptors that go back to the cell surface on the liver to repeat this cycle. So the presence of PCSK9 actually hinders the body’s ability to regulate and lower LDL cholesterol. PCSK9 inhibitors simply are monoclonal antibodies, fully human monoclonal antibodies, that bind up and eliminate PCSK9 from the body. And there are two out there. One is evolocumab, the other one is alirocumab. And evolocumab was the first that was studied in an outcomes trial called the FOURIER trial. This was a randomized double blind trial in over 27,000 patients with ASCVD or secondary prevention patients. And these patients also had high risk features. They had to be on maximally tolerate statin therapy, yet be above the LDL threshold of 70. They also allowed patients to have a threshold using non-HDL of 100 or greater too. For some patients, that was very relevant. These patients on maximally tolerate statin therapy yet still with higher LDL cholesterol were randomized to placebo or evolocumab for 2.2 years. The primary endpoint of cardiovascular events, if you look to the right, was significantly lower with evolocumab. We see a relative risk reduction of 15%. That was highly statistically significant and this is only after 2.2 years. So we see perhaps more bang for our buck in reducing cholesterol compared to ezetimibe, but one thing that we should note is the difference in LDL achieved in this particular trial. Those randomized to placebo had LDL values of approximately 90 versus those with evolocumab had LDL values in the thirties. So a big difference probably explaining if you follow the CTT analysis where lower is better, the more reduction in LDL cholesterol, more cardiovascular event lowering that we see. So that actually sort of proved true in the FOURIER trial. The second outcomes trial that we have with PCSK9 inhibitors is with alirocumab. This is the ODYSSEY Outcomes trial. This, similar to FOURIER, was a randomized double blind trial. It looked at almost 19,000 patients and they were very high risk ASCVD patients because they had a recent ACS event. They also had that inclusion of an LDL threshold of 70 or greater, or a non-HDL threshold of 100 or greater to be eligible for this trial. They also included ApoB, which is another lipoprotein that has a strong relationship with cardiovascular events, just like LDL cholesterol does. These patients also require to be on maximally tolerate statin therapy, and after that, patients were randomized to either addition of placebo or alirocumab for a mean of 2.8 years. And the primary endpoint was major adverse cardiovascular event endpoint, including CHD death, all the way through hospitalization for unstable angina. If we look to the right, very similar to the FOURIER trial, there was a 15% relative risk reduction at a median of 2.8 years, and this was highly statistically significant. So it’s good to see confirmation that with both PCSK9 inhibitors and very high risk ASCVD patients that there was a reduction. If you think about how this is incorporated into our guidelines, this is in particular why for clinically ASCVD patients are considered very high risk, PCSK9 inhibitors after statin therapy is an option. In our guidelines, it does state that patients should be treated with ezetimibe prior to a PCSK9 inhibitor, primarily based on cost, not based on higher efficacy because you get more LDL reduction with the PCSK9 inhibitors. So that is a relevant consideration that the guideline recommends that though the product labeling for these drugs, PCSK9 inhibitors, do not require treatment with ezetimibe before initiation. And these trials didn’t require that either. If we go further into our guidelines, we did talk about secondary prevention, but I want to focus in on primary prevention for the other three statin benefit groups. We have patients with very high LDL cholesterol values, primary prevention diabetes patients, and then other primary prevention patients. If we go to the guidelines, we see a second algorithm, a primary prevention algorithm, and this applies and gives us guidance on how to treat these patients. But the very first statin benefit group that’s in primary prevention are those with LDL cholesterol of 190 or greater at baseline, meaning off of statin therapy. Now, you don’t even need to do a risk assessment with a ten year pooled cohort equation, you go right to treatment in this population because these are patients that have a lot of cholesterol in their system and a high risk of developing cardiovascular events. What is recommended here is high intensity statin therapy, and this is a class I recommendation, just like high intensity statin therapy was for clinical ASCVD based on high confidence that benefit outweighs risk. But now we see further recommendations and this is where the I’ve shared with you thus far, sort of high level recommendations, but I’m going to