COMMENTARY

SGLT2 Inhibitors in HFrEF: Putting EMPEROR-Reduced in Context

Ileana L. Piña, MD, MPH; Milton Packer, MD

Disclosures

August 31, 2020

This transcript has been edited for clarity.

Ileana L. Piña, MD, MPH: Hi. I'm Ileana Piña, professor of medicine at Wayne State University. On my blog today we are at the virtual European Society of Cardiology (ESC) meeting. I'm thrilled to have with us my good friend from Baylor, Milton Packer, who presented a very new and important trial. Milton, welcome. Give me the high points of your trial, and why has this been billed as so important?

EMPEROR-Reduced Trial

Milton Packer, MD: It's always a delight to be with you. Earlier we had a chance to present our results from the EMPEROR-Reduced trial at the ESC. This is a trial of 3730 patients with heart failure and a reduced ejection fraction (HFrEF), with or without diabetes. Most of the patients had ejection fractions of 30% or less. We specifically enriched the trial for patients with more severe disease, and that distinguishes EMPEROR-Reduced from an earlier trial, also with an SGLT2 inhibitor, called DAPA-HF. Both DAPA-HF and EMPEROR-Reduced studied HFrEF in patients with and without diabetes, but DAPA-HF included patients with milder HF and we studied more severe patients. That also is evidenced by the fact that 20% of our patients were taking a neprilysin inhibitor (sacubitril/valsartan) at baseline vs only 10% of DAPA-HF patients. Otherwise the trials are very complementary.

The EMPEROR-Reduced trial randomized patients to empagliflozin 10 mg once daily or placebo for an average of 16 months. We specified only three major endpoints and they were ranked in a hierarchical manner. The first, which was our primary endpoint, was a composite of cardiovascular death and hospitalization for heart failure. Empagliflozin reduced that risk by 25%. Our second endpoint was total hospitalizations for heart failure — first and repeated events. Empagliflozin reduced that risk by 30%. The third endpoint was the slope in the rate of decline in glomerular filtration rate (GFR), and that was supported by a renal composite endpoint of hard renal events. Empagliflozin significantly slowed the rate of decline. And it reduced the risk for serious hard renal events by 50%.

We achieved success on all three endpoints. They were all clinically important and highly significant (all with P < 0.001). We also found an excellent safety profile — the drug was very well tolerated. Aside from an imbalance in genital tract infections, there were none of the traditional side effects of heart failure drugs — no excess in hypotension, no volume depletion, no potassium problems, no renal insufficiency issues. We were very excited about this. We think this trial together with the DAPA-HF trial are very reinforcing and complementary, and they both support the use of SGLT2 inhibitors as a new cornerstone for the treatment of patients with HFrEF.

Is This a Class Effect? How Do These Drugs Work?

Piña: Do you think that it's going to be a class effect? Is that how the guidelines are going to look at it?

Packer: The results of the trials are not just concordant with each other, but they are also really concordant with the trials in diabetes. A 30% reduction in heart failure hospitalizations and a 50% reduction in renal events, which we saw in HFrEF, is what was seen in large-scale outcome trials in type 2 diabetes. And it's also being seen in trials of chronic kidney disease. There is an enormous concordance of data. We have more large-scale trials with SGLT2 inhibitors in different aspects of the cardiovascular disease spectrum than we have with almost any other class of drugs. I don't see any difference among members of the drug class. We studied empagliflozin and DAPA-HF studied dapagliflozin, so we do have specific data with those drugs.

Piña: A lot of questions have been raised as to how these drugs work. It's not just glucose in the urine doing this. Is it the improved renal function? Or do you believe the theory of the shifting metabolism in the myocardium?

Packer: I do not believe the theory of shifting metabolism. I don't think it's a natriuretic effect. I absolutely do not think it has anything to do with glucose lowering. I've written a whole host of papers about this in the past 6 months. What is really interesting about these drugs is that they fool the body into thinking that it is being starved. And when the body activates nutrient deprivation sensors, those exert a dramatic protective effect on both the heart and the kidneys with respect to cellular stress and cellular survival. This involves pathways such as autophagy, but it also involves autophagy-independent pathways. I really think that there is a direct, cytoprotective effect of these drugs on the heart and kidney.

Mortality Benefits

Piña: That is fascinating because we have not seen drugs like this before. Another tough question that came up with the DAPA-HF trial is about the mortality. As heart failure cardiologists, we keep believing that higher hospitalizations mean higher mortality. Now we're seeing in these trials that those two are split. Tell us about the mortality benefits in both of these trials.

