FEATURED Published in Primary Care and Peter Libby MD Interview by Aman Shah MD Get Topic Alerts New Data and New Concepts in Managing Triglycerides Player Information About Brightcove This multimedia content was independently funded and produced by PracticeUpdate. Publication does not constitute representation by PracticeUpdate that the data presented are correct or sufficient to support the conclusions reached. Dr. Shah: So, it seems like triglycerides are making a comeback. They seem to be a little bit more important than we thought they were. What is the state of the data on this? Dr. Libby: Well, you know, there’s a very interesting story about medical thought and how we tend to be like the little kids on the soccer field following the ball. There was absolutely consistent and compelling evidence that high-density lipoprotein, good cholesterol, HDL, was protective. And we spent years and years chasing after HDL as a therapeutic target in the firm belief that it was protective, based on observational data. Meanwhile, we know that HDL and triglycerides tend to vary inversely—the higher your triglycerides, the lower your HDL. And when the epidemiology community would take triglyceride concentration and look at cardiovascular outcomes, yes, there was a relationship, but they adjusted it for the HDL. And that attenuated the risk, and even if you adjust for non-HDL cholesterol, you flatten the risk. So people have, for generations, discarded triglycerides as a causal risk factor and that has really undergone quite a change recently. Dr. Shah: That’s interesting. But on the other hand, it seems like omega-3 fatty acids, which could have been addressing the triglycerides, have caught on with the general public, but there wasn’t a scientific consensus on what these agents do. So, has that picture changed? Dr. Libby: Well, you know, we bet a lot on the HDL side of that teeter-totter. And what’s come out in the last few years, based on human genetics and a re-evaluation of the observational epidemiology, based on the consistent failure of interventions that raise HDL to improve cardiovascular outcomes, we’ve really undergone a revision, or at least I have, where the human genetic evidence, which has cast doubt on the protective effect of HDL, has become ever more strong in support of triglyceride-rich lipoproteins as a causal risk factor for atherothrombotic events. Now, triglycerides what we get on the lab slip is just a biomarker for a class of lipoprotein particles known as triglyceride-rich lipoproteins or remnant lipoproteins. I like to call them TGRL, triglyceride-rich lipoproteins. And there’s really compelling evidence, I won’t go into here based on some terrific human genetics, that those particles are causal in atherothrombosis giving us a new therapeutic target, which is the TGRLs rather than trying to raise the HDL. You bring up omega-3 fatty acids, which do decrease the triglyceride-rich lipoproteins. And we got a real boost to the idea that this would have clinical payoff with the presentation by Deepak Bhatt in November of 2018 at the AHA of the REDUCE-IT Trial, which caused us to stand up to attention because there was a 25% reduction to the primary endpoint with 4 g a day of eicosapentaenoic acid. Not the stuff you get at the nutrition store, at the supplement store, but a pharmaceutical grade that is quality controlled, assayed, and purified. Dr. Shah: So, was that the difference? Because previous studies did not quite show clear evidence omega-3 fatty acids working for triglycerides. So, was it the increased dose, was it the pharmaceutical grade, category of this agent, or what was the difference in this study that showed such a dramatic benefit versus previous ones? Dr. Libby: Well, I think it’s a matter of dose, by and large, because a lot of the previous studies used much lower doses like 1 g a day. The only study that was positive was the JELIS study performed in Japan, where they already have a high fish intake and they used 1.7 g of eicosapentaenoic acid. So, I think that was the dose in the JELIS Trial, which was positive. And you know the VITAL study, which our colleague JoAnn Manson presented at the same meeting at the AHA in 2018, used a much lower dose of omega-3 fatty acids and did not show a cardiovascular benefit, at least in the primary endpoint. So, what we have today is evidence that a high dose, 4 g a day, 2 g b.i.d. (twice a day), of a purified grade of eicosapentaenoic acid, it’s called icosapent ethyl is the pharmaceutical name, is beneficial. And at this meeting, we’re at the ACC meeting in March of 2019 in New Orleans, Dr. Bhatt is going to present some more data on subsequent follow-on analyses, which I think will reinforce this idea. I don’t know the answers because he hasn’t presented it yet, but stay tuned. Now, we’re very fortunate because there is another properly designed trial with another pharmaceutical grade omega-3 fatty acid preparation and that is the STRENGTH trial, which will not report out maybe until 2020 or maybe even beyond. But that’s using a different mix of omega-3 fatty acids. It’s using a mixture of eicosapentaenoic acid and docosahexaenoic acid, two fish oil-derived omega-3 fatty acids. So, it’ll be very interesting to see the results of that trial comparing with REDUCE-IT. So, we’re on a very exciting time. Dr. Shah: That is interesting. Dr. Libby: And I would hasten to