Icosapent ethyl in post-CABG patients with diabetes

Hello, colleagues. I'm Professor Subodh Verma from the University of Toronto, but I'm here today at the EASD meeting in Madrid. Where we are presenting an analysis from the REDUCE-IT trial in a subgroup of individuals living with type 2 diabetes who also have had prior history of coronary artery bypass graft surgery.

Shown in this slide are my relevant disclosures.

As all of you know, the REDUCE-IT trial was a large randomized double-blind controlled trial that enrolled individuals who either had diabetes and one risk factor or had established atherosclerotic cardiovascular disease. People were enrolled if they had elevated levels of triglycerides. A triglyceride level of greater than or equal to 1.7 millimoles per liter, or less than 5.6 millimoles per liter. These individuals were randomized to receive icosapent ethyl 2 grams twice daily versus placebo in an event-driven trial with a 5-point MACE as the primary outcome comprising CV death, non-fatal MI, non-fatal stroke, coronary revascularization, and unstable angina requiring hospitalization.

We have, prior to this, reported the primary results of the REDUCE-IT trial, which are shown here on the left. A 25% relative risk reduction for the primary endpoint, absolute risk reduction of 4.8%, number needed to treat of 21, and a highly persuasive P value. On the right of this slide, you see the key secondary endpoint, which is the so-called "Hard 3-point MACE", which was reduced by 26% with icosapent ethyl versus placebo. We also looked at total events, i.e. first and subsequent events, and they were reduced by 31% with icosapent ethyl in the total trial, in the overall trial, with a highly persuasive P value.

Now let's talk about the rationale for why we did the diabetes prior CABG analyses in REDUCE-IT. As all of you know, people living with diabetes are at high cardiovascular risk, and coronary artery bypass graft surgery is the preferred mode of revascularization in people with diabetes and multi-vessel coronary artery disease. However, despite revascularization, there is considerable residual risk that remains in patients following bypass surgery in the context of coincident diabetes. The effects of icosapent ethyl in this population are not known, and that was the rationale for doing this post-hoc analysis. About 800 individuals in the overall REDUCE-IT trial, which enrolled over 8,000 patients, had a history of type 2 diabetes and a prior history of coronary artery bypass graft surgery.

As you can see here, the mean age was around 67, about 18% were female, and the majority of individuals, 98.7% had a history of type 2 diabetes. Background LDL cholesterol was 72 milligrams per deciliter, HDL cholesterol 38 milligrams per deciliter, and you see the median triglycerides were 229 milligrams per deciliter. These patients were well treated. Most of them were treated with oral antihyperglycemic therapies. Background use of antihypertensive therapies. Lipid-lowering therapies was excellent. 95% of individuals were taking moderate to high-intensity statins as shown in this slide.

Here we show you the primary composite outcome in this post-hoc analysis of people living with diabetes and concomitant coronary artery bypass graft surgery. The first point I'd like to make here is in red, just reminding you of the very high-end recalcitrant risk that patients with diabetes who've had a prior history of coronary bypass graft surgery have in the placebo group. The event rate for 5-point MACE was 42.4% in placebo-treated patients. That was reduced to 31.2% with icosapent ethyl yielding a hazard ratio of 0.72 for the primary composite 5-point MACE. This resulted in a large absolute risk reduction of 7.9%, a number needed to treat of 13.

Now, what about the hard 3-point MACE? This is shown in this slide. Again the placebo event rate in this population was exceedingly high. 35.9% reduced to 21% with a hazard ratio of 0.59 and a number needed to treat of 11, an absolute risk reduction of almost 10% in this population for the 3-point MACE reduction. We then looked at total events i.e. time to first event plus subsequent events. You can see here that the total events were reduced from 276 in the placebo to 228 in icosapent ethyl-treated patients yielding a relative risk reduction of 0.72 and a P value of 0.049.

Now, shown here are subgroup analyses really comparing the efficacy that we have observed in this subgroup relative to other subgroups in the trial. As you can see here, in individuals with diabetes who've had a prior history of bypass surgery, the point estimate is 0.72, which is entirely consistent with all of the other analyses within the trial, including people with a prior history of ASCVD who do not have diabetes, as well as individuals with a prior history of ASCVD who have diabetes. Essentially, the efficacy of icosapent ethyl seen in this subgroup seems to be consistent with what we've seen in the entire trial. Safety was generally consistent with the full study, overall tolerability and adverse events of icosapent ethyl and placebo in patients with diabetes and prior CABG were also consistent with the entire study. As was seen in the full study, bleeding events appear slightly higher with icosapent ethyl in this subgroup, but without statistical significance between treatments. AFib or Aflutter events were more prevalent and we know that with icosapent ethyl in people with diabetes and prior CABG, but there was really no statistically significant difference between groups in this regard.

We acknowledge limitations of this sub-analysis. REDUCE-IT was designed and powered for the primary composite endpoint and not powered for subgroup analyses. These data are post hoc, therefore hypotheses-generating. Randomization was not stratified by prior history of CABG. No adjustments were made for multiple comparisons.

What are the key conclusions and takeaways from this presentation? First, in REDUCE-IT, patients with a history of diabetes and CABG at baseline, icosapent ethyl treatment was associated with significant reductions in ischemic events with a safety profile that was not significantly different from placebo. For the primary 5-point MACE, the relative risk reduction was 28% with an NNT of 13. For the 3-point MACE, the relative risk reduction was 41% with an NNT of 11. Therefore we would suggest, with acknowledging all the limitations that I've discussed, that IPE should be considered as part of secondary prevention in post-CABG patients with a history of diabetes who meet the REDUCE-IT criteria.

Thank you very much.