Cardiology · 2019
DAPA-HF (Dapagliflozin in heart failure with reduced ejection fraction)
Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure
When SGLT2 inhibitors entered clinical use in the early 2010s, they were understood as glucose-lowering agents for type 2 diabetes. Unexpected reductions in heart failure hospitalizations in the cardiovascular outcomes trials that followed, particularly in EMPA-REG OUTCOME, raised a question the original trial designs had not been built to answer: were these drugs actually treating heart failure, or simply reducing it as a downstream consequence of better glycemic and blood pressure control? DAPA-HF was constructed specifically to resolve that ambiguity by enrolling HFrEF patients regardless of diabetes status and powering the trial on heart failure endpoints.
John McMurray at the University of Glasgow led the trial, with Mikhail Kosiborod contributing key analysis of the diabetic and non-diabetic subgroups. DAPA-HF enrolled 4,744 patients with HFrEF, defined by an ejection fraction of 40% or below, and randomized them to dapagliflozin 10 mg daily or placebo on top of otherwise optimized standard therapy including ACE inhibitors or ARNIs, beta-blockers, and mineralocorticoid antagonists. The primary endpoint was a composite of worsening heart failure events (hospitalization or urgent visit requiring IV therapy) or cardiovascular death.
The dapagliflozin arm reached the primary endpoint significantly less often, with a 26% relative risk reduction that appeared within weeks of starting treatment. Renal and metabolic benefits were also observed. Crucially, the benefit in patients without diabetes was statistically indistinguishable from the benefit in those with diabetes: the drug was doing something in myocardium and kidney biology that did not depend on glucose lowering. That result made the categorical distinction between a diabetes drug and a heart failure drug untenable.
Cardiologists who had never written an SGLT2 inhibitor prescription began doing so after DAPA-HF was presented at the ESC Congress in 2019 and simultaneously published in the New England Journal of Medicine. The 2021 EMPEROR-Reduced trial confirmed equivalent benefit with empagliflozin, providing a second member of the class with a heart failure indication. The 2022 ACC/AHA heart failure guidelines gave SGLT2 inhibitors a class I, level A recommendation for HFrEF patients regardless of diabetes status, placing them alongside ACE inhibitors, ARNIs, beta-blockers, and mineralocorticoid antagonists as the four-drug foundation of HFrEF management.
The mechanism by which SGLT2 inhibitors benefit the failing heart remains an area of active investigation; proposed explanations include reductions in preload and afterload through natriuresis and osmotic diuresis, direct effects on myocardial sodium and calcium handling, and improvements in myocardial energetics through increased ketone availability. No single explanation has been proven, but the clinical benefit across trials is consistent and the guideline status unambiguous.
Key People
- John McMurray — Principal investigator of the DAPA-HF trial
- Mikhail Kosiborod — Co-investigator; led diabetic subgroup analysis
- Silvio Inzucchi — Co-investigator; contributed diabetes and metabolic expertise to trial design
- Piotr Ponikowski — ESC heart failure guidelines chair; incorporated DAPA-HF findings into guidelines
N Engl J Med. 2019;381(21):1995-2008.
Related landmarks
- 2017 · FOURIER (Evolocumab / PCSK9 inhibition) and the PCSK9 era (Cardiology)
- 2015 · SPRINT (Systolic Blood Pressure Intervention Trial) (Cardiology)
- 2009 · RE-LY (Dabigatran versus warfarin in atrial fibrillation) (Cardiology)
- 2003 · Primary PCI versus thrombolysis for acute STEMI (Keeley meta-analysis of 23 trials) (Cardiology)