say that we don’t know the mechanism of the benefit seen in the REDUCE-IT Trial. Yes, the omega-3 fatty acids do lower triglycerides and they actually have a label today from the FDA for extreme hypertriglyceridemia above 500 mg/dL puts you at risk for pancreatitis. So, we can write on label for these omega-3 fatty acid preparations for the triglycerides above 500. But it’s really exciting because there’s also an anti-inflammatory effect, so maybe this intervention is working through mixed mechanisms. A decrease in triglyceride-rich lipoproteins and a decrease in inflammation. Now, those two may be related. It’s little appreciated that LDL, low-density lipoprotein, bad cholesterol, is actually only weakly pro-inflammatory, as gauged by, say, a measurement of C-reactive protein, our biomarker of inflammation. Whereas triglyceride-rich lipoproteins consistently show a much greater slope in that relationship as shown by the work of Børge Nordestgaard and I think Anette Varbo and others. Dr. Aman Shah: And I believe you’ve done work on that too. Dr. Libby: Yeah. Well, you know, I’m just a spectator in the triglyceride field, although we’re doing another trial right now with Dr. Ridker and Dr. Aruna Pradhan, which is called PROMINENT. Which is taking another shot on the role of lowering triglycerides and other effects with a selective PPAR-alpha modulating agent known as pemafibrate. The trial is PROMINENT and I’d love to come back and talk about it some other time. Dr. Shah: Yes. Dr. Libby: But we’re, again, at an exciting threshold. It looks like triglyceride-rich lipoproteins are causal for atherothrombosis, and HDL raising has proven disappointing, but it’s been maybe replaced or supplanted by triglycerides. And we are getting clinically actionable because we have omega-3 fatty acids and perhaps other agents, which will allow us to attack triglycerides and improve patient outcomes. Dr. Shah: So, what’s the adverse event profile of these agents? Is it a concern then that if dosages are, say, 4 g, that you should not be using them in more patients than just the ones who have extremely high triglyceride levels? Dr. Libby: Well, I think we have to go by the entry criteria of the REDUCE-IT trial, which did focus on individuals who have increased cardiovascular risks and who had increased triglyceride concentrations. But the safety profile looked pretty good. There was not an enormous bleeding risk price you had to pay and the only signal, which I think we need to keep our eye on, was really to me paradoxical, an increase in incident atrial fibrillation. Now, whether that’s a play of chance or it’s real, we’ll find out. But it’s interesting that in REDUCE-IT, there was not an increase in ischemic stroke. And you know, I would think if we were pushing people into atrial fibrillation, we might see a signal in terms of ischemic stroke, which the investigators, led by Deepak Bhatt and Gabriel Steg, did not see. So, very exciting times. Dr. Libby: It looks like it’s tolerable and efficacious. And it’s another tool in our bag of tricks to try to improve our patients outcomes.
FEATURED Published in Primary Care and Deepak L Bhatt MD, MPH, FACC, FAHA, FSCAI, FESC Interview by Aman Shah MD Get Topic Alerts Role of Triglycerides in Cardiac Disease This multimedia content was independently funded and produced by PracticeUpdate. Publication does not constitute representation by PracticeUpdate that the data presented are correct or sufficient to support the conclusions reached. Dr. Shah: So you have published some really important research recently on triglycerides, and I wanted to get a sense of how you view triglycerides in cardiac disease. Are they causative of disease? Dr. Bhatt: Great question, and there’s been a lot of discussion and controversy on this point for years. So, first, I would say it’s important to realize that triglycerides are a potent independent risk factor, risk marker. So if someone has elevated triglycerides versus someone who doesn't, they are at elevated cardiovascular risk, independently of diabetes, obesity, things that tend to be also associated with high triglycerides. So high triglycerides, that identifies patients at increased risk. Now, then, is it actually a causal risk factor, or is it just something that can’t be modified? It’s a key question. Modifiable or non-modifiable? And I think the answer’s a bit of both. So, for sure, triglycerides demarcates risk, but I do think things that lower triglycerides safely probably also are associated with reducing cardiovascular risk. For sure, natural things that do it would, so better control of diabetes, losing weight in particular, bringing triglycerides down that way, regular aerobic exercise, smoking cessation, that’s associated with cardiovascular benefit, and it does appear that triglycerides are causal. Recent Mendelian randomization studies show that...and in case anyone listening isn’t familiar with that, that’s nature's randomized clinical trial. That is, people are born with genes that may be associated with elevated triglycerides versus people that are born with genes that aren’t, and it gives them a lifetime exposure in using those sophisticated methods. It does seem that triglycerides aren’t just a risk marker, but are part of the causal pathway. Though, the degree of triglycerides elevated, or consequently, reduction that’s necessary to affect risk is much larger