Role of icosapent ethyl for secondary CV prevention in diabetes  

Cosentino:       

Good morning. My name is Francesco Cosentino, and we are here today with Prof. Subodh Verma to discuss about his post-hoc analysis on the REDUCE-IT trial with icosapent ethyl, which selected patients with history of diabetes and prior coronary artery bypass grafting. Please, Subodh, if you want to briefly introduce the results of your analysis.

Verma:               

We know that people who have diabetes who have multi-vessel disease, the preferred mode of revascularization is with coronary artery bypass graft surgery. Now, despite improving surgical outcomes, there is a considerable residual risk in people who have multi-vessel disease, who've had bypass surgery, particularly when they have coincident diabetes. We are looking for solutions beyond LDL lowering, beyond our usual pharmacological and non-pharmacological approaches to reduce risk, particularly in this group of people that may have hypertriglyceridemia as a risk factor.

That was the rationale to look at the REDUCE-IT trial. As you know, the REDUCE-IT trial is a landmark trial. It has already changed guidelines throughout the world for the use of icosapent ethyl 2 grams twice a day to reduce cardiovascular events.

In this post-hoc analysis, we had about 800 patients who met the criteria of having a prior history of diabetes and a prior history of coronary artery bypass graft surgery. Of course, people had to have a triglycerides of greater than 1.52 to get into the trial. What we found in this trial was that, first of all, for the five-point MACE and the three-point MACE, the overall benefit was consistent with what we saw in the REDUCE-IT trial. Of course, numbers are small, but the hazard ratio for the primary analyses of the five-point MACE was 0.72. The hazard ratio for the three-point MACE was 0.59. Despite the fact that it's post-hoc and its limitations, I think it is very instructive given the fact that we don't have many tools to use in secondary prevention in this high-risk population.

Cosentino:       

This is very, very solid results of a trial because we need to remember that REDUCE-IT trial is the first non-LDL targeted trial to prove cardiovascular benefit independent of triglyceride-lowering effects. If these may open up discussion on the potential mechanism of the IPE, which may go beyond because we know that icosapent ethyl basically increase the activity of lipoprotein lipase, reduce liver lipogenesis, but has also important anti-inflammatory properties. Do you think that these anti-inflammatory properties are somewhat more important than the triglyceride-lowering effect?

Verma:               

This is a wonderful question about how does this work? You're absolutely right. Initially, when the trial was designed, the thought was that this may be mediated through triglyceride-lowering, and subsequent analyses from the trial have demonstrated quite convincingly that the baseline level of triglycerides, or the triglyceride level that was achieved after one year, the efficacy was agnostic to all of that, suggesting that that was probably a good way to risk stratify the population and identify higher risk patients but was not the mediator of this benefit. It really begs the question as to how is this working. I agree with you wholeheartedly that their data is emerging that these agents are anti-inflammatory vascular protective strategies.

Cosentino:      

Sorry to interrupt you. I'm thinking about the results of the EVAPORATE trial. It's a small trial but mechanistic studies with very much--

Verma:               

I agree with you. The mechanistic studies with EVAPORATE suggested that, even within the short term, there was plaque regression and the so-called the vulnerable plaque was reduced significantly within an 18 month period. There's a large amount of basic science that has now been generated that suggests that these agents are vascular protective. They protect the endothelium. They really integrate within the vascular endothelium eliciting profound anti-inflammatory benefits. The way in which EPA integrates within the endothelium seems to be quite unique and is not shared by strategies that are EPA plus DHA-based. Remember, icosapent ethyl is a highly purified ethyl ester of eicosapentaenoic acid. Sure, it has its ancestry and fish oil, but this is not a fish oil per se. In Canada, Francesco, we have been very careful in our guidelines to say that whereas IPE is a class one recommendation, similarly, we also strongly recommend against over-the-counter Omega-3 fatty acids as a substitute because we know that that is biologically not being shown and has never been tested.

Cosentino:       

Talking about guidelines, most of the international bodies' recommendations are following very much the inclusion criteria of REDUCE-IT.

Verma:               

That's right, yes.

Cosentino:       

Which is somewhat limiting because we are discussing that the effect is going beyond hypertriglyceridemia. Don't you think that we may have enough evidence to extend eventually the indication?

Verma:               

Now, listen. Conceptually, I agree with you, but in the absence of a clinical trial, I think guideline writers are restricted to what was done in the trial and the inclusion criteria. Conceptually, this concept that the benefit could be observed in a broader population, even people who were not identified based on triglycerides is plausible but needs to be tested. I think you and I have had a long-standing interest in diabetes and cardiovascular risk reduction, and it's such a easily identifiable high-risk population for which we need solutions. It's not just diabetes and CABG is a high-risk population, diabetes and prior MI is a high-risk population. The guidelines that you wrote and first author on a few years ago really put this on the center stage that diabetes needs to be prioritized with antihyperglycemic therapies. I remember your guidance changed the entire discussion around prioritizing GLP-1 and SGLT-2 inhibitor early on. I think this data just adds yet another mechanism and another way to counter residual risk. Look at the residual risk in this population. 41% have a five-point MACE event over 4.9 years.

Cosentino:       

Yes, and definitely these are patients relatively well controlled in terms of LDL cholesterol.

Verma:               

Exactly.

Cosentino:       

Still, the residual risk, which may be inflammatory or metabolic, is there, and we need new tools to tackle it.

Verma:               

No, I agree with you. Just beyond statins, despite being on statins, despite having good LDL cholesterol levels, you see that the event rates are so high.

Cosentino:       

One last question. You mentioned about the side effect of increased incidence of atrial fibrillation. Do you think that this is something that we should consider when we want to implement this treatment?

Verma:               

I think with the REDUCE-IT trial, there was a 1% excess as in adjudicated AFib or Aflutter requiring hospitalization, we know that. At the other end, there was a 28% reduction in the rates of stroke as you know. I have a lot of clinical experience and I haven't seen it clinically yet. If someone has AFib, I would still use it. If someone develops AFib, I would still continue to use it and anticoagulate them if required. I think that the mechanism of why AFib/Aflutter develops in a small number of people with this therapy remains unclear. I do believe that it is a real observation. How we use it, I don't think it should be an impediment to how we implement icosapent ethyl in our practice.

Cosentino:       

I think that in order to identify the patient who benefit most of this treatment, do we need to go still for the lipid profile but the atherosclerotic cardiovascular risk profile has to play an important role in the implementation of this new drug.

Verma:               

I agree. Now, as you said, what is the knowledge is of no value unless you implement it. What is the point? We need to find better ways. I think one way is to find therapies that have quite a large magnitude of benefit, that are well tolerated by patients, and as a community, have these ongoing discussions. It's not competing. This is not competing with statins. Statins are not competing with GLP-1 or SGLT2. We need all complementary approaches to reduce risk.

Cosentino:       

Thank you, Subodh. It's been a real pleasure to dialogue with you on this important topic.

Verma:               

Same here. Always.

Cosentino:       

Thank you very much.