The DAPA ACT HF-TIMI 68 trial (NCT04363697) has posted full results in Circulation, and they deliver a sobering message for cardiologists who anticipated a clean win for in-hospital SGLT2 inhibition.

The international, multicenter, randomized, double-blind, placebo-controlled Phase 4 trial enrolled 2,401 patients admitted for acute heart failure (AHF) across multiple countries. Sponsored by the TIMI Study Group with AstraZeneca as collaborator and funder, the study randomized patients who had been stabilized during their hospitalization — no earlier than 24 hours and up to 14 days after presentation — to dapagliflozin 10 mg once daily versus placebo, continuing blinded treatment for two months. Patients were enrolled regardless of left ventricular ejection fraction, type 2 diabetes status, or whether the presentation was de novo or worsening chronic heart failure.

Primary endpoint: neutral

The primary endpoint — time to first occurrence of cardiovascular death or worsening heart failure (defined as worsening HF during the index admission, rehospitalization for worsening HF, or an urgent HF visit) at 2 months — was not significantly reduced by dapagliflozin. Berg et al. report a hazard ratio of 0.86 (95% CI, 0.68–1.08; p = 0.20), consistent with a clinically plausible but statistically non-significant 14% reduction that the trial was not powered to confirm at this magnitude.

All-cause mortality: a signal that doesn’t cross

A notable secondary finding was all-cause mortality, for which dapagliflozin produced a hazard ratio of 0.66 (95% CI, 0.43–1.00) — trending toward benefit but just failing to reach statistical significance. The point estimate, if real, would represent a substantial reduction; investigators caution that the 95% CI includes 1.00 and the trial was not powered for mortality as a primary endpoint.

Context: why EMPULSE and SOLOIST-WHF showed benefit

EMPULSE (empagliflozin, in-hospital initiation) and SOLOIST-WHF (sotagliflozin, peri-discharge) both demonstrated benefit on composite hierarchical or event-rate endpoints. DAPA ACT HF-TIMI 68 is the largest of these trials by enrollment and the first powered specifically for cardiovascular death or worsening HF as a time-to-event primary endpoint. Its neutral result raises three unresolved questions: whether benefit with other SGLT2 inhibitors is drug-specific; whether endpoint construction (hierarchical vs. time-to-first-event) drives the apparent discrepancy; or whether a two-month window is simply too short to capture a mortality signal in a broadly enrolled AHF population that includes patients unlikely to respond to contractility-independent mechanisms.

Key safety endpoints pre-specified in the protocol — symptomatic hypotension and worsening renal function — did not show significant differences between arms in the Berg et al. report.

The design rationale was published in JACC Heart Failure in May 2025 (Berg DD et al., DOI: 10.1016/j.jchf.2025.03.014).