than a similar degree of LDL change. That is, you have to drop triglycerides by a lot, whereas dropping LDL by a much smaller proportion provides a similar degree of cardiovascular risk. Dr. Shah: Could you amplify on that a little bit? Even in percentage terms, you would have to go down from, say, somebody who’s very elevated at 500 all the way down to 100 to get the same benefit as... Dr. Bhatt: Well, the genetic analyses ask the question just quite that way, but you know, for example, a 5-mg/dL change in LDL cholesterol might be associated with a certain level of risk change. You know, you might need a 20-mg/dL change in triglycerides to get that sort of change, or actually, in fact, even more than that. So it just means that, yes, triglycerides are associated with risk, but just lowering triglycerides a little bit pharmacologically probably wouldn't be expected to have the same degree as the same mg/dL reduction in LDL cholesterol, but you know, that’s Mendelian randomization-type studies. The epidemiology, though, clearly shows an independent relationship, between high triglycerides and cardiovascular risk, and what’s interesting is what that range is. I think it’ll be a situation where we look back years from now that’s analogous to LDL cholesterol where we kept dropping what normal is. And you know, with triglycerides, they do tend to be more variable, even in a fasting state, but probably a better way of assessing a triglyceride level in a person isn’t just one measurement, but you know, a couple of measurements and averaging out. And there’s also folks that believe really even the fasting triglyceride doesn't capture everyone who’s at triglyceride-associated risk, and really, postprandial triglycerides are a better marker. Some people have a real surge in postprandial triglycerides even if their fasting triglycerides are normal, and that’s also pretty bad. Of course, someone starting high that goes higher, that’s the worst, and I wouldn't be surprised if, you know, we redefine normal triglycerides. They’ve sort of already been dropping from, like, 200, to 150, to maybe even 100 in terms of what’s normal, just like LDL, you know, kept dropping after trials came out showing that if you lower LDL even further, it improves cardiovascular outcomes further. So I think we’re just at the start of that same sort of revolution, but in triglycerides. Dr. Shah: And in clinical practice, do you then try to set a target, or do you try to just reduce it and keep monitoring the patient and then seeing what the outcomes are? Dr. Bhatt: It’s a terrific question. What do you do about it therapeutically? So sort of the first steps are make sure that the patient’s weight is appropriate. If not, weight loss would make sense. If they have diabetes, better diabetes control. Smoking, stop smoking. Alcohol excess, you know, stop that. So, you know, just to do the basic stuff to try to get triglycerides in range. And then, you know, if the triglycerides are elevated and the LDL’s elevated, and the patient otherwise meets guideline-directed therapy for statins, initiate statins, and crank up the dose as appropriate to get the LDL levels down, and that’ll have some effect, as well, on triglycerides. And then, if they’re still elevated and the patient’s someone with cardiovascular risk, then I say, you know, there’s the REDUCE-IT trial, of course, where we took patients with triglyceride ranges on enrollment that were supposed to be 135 to 500. In fact, we got patients even with lower triglyceride levels in there, and showed that if they had atherosclerosis or if they had diabetes plus one additional risk factor, there was a substantial reduction in cardiovascular risk. So I think I would use icosapent ethyl, which was what we studied there. I’m not necessarily convinced that other triglyceride-lowering therapies, per se, would provide the same cardiovascular benefits. They might, but that needs to be studied in appropriately designed and power randomized clinical trials first.
FEATURED Published in Primary Care and Clyde W Yancy MD, MSc, MACC, FAHA, MACP, FHFSA Interview by Aman Shah MD Get Topic Alerts Lipid Management and Diet This multimedia content was independently funded and produced by PracticeUpdate. Publication does not constitute representation by PracticeUpdate that the data presented are correct or sufficient to support the conclusions reached. Dr. Shah: So, could you give us an overview on how you approach diet in patients who have high levels of cholesterol? Dr. Yancy: So, this really is a very important conversation because prior to being prescriptive about a diet, we have to understand what problem are we trying to solve. For a patient that is at very low risk, we really have to be fairly conservative. Yes, all of us, the entire general community, should follow a reasonable heart-healthy diet, and all of us, the entire community, should be concerned about the burden of obesity, but when we start talking about unique and dietary changes that constitute an intervention, what’s the problem that we’re trying to solve? The problem we’re trying to solve is that, in those that are at an increased risk, are we able to exercise the strategies that can modify that risk, and as well, in anticipation of the potential of medical therapy to lower cholesterol, can we first establish a good dietary platform? So you can see how important it is to calibrate