share some other ones with you, which are either monitor or weaker recommendations and this is only for that primary prevention LDL of 190 or greater baseline group, knowing that they’re high risk for heart disease, a statin alone might not do it. And if you think of LDL of 190 or greater, some of these patients may present with an LDL cholesterol of 300, and even despite high intensity statin therapy, they may get a 50% reduction and may still have a lot of cholesterol in their system. So the recommendations here, we see recommendations where ezetimibe is probably the strongest nonstatin, as far as evidence in this population, but we also see that for some patients, a bile acid sequestrant. a PCSK9 inhibitor may be an option. We see different rankings for the class of recommendation and level of evidence, but this is a population that often needs therapy beyond maximally tolerated statin therapy simply because of their high burden of LDL cholesterol. Bile acid sequestrants are considered a nonstatin drug. They work in the gut, they are not systemic agents, so bile acid sequestrants are not absorbed, but they’re ingested as powders or pills where they decrease bile acid pooling in the liver. This actually decreased intrahepatic cholesterol pooling causes two things to happen, what is a compensatory response where our our body tries to make more cholesterol by stimulating HMG core reductase, but the predominant effect here really is an increase in LDL clearance receptors, which results in a net reduction of LDL cholesterol, comparable to what we see with ezetimibe of approximately 15 to 20% on average for most patients. Now, with these medications because they bind up bile acids and are excreted in the feces, as a bound up product, GI complaints are common. Everything from constipation to dyspepsia to bloating. There’s also a potential for drug-drug interactions because in addition to binding bile acids, these products may also bind up other prescription medications or over the counter medications. There is one cardiovascular event reduction trial. It’s a very old one. It’s called the LRC-Primary Prevention Trial, and it demonstrated a 19% reduction in fatal CHD or nonfatal MI, in primarily men, who are treated with cholestyramine after multiple years. So historically, back in time, there’s one outcome study that shows as an addition, maybe it has some value. But GI complaints and tolerability and difficult use is the biggest complicating factor for this particular drug class. If we go back to the primary prevention algorithm, we’ve talked now about secondary prevention and very high LDL as a baseline as far as two or four statin benefit groups, but what’s number three? Number three are our patients with diabetes. And in particular, we have strong evidence when they’re between the ages of 40 and 75, a class I recommendation to use at least moderate intensity statin therapy. And in your patients based on a class IIa recommendation, which is a moderate recommendation, if they are deemed to be higher risk for cardiovascular events, higher than an average patient with diabetes, then we have the option to use high intensity statin therapy as a replacement. Some other recommendations that we have for primary prevention diabetes patients is really, you know, when we do have higher risk, such as multiple ASCVD risk factors, that’s why we may step it up to high intensity and really try to aim to reduce LDL cholesterol by at least 50%. So perhaps treating them like the first two statin benefit groups that I spoke of. There’s also recommendation for patients that are older than the age of 75. It’s a moderate recommendation, but you can continue therapy under that circumstance. There’s many more recommendations based on age if you dive into the guidelines. But there also is a recommendation here for patients when they have higher risk scores that, in addition to maximally tolerated statin therapy, specifically identifying ezetimibe as being valuable in this population. So again, we see other mentions beyond statins of nonstatins that may have value in controlling cardiovascular risk by lowering LDL cholesterol in patients with hypercholesterolemia, in particular here, primary prevention diabetes patients. So we can’t leave this primary prevention algorithm without talking about the biggest primary prevention group, which is not those with high LDL as a baseline of 190 or greater, not those with diabetes, but basically everybody else. So this is the the bulk of our primary prevention population and I do want to emphasize, particularly for this group, and it applies to all the groups that want to assess ASCVD risk, particularly in this group, and emphasize healthy lifestyle as a cornerstone of treatment and prevention. But you may have some patients who are under the age of 20, and if there is a diagnosis of familial