Q&A on EMPEROR-Preserved With Javed Butler, MD

Heading into the European Society of Cardiology (ESC) Congress 2021, all eyes appeared to be on empagliflozin as cardiologists and other clinicians awaited the results of the EMPEROR-Preserved trial, which Eli Lilly and Company and Boehringer Ingelheim announced as the first and only successful trial for heart failure with preserved ejection fraction (HFpEF) in early July.

Results of the phase 3 trial suggest use of empagliflozin was associated with a statistically significant 21% relative risk reduction for the composite end point of hospitalization for heart failure or cardiovascular death. Further analysis of results suggests this effect was mainly driven by a 27% relative risk reduction for hospitalization for heart failure and the reduction seen for cardiovascular mortality failed to reach statistical significance.

"These impressive results will bring hope for the millions of people who currently have limited therapeutic options for a very serious, life-threatening condition," said Jeff Emmick, MD, PhD, vice president of Product Development at Eli Lilly and Company, in a statement. "Now there is a light at the end of the tunnel. If approved, Jardiance would become the first clinically proven therapy across the full heart failure spectrum. The results of EMPEROR-Preserved offer an opportunity to fundamentally change the future for people with heart failure."

As with every potentially paradigm-shifting trial in cardiology, the results of EMPEROR-Preserved became the subject of discussion and debate shortly after release. With an interest in learning more about the results and how they are interpreted by those with involvement with the trial, Practical Cardiology sat down with co-principal investigator Javed Butler, MD, professor and chairman of the Department of Medicine at University of Mississippi Medical Center, for more insight.

Practical Cardiology: Could you discuss the significance of results and also address concerns over a lack of effect on cardiovascular mortality?

Javed Butler, MD: So, the way I interpret the results is that the heart failure, hospitalization benefit was pretty impressive in 3 different ways. One, the magnitude of benefit. Second, the consistency of benefit across EF range. Third, the consistency of benefit in the two sexes.

So, where the field is right now, we've had previous trials that have started showing some benefit but have been primarily limited to ejection fractions of 50-55% or less. There is sort of a raging debate going on in the heart failure world anyways, whether 40 -50% should be lumped with HFrEF or HFpEF, but most of the HFpEF trial have included 40-50% in HFpEF because that's where the evidence gap is.

So, sacubitril/valsartan got an indication for chronic heart failure, but then there was this clause that results are more significant for EF below normal and then there was a significant sex interaction. We have seen the sex interaction in spironolactone, as well. In fact, there was there were some calls after saying maybe HFpEF should be defined differently in men and women because of that sex interaction.

So, what we are finding here is the primary endpoint, cardiovascular death, heart failure hospitalization, total heart failure hospitalization reduced with 20 to 28-29%, relative risk reduction. So, pretty sizable risk reduction, the interaction p-value of 40-50, 50-60, and greater than 60 was negative. So, they're consistently seeing the benefit. Additionally, the men versus women benefit was of equal strength.

On the positive side, we can say is that this is the first unequivocal positive trial in patients with HFpEF and it's for all patients with HFpEF, regardless of gender or ejection fraction. Now, the question comes up of cardiovascular mortality. The bottom line is that cardiovascular mortality was not improved. One would like to look at the results with some whiff of optimism and say there was a 9% directional benefit, but at the end of the day, that was not statistically significant.

The trial was very well-powered and had the number of events and the size of the trial. So, I don't think that we can blame it on the power per se. The question is, why not the mortality benefit?

Well, there are 3 explanations. One is that there is no mortality benefit and that's that—this drug does not improve mortality. Two, is that patients with HFpEF are older patients. And this has been very well-documented in literature, that in HFrEF 80% of the mortality is cardiovascular and its basically progressive pump failure and sudden cardiac death. The pathophysiology of all of that is related to neurohormonal activation. So, it's single pathophysiology and 80% of the mortality is covered by that single pathophysiology. In HFpEF, we see more noncardiovascular mortality and more diversity within cardiovascular mortality.

So, the first thing is that empagliflozin doesn't reduce mortality. The second thing is that with all of these competing risks for death, maybe mortality will be reduced by a combination therapy and not a single therapy and maybe that is an unattainable goal in these octogenarian patients. The third, which I would like to believe, but I am saying this completely as an opinion—I have no data to support this—but what I would like to believe is that there is such a strong link in hospitalization and mortality, that it makes no sense that you will improve hospitalization and not improve mortality, right? Because hospitalization is worsening heart failure, worsening heart failure leads to mortality. So, there's a direct link that you're not seeing here and then, maybe, 2 years of follow-up is not enough in order to improve mortality in HFpEF. In HFrEF, in 2 years, you can show mortality benefit because the pathophysiology is very narrow and singular, but in HFpEF its all of these things. Maybe those beneficial effects will take longer time and maybe take 4 or 5 years. In that case, with a 2-year follow-up, you start seeing the directional benefit at 10%, which is not statistically significant, but going in the direction of hospitalization, and maybe it will take a longer trial. I have no idea, but that that keeps me in business of trials—to find a mortality cure.

Practical Cardiology: What does it say about the rapid ascent of this class to relevance for cardiologists, that it's headlining the largest conference of the year for 3 years in a row?

Javed Butler, MD: The 2 quick comments. One, the simplest comment is that the cardiologist just needs to adopt these therapies and we'll start getting to feel a little bit comfortable. At the end of the day, cardiologists put catheters in people's hearts in the middle of the night and this is a pill—it's not really that big a deal. So, I think we'll need to become more rapid adopters of these therapies with all of these trials coming out, but to answer the real question that you're asking: human biology is very interrelated. The heart and the kidney, and diabetes, and prediabetes, and adiposity. All of these things can lead to inflammation and oxidative stress and endothelial dysfunction, and reactive oxygen species. All of these things are much more interrelated.

We sort of have 2 kinds of therapies out there, right. So, 1 is very, very, very focused on a specific mechanism. Like omecamtiv mecarbil, it eases contractility—it's very, very specific. Then we have these therapies that are generic, like ACE inhibitors and beta-blockers and SGLT2 inhibitors that affect a whole bunch of different pathways. By affecting a whole bunch of different pathways, they have beneficial effects on a whole bunch of different organ systems as well.

To me, we started with diabetes, and that serendipity really worked out, but if you look at the mechanism of action of SGLT2 inhibitors, if we had not focused on their glucose, uric effect first and if we would have started looking at all of their biologic effects, honestly, we would have said that this drug also has glucose-controlling effect. This is a cardiovascular risk-modifying agent is just history, but its not biology on the basis of which it became a diabetes drug first.

So, there is no doubt these are good diabetes therapies. I'm not at all either dinging the importance of hemoglobin A1c control or the importance of SGLT2 inhibitors as diabetes therapy, but the bigger picture is that we are now seeing benefit in CKD patients and now in HFrEF patients and HFpEF patients. Now, there are even post-MI studies going on and all that kind of stuff. These are really cardiovascular risk-modifying agents that have glucose control effects as well.

It is completely within the wheelhouse of cardiologists to adapt these mechanisms and the fact that this nonspecific wide pharmacodynamic effect easily makes sense, that they have cardiac benefit and renal benefit and adiposity benefit and vascular function benefit, because the underlying pathophysiology is common for all of these things.