PACE-CME

-Hello, I'm Peter Libby from Boston's Brigham and Women's Hospital in the Harvard Medical School. We're wrapping up the annual scientific sessions of the American Heart Association in windy Chicago, Illinois, and I'm glad to be here with some of my colleagues from Europe and from UK. You want to introduce yourself, guys? -I'm Gabriel Steg. I'm a professor at Université de Paris in Paris, France. -I'm Kausik Ray. I'm a professor of Public Health and a cardiologist in Imperial College London in the UK.

-This has been a very exciting meeting for preventive cardiology, where we've had some consequential late-breaking clinical trials that I think have important implications for practice. We'd like to have a brief discussion about the bottom line of these trials and what we think it means for the practicing clinician.

Kosh, I was involved with PROMINENT and you're a non-combatant, so maybe you can explain to our audience PROMINENT. -We've known for a while that people with high triglycerides have a high residual risk of cardiovascular events, and we've got a lot of data from fibrates suggesting, at least in the pre-statin era, that they might actually reduce cardiovascular events. In the post-statin era, we've never really seen that. PROMINENT was a very large study, enrolled people with established cardiovascular disease or high-risk primary prevention with elevated triglycerides and a low HDL with a fibrate called pemafibrate. In this study, even though there was a reduction in triglycerides that were significant of the order about a third, there was no change in apoB. There was no change in LDL cholesterol, and overall, the cardiovascular events were neutral. When you break it down by different components, again, there was really no signal for benefit in a large well done clinical trial.

-The important thing about PROMINENT was that we really enrolled the population that the posthoc analyses of the other fibrate trials, suggested will benefit, those with high triglycerides and low HDL. -We really thought we had a winner, and it was very disappointing from both a scientific and a clinical point of view. Where does that leave us with this class of drugs, the fibrates? -I think there's clearly a role for fibrates in terms of preventing pancreatitis of people with much, much higher triglyceride levels. There were signs that there could be some benefit in NASH. For example, in the PROMINENT trial, they will require further exploration, but as a means to reduce ASCVD on top of statins in the population that was studied, I don't think there's any added benefit in terms of that. We need to look at alternative options.

-I think an interesting observation from PROMINENT is that there was quite a substantial decrease in triglycerides. Maybe not as much as we would like, but still a substantial decrease in triglycerides, and yet the fact that we don't see cardiovascular benefit really raises questions as to what is the mechanism that should drive the reduction in triglycerides. It's not sufficient to lower that number. There has to be something that translates into reduced risk. I think the observation that apoB was not reduced, in fact, was moderately increased, really sheds light on our thinking should go beyond pure numbers, and really, mechanisms. It seems that the way pemafibrate, and probably, in general, fibrates achieve triglyceride level reduction may not be one that translates into cardiovascular benefit because it does not reduce the amount of apoB particles. -Yes, and it really reinforces the importance of apoB and lowering LDL.

