Paradigm Shifts in Lipid Lowering - Episode 8

EPA in the Prevention of CV Risk

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Panel of experts discuss the use and safety profile of purified icosapent ethyl compound (EPA) in prevention of CV risk.

Keith C. Ferdinand, MD: Norman, give me a short take on where EPA [eicosapentaenoic acid] makes it into this commentary of lipid-lowering agents changing the lipid profile for patients who have high risk.

Norman Lepor, MD, FACC, FAHA, FSCAI: Great question. I was a PI [primary investigator] on the REDUCE-IT trial, which was a CV [cardiovascular] outcome trial assessing the impact of eicosapentaenoic acid, in terms of its ability to impact cardiovascular events in a patient population that was mild to more moderately hypertriglyceridemic. 

As an investigator, I remember the phone call we received from the sponsor about a day or 2—Manesh is smiling; he was probably on that call too. I remember being at the TCT [Transcatheter Cardiovascular Therapeutics] meeting, and they said we want you to be out of the public area. When they told us there was this 25% cut in CV outcomes with a P value of something like less than .00000001, it blew us away. It blew me away. 

And the data looked real. You looked at all the different CV events on their own, and there were significant reductions. The EPA is the real deal, and what we’re going to find from the label recommendation is to use it with patients who have triglycerides over 150 mg/dL, although its mode of action seems to be unrelated to actual triglyceride reduction. 

There are some theories that the EPA actually enters the vascular wall and impedes the development of plaque progression and impedes plaque rupture and thrombosis. It’s the real deal. It seems that with all the clinical trials we have seen, these mixtures of DHA [docosahexaenoic acid] and EPA have not worked out in terms of cutting events. 

I am very assertive in using EPA in the patient population with the elevated triglycerides. But I have a theory, and then I will let others opine. Just as we have seen the goals for LDL [low-density-lipoprotein] reduction going down and the recommendations in terms of when we start to initiate treatment and such, I think we’re going to see the same thing with triglycerides. What we are going to see going forward is that “normal” levels of triglyceride aren’t really normal, and they are pathologic.

I have a funny feeling that we are going to see the use of drugs like EPA at least being studies in a non-hypertriglyceridemic patient population, and we may see efficacy there. But I have definitely introduced it into my clinical practice in an assertive way, on top of very aggressive LDL aggression in terms of really taking a global approach to mitigating cardiovascular risk.

Keith C. Ferdinand, MD: I asked everyone to give me their take-home message on how they think inclisiran is going to be built into our practices in the future, so let me hold on hat. How is EPA, eicosapentaenoic, going to be built into our practices? Norm told me about the studies and the wonderful results that came from those studies. It is here; it’s approved. Linda, Manesh, Dean, how does it affect your practice?

Dean Karalis, MD: I can start. I think Norm is correct. If you look at the cardiovascular risk associated with triglycerides, that risk starts to rise sharply when the triglycerides are over 100 mg/dL.

The second is if you think back to a number of years back, when the American Heart Association came out with guidelines on hypertriglyceridemia, they actually called a normal triglyceride or an optimal less than 100 mg/dL. Norm is correct on this. Triglyceride levels between that 100-and-200-mg/dL range, which are often the levels that are overlooked by clinicians when they see that in their patients, should be a red flag as a marker of increased residual risk. 

It appears that the mechanism by which EPA works is through multiple mechanisms and not just triglyceride lowering. Plaque stabilization, inflammatory, anti-inflammatory effects. If you look at the study, patients could get into the REDUCE-IT trial if their triglycerides were from 135 mg/dL or higher. In the group of patients with triglycerides of 15 to 150 mg/dL, it appeared to have the same benefit as those who had triglycerides that are higher.

We’re going to approach treating cardiovascular disease in a multifaceted approach—targeting LDL, using other agents that have cardiovascular benefit like EPA—just like we’re seeing now with the SGLT2 inhibitors and the GLP1 agonists. The future is going to be on combination therapy to drive down cardiovascular risk in these high-risk patients.

Keith C. Ferdinand, MD: Linda, Manesh, how does EPA fit into your practice?

Linda Hemphill, MD: It is very hard to argue with a P value of .000001.

Keith C. Ferdinand, MD: It was too good to be true.

Linda Hemphill, MD: Yes, I am using it in my secondary prevention patients who I have achieved—or wherever they are regarding their LDL, if their triglycerides are over 150 mg/dL.

Keith C. Ferdinand, MD: Manesh?

Manesh Patel, MD: Yeah, that is the message for me. We are at a great place with lipid and risk reduction in that we have multiple options. We are almost at the place where, like with heart failure, we are going to have to think about sequencing things and which 1 goes when, but almost everybody says statins are first, and we recognize that’s what has to be first, and we’ll talk about tolerance and everything.

If I can get LDL to goal in secondary prevention patients, or even toward it, and triglycerides as Norm and others have just said really well, we have underrepresented and under-recognized that risk, likely because we haven’t had therapies that work. Once you have a therapy that works, you start paying attention to things a little more because you have something to do for that patient.

We are using it now, and there’s going to be increasing use. There probably are more studies coming too. The patient who gets high-dose EPA, as we just described, is the patient for me who is secondary prevention, with an LDL hopefully near goal, who still has an elevated triglyceride. The higher the triglycerides, the more likely the person is going to get the therapy. Obviously, there’s a risk of cost and all the other things we do for our patients to get them on it.

Keith C. Ferdinand, MD: If you enjoyed watching this HCPLive® Peer Exchange, if you enjoyed the content, please subscribe to our e-newsletters to receive upcoming Peer Exchanges and other great content right in your in-box. Thank you very much for listening to this program.

Transcript Edited for Clarity