hypercholesterolemia, maybe we would treat them with statin therapy, but we’re not going to treat many people under the age of 20 unless they have that FH, or familial hypercholesterolemia diagnosis. Still, looking at that end of the age spectrum, patients age 20 to 39, it’s very important this population to calculate their risk of ASCVD, but we can’t do a ten year calculation because they’re too young. We can only calculate if they’re age 40 or greater. But what is recommended is to calculate their lifetime risk for ASCVD to really promote healthy lifestyles, for preventing disease. Now, some of these patients may be treated with a statin if they have a very strong cardiovascular risk factors such as a primary relative, being a sibling or parent, that has a history of premature ASCVD, we might treat them. Or if they have LDLs that aren’t quite 190 or greater, but in the higher end, like 160, 189, maybe we treat them, but absent that, most of those patients, we don’t have the strongest data. We do have very strong data in patients age 40 to 75 who have LDLs between 70 and 189, without diabetes. And here’s where the ten year pool cohort equation is strongly recommended to risk stratify patients. If patients, based on their ten year ASCVD risk score, score low, meaning that it’s less than 5%, they’re considered low risk. And what’s recommended is a class I recommendation to emphasize lifestyle modifications under this circumstance. Conversely, all the way to the right, if you have a patient age 40 to 75 and you do their ten year risk calculation and they score out as 20% or higher, they are defined as high risk for future ASCVD events. We treat them like our other population and what is recommended is high intensity statin therapy to reduce LDL cholesterol by at least 50%, and that’s a class I recommendation. Going on the concept here that you have to have a lot of other things ongoing to score 20% or higher, and if you don’t have diabetes, right? So uncontrolled hypertension, really low HDL, smoking, perhaps, or maybe it’s higher end of the range, so we treat them more aggressively. But right in the middle is sort of the conundrum, the harder to manage population, because we have to think a little further. These are patients that are borderline risk or intermediate risk, borderline 5 to 7.4% ten year risk and intermediate is 7.5 to 19.9. Now, in that intermediate risk, we do have a class I recommendation, so most of our primary prevention statin based trials had patients that had intermediate risk or so. And what’s recommended here is after risk discussion with your patient and looking for risk enhancing factors, with your clinical judgment, if it favors treatment, what’s recommended? It favors treatment is to use moderate intensity statin therapy to achieve an LDL reduction of 30 to 49%. Borderline risk patients, we just don’t have as much data there. They may be candidates for moderate intensity statin therapy based on the same risk assessment and evaluating risk enhancing factors, but we don’t have as much data, so it’s considered a weak IIb recommendation and that’s why it’s in orange. Now, something I do want to mention that in this population, even after evaluating risk and having a risk discussion with your patient, you may be unclear whether to treat or not. And there may be a good reason here to go with the recommendation to consider measuring coronary artery calcium to add an additional element to your risk discussion that would favor statin therapy if there were known calcification seen when you measure for coronary artery calcium. Now, I don’t want to go too far into elderly patients, but I do want to mention that there are some recommendations for patients who are aged greater than 75 years of age. There is not the highest level of recommendation for them, but based on a patient presentation you may treat or you may not treat, I would refer you to read the core guidelines for more information on that population. But I mentioned risk enhancing factors which are important to evaluate in your intermediate risk or your borderline risk patients. So ten year risk scores of 5 to 19.9. What the deal here is, we don’t know 100% which patient should be treated with statin therapy, you have to use your judgment, if they’re in the higher end of that range, may be go for it, right? With confidence. If they’re in the lower end of the range, look for risk enhancing factors. These are things that we know increased risk of cardiovascular disease, but they’re not part of the pooled cohort equation. And this is where I think it’s a very value added feature in the newer guidelines. So family history of premature ASCVD in a primary relative, maybe having LDL cholesterol is near the higher end of that range, metabolic syndrome. I really like seeing things like CKD, chronic inflammatory conditions, like rheumatoid arthritis, lupus