Reducing Cardiovascular Risk in the Patient with Elevated Triglycerides

Hello, my name is Dr. Alan Brown. I’m Director of the Division of Cardiology and the Lipid Clinic at Advocate Lutheran General Hospital in Park Ridge, Illinois, and Clinical Associate Professor of Medicine in Cardiology at Loyola University Medical Center in Maywood, Illinois. Today, we’re going to be discussing reduced cardiovascular risk in a patient with elevated triglycerides. My disclosures include the following: I’m a speaker for Amgen, Regeneron and Sanofi and have participated in advisory boards for Amarin, Kastle, Kowa, Pfizer, and Sanofi. The objectives of today’s presentation are to understand the effect of hypertriglyceridemia on their risk of coronary atherosclerosis, to review treatment strategies to reduce the risk of pancreatitis as well as CHD events, and then discuss appropriate therapies and some clinical trials that are underway to further elucidate the data on risk and treatment of hypertriglyceridemia. So over the past many years there’s been a focus on LDL cholesterol as the primary goal of therapy and starting back in the mid-eighties, we found out that treating lipids, even in those days with the bile acid resin, showed a reduction in cardiovascular events commensurate with the degree of reduction in LDL cholesterol or total cholesterol. And over the decades, there have been many more clinical trials, some of which are listed on this slide, each one showing that with more intensive lowering of LDL, we continue to see a reduction in cardiovascular risk. As many of you know, in 2013, the American College of Cardiology and American Heart Association published a new set of guidelines that looked at prospective randomized clinical trials that had been done in the statin era and tried to answer the question, ‘should there be a target number below which we should treat for LDL cholesterol, and should there be a target number below which we should treat for non-HDL cholesterol?’ I’m sure you all know that non-HDL is total cholesterol minus HDL. That’s an attempt to measure all anthropogenic particles, not just LDL cholesterol, and has been shown to be a better risk predictor for cardiovascular events than LDL alone, particularly in people with elevated triglycerides, so it’s a very pertinent concept of what we’re going to be talking about today. And as you all are aware, when they embarked on reviewing clinical trials that were prospective, randomized and good scientific data and also reviewing well done meta analyzes that had been performed in the past ten years, they were unable to identify an appropriate target number for LDL or non-HDL, and one of the reasons they couldn’t come up with a target that they could hang their hat on and recommend to the physicians was because the way the clinical trials had been designed, patients were enrolled with a variety of LDL numbers at baseline, and when they were placed on treatment, they had reached an average a lower LDL cholesterol, but the individual patients had a wide spread of LDL levels, even on treatment. So you might imagine that if you’re trying to do a clinical trial to determine what a target for LDL or non-HDL would be, you would have to treat one group and adjust their medication to get them all to a particular number, let’s say an LDL of 90. And then on treatment, the more intensive group, you’d have to treat and adjust their medicines to get them all to an LDL of approximately 70. If you did that, you could say that 70 is a better target LDL than 90, as long as the study showed an improvement in clinical outcomes. On the other hand, when there’s a wide splay of LDL levels, both at baseline and at treatment and when the intervention was using, for example, ten milligrams of atorvastatin versus 80 milligrams of atorvastatin, all they could say was that 80 milligrams was better than ten milligrams, but they were unable to come up with a target number for LDL and unable to say what the incremental value is of reaching a lower number of LDL versus the higher number. So with that lengthy introduction, you all realized that the guidelines recommended using the right dose of statin, not treat to a particular number and to use that in the patients with appropriate risk and based on the trials that they had in front of them to review. As you all know, they showed that patients who are at high risk with established atherosclerosis, diabetes, recent acute coronary syndrome, for example, should be treated with high dose statins because the clinical trials suggested that those that were on high doses of statins did better than those that were on more moderate doses. And when they reviewed primary prevention data - studies that were done in patients without atherosclerosis, but who had at risk factors - those studies suggested that moderate dose statin was better than placebo. So at the end of the day, they said treat the right patient with the right dose of statin based on risk. They were also charged with looking at other lipid lowering agents beyond statins and asking what the relative value was of adding those other lipid lowering agents to statins, and we’re going to talk a little bit about that today because that’s where the issue of hypertriglyceridemia comes in. The consideration of adding additional therapy on top of statins in those patients with low HDL and high triglycerides, and what do we do in that situation? Now, there is some new guidance based on the trials that have come out since the 2013 guidelines, and many of