How a Diabetes Drug Class Became Heart Failure Therapy

A class of drugs designed to lower blood sugar became a cornerstone of heart failure treatment because large trials, run to prove the drugs were safe for the heart, kept showing something no one had asked for: fewer heart failure hospitalizations. The EMPA-REG OUTCOME trial raised the signal in 2015. DAPA-HF and the EMPEROR trials then tested it directly in people with heart failure, including those without diabetes, and found consistent benefit. By 2022, major guidelines recommended these agents across the full range of heart failure. This is a clear case study in how outcome trials, not marketing, can reshape what a drug is for.

A safety mandate that produced an unexpected finding

The story starts with a regulatory decision. After concerns that some diabetes drugs might raise cardiovascular risk, the U.S. Food and Drug Administration issued 2008 guidance requiring that new type 2 diabetes therapies demonstrate they did not increase cardiovascular danger. The point was reassurance, not discovery. Sponsors ran large cardiovascular outcome trials expecting, at best, to show their drug was neutral.

The sodium-glucose cotransporter 2 (SGLT2) inhibitors work by blocking glucose reabsorption in the kidney, so excess sugar is passed in the urine. That mechanism also causes the body to shed sodium and water. In the EMPA-REG OUTCOME trial, published in the New England Journal of Medicine in 2015, empagliflozin was tested in more than 7,000 people with type 2 diabetes and established cardiovascular disease. It met the safety bar and then exceeded it, reducing cardiovascular death. Buried in the secondary findings was a roughly 35 percent relative reduction in hospitalization for heart failure. That was not what the trial was built to answer, so it functioned as a hypothesis, not a verdict.

Here the discipline of evidence appraisal matters. A striking result in a secondary endpoint, in a population selected for diabetes rather than heart failure, is a lead to be tested, not a conclusion to be acted on. The right response was not to start prescribing but to design trials that asked the heart failure question head-on.

Testing the signal on its own terms

Two programs did exactly that, and their design choices are what make the evidence persuasive.

DAPA-HF, published in 2019, enrolled patients who had heart failure with reduced ejection fraction, meaning a weakened pump. Critically, it included people with and without type 2 diabetes. If dapagliflozin only helped through glucose control, the benefit should have shrunk or vanished in participants without diabetes. It did not. The drug reduced the composite of worsening heart failure or cardiovascular death by about a quarter, and the effect was consistent regardless of diabetes status. That single design feature reframed the drug: this was cardiac therapy that happened to have started as a diabetes medicine.

EMPEROR-Reduced, published in 2020, tested empagliflozin in a similar reduced-ejection-fraction population and reached a concordant result, cutting the risk of cardiovascular death or heart failure hospitalization. Two independent trials, two different molecules in the same class, pointing the same direction. A meta-analysis of EMPEROR-Reduced and DAPA-HF published in The Lancet in 2020 pooled the data and confirmed that the class reduced heart failure hospitalization and improved outcomes in reduced ejection fraction whether or not diabetes was present. Replication across separate trials is one of the strongest things evidence can offer, because it makes a chance finding or a single-study quirk far less likely.

Extending the question across the ejection fraction spectrum

The harder frontier was heart failure with preserved ejection fraction, where the heart muscle stiffens but the pump fraction looks normal. For years this condition had defeated drug after drug in clinical trials, and clinicians had little to offer beyond managing symptoms and other conditions.

EMPEROR-Preserved, published in the New England Journal of Medicine in 2021, tested empagliflozin in nearly 6,000 patients with an ejection fraction above 40 percent. It reduced the combined risk of cardiovascular death and heart failure hospitalization, with the benefit driven mainly by fewer hospitalizations. It was the first large trial to show a clear, statistically convincing benefit for any drug in this group. A parallel dapagliflozin trial in the preserved and mildly reduced range reinforced the finding. The class now had evidence spanning the ejection fraction spectrum, from a weak pump to a stiff one.

When evidence changes an indication

The final step was translation into guidance. The 2022 American Heart Association, American College of Cardiology, and Heart Failure Society of America guideline for the management of heart failure gave SGLT2 inhibitors a Class 1 recommendation, its strongest, as part of standard therapy for heart failure with reduced ejection fraction. For heart failure with mildly reduced and preserved ejection fraction, the guideline assigned a Class 2a recommendation, meaning the treatment is reasonable, reflecting evidence that was strong but somewhat more modest in magnitude. The gradation matters here: guideline writers do not treat all positive trials as equal. They weigh the size of the effect, the consistency across studies, and the population studied, then calibrate the strength of the advice accordingly.

What makes this history instructive is the sequence. A safety requirement forced large, well-run trials. Those trials surfaced an unplanned signal. Rather than acting on the signal, investigators tested it directly, in the right patients, including those for whom the original glucose-lowering rationale did not apply. Independent trials replicated the result and then extended it. Only after that did the indication change. The mechanism almost certainly involves the drugs' effects on fluid handling, cardiac energetics, and the kidney, and researchers are still clarifying exactly how the benefit arises. But the clinical case was made by outcomes measured in patients, not by a tidy story about mechanism.

This article is educational and not a substitute for individual medical advice; decisions about heart failure treatment belong to a patient and their own clinicians.