or HIV or premature menopause, other pregnancy associated complications, because we know that these increase risk of future cardiovascular events, so they’re incorporated in the guidelines as risk enhancing factors. Also some high risk ethnicities like South Asian patients. So if these are present, multiple or maybe even one solitary risk enhancing factor, it gives you more confidence in your borderline or intermediate risk patient to really treat with statin therapy, because we know that their risk is probably higher than their predicted or calculated ten year ASCVD risk number. There’s some other risk enhancing factors and not part of the history. They’re lipid/biomarkers. It could be selective in some of these, but persistently elevated primary hypertriglyceridemia not even that high, 175 or greater, more than one measurement. They recommend at least three measurements that would be a risk enhancing factor and then if you do actually do advanced lipid testing, maybe you look at a C-reactive protein level that’s elevated, an Lp(a) level that’s elevated also risk enhancing factor, as is ApoB or ankle brachial index in the absence of PAD symptoms, that’s less than 0.9 would also be considered risk enhancing. Beyond LDL lowering, which is where we see most of our nonstatin medications, we have to think of high triglycerides and with hypertriglyceridemia there are some specific recommendations in the 2018 guidelines. One is to rule out secondary causes of high triglycerides. Another is perhaps if patients have a ten year risk or 7.5 or greater to not use a triglyceride lowering drug, but maybe still use a statin because of the cardiovascular benefits. But we do also see a recommendation especially in very high triglycerides of 1000 or greater, where we’re trying to prevent pancreatitis, a recommendation for using a omega-3 fatty acids or fibrates. So this is where we still see some nonstatin drugs beyond LDL to treat hypertriglyceridemia. And omega-3 fatty acids are very interesting. Their mechanism of action is sort of vague. We don’t 100% know, but we know that it has to do with the liver and anything with a blue arrow going up or down is the proposed mechanism for omega-3 fatty acids. Perhaps these medications decrease lipid production in the liver, they may increase beta oxidation, they may decrease triglyceride production directly or decrease ApoB production directly or or even stimulate lipoprotein lipase. And all these mechanisms which are proposed overall result in a lowering of triglycerides with omega-3 fatty acid therapy. Now, I do want to clarify that there’s different types of omega-3 fatty acids. There are two prescription products. One is omega-3 acid ethyl esters that contain both EPA and DHA, two of the three omega-3 fatty acids which lower triglycerides. And then there’s icosapent ethyl, a prescription only product which contains only EPA, no DHA. They’re both dosed the same way, they both need to be taken with food. Now, one difference between omega-3 acid ethyl esters, which is one prescription product, and icosapent ethyl, the second product, really relates to the lack of DHA. We do know that when you look at LDL changes that omega-3 fatty acid products that contain DHA may increase LDL, where icosapent ethyl being EPA only, does not. There are over-the-counter fish oil products which may contain some omega-3 fatty acids, but these are unregulated products, are not considered drugs, so there are those uncertainties ... I know that a lot of patients may use omega-3 fatty acids as a replacement for omega-3 fatty acid prescription medications, but that’s an unregulated practice, though it does occur, and it really is because of cost. But the over-the-counter fish oil products, the omega-3 fatty acids they contain are a mixture of both EPA and DHA, just not a high concentration that we see in the prescription products. These prescription products, the first two listed up here are approved by the FDA to treat very high triglycerides defined as 500 or greater as a strategy to reduce the risk of pancreatitis. One of them, though, icosapent ethyl, the EPA only product, which does not raise LDL at all, is also approved to reduce the risk ASCVD events in patients with triglycerides that are between 150 and 499 and it’s in certain patients. And the patients that it’s improved in are because of the REDUCE-IT trial, secondary prevention patients and certain primary prevention and diabetes patients. While the REDUCE-IT trial is the reason we had that indication for icosapent ethyl and what was the REDUCE-IT trial? It was a randomized, double-blind trial in over 8,000 patients that had either secondary prevention ASCVD or primary prevention diabetes with other cardiovascular risk factors. Now these patients, as far as an inclusion, they had to have a fasting triglyceride value between 135 and 499, so in that