you know that the new class of agents, the PCSK9 antibodies, have been released since the new guidelines were published in 2013, so there needed to be some guidance in the literature as to how to use those drugs, and then the IMROVE-IT trial, which was a trial of placebo plus statin versus ezetimibe plus statin was also published, showing an incremental reduction in cardiovascular risk when adding ezetimibe and that was not directly addressed in the 2013 guidelines. So on the screen is the reference for the 2016 expert consensus decision pathway for the role of non-statin therapies and this, so it’s not a guideline, it is sort of a white paper from the ACC and the National Lipid Association suggesting some guidelines on how to consider adding additional agents on top of statins. And if you read this document, which I encourage you to do, you’ll see that they have given you the option of using numbers again, not just high dose of statin versus moderate dose, but in those patients who are at particularly high risk, you have the optional choice of using an LDL threshold of over 70 in the highest risk patients, meaning that if the LDL is over 70, you could consider adding additional therapy or if the non-HDL is over 100, and then those patients with established CHD, but no other confounding risk factors, you have the option, of course, using the right dose of statin, but if the LDL remains above 100 and you have the option of adding additional therapy, or if the non-HDL remains above 130, you have the option of adding additional therapy. All of these recommendations give you the option again of considering a number not as a target that you have to reach, but as a threshold above which you would add an additional drug. So let’s get to the topic of today’s presentation about hypertriglyceridemia, and I’m going to try and give you some practical ways to think about it. If you look at the broad population of the United States and you try to show that triglycerides are an independent risk factor for cardiovascular disease, it isn’t that clear. In fact, in a broad population, triglycerides themselves don’t seem to be a risk. However, in particular individuals, those with a low HDL and high triglycerides and those with high LDL and high triglycerides, it seems to be a risk factor. So what do I mean by that? Well, this is sort of like the little old man driving in traffic. If you just look at him, he looks very innocent. He’s driving at ten miles an hour. He’s going slow. But he doesn’t seem to be causing any trouble. But when you get up in the helicopter and look at all the traffic, you see that though this man looks innocent when you just look at him, people are crashing all around trying to avoid this little old man. So you really have to look at the milieu of lipids and patients with hypertriglyceridemia to get a better idea of whether it’s a risk factor or not. And in fact, a person who drinks a lot of alcohol, who has high triglycerides and who also has high HDL and relatively low LDL doesn’t seem to have too much increased risk for cardiovascular disease. They’ve got increased risk for death due to a variety of other causes, but not cardiovascular disease. While on the other hand, a patient with metabolic syndrome who has low HDL and high triglycerides may be the highest risk individual that we deal with. So elevated triglycerides are a risk factor when the traffic pattern shows an LDL/HDL ratio of greater than 5. The translation of that is in those patients who have a low HDL or a high LDL, or both, raising triglycerides markedly amplifies their risk for cardiovascular event. And it’s interesting that when trying to look at what is the biggest predictor of risk in those patients with high triglycerides, since looking at triglycerides alone is not so helpful and trying to do some complex ratio is difficult. Either Apo B or non-HDL are both very good predictors of risk in those patients with triglycerides over 200. So so let me summarize for you how to think about it. If the patient’s triglycerides are below 200, LDL is very good predictor of risk for cardiovascular event in most patients, but when the triglycerides are above 200 using non-HDL, in other words, total cholesterol minus HDL or using Apo B or LDL particle number, which is described as LDL-P, any one of those three. In other words, a measure of numbers of particles is a better predictor of risk than looking at LDL or triglycerides alone. So as an important rule of thumb, when you’re considering treating patients with high triglycerides, if the triglycerides are over 500, we’re more concerned about the risk of pancreatitis, and as you know, that risk goes up significantly with triglycerides over a thousand and it only takes one or two beers if your triglycerides are over 500 to get you over a thousand, or just some dietary indiscretions. So over 500 we recommend treat the triglycerides as the primary goal of therapy, using, for example, a fibrate or using omega-3 fatty acids to lower triglycerides. And that’s not to reduce risk of cardiovascular disease primarily, it’s to reduce the risk of pancreatitis. On the other hand, if triglycerides are between 200-499, you want to assess the cardiovascular risk and then you want to address the non-HDL, the Apo B or LDL-P, and we’ll talk about how you might do that. If you think about the math of non-HDL, it’s total cholesterol minus HDL. First of all, you need to understand that the goal for that number is 30 points over whatever your threshold would be for LDL. So