COMMENTARY

Empagliflozin in HFpEF: Putting EMPEROR-Preserved in Context

Ileana L. Piña, MD, MPH; Javed Butler, MD, MPH, MBA

Disclosures

August 31, 2021

This transcript has been edited for clarity.

Ileana L. Piña, MD, MPH: Hello. This is Ileana Piña. we're recording during the European Society of Cardiology meeting, which happens every year toward the end of August.

I am thrilled to have a good friend with me today, Dr Javed Butler, chair of internal medicine at the University of Mississippi, Jackson. Javed is going to talk to us about heart failure with preserved ejection fraction (HFpEF). We have discussed before the frustration that we sometimes feel when trying to treat these patients because we haven't had a really successful drug where we can say, "This is it."

However, we were very encouraged when we heard that the EMPEROR-Preserved trial of empagliflozin was positive. Javed and our other colleague, Stefan Anker, have really been at the head of this. So tell us about this trial and why this is so important.

Javed Butler, MD, MPH, MBA: Thank you for inviting me to talk to you. EMPEROR-Preserved looked at the sodium–glucose cotransporter 2 (SGLT2) inhibitor empagliflozin in patients with HFpEF, which was defined as an ejection fraction (EF) > 40%. The trial was designed and powered to address three endpoints: cardiovascular death or heart failure hospitalization; total heart failure hospitalization (first and recurrent); and renal function preservation, measured as changes in estimated glomerular filtration rate (eGFR) slope.

Having said that, obviously, while this trial was being done, science continued to progress so we also looked at a bunch of subgroups, although the trial was not designed for it and we did not necessarily have the power for these.

One is whether there is a difference between an EF of 40%-50% vs > 50% because there are data coming out that suggest 40%-50% is different from > 50%. Then the other was the sex-based differences. In some of the other trials, it looked like maybe HFpEF should be defined differently between men and women and that maybe women respond more than men. And then the issue of obesity comes up as well.

EMPEROR-Preserved was a typical large global trial of 6000 patients. We found a highly statistically significant 21% relative risk reduction in time to cardiovascular death or heart failure hospitalization. There was a 28% relative risk reduction in total hospitalization for heart failure, again highly statistically significant. I think we'd agree that the 21% and 28% relative risk reductions are also clinically relevant.

And then the eGFR slope was significantly preserved, with a mean change of 1.36 mL/min/1.73 m2 per year. Overall, the trial achieved all three goals. But then some of the subgroup analyses are interesting, with the caveat that we really have to digest these data and we haven't done that completely.

The bottom line is that for the primary endpoint, there was no heterogeneity on the basis of sex, or on the basis of EF above or below 50%, so that's good news. We may have a HFpEF drug that works across the spectrum of these subgroups. However, while there was a 9% directional benefit in the reduction of cardiovascular death, it did not achieve statistical significance. I'm sure we'll learn a lot from secondary analyses of these data and from the DELIVER trial of dapagliflozin that will be coming out. The dialogue will continue.

Piña: You brought out two very important points, and I was very happy to see that the effects seem to be very balanced between men and women. That's important because we know that the primary population of real HFpEF is women, and it's women that are very hard to control and get them feeling better. I'm not surprised that there wasn't a significant reduction in mortality because what we're seeing with a lot of these trials with a lot of different drugs is an effect on hospitalization but not on mortality. Maybe we have achieved the best mortality benefit with what we've already done. Reducing symptoms in this population is really important. Tell me about the group with EF > 50%, because you did have some patients that are between 50% and 60%.

Butler: It was a pretty sizable proportion. Almost a third split between EF 40%-50%, 50%-60%, and > 60%, and the interaction P value was .21 and the hazard ratio was < 1 for all three groups. Now, obviously as you go across the spectrum of EF, you start seeing the change that you have alluded to.

At the higher EF, you have more women, more obesity, and lower eGFR. We really need to dissect these a bit more, and I am sure when we get some time to digest these data that there's heterogeneity in HFpEF. Just because the trial is positive in all subgroups doesn't mean that the heterogeneity goes away. I'm sure that within this trial also there is heterogeneity, but we need more time to understand these things. But overall we did not see a difference.