elevated range, not very high, but elevated range. And they also had to have what I call somewhat controlled LDL cholesterol. The median was 75, but the range was 41 to 100. Now these patients, being on statin therapy to get their LDL controlled, randomized to icosapent ethyl at the full dose of four grams a day or placebo for 4.9 years. If you look at the primary endpoint of study on the right, there was a statistically significant large difference in cardiovascular events with those treated with icosapent ethyl versus placebo. And we see that this is highly significant and the relative risk reduction was 25%. The number needed to treat was actually quite low because that difference, that net difference, is quite large between the two lines there, the red line and the blue line or the number to treat is in the twenties for the primary endpoint. So an outcomes trial supporting omega-3 fatty acids in patients not with triglycerides above 500, but in that lower range, the FDA labeled it between 150 and 499 only in ASCVD patients or diabetes primary prevention patients with other risk factors who were already treated with statin therapy, get that LDL between 41 and 100 and I might want that LDL lower in a lot of those patients, right? But at least we have positive outcomes data, based on this trial with icosapent ethyl. This REDUCE-IT trial got a lot of traction. Not only did the FDA approve an indication for cardiovascular event lowering, but the American Diabetes Association, the European Society of Cardiology and the National Lipid Association all have statements that endorsed the the addition of icosapent ethyl to statin therapy in patients who are clinically ASCVD or primary prevention diabetes patients. There’s some differences in their position statements on how they recommend these drugs, but most of them really revolve around the inclusion criteria for that REDUCE-IT trial. So we see a very literal application of evidence to statements, and that’s important. Why is this not included in the 2018 guidelines? It’s because it was published after the 2018 guidelines were already finalized. So there wasn’t that opportunity to add it to that guideline recommendation, even though it was officially published in 2019, it was released in 2018. So that’s simply the reason why this is not commented on in those AHA/HCC Multi Society 2018 Cholesterol Guidelines. Now I do want to talk about a new nonstatin agent. It’s called bempedoic acid. So this is a new novel agent, it’s a citrate lyase inhibitor. It was approved in February of 2018 as an adjunct to diet to maximally tolerate statin therapy but only in two populations and those with heterozygous familial hypercholesterolemia, and most of those people are going to have LDLs of 190 or greater, so they may fit that statin benefit group, or those with established ASCVD who need additional LDL lowering. Now this drug works in the liver, so bempedoic acid actually, it is converted in the liver via very long chain acyl CoA synthetase, an enzyme. It’s converted to the active form of bempedoic acid. And this basically, the active form inhibits ATP citrate lyase, which is the precursor to the HMG-CoA reductase pathway. So you’re inhibiting that pathway to very high level, or a very early phase. What do we know about bempedoic acid? It is dosed once daily 180 milligrams with or without food. And if you look at the LDL reduction, it’s sort of variable. If you go to the package insert, it says about 15 to 17%, and that’s really based on the CLEAR Serenity trial, which was in addition to statin therapy, but when you use this monotherapy, which is not really its labeled indication, you want to use with statin therapy, you may get a little bit more efficacy up into the lower 220s perhaps, based on a few other CLEAR Harmony and CLEAR Tranquility studies. Some things we know about this drug. It’s a novel agent, so I always want to very clearly look at the side effect profile. There is an increase in uric acid, so about 0.8 milligrams per deciliter, which may be problematic in some patients with a history of gout. There’s been reports of tendon rupture and some other reports of other things. We see this often with newer drugs, but we need to keep our eye on this and get some post-marketing surveillance data to confirm whether these side effects sort of are bigger or smaller than what originally depicted. There are some drug-drug interactions with simvastatin and pravastatin, where we can still use those drugs but have a restricted maximum dose. And of note, it will be nice to have clear outcomes with this study, with this drug, which in CLEAR Outcomes is the study that’s evaluating cardiovascular event lowering with the addition of bempedoic acid to statin therapy. We also have a inclisiran, which is not yet approved, but inclisiran is a very interesting drug. It is sort of think of