if you’ve determined that this is a diabetic patient with coronary disease and you’d like to treat more aggressively if their LDL is over 70, in other words, 70 is your threshold for adding therapy in a patient that’s at extremely high risk, then your non-HDL should be below 100. So the threshold for treating the non-HDL would be 100 or 30 points over whatever your LDL threshold is. And in the same vein, if you had a patient that had stable coronary atherosclerosis where your LDL threshold for treatment would be 100 and you’d add additional therapy to your statin if you were over 100, then you would add additional therapy for a non-HDL over 130. So let’s take a look at what we’re talking about with non-HDL. You can see in this slide that over to the left lower corner of the slide, you have HDL2 and HDL3, very small particles. We don’t believe that HDL is primarily androgenic, but everything to the right of that in this slide, from LDL all the way up to chylomicron remnants, are particles that can participate in atherosclerosis. As you know, LDL is primarily cholesterol, about 98% cholesterol, whereas the intermediate density lipoprotein’s IDL all the way to chylomicron, have significant amount of triglyceride within those particles. So in patients that have metabolic disorders that increase their VLDL or their VLDL remnants or chylomicron remnants, you’re going to see elevated triglycerides in their blood because those particles carry triglycerides. I should point out that dietary fatty acids and cholesterol get into the bloodstream by a particle that’s made in the gut called chylomicrons, whereas the liver makes VLDL. Chylomicron particles themselves are too large to get into the wall of the artery and don’t cause atherosclerosis, but once those particles are in the circulation and in the capillaries where some of the triglycerides are removed and they’re made into chylomicron remnants, those particles are atherogenic. So when we measure triglycerides on a blood test, we’re actually getting a measure of particles that have triglycerides carried within them that are shown in this slide and non-HDL total cholesterol minus HDL, basically removes all those particles. It removes the HDL, which are the non-atherogenic particles, and gives you a measure of all those particles that are atherosclerotic to the right. The reason chylomicron microns are usually not included in that number is because the patient’s been fasting for 12 hours and after a 12 hour fast, the chylomicrons have either been broken down to remnants or cleared from the serum. So let’s talk about non-HDL as an assessment of risk. Remember, the calculation is total cholesterol minus HDL. The non-HDL goal for therapy, where you would not where you would consider adding additional therapy would be if the non-HDL number is 30 points over wherever you’d like to see the LDL number. And the significance of non-HDL, as I mentioned, is it encompasses all known and potential atherogenic lipid particles. It is linearly proportional Apo B, so the nice thing about it is it has no cost. You can calculate it from a standard lipid profile. Apo B is a little bit more accurate, particularly on the upper and lower ranges, and therefore some people would advocate to order an Apo B, which is also not terribly expensive these days. The other measure of particles would be to look at the total number of LDL particles, which is measured called, which is a measurement called LDL-P or LDL-particle number. Any one of these three measures - non-HDL, Apo B or LDL-P - are better predictors of risk in patients with elevated triglycerides than LDL or the triglycerides alone. We talked about the traditional targets going back to ATP III, and these numbers are fairly similar in the new HCC document on the use of non-statins that we don’t call the LDL thresholds goals anymore. We call them thresholds because it’s really not a a goal or a target. We’re not shooting for 70. We’re saying that if the numbers are above 70, we’re going to add additional therapy. We don’t really care exactly where they land, we just want them below these numbers. So the thresholds for the very high risk, as we discussed, would be LDL of 70 or greater, you would add additional therapy. If they have stable coronary disease, 100. If they have risk factors without coronary disease, 130. And of course 0-1 risk factors, traditionally we wanted it below 160 even in patients without other risks. And then you can see that the non-HDL thresholds would be 30 points over the LDL threshold. There’s still a lot of discussion about these numbers and whether appropriate, and I would just point out that you should start with the 2013 recommendations and place patients on the right dose of statin based on their risk. And then when you remeasure their numbers, then these optional thresholds come into play. You might be asking yourself, why would I be starting with a statin in a patient with triglycerides of 350 and a low HDL? And the answer is that in every statin trial, the patients with the low HDLs and high triglycerides, which, as you might guess, are predominantly the metabolic syndrome patients were the ones that had the majority of events, so they were the highest risk group, the metabolic syndrome patients with low HDL and high triglycerides. But in addition to that, they were also the group that got the most benefit from the statin therapy in those trials. So it’s actually the low HDL, high triglyceride patients who had the greatest reduction in cardiovascular events when