Piña: I think it's a very important group because it's a group that we commonly see in the clinic. Again, many of them are women, many of them are obese, and many of them have had hypertension for years, and we make this HFpEF diagnosis based on symptoms — shortness of breath with activity. Obviously, if we could have catheters in, we could see how high these left atrial pressures go whenever there's activity. Now we're talking about cardiac rehab for this group, and we've interviewed Dalane Kitzman on this blog about REHAB-HF. But what about the idea that we need to define phenotypes for HFpEF? What would you say to that?

Butler: Well, the first phenotype is what we observe in front of our eyes. What we really need is to understand the various pathophysiologic pathways that drive the outcome, so that's a little bit different. And then I think we will learn that we can have more targeted therapies. Take the example of amyloidosis and how much we are learning. But the big question is, are there more amyloidosis-like hidden pathophysiologies that are different diseases within HFpEF, where we can understand the biology of the disease a little bit better? That's one way of thinking about phenotype.

The other way of thinking about phenotype is that some people, based on their comorbidities and demographic characteristics, etc., have a phenotype that is more or less likely to respond. That is a no-brainer. If you look across these groups of patients, of course, some people will be more advanced or will have a mix of comorbidities that may make them more or less responsive to the drug. We use the term "phenotype" a bit loosely and we mix these concepts together.

Piña: I remember that the PARAGON-HF trial excluded the very obese. I couldn't enroll patients in that trial because all of my women in New York were very obese. What did you do with BMI and weight in EMPEROR-Preserved?

Butler: We did have a BMI exclusion; it was 40 or 45. I may need to check that. [Editor's note: BMI ≥ 45 kg/m2 was an exclusion criterion.]

Piña: Again, you and I have talked about this, but we need to look at that group, particularly women with higher EFs and with hypertension and obesity. My final question for you: Tell me about the aging of the heart. These are all older, in the high 70s. What's happening with the senescence of the heart (as Ed Lakatta wrote about the aging heart)?

Butler: If you think about all of the therapies that have worked in patients with heart failure, such as RAS modulation, aldosterone, and beta-blockers, none of these are really targeted therapies; they have systemic effects. When you come to SGLT2 inhibitors, while they may have been discovered as anti-hyperglycemic therapies, if you look at the entire pharmacodynamic profile, they have effects on the target structure and function and on the vascular structure and function, adiposity, and renal function. All of these things can worsen with aging endothelial function, aortic stiffness, fibrosis.

Piña: Compliance.

Butler: Exactly. SGLT2 inhibitors have beneficial effects on all of these things, so I'm not surprised that patients with HFpEF who are obese and older see a benefit in terms of chronic kidney disease with SGLT2 inhibitors.

Piña: We don't always recognize how much renal function the patients are losing until we look at it across time. The fact that there's preservation of renal function, maybe that's why the mortality doesn't really drop a lot, because we're not harming the kidney; on the contrary, we're protecting the kidney.

Butler: A couple of very quick comments. One is that we don't have the appetite to do the really long-term trials that you need if you want to show a mortality benefit. This is not like the trials from the 1980s, 1990s, which were powered for mortality; contemporary trials are powered for combined endpoints, and the minute you hit the number of endpoints, you stop.

In terms of those renal endpoints, it's a bit humbling that there are a lot of things that we don't do in clinical practice. Every single patient that we see has an eGFR in their electronic medical record, but we don't have that mindset to track the GFR and the decline and act accordingly. Having said that, there is so much interest in the field of CKD that hopefully that dynamic will change.

Piña: I hope that the trial continues with long-term follow-up. It would be very interesting to see in another 24 months what has happened to those patients.

I want to thank you for your time. We have some very interesting papers coming out of the ESC, and I'm hoping to work with you on those higher-EF patients. Javed, congratulations to you and Stefan on a well-done trial and the first time that we can say that these groups in HFpEF benefit, which is a wonderful thing.

To my audience, I hope that you can apply this to your practice. I hope that when you look at the patient you see them as individuals and try to practice precision medicine, and remember that stability is nothing more than an illusion in heart failure. Thank you for joining me, and have a great day.

Ileana L. Piña, MD, MPH, is a heart failure and cardiac transplantation expert. She serves as an advisor/consultant to the FDA's Center for Devices and Radiological Health and has been a volunteer for the American Heart Association since 1982. Originally from Havana, Cuba, she is passionate about enrolling more women and minorities in clinical trials. She also enjoys cooking and taking spin classes.

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