it as genetic therapy. It’s a synthetic double stranded 21-23mer oligonucleotide. So this oligonucleotides actually inhibit things, and on this oligonucleotide, we had the GalNAc sort of end to this which results in this particular drug getting pulled into hepatic-specific uptake into the liver where is pharmacologically active and what it does there. it’s chemically modified, this inclisiran product, to prevent what’s called RNAse degradation, so an enzymatic process where you normally would break down RNAse, this drug looks like an RNA because it’s a modified oligonucleotide, but when it does that, when it works, there’s a dicer that separates the antisense strand of this inclisiran product and incorporates into what’s called the RISC, the RISC, which is an RNA induced silencing complex. It’s important that we have this oligonucleotide that can go into liver that’s modified to not get broken down by typical RNA enzymes that break down these things, and that it separates it where it’s active in that RISC area because what RISC does is it degradates PCSK9 mRNA. So when you degradate PCSK9 mRNA, your body doesn’t make PCSK9 and that’s how this drug works. Genetically engineered to decrease in vivo production of that protein. So if we get rid of it that way, it’s in a way sort of like a monoclonal antibody, like a PCSk9 inhibitor, but we’re just not making that protein, which is nice. This drug inclisiran is submitted for FDA approval for secondary prevention patients and also for those with familial hypercholesterolemia. It is submitted as a subcutaneous product given initially that it’s three months and then every six months thereafter. There’s been a series of LDL lowering studies looking at the, called the ORION-9, 10, and 11 which looked at LDL lowering. And in heterozygous FH patients, there’s approximately 40% LDL lowering, but for those with ASCVD or high risk status, it’s approximately 50% lower. And this is a drug that’s administered once it’s already built up in your body with the initial dose, and then three months, every six months, there’s an ongoing outcomes trial called ORION-4, so we’ll know whether the use of this drug in combination with statin therapy, perhaps in some patients, and then without in others, we’ll know whether it further reduces cardiovascular events and what this study is supposed to be completed in 2024, but it’s nice that it’s planned for just, like the CLEAR Outcomes trial is for bempedoic acid. I do want to leave you with some other recommendations. These are class I recommendations with good levels of evidence. We’ve talked a lot about statin medications and nonstatin drugs. We know that statins are the cornerstone because they’re proven so well to reduce cardiovascular events. But what is also recommended are strategies for implementation of the guidelines and recommendations, things such as pharmacist-led interventions that can improve adherence are strongly recommended, in addition to other multi-modal strategies. There’s also recommendation for clinicians and health systems to identify patients who need guideline directed medical therapy and to implement that therapy. And at the end here, what is recommended is common sense, and it really is before you prescribe a medicine to have that patient clinician discussion to promote shared decision making, so if you get your patient’s buying in agreement early on before they start their medicine, there’s a higher likelihood that they will be adherent with their medicine and their treatment regimen, lifelong. So in conclusion, what I’d like to sort of summarize is first, evidence-based guidelines and other expert recommendations, in general, really reserve the use of nonstatins to patients who are already on maximally tolerated statin therapy. Maximally tolerated could be the highest dose or the highest dose that they can tolerate. There may be some patients that are statin intolerant and their maximally tolerated dose is zero. But after statin therapy is when we have all the guideline recommendations identifying when to consider a nonstatin drug for LDL lowering. Secondly, we do have outcomes data with some of our nonstatin drugs. Ezetimibe and PCSK9 inhibitors and icosapent ethyl for patients who are higher risk, whether it be very high risk ASCVD patients for the case of ezetimibe or PCSK9 inhibitors or secondary prevention patients and also primary prevention diabetes patients for icosapent ethyl. So we have more than just theory, we have proof in those populations. And lastly, we do have some novel agents, bempedoic acid and inclisiran that are focused on LDL lowering, and they have a unique mechanism of action that may add to our armamentarium of agents to reduce cardiovascular risk and events in patients with lipid disorders. So thank you very much for your attention and I hope that you learned a lot from this presentation.