given statins. That follows a very simple law that the patients at the most risk will always get the most benefit from a therapy that works. So the first thing to remember is that statins should be used based on the patient’s risk, regardless of their numbers and we’ll delve into that just a little bit more. But even with low HDL and high triglycerides, you should start with a statin and a high risk patient, and that will reap rewards in terms of reduction in their events. The second thing to remember is that statin therapy will reduce triglycerides 30, 40, 50%, depending on how high the triglycerides are when you add the statin and also the potency of the statin dose that you use. So it is reasonable to start a statin if the triglycerides are below 500 as the primary therapy and then recheck your numbers and you may be surprised that the triglycerides come down a significant amount. Again, if the triglycerides are over 500, the initial step would be to treat the hypertriglyceridemia with a fibrate, or omega-3 fatty acids followed by the addition of a statin and make that choice of the statin after you see the numbers on the fibrate or the fish oil. And we alluded to particle numbers as a way to assess risk in patients with high triglycerides. And this is just an example of patients that had type 2 diabetes in a large clinical trial whose LDL levels appeared to be fairly well controlled, and then the upper section of the slide, you see that the patients had LDL cholesterol between 70 and 99. And in the lower part of the slide, they were more aggressively treated where their LDL had actually dropped below 70. I guess the most important thing is to see that the particle numbers were still in the high risk range, and the group that had LDL less than 70 and approximately 40% of the patients. So just looking at LDL alone will not be adequate to make sure patients are not undertreated. And in those patients with low HDL and high triglycerides, you’re going to make particular errors if you just focus on LDL. So in this case, one could make the case for looking at LDL particle number and intensifying your therapy with statins to further lower your particle numbers in those patients where the particle number is over 1000 and the other cases that could be made are to do the same approach with non-HDL or Apo B. Whichever one of those three you use, non-HDL, Apo B or LDL-particle number, you’re going to more appropriately treat the higher risk individuals than you will if you just look at LDL as this slide illustrates. Some rules that make it a little easier to assess LDL-particle number if you choose to order that on your patients, are that numbers matter more than size. And what do I mean by that? You know, over many years, we had data suggesting that those patients who had small, dense LDL cholesterol were the higher risk individuals. And then we also knew that those that had higher numbers of particles were at higher risk. So which is better and what should we use? So I’ll try and clarify that for you. It turns out that if I’m holding a bucket of cholesterol and I ask you to take a particle out of that bucket and you see that that particle is small, you can make a pretty good guess that there’s probably a lot of particles in the bucket. The size of the particle is an indirect measurement, or an indirect clue, as to how many particles there are in the circulation. So a patient with small dense particles is highly likely to have too many particles. And in that sense, knowing that the particles are small is helpful in identifying their risk. The problem is that a patient who has too many large particles is also at increased risk. In a classic example of that, as a patient with familial hypercholesterolemia, those patients have poorly functioning LDL receptors, so they have too many LDL particles in the blood, but they’re not small particles. They’re very large particles, and too many of those large LDL particles. And their risk is also remarkably increased, almost 20 fold increased. So in summary, any measure of numbers of particles gives you all the information you need. If you don’t have a measure of numbers of particles, and then finding small, dense particles tells you this is a patient with too many and probably at higher risk. But if you have a measure of particle number and that can be, as I mentioned so many times already, non-HDL, Apo B or LDL-P, then there’s no additional information to be gathered by looking at the sizes of particles. So therefore, I generally recommend assessing particle number by one of those three methodologies rather than focusing on size of particles. The other pearl of wisdom for you is if you’re trying to remember what is a normal number for LDL-particle number, just to add a zero to your threshold for LDL. So if you had a very high risk patient where you felt you were going to add therapy above an LDL cholesterol of 70, then the corresponding LDL-particle number would be 700. If your threshold for LDL in this particular individual patient was 100, then your threshold for considering adding therapy for LDL-particle number would be 1000. And we don’t have any established guideline targets for any of these numbers other than some recommendations. And then in the new consensus document for non-HDL and LDL cholesterol. But we do have some softer recommendations. This is from an article in Diabetes Care in 2008 that gives us some guidance as to what we might consider appropriate thresholds for Apo B that would stimulate us to add additional