Dr Børge G. Nordestgaard on Unexplained Omega-3 Mysteries in REDUCE-IT vs STRENGTH

Both REDUCE-IT and STRENGTH recruited people with very high triglycerides and tested different formulations of omega-3 fatty acids, but the results were different. About 12% of the difference can be explained, noted Børge G. Nordestgaard, MD, DMSc, Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, but 13% cannot be, given that REDUCE-IT had a 25% reduced risk of atherosclerotic cardiovascular disease.

Both REDUCE-IT and STRENGTH recruited people with very high triglycerides and tested different formulations of omega-3 fatty acids, but the results were different. About 12% of the difference can be explained, noted Børge G. Nordestgaard, MD, DMSc, Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, but 13% cannot be, given that REDUCE-IT had a 25% reduced risk of atherosclerotic cardiovascular disease.

Nordestgaard was principal investigator on a study that examined findings from the 2 trials. These results were presented today at ESC Congress 2021 by lead investigator Takahito Doi, during the session, “Explanations for Contrasting Results of REDUCE-IT vs. STRENGTH,” with simultaneous publication in the European Heart Journal, the official journal of the European Society of Cardiology.

Transcript

Why did you do a study on the contrasting results of the REDUCE-IT and STRENGTH trials?

The background, why did we do a study like that? I think the answer is 2-fold.

One is that the 2 trials, the REDUCE-IT trial and the STRENGTH trial, are both trials that recruited people with very high triglycerides and then they gave them triglyceride-lowering drugs, omega-3 fatty acids. And so I would like to understand how much of the effect in REDUCE-IT could be explained by the triglyceride reduction. The other objective, of course, is to try to understand why did 2 such similar studies come to contrasting results, to very different results? It's a big mystery, really.

So, what did we do? We tried to mimic these 2 trials. We have a very large study in Copenhagen called the Copenhagen General Population Study with a total of 106,000 individuals. And within this cohort of people, we took out the ones that mimic the participants of the REDUCE-IT trial—this was about 5700 people—and we took out some other people. Some of them might be overlapping, but the ones that mimic the participants of the STRENGTH trial, this was 6700 people roughly. And then, within these 2 cohorts mimicking the 2 trials, we looked at—based on what happened in our study—what would the effect be of the change in triglycerides, the change in LDL cholesterol [LDL-C], and the change in CRP [C-reactive protein] in the active oil arm and the comparator oil arm of the 2 trials. And then of course looking also at the between-arm differences.

If we first look at what did we find for REDUCE-IT—so in these 5700 people—what you saw here was that in the active oil, EPA [eicosapentaenoic acid], by the changes in triglycerides, LDL, and CRP we could explain a 4% reduced risk of EPA. That's not very much compared to we know the overall effect was 25% reduced risk. But then very surprisingly, we found that when we looked at the effect of triglycerides, LDL-C, and CRP in the comparator oil, the mineral oil group, they could explain a 7% increased risk in the comparator oil. So when we look at the between-arm differences of the EPA vs mineral oil, just the effect, as reported in the REDUCE-IT trial itself, on triglycerides, LDL-C, and CRP, could explain a 12% reduced risk. But in fact, REDUCE-IT observed a 25% reduced risk of atherosclerotic cardiovascular disease [ASCVD]. So you could say that we could explain 12%, most of it is actually because comparator oil, mineral oil give a larger effect—but we don't explain all of it because there’s 13% we cannot account for.

When we then look similarly in the STRENGTH trial, and then look at the EPA plus DHA [docosahexaenoic acid] arm, how that affects triglycerides, LDL, and CRP, the result was very similar to EPA in the REDUCE-IT trial. It was actually a little bit more: minus 6% ASCVD risk. But the comparator oil, corn oil, it had no deleterious effect. It only had, if anything, a 1% protective effect—sort of between our difference in the STRENGTH trial, was a 4% reduced risk. And this, of course, comes very nicely with the [inaudible] of the STRENGTH trial, which was really the confidence interval of the oil, after all of the minus 4% that we found.

So that said, summing up all what we showed, the comparator oil arm in REDUCE-IT explains part of the difference, but there's something, 13%, that we don't account for, and the EPA vs EPA/DHA in the 2 trials give similar results.