Icosapent Ethyl for Cardiovascular Risk



Alan Brown, MD: We could talk for hours on this. We need to get to some of the other, newer agents. I'm going to start with Matt on this one, because he is an eicosapentaenoic acid [EPA] expert. We had the REDUCE-IT trial [NCT01492361], which showed that giving the branded form of EPA showed a remarkable reduction in cardiovascular events, compared with placebo. It seemed to have little to do with the lipid changes. The lipids did change, but not anywhere near enough that any of us would say it could explain the benefit that was shown in that trial.

I was shocked by that, and a little skeptical. It was the first trial with an omega-3 fatty acid, which showed compelling evidence that there was event reduction, much less such remarkable event reduction. You did the EVAPORATE trial [NCT02926027], which showed some imaging evidence that supports the outcomes. That helps me. I feel better about it.

Tell us a bit about eicosapentaenoic acid. Who are the right patients for it? Also, provide some background for what you showed in your EVAPORATE trial.

Matthew J. Budoff, MD: It's a pure EPA. When you look closely at the fish oils or the omega-3s, they include DHA [docosahexaenoic acid] and EPA. DHA consistently raises LDL [low-density lipoprotein] while lowering triglycerides. EPA consistently doesn't raise LDL while lowering triglycerides. That partially explains some of the differences that we've seen with the EPA trials, JELIS [NCT00231738] and REDUCE-IT, as compared with a host of combination therapies. Most recently, the STRENGTH trial [NCT02104817] with high-dose EPA and DHA did not show a benefit.

There is some biological plausibility to why EPA works in the outcome studies. REDUCE-IT showed a 25% event reduction on top of maximally tolerated statins. It surprised a lot of us, Alan. We did not expect it to be quite that robust, especially because the triglyceride reductions were modest. It also stabilized plaque.

There are some great data from R. Preston Mason, PhD, MBA, out of Harvard Medical School showing that it has some plaque stabilization characteristics and lowers inflammation. The inflammation story is still viable. It would be interesting to see, because bempedoic acid also lowers inflammation, where their outcomes studies point us. But it has some biological plausibility.

We did the EVAPORATE trial to say, does it affect plaque progression? We did CT [computerized tomography] angiography at baseline. It was 4g icosapent ethyl versus placebo. We followed them for 1 and a half years. There was some plaque regression, or at least statistical slowing of progression, compared with the placebo group in that study. EVAPORATE just gives us 1 potential mechanism of action. Maybe this is working at the plaque level, and there are a lot of data out of Japan on this already. They have a different version of EPA which they've used in Japan, and there are a lot of IVUS [intravascular ultrasound] data and other intravascular ultrasound studies that they've done.

This is just a supplement to the available literature, but it does look like it lowers plaque. It looks like it lowers events, as shown in 2 randomized trials now. I do incorporate into my practice for those patients with high triglycerides. The indication now is for patients with triglycerides above 150mg/dL. The guidelines specify 135mg/dL. There is a slight difference between the FDA indications and most of the written guidelines. I use it in patients with triglycerides above 135mg/dL, as in the REDUCE-IT trial and the EVAPORATE trials. I also use it in patients who have ASCVD [atherosclerotic cardiovascular disease] who need additional risk reduction, or in primary prevention diabetes when a patient’s triglycerides are still elevated.

Alan Brown, MD: OK, that was very eloquent. I don't think it's been incorporated in to any United States guidelines, but we have expert consensus documents from NLA [National Lipid Association] and ACC [American College of Cardiology] as to which patients it would be appropriate for.

Matthew J. Budoff, MD: I think it's in the most recent American Heart Association statement, as well.

Seth J. Baum, MD: The ADA [American Diabetes Association] had a strong statement about it.

Alan Brown, MD: That's right. They did incorporate it into ADA guidelines.

Matthew J. Budoff, MD: Alan, that point is important. Deepak Bhatt presented REDUCE-IT at the same exact session where the new cholesterol guidelines were presented. They were within minutes of each other, so there's no way they could have incorporated REDUCE-IT into the 2018 cholesterol guidelines. That's when the data became known.

Seth J. Baum, MD: There is 1 additional comment I’ll make about omega-3 fatty acids. The omega-3s are EPA, DPA [docosapentaenoic acid], and DHA. They all have very different biologic activities. While EPA tends to incorporate itself into plaque, DHA doesn't. DHA crosses the blood-brain barrier and is found in the brain, and EPA is not. DHA is the precursor to a protectant that is the strongest neural protective substance currently identified.

My fear is that people are going to stop thinking about consuming DHA, just take EPA, and say, “OK, that's enough.” We need to eat fatty fish, which has a lot of DHA in it. When we get to the point at which we measure levels—and I do measure levels on these—we can treat in a more personalized fashion.

Alan Brown, MD: Good.

Pamela Bowe Morris, MD: I wanted to make 1 more comment. Regarding comment about the benefits being unrelated to measured lipid levels, there's a remaining issue. The data that have not been published, which were presented, are the data on remnant cholesterol. There is the potential. We know that remnant microproteins are incredibly important in patients who have elevated triglycerides. Those data will be very important for us to be able to say that the benefits are unrelated to lipid levels in total with confidence.

Alan Brown, MD: That's fair. J.R. Nelson, MD, FACC, FNLA, of California Cardiovascular Institute, has published a couple of papers on this and shown improvement in remnant particles. Again, if you do the math, you would have a modest improvement in remnants. I can't say for sure. There is a school of thought that it might be explainable by the lipids. I get your point. It's very interesting. No matter how it works, adding EPA in these high-risk patients with diabetes, established atherosclerosis, and triglycerides over 150mg/dL who were enrolled had a number needed to treat similar to statin vs placebo. Those were very impressive results.

Transcript Edited for Clarity

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