therapy. And we’ve talked a little bit about how to assess non-HDL, how to assess LDL-particle number, and I wanted to give you some guidance in terms of what you might consider for Apo B if you’re a person who wants to use Apo B as your risk assessment tool. So the highest risk patients you would use less than 80 as a threshold for adding additional therapy for Apo B. And those patients who are high risk but not at the highest risk, for example, stable atherosclerosis, you would use an Apo B of less than 90 and this was a recommendation again that was published in Diabetes Care from the American Diabetes Association/ACC Consensus Statement. Okay. I’m going to shift gears for the last few minutes here about choice of therapy, and I want to try to give you the background information, why we’re so focused on statins. So going back many, many years into the seventies, we did a study with nicotinic acid or niacin compared to placebo in almost 8400 men who had established coronary disease and dyslipidemia. This study included a clofibrate arm, which, as you know, you know, was not good for patients, so that portion of the study was discontinued and it even included an estrogen there, but the men had intolerable side effects. So estrogen was not considered as a viable treatment for men. So keep in mind, this was before the statin era. So it was niacin versus placebo in people with this in men who had established coronary disease and previous myocardial infarction. There were approximately 2789 patients treated with placebo, and then the niacin group, 1119 patients. And the primary end point was total mortality. So after the first five years of the study, which was the completion of the study, there was no difference in mortality or all cause mortality in this patient. However, there was a reduction in recurrent nonfatal heart attack, which was statistically significant with a P of less than 0.04, so there was a 27% reduction in non-fatal heart attack in patients who received niacin versus placebo. And after the study follow up was extended up to nine years, there actually was a reduction in all cause death by about 11% in that group of niacin versus placebo. So keep in mind, there were no statins used in these studies. This was placebo versus niacin. These patients did have modest elevation in their triglycerides and they did seem to have a significant reduction compared to placebo with the addition of niacin. So why has niacin sort of fallen by the wayside? Well, as you probably know, in the more recent era, they’ve compared niacin plus statin to placebo plus statin, and when added to a statin and there did not seem to be a significant benefit for adding niacin. But compared to placebo, we do have data that it is better than nothing and that’s something to keep in mind in those patients who may not be able to take any statin therapy and who don’t have contraindications to niacin. And so though I’m not a huge fan of the use of niacin, there are occasional patients that can’t take anything else who have high risk and may be appropriate for niacin therapy. Now, in the current era, we have some newer trials with niacin, and I think many of you are familiar with the AIM-HIGH trial. This was patients on a baseline therapy of statin, in this case simvastatin, given either placebo plus that statin or given simvastatin plus an extended release niacin and this is the study design for your review that patients were over 45 years old, they had vascular disease so it’s a secondary prevention trial and I just want you to take a minute and look at the inclusion criteria in terms of the lipids. The LDL had to be less than 160. The HDL had to be less than 40, and they accepted triglyceride levels from 150 to 400. The endpoints that they were looking at in this trial were coronary death, nonfatal MI, ischemic stroke, or hospitalization for high-risk non-STEMI. The secondary endpoints are as listed on the slide. So here’s the interesting part of this study. We were all excited about it because we were hoping that we’d be enrolling patients with elevated non-HDL and see whether adding something on top of a statin gave additional benefit. But look at the vast majority of patients that were enrolled. 3196 of those patients actually had a HDL of 35, which was low, and that was satisfying that we were getting the right patients, but their median triglyceride level was 161. There were a much smaller group that were not on statin when they enrolled in the trial, who had an HDL of 33 and triglycerides just over the 200 number, the 215, but the vast majority, 90% of the patients had a non-HDL of 107. So these were very well treated patients. So in reality, what was being studied in this group - not patients with high triglycerides and low HDL, but patients who had isolated low HDL. And the question that was really answered by this study was if you have a patient with established atherosclerosis whose LDL is well treated on a statin, roughly 70, but who still has a low HDL, is there any benefit to adding niacin to try and raise that HDL? That was really what the study answered, even though they set out the answer a question about elevated triglycerides. And the resounding answer was no, there’s no benefit to adding niacin. In fact, there was absolutely no difference in the group that was on simvastatin alone versus simvastatin plus niacin, despite the fact that the HDL came up significantly in that group that had niacin. So I think we can say that many of us over the years struggled with trying to