Gabriel, you've been involved in the development of the omega-3 fatty acids. There was an important trial, RESPECT-EPA, that was presented. I think that that also provides some information for us to make a context around this issue of the omega-3 fatty acids, which has been a very controversial and hot topic. -Yes, it's a fascinating field. As you know, we have had a host of clinical trials that have looked at various combinations of omega-3 fatty acids, mainly combinations of EPA and DHA on one side and purified EPA on the other. The EPA plus DHA trials have generally been negative, and sometimes completely negative, including the most recent ones, which were large trials, very well conducted, VITAL, ASCEND, STRENGTH, completely negative, showing no hint of benefit with EPA and DHA, even with relatively high doses of EPA and DHA in STRENGTH. In contrast, there had been two trials of purified high-dose EPA. JELIS in Japan almost 10 years ago, which was a combination of primary and secondary prevention patients treated with 1.8 grams of EPA per day versus control, which was no placebo. It was usual care and that trial had shown a substantial reduction in cardiovascular outcomes, both in the primary and secondary prevention cohorts. That trial had been criticized because there was no placebo, it was open-label, and the use of statins at the time, particularly in a Japanese patient population, was quite low. Therefore, the relevance of this to routine clinical practice in contemporary times was really debated. Then we did REDUCE-IT, and REDUCE-IT was, I have to confess, even to our own surprise as trialists, a resounding positive result both in primary and secondary prevention with a 25% rate of risk reduction in cardiovascular outcomes. Now, REDUCE-IT has been questioned. The results of REDUCE-IT have been questioned because there were issues around whether the placebo is inert or not. The placebo was mineral oil, and we did see and report, even in our primary paper, that, in the placebo arm, there was a modest increase in high-sensitive CRP and LDL cholesterol level after a year of treatment. Now, we doubt that this would account for the 25% reduction in cardiovascular outcomes that were seen, but still, I think it was a fair question to ask, particularly, as we saw consistent elevation of other biomarkers that are in the inflammation pathway, recently reported in the placebo arm. Really, I think it's a legitimate question. Therefore, RESPECT-EPA was the third trial that was widely anticipated because we would have an answer of whether things are consistent with REDUCE-IT, or rather consistent with STRENGTH. What RESPECT-EPA did was, again, in Japan, a study versus usual care, but on top of well-conducted statin therapy in a contemporary treated patient population, and interestingly, the EPA levels at baseline in that patient population, even though they were Japanese, were quite lower than in JELIS, and more consistent with what we see in the Western world. What RESPECT-EPA showed is very interesting because they did show a 21% reduction in cardiovascular outcomes of borderline non-significance if you attach a lot of importance to the P values. I think the reality is the trial was much smaller than the other two trials, largely underpowered because it was powered for a 30% relative risk reduction. Still, the effect on all cardiovascular outcomes is very consistent with what was seen both in JELIS and in REDUCE-IT. It's a signal of efficacy with purified EPA. In my opinion, this really helps us clarify that it's probably EPA that matters. If you give high doses EPA, you seem to have consistent benefit. If you give lower doses of EPA or EPA plus DHA, you don't see a benefit in any of the trials.

-That leaves us with some mechanistic questions. Is it triglyceride lowering that is accounting for the benefits with the omega-3 fatty acids? We have a disappointment where we have a lowering of triglycerides with the pemafibrate but no clinical benefit. Can you go through, with us, the triglyceride story with the icosapent ethyl and the other omega-3 fatty acids? -It's really interesting because, in REDUCE-IT, we purposely enrolled a population that had elevated triglycerides between 135 and 500. We thought this was the best population to treat because we know EPA will lower, to some extent, triglycerides. Not a whole lot, but it does lower triglycerides. What we saw, however, is there was no hint of a relationship between baseline triglyceride levels and benefit, or even changing triglyceride levels on therapy, or achieved triglyceride levels on therapy and benefits. Suggesting that while the drug does lower triglycerides, but it does not benefit via the triglyceride mechanism. I think that's really fascinating. -It doesn't look like EPA is exerting its clinical benefit observed in the REDUCE-IT trial, and in RESPECT-EPA based on triglyceride lowering or an anti-inflammatory effect. Where does that leave us? I wonder if it couldn't be that EPA is a precursor for some of these inflammation-resolving mediators, the E resolvins. These, all good clinical trials, it raises questions which raise new research questions that we can try to address both in the laboratory and in the clinic.

I guess the other issue is what do we do with the growing population of patients often with diabetes or insulin resistance, metabolic syndrome, with obesity, low HDL, and high triglycerides? What do we do with the patient who comes in, who meets the entry criteria, for example, for REDUCE-IT? It's a growing population globally. Certainly, in my part of the world and also in your parts of the world. Practicing doctor processing the results of the two trials that were presented here, what's the bottom line for practice? How do we actually manage these people, and reduce their cardiovascular risk? -I think the way you want to start, in the first place, is avoiding the determinants of insulin resistance, which is obesity. We've got to start, as a preventative society, organizations really need to push prevention upfront. Then you've got to worry about, as you say, what do I do once they have this? I think the first line is it's obviously a global approach. There's lifestyle, you need to control conventional risk factors. You've got to do that bit first. Use the statin therapy at an appropriate dose based on risk. Then if these patients fulfill the REDUCE-IT criteria, and we've seen now three studies, there isn't an option with a fibrate. Basically, in these people, they should be offered icosapent ethyl at a dose that basically has been approved. It was interesting because people get confused with omega-3s and fish oil. This is not over the counter. You cannot go to a department store and buy something over the counter. This is highly, highly purified. If you do that, 25%, 20% relative risk reduction is a really clinically meaningful effect. In one of the analyses, you didn't mention here, but that we know it's most impressive, is the total events, these are people at high risk of multiple recurrent events. The difficulty, I think, is that we as doctors are often used to seeing a change in something. That makes us feel that it's working. What we have to do is a lot of education using residual elevation of triglycerides as a marker of risk, but then a bit like we do with antiplatelets, for example, we don't measure platelet function afterwards. We've got the trial data, and we apply that, and getting these people onto those medications would substantially reduce the burden of cardiovascular risk.

