Now when the first EMPA-REG trial came out in 2015, we really did not know as much. What have we learned about SGLT2 inhibitors’ mechanism of action that produced the results in EMPEROR-Preserved? But today, all I can say is that, above 65%, that 10% of the population is where we would not see benefit. I don't know what I'm saying is true or not. One is people who had shortness of breath and met the criteria for the trial and came in, but really did not have the syndrome of HFpEF-so maybe they had amyloidosis, maybe they had something else going, advanced CKD -and then the true HFpEFers, maybe the response was different between the 2 groups and it just all got neutralized. So not having looked into it in detail, my bias says that the greater-than-65% represents 2 distinct populations. What about the other 10%? We are, as you might imagine, doing a really deep dive and trying to sort of understand that. So the benefit, both in men and women, is accrued in 90% of the population that was seen. ![]() One is that people with ejection fraction greater than 65% represent 10% of the population. Well, there are 2 interpretations of that. And 65% seems to be the place where there is a deflection point and we don't see the benefit. The 2 things that we learned are that we are seeing a consistent benefit, and interestingly enough, a consistent benefit with both men and women-so we are not seeing that major sex interaction that we have seen in the trial-all the way up to ejection fraction of 65%. And we looked at it across the ejection fraction spectrum. But then the question is, where do these things go? So, we looked at cardiovascular and heart failure hospitalization, heart failure hospitalization, and total heart failure hospitalization. So that was 41% to 49%, 50% to 59%, and 60%-plus, so that's what we showed. What we presented, or what came out in New England Journal of Medicine, was prespecified analysis that both the journal and everybody holds us to. So, what we did was we have already done a lot of a subgroup analysis to try to sort of understand and tease that signal more. We have this whole history of showing that as ejection fraction goes up, the benefit is less. Now, if empagliflozin in EMPEROR-Preserved was the first trial ever done, I think that trend that you're talking about in the primary end point with ejection fraction, we probably would have ignored it by saying that, “Oh, it's just noise with little interaction, the P value is completely nonsignificant, and there is nothing there.” Except we don't have these results in isolation. And also there was a significant sex interaction: that women tended to benefit more, and benefit to a higher ejection fraction level, than men, who benefited less and at a lower ejection fraction. One is that most of the other drugs have shown benefit in ejection fraction 55% or less. What we have learned in the previous trials of HFpEF are a couple of things. ![]() I don't think we can ignore all the previous trials, and we have to look at the new evidence in the light of all the previous trials. There was a clinically meaningful and statistically significant 21% reduction in the combined primary end point, making this trial the first to show benefit for patients with heart failure with reduced ejection fraction-for which targeted treatments have been hard to pin down.Ĭan you explain the difference in empagliflozin effectiveness for ejection fractions above 50%? And I believe these things work in concert, noted Javed Butler, MD, MPH, MBA, chairman for the Department of Medicine at the University of Mississippi, in an interview for ESC Congress 2021, this year's virtual meeting of the European Society of Cardiology.īutler, a co-lead investigator of the EMPEROR-Preserved trial presented at the ESC Congress, said the study aimed to address 3 questions: (1) time to cardiovascular death and heart failure hospitalization (2) total heart failure hospitalization, first and recurrent and (3) renal function preservation in terms of eGFR (estimated glomerular filtration rates). Whatever your theory of heart failure with preserved ejection fraction (HFpEF) is-the physiology is really complex-sodium glucose co-transporter 2 (SGLT2) inhibitors seem to be attacking every one of those.
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