treat low HDL in patients who were on statins by adding niacin that actually did nothing, and that’s not appropriate. But this study didn’t answer the question of what about those patients who had high triglycerides and low HDL so that their non-HDL remained elevated on the statins? And so we didn’t get any information on that group, because they weren’t really the majority of patients enrolled in the study. In fact, so few of them were enrolled, it was hard to even do a subgroup analysis on those patients. Now what do we know about fibrates? So we’ve got studies going back many years looking at adding fibrates and in the Helsinki Heart Study using gemfibrozil versus placebo, we saw a significant reduction in risk and then we have several other studies looking at fibrates and we’re just going to touch on a few here to give us some guidance about why we should think about using fibric acid derivatives. So Helsinki had, as many of you know, was 4000 men that were enrolled. These were patients who had they were initially free of coronary disease, but they had high triglycerides and low HDL cholesterol. And in fact, when they looked at the patients who received benefit and as you can see from the outcomes, there was a significant reduction in cardiovascular events and patients who got gemfibrozil versus placebo. Again, this was before the statin era, 34% fewer cardiac events in the patients who received gemfibrozil versus placebo, but who really got the benefit, as noted in yellow on the bottom was those people who had a high LDL and/or a low HDL, so that the ratio of LDL, the HDL, was greater than five, and those with triglycerides, over 200 in that group, there was a 71% risk reduction. So very significant benefit, and the dismetabolic patients that we’ve kind of been alluding to who would have a non-HDL that’s still elevated. Again, gemfibrozil versus placebo. The VA-HIT trial is also very interesting trial. This was a trial again using gemfibrozil and men with established coronary disease who had a low HDL. They had to have LDL cholesterol less than 140. So their mean LDL was 111 and in this case, their triglycerides weren’t that elevated. They enrolled patients less than 300, but their mean triglycerides were 161. Again, a placebo controlled trial of gemfibrozil versus placebo, not on a baseline of statins and patients who had established coronary disease. What was very interesting about this study was that it was one of the few studies in the literature where the treatment did not change LDL at all. So the purist would say we could actually see what the benefit was of just lowering triglycerides and raising HDL without doing anything to LDL. And I don’t think we have any other trial where we’ve been able to do that without adjusting LDL. And what you see in the orange boxes is that there was a 22% reduction in nonfatal MI CHD death and a 24% reduction in stroke and stroke related that. So patients who received gemfibrozil versus placebo who had atherosclerotic disease got a significant benefit, even though the only numbers that were manipulated were the triglyceride and HDL. All of these things gave us some hope that maybe drugs added onto statins that modulated HDL and triglycerides would give additive benefit beyond that that we saw with statins that primarily lowered LDL, although they have modest effects on HDL and triglycerides, as we mentioned. So for the sake of time, I’m not going to dwell too much on that field study, but the field study was one of the first studies to look at fenofibrates. We know that gemfibrozil added to statins causes a significant increased risk of myositis and therefore it’s fallen out of favor, and generally we don’t use gemfibrozil anymore. So this study was a group of diabetic patients, almost 10,000 patients randomized to fenofibrate plus whatever the primary physician thought was appropriate therapy versus placebo in patients with diabetes. They were followed up for five years. And let me just say that about halfway through this study, a statin trial came out showing that all diabetics, regardless of their LDL level, got benefit from statins. And so many of the investigators in this trial, felt it was unethical not to add statins to patients in the trial since they had diabetes in order to try to do what they felt was right for their patients. And many more patients were given statins in the placebo group than in the group that was receiving, you know, fibrate. And at the end of the day, that made the study almost non interpretable. But the results were that there was no overall benefit in patients who received fenofibrates versus placebo in this group of kind of a mixture of background therapies. So on the far left, two bars, the primary end point of CHD events was not significant, but that P-value of .16. But because of all the drop ins on statins and the placebo arm, it probably diluted the results and we have no idea what to do with these results. I will tell you that the subgroup analysis, which you can see on these slides for non-fatal MI, CHD death, total CVD events, coronary revascularization, some of them do look significant, but the purist would say if the primary end point wasn’t significant, they would not feel that it’s more than hypothesis generating to look at the secondary endpoints. That’s an arguable point. The one thing that we did see was a reduction in small vessel disease and patients receiving fibrates. So those diabetics had less neuropathy, less eye problems, less renal problems when they were on, you