Packer: In both DAPA-HF and EMPEROR-Reduced, the success on the primary endpoint was primarily driven by hospitalizations for heart failure. The effect on hospitalizations for heart failure was at least twofold greater than the effect on cardiovascular death. In VICTORIA, there was a similar pattern. At least for these classes of drugs [SGLT2 inhibitors], it may be related to the median duration of follow-up. In the VICTORIA trial the median duration of follow-up was 10 months; in EMPEROR-Reduced it was 16 months. Trials that we did in the past had longer durations of follow-up. And, of course, we expect patients who are suffering heart failure hospitalizations to in fact have an adverse lethal consequence. But from a trial design point of view, that takes time, and it's really hard to pick up that mortality benefit in trials of relatively short duration.

Piña: Are these patients going to be followed now for a longer term to take a look at what happens to mortality? I'm sure that when the blind was broken, the patients were going to be given the real drug.

Packer: I would be delighted to be able to follow these patients long term, and I think we will see a mortality difference if we were able to do that, even if patients were to take open-label therapy. Because remember, the two groups are still different. One has gotten empagliflozin for a couple of years before the other, so I think a mortality difference would emerge. But because of worldwide privacy laws, our ability to follow mortality is limited. It's much easier to do that in the United States than almost any other part of the world.

Piña: Maybe it could be done in the patients that were enrolled in the United States. That was not a huge amount, if I remember correctly, but a reasonable amount.

Packer: It was a meaningful amount and we can do that through the National Death Index, for example.

NT-proBNP

Piña: I would be remiss if I didn't ask about NT-proBNP. What did you find?

Packer: There was a significant reduction in NT-proBNP at 52 weeks, but it was modest. And it was modest in the trial with dapagliflozin. I understand that some people think of these drugs as being natriuretics, but the effect on urinary sodium excretion with these drugs is modest and short lived. After about 5 or 6 days it's gone.

Piña: The kidney readjusts very quickly.

Packer: The kidney is really smart. I think that the effect we are seeing, and what has been seen in other trials on natriuretic peptides, is not the driver of the benefit on heart failure. It is the result of the effect that these drugs have on the heart; the reduction in natriuretic peptide is a reflection of a favorable effect on remodeling.

All Hospitalizations as Outcome

Piña: Remodeling may take a little bit longer to really see, but we're seeing links between NT-proBNP dropping and reverse remodeling. We're seeing that in other trials, especially with the ARNI [angiotensin receptor/neprilysin inhibitor], which is very significant. The other interesting thing about this trial is picking up all the hospitalizations. A lot of the statisticians around the world have been moving us toward that. Before, when you and I were doing beta-blocker trials, we used the first hospitalization. Now we're picking up the total burden of the hospitalizations, which can be very significant in these sick people.

Packer: We did it two ways. Not only did we look at first and repeated hospitalizations for heart failure (so all hospitalizations for heart failure), we looked at all hospitalizations for any reason — first and repeated events. I don't think many trials have done that before. We found a significant reduction in risk with empagliflozin on total hospitalization for any reason, first and repeated events, during the entire course of double-blind therapy.

Piña: A good message to our audience here is, "I bet this is going to be in the guidelines." The new guidelines for heart failure are being written as we journey. I can tell you that the American Heart Association and Get With the Guidelines are very interested in looking at the SGLT2 inhibitors because you can start either drug regardless of what you are doing with the whole RAAS system, because it seems to be totally independent. It's another parallel path that can be chosen; you even may be able to adjust the diuretic depending upon how the patient looks. You should not have to wait until you get somebody well [controlled] on ACE inhibitors, ARBs, ARNIs, beta-blockers, or mineralocorticoid receptor antagonist to start these drugs. We're even hoping that the primary care [providers] are going to start to look at this earlier, because right now it seems to me like it's only been given to the patients with diabetes. But the data are so powerful in the nondiabetics, and that has been seen pretty much across the board.

Packer: I completely agree. In terms of adoption in clinical practice, it's really worth noting that both dapagliflozin and empagliflozin are one dose given once daily, not requiring uptitration, and not replicating the adverse-effect profile of other drugs for heart failure. This fits very nicely into our current regimen.

Piña: Renal function is so important. Everybody looks at the creatinine, and if it bumps up, they stop the drugs. This therapy may actually be beneficial to the kidney. Certainly, slowing down the decline in GFR is a big deal.

Packer: It's a big deal. This is the first heart failure trial that has ever seen a 50% reduction in major renal events. That is unprecedented.

Piña: Think about it: It may even then give you room to go ahead and uptitrate the RAAS inhibition that you still need to do anyway, because it almost feels like the kidney is more protected.

Milton, I want to thank you on behalf of our viewers for this important program and involving many of us with it. Hopefully it's going to change practice and hopefully it will change our patients' outcomes in the end. Thanks again for joining me today.

Packer: It was a delight, as always. Thank you.

Piña: Thank you to my audience. This is Ileana Piña, signing off. 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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