-Gabriel, we've heard the UK point of view. Speaking for Europe, tell me what your approach would be to translate the results of these two late-breaking clinical trials into practical clinical daily practice. -First, I'd like to make the point that even though UK is out of the community, it is very much a European country. -Thank you. -We love our British brothers. I certainly hope we continue to collaborate on so many fronts. -Brothers and sisters. -Brothers and sisters. -The thing I would emphasize is I think triglycerides are a marker of risk, but I don't think we should worry about triglycerides. We should worry about residual risk. We know we have to address all the risk factors, including LDL cholesterol, with statins and other therapies. Once we've addressed that, we know there's residual risk. A good marker of that risk is obesity, insulin resistance, elevated triglycerides, and we know what to do about it. These are the best candidates for icosapent ethyl. Now, it may not work via triglycerides, but it doesn't matter. It reduces risk. That's what we are after.

-Kosh, I know you've been very interested in implementation, and how do we overcome clinical inertia. Our practitioner community is really wedded to the idea that fibrates which lower triglycerides could reduce cardiovascular events. I think, with the pemafibrate trial, PROMINENT, that it really cast doubt on the clinical efficacy of the whole class of drugs. Of course, pemafibrate was a special kind of PPAR agonist, a selective PPAR-alpha agonist. Still, in a well-designed trial, well-conducted despite the pandemic, and using an agent that was potent and selective, we were unable to show a reduction in events. How do we go about raising the consciousness of our practitioner colleagues about how to approach patients and whether fibrates should be part of our pharmacopeia? -I think there are three things we have to do. The first thing is, amongst our physician colleagues, move away from thinking about numbers, and thinking about risk, and thinking about event rates. We've got a real problem with noncommunicable diseases, and it's the end part, the non-part. If this was cancer, if this was heart failure, you'd think very differently about it. We've got to do that bit of education. The second thing that we've basically also got to do is educate them about taking away therapies that are clearly ineffective and that are not going to add anything even though you feel a bit more comfortable because a number that you believe in actually looks a little bit better. Then we've got to educate them about using treatments that clearly are effective. If I can add in maybe a fourth thing, we actually went through, and this was a UK perspective, we spent a little while ago talking and arguing a lot about using non-HDL because it was going to simplify everything. We've really got to get people back to looking at the full lipid panel because if you don't measure the full lipid panel and measure a triglyceride level, you're never going to identify the patient that would benefit. We got to remember that. -Yes, I'm an apoBeliever. The only advanced lipid testing I do in my practice is actually the apolipoprotein B. Of course, Lp(a) is another conversation, which I am now measuring once in everyone.

What's your perspective on the take-home message for our audience? -As Professor Ray mentioned, we have an embarrassment of riches in terms of prevention, which forces us to think about implementation. I completely agree with the idea of trying to win down the preventive medications to what is really meaningful and important. Maybe we need one fewer glucose-lowering agent that only will improve HbA1c, but not improve outcomes, and one more preventive medication for lipids, Lp(a), triglycerides, or something else. -It's very exciting times in prevention. I'm really delighted to have the international perspective input from my colleagues here and trying to process this late-breaking data, which I think really should inform our daily practices when we go back home. I'd like to thank both of my co-participants here and our audience also. Thank you very much.