know, fibrates. So that alone was a positive result. And then lastly, we have the ACCORD study. And the question here was in diabetic patients with statin alone versus statin plus, you know, fibrates reduce cardiovascular disease amount. So this was almost 5500 patients. This was a much more well controlled study where clearly all the patients received statin, half receives statin plus that placebo, and the other receives statin plus active fenofibrates. So much better done study followed up for 4.7 years. Overall, there was a 2.2% event rate in the fenofibrate group and a 2.4% in the placebo group. So adding fenofibrate on top of a statin did not significantly change the outcomes. The one thing that looked somewhat promising is the last point on this slide that if the patients had an elevated triglyceride over 204 and a low HDL, less than 34, then there was a 12.4% event rate in the feno group versus 17.3% in the placebo group, which though it wasn’t statistically significant, it was right on the border with a P value of 0.057. So overall, adding fenofibrate to a statin in these patients did not reduce cardiovascular events, but there certainly was a very strong implication that in those high triglyceride, low HDL patients that adding in fenofibrate might be benefitting those patients. And so we still have this underlying concern about what do you do in a patients on a statin their LDL is well controlled, but their non-HDL is still elevated because their triglycerides are elevated and have a low HDL and does add in combination therapy such as fenofibrate actually reduce their risk. And the answer is we’re not sure because the studies weren’t powerful enough to show that. And certainly we didn’t study those patients in the niacin trials. So going back to the old statin trials, Heart Protection Study, a couple of things to point out before we get too upset about the 2013 guidelines, it doesn’t matter why you have elevated risk, whether it’s a previous MI, cerebrovascular disease, peripheral vascular disease, cardiovascular disease or diabetes, when you add a statin, you get the same reduction in risks. So the concept of treating risk rather than the numbers is, you know, very important concept and ‘Start a Statin Stupid’ is a very good rule even on those patients with elevated triglycerides. And in fact, if you looked at tertiles of LDL, whether it was below 100 and 100 to 130 or over 130 baseline LDL cholesterol, if the risk was equivalent, in other words, a patient with established DAD or established atherosclerosis, they got an equivalent reduction in risk. So again, starting a statin based on risk rather than the numbers makes sense. The question is, if the numbers remain high after you add the right dose of statin, what do you do next? And most of us believe you should intensify your therapy. So if the numbers are low when you add your statin, you still add a statin to a high risk individual. If the numbers are high, you add the appropriate dose, but if the numbers remain high after therapy, intensify your therapy. So the last thing I wanted to discuss are some trials that are underway that are actually trying to answer the question about does adding a therapy on top a statin, specifically in those patients who have high triglycerides and low HDL, actually further reduce risk? So the first study that is underway right now is called the Reduce-IT trial. This is a trial of amaranth, fish oil, icosapent ethyl, which is pure EPA, fish oil versus placebo in patients who have elevated triglycerides as well as other cardiovascular risk factors. So those patients are randomized to their statin therapy, the appropriate therapy plus either placebo or the addition of EPA fish oil, and they are being followed for cardiovascular outcomes. There’s over 8000 patients in the trial. The trial is currently in progress and we hope to see the results of that study sometime in 2018. In addition, there’s another trial called The STRENGTH Trial, which is a different fish oil omega-3 carboxylic acid, which has both EPA and DHA in it. And the study was designed very similarly. Patients had to have triglycerides over 200, but less than 500. Their LDL had to be less than 100, or they at least had to be on high intensity or maximally tolerated statin. Ezetimibe could be added and they were randomized to their statin or ezetimibe or both therapy either to receive a placebo that was corn oil or a fish oil called epanova, which included both EPA and DHA. And that study is also under way, and I would expect that sometime in 2018 or 2019, we’ll see the results, the primary outcome was the time to first recurrence of any major adverse cardiovascular event, including cardiovascular death, nonfatal MI, nonfatal stroke, need for emergent or elective revascularization or hospitalization for unstable angina. And then there’s a series of secondary outcomes in these trials that will also be looked at if the primary outcome is significant. So I think strengthened REDUCE-IT, our last hope to have studies that are designed that target non-HDL elevation after the patient is on statin therapy, so starting a statin first, getting the LDL to target, making sure the patient is on the right dose of statin, that the triglycerides remain elevated and the non-HDL remains elevated. You have two choices. You can either aggressively further lower the LDL or you can add a second agent to lower the triglyceride. At least in the case of niacin and fibrates, we did not see any significant benefit in adding additional