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Recent Studies of SGLT-2s in Patients with HFrEF


Nihar Desai, MD, MPH, reviews details of the DAPA-HF trial evaluating dapagliflozin in patients with heart failure and reduced ejection fraction.


Neil Minkoff, MD: Where do you see the role of the SGLT2 inhibitors in heart failure, starting with patients with diabetes?

Nihar Desai, MD, MPH: It’s a great point. Having Steve’s perspective on this is just incredible. In many ways, because of his advocacy in thinking deeply about our patients and what they need and deserve, and the evidence that practitioners need to make the best decisions for the patients they’re caring for, the whole world has been transformed over the past number of years. To his point, we saw the data in EMPA-REG OUTCOME, CANVAS, and DECLARE-TIMI58 trials. Then we also saw complementary data in real-world analyses, which showed that the signal for heart failure was incredibly compelling with the SGLT2 inhibitors.

The next piece of the puzzle that connected all the dots was the DAPA-HF study. That was a trial of patients with reduced ejection fraction heart failure on standard background medical therapy who were randomized to receive dapagliflozin versus placebo. It was a large trial with almost 5000 patients. The standard primary end points were cardiovascular death and hospitalization for urgent heart failure. What you saw was about a 25% reduction in that composite end point with directionally consistent effects across the CV [cardiovascular] death and the overall hospitalization end points. The most provocative part of this trial was that only about half the patients in this study actually had diabetes. As Steve mentioned as he laid out the history of this in such a compelling way, the SGLT2 inhibitors were developed as “diabetes medications.” What they have emerged as are cardiovascular risk-reducing medications and also highly effective therapies for heart failure, whether you have diabetes or not. The investigators from the DAPA-HF study just published the diabetes and the nondiabetic subgroup paper, and they showed that the effects are virtually identical. Whether the patient has diabetes or not, the addition of dapagliflozin to standard background medical therapy for heart failure was shown to be highly effective at reducing morbidity and this standard composite end point.

Neil Minkoff, MD: Which trial was that again?

Nihar Desai, MD, MPH: That is DAPA-HF with dapagliflozin. Neil, to your point, all the other trials that Steve walked us through—EMPA-REG OUTCOME, CANVAS, and DECLARE-TIMI58—were in patients who had diabetes. DAPA-HF was very provocative. The entry criterion for DAPA-HF was that you have to have systolic heart failure. Half the patients had diabetes, but the other half didn’t, and the impact of dapagliflozin was consistent whether the patients had diabetes or not. That is the next step as we move to thinking about the best medical therapy for our patient with reduced ejection fraction heart failure. To Steve’s point, the SGLT2 inhibitors have to come forward among a somewhat crowded field. But after you get through the standard background of beta-blocker, ACE inhibitor, and MRA, the SGLT2 inhibitors have really emerged. Dapagliflozin is the first, but there will be additional studies that will follow with empagliflozin and the other SGLT2 inhibitors. We’re all eagerly awaiting those results.

The 1 final point that I’ll make on that—and this will touch on something we talked about awhile ago—was that most of what we’ve talked about thus far in terms of therapy for heart failure, and this was also true of DAPA-HF, has been in patients with systolic heart failure. What’s also quite important and interesting, for the field and our patients, is that the SGLT2 inhibitors are also being trialed in patients with preserved ejection fraction heart failure. If the trials go the way that we all hope they will, they could potentially represent the first therapy to improve outcomes for that set of patients who, until now, have very little by way of evidence-based therapies. It’s a very exciting time.

Steven Nissen, MD: May I just jump in for 1 moment, Neil? It was, to me, a very big surprise. I knew these drugs were weak diuretics, but I didn’t expect that they would have this big effect. I want to make the point that it clearly is not their diuretic effect. There’s a bit of diuretic effect from the drugs, but hydrochlorothiazide doesn’t prevent heart failure.

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