the question. I can abbreviate the answer and say everyone needs to follow a heart-healthy diet. That is correct, but in those that are at increased risk, the directives need to be more explicit. So let’s take that category. That means we have to first have a conversation with our patients about risk. We can use any number of available risk calculators. One from MESA, one from the American Heart Association, the American College of Cardiology, the ASCVD risk calculator, even Framingham, but by some risk estimator with which you have confidence, identify whether or not a patient is at least at intermediate risk and particularly at high risk. Using the ASCVD calculator, high risk is greater than a 20% likelihood of an event over the next 10 years. Intermediate risk is 7% to 20% likelihood. Once you’ve identified that and realized that the next step in the treatment algorithm is medical therapy, specifically, a statin or a non-statin if statins aren’t sufficient, one then has to be very exacting about the diet. In general terms, we think the evidence is available to suggest that the Mediterranean diet is appropriate, but the Mediterranean diet is not just a little bit more fruit or a few more vegetables. It really is a rigorous transition, where one’s diet is principally fruits, vegetables, fiber, olive oil, and then thinking about much more fish and much less red meat. And so there are a lot of iterations of that Mediterranean diet that, if one is glib, you miss the importance, and so that’s a key consideration. As well, we would be remiss if we didn't say the closer a patient at higher risk and highest risk gets to a plant-based diet, the better off that person happens to be. And so that’s why we can be so prescriptive if we know a patient is at high risk, because then we can say you really need to follow this more rigorous diet, as opposed to the general population where we can say, look, be cognizant of what you eat. Think about obesity. In general terms, be heart healthy. That’s the difference. Dr. Shah: That makes sense. And one thing you alluded to was almost a titrating of dietary recommendations with subsequent potential medical therapy of statins. Could you give us some pointers on how you do that? How aggressively do you try to follow through on diet before putting people on them, and how do you titrate these two modalities? Dr. Yancy: Yeah, so this is one of the most important challenges we have in all of medicine, but particularly in cardiovascular medicine, short of giving a prescription and then doing diet recall or even a calorie count, which is very hard to do, even in a hospitalized setting. It really is based on subjective endpoints, based on history, maybe weights. So what we can do is say, here is a diet plan. We frequently invoke a member of the care team to really help effectuate that, whether it’s a nutritionist or a nurse trained in prevention, and give a time span—3 months, 6 months; typically, that’s the window. At that point, then we go to step two. We reassess, and if we aren’t where we need to be, then we go to step two. It’s also important to expand this conversation so that we’re not just talking about those with high cholesterol or dyslipidemia, if you will, but also the hypertensive patient. Diet is a big, big piece of that, and increasingly, we’re beginning to understand that diet is relevant for heart failure and for heart failure prevention. So, at a certain point in time, as you suggested, the conversation about diet takes on a lot more oomph, if you will. Dr. Shah: That makes sense, and in terms of target, do you stick with the 130? Do you go lower is better in many patients? I guess my real question is, is there something like too low for an LDL? You’ve overdone it? Do you get to that point? Dr. Yancy: So this is really a great question because the traditional mindset was a goal LDL reduction, and in 2013, talk about disruptive. We really basically said that’s no longer the threshold to respect. The threshold to respect is, in the patient at risk, use a disease-modifying therapy, statin therapy, and give the therapy in the doses shown to modify the natural history of the disease...I won’t say regardless of the LDL reduction, but as the primary objective. If the LDL reduction follows suit, excellent. If not, continue with the therapy as prescribed. The most recent iteration says try to get at least a 50% reduction in whatever the baseline LDL is. I’m comfortable with that because we begin to start looking at the initiation of statin therapy when the LDL is at 160 or higher, particularly at 190, we really are very aggressive about initiating statin therapy. But even at 160, particularly if another discriminator, like a CAC score, is present, then we want to go and start a therapy. If you get a 50% reduction and 160 to 80, that’s success, and so we’re comfortable with this new concept of the 50% reduction. But the real genius in your question is that we can answer this whole concept of is there such a thing as too low? In an era of the PCSK9 inhibitors, we’ve seen LDL reductions down to less than 20 with no consequences, and we believe with a significant relief from the burden of ASCVD events. That really has been breakthrough technology, breakthrough therapy. Dr. Shah: Well, that is fascinating to even think about. So it seems like this is going to be very important information moving forward.