agents to the statins. And in fact, in the niacin case, we actually had increased toxicity with a higher incidence of diabetes and infections and bleeding, compared to statin alone. However, people with elevated triglycerides were a minority in those studies, making it hard to know whether there would have been benefit in people without elevated non-HDL. We have a little inkling from the fenofibrate data that maybe by subgroup analysis people at high triglycerides might have gotten benefit, but overall the study did not show benefit, so the primary endpoint was negative. And then we have these two fish oil studies added to statins, the results of which remain to be seen. So what are the key clinical take home points? LDL remains the principal target of therapy for patients with established CAD. Again, use the right dose of statin in the right risk patients. High doses of statins for people who are at high risk, moderate doses of stands for those at moderate risk based on the available clinical trials, and even if the LDL is low to start with, that strategy is appropriate. Now once you’ve added high or moderate dose of statin, if the LDL remains elevated or the non-HDL remains significantly elevated, you now have the option to add non-statin therapy on top of those agents to try to get LDL below a appropriate threshold at non-HDL, below an appropriate threshold. The evidence for HDL raising and lowering providing additional benefit on top of statins to reduce cardiovascular risk is disappointing. It may be related to study design, but whatever it is what it is, we don’t have good data that adding fenofibrate or niacin on top of a statin is a significant reduction in risk in those patients. And more studies need to be done as mentioned, and we’ll see what happens with the fish oil trials. The other takeaway point is that non-HDL, LDL-P and Apo B are all better predictors of risk than LDL in patients with elevated triglycerides because those three measures, and you can pick whichever one you want, they are actually measuring particle number as opposed to just total amount of cholesterol within particles. And so in patients who have normal triglycerides, LDL is quite good and I would say adequate in the vast majority of patients, but when the triglycerides start to rise, you should look at non-HDL, LDL-P or Apo B . I’ll let you make your choice. We still need a trial of patients with high non-HDL who are on a baseline therapy of statins to see whether adding additional therapy actually reduces cardiovascular events. So again, how do you get non-HDL down in a patient who already on statins? Consider the patient’s age, the other drugs they’re on, whether or not they have side effects on their medications and, you know, whether they can afford the drugs that you’re thinking about prescribing. And you have two options. Statins are the mainstay of treatment, and though they lower LDL, they also lower non-HDL, so if the patients on a modest dose of a statin and their non-HDL remains elevated, even after you’ve gotten their LDL below their threshold, you can just increase the statin and drive the LDL lower. That’ll bring that total minus HDL down. So your non-HDL will come down. And the other option would be to add combination therapy. And in those patients where you don’t have the option of intensifying the statin therapy or you’re just uncomfortable with the triglyceride level being 300 or above, you could always add a fibrate or you could add omega-3 fatty acids. I generally stay away from niacin because of the side effects and the potential for harm that was shown in a HPS2 -THRIVE study. So triglycerides over 200 in a patient with a LDL/HDL greater than 5, these patients have supportive but not conclusive data for the benefit of combination therapy to treat their non-HDL. It certainly would be reasonable and as a general rule, I recommend to everybody follow national guidelines until trial evidence suggests differently. In individual patients, you may have to deviate from what the guidelines say because those patients require specific choices of therapy due to side effects or their beliefs, etc. But for the vast majority of your patients, it’s always a good idea to follow national guidelines, which are based on a well-done randomized prospective trials as well as well-done Meta analyzes. So current evidence is lacking regarding the benefit of raising HDL. We’ve had terrible disappointments and drugs that just raise HDL, as well as the combination of HDL raising and triglyceride lowering. But the niacin and fenofibrates, as I’ve described, the jury here, remains out regarding the more novel techniques for raising HDL, most of which have been proven to not give any clinical benefit. I do believe that the last two decades have focused specifically on LDL lowering, and the next decade is going to focus on a combination of things, probably total particle numbers, triglycerides, non-HDL or Apo B, as well as addressing the epidemic of obesity and metabolic syndrome, which will focus primarily on lifestyle modification. And don’t forget that in order to adequately reduce residual risk in patients after they’re on appropriate lipid therapy, that lipids aren’t the only thing that causes atherosclerosis. So you need to address all the cardiovascular risk factors, including quitting smoking, blood pressure control, dietary habits and weight reduction if you really want to see a remarkable reduction in cardiovascular events in the population. Thank you very much for your attention.