DAPA ACT: Dapagliflozin Fails to Lower Cardiovascular Risk in Patients with HF

Dapagliflozin, an SGLT2 inhibitor, did not significantly reduce short-term risk of cardiovascular death or worsening heart failure (HF) in patients admitted with HF, according to results from the DAPA ACT HF-TIMI 68 trial.1

Presented as late-breaking research at the European Society of Cardiology Congress 2025 in Madrid, the trial involved the administration of dapagliflozin to patients currently hospitalized for HF. Despite the lack of significant cardiovascular death risk reduction, the trial did exhibit positive effects when data were combined.1

HF is the leading cardiovascular reason for hospital admission worldwide, with rates increasing dramatically over the last 10 years. Patients hospitalized for HF also have a high risk of death and other adverse outcomes in the early post-discharge period. Previous clinical trials have suggested that initiating and optimizing disease-modifying chronic heart failure therapies, including beta-blockers and mineralocorticoid receptor antagonists, in the early post-discharge period may improve both short- and long-term outcomes.2

“However, there are limited data on initiating sodium-glucose cotransporter-2 inhibitors in patients hospitalized for HF,” David Berg, MD, MPH, investigator in the TIMI Study Group at Brigham and Women’s Hospital and principal investigator of DAPA ACT, said in a statement. “We designed the trial to test the hypothesis that in-hospital initiation of the SGLT2i, dapagliflozin, as compared with placebo, could safely and effectively decrease the early risk of cardiovascular death or worsening HF among patients hospitalized for HF.”1

The trial was a double-blind, placebo-controlled, randomized trial conducted at 210 sites in the USA, Canada, Poland, Hungary, and the Czech Republic. For inclusion, patients had to be ≥18 years of age and be hospitalized with a primary diagnosis of HF, including signs and symptoms of fluid overload, as well as elevated natriuretic peptide levels during index hospitalization.1

A total of 2401 patients were included in the study and randomly assigned in a 1:1 ratio to dapagliflozin 10 mg daily or placebo at least 24 hours and no later than 14 days after hospital admission and as early as possible following initial stabilization. The median age was 69 years, and 33.9% of patients were women. Investigators noted a primary efficacy outcome composite of cardiovascular death or worsening HF over the first 2 months.1

Ultimately, the primary outcome occurred in 10.9% of patients assigned to dapagliflozin and 12.7% of patients in the placebo group (hazard ratio [HR], 0.86; 95% CI, 0.68-1.08; P = .20). Cardiovascular death occurred in 2.5% of patients with dapagliflozin and 3.1% with placebo (HR, 0.78; 95% CI, 0.48-1.27), and a worsening HF event occurred in 9.4% and 10.3% of patients, respectively (HR, 0.91; 95% CI, 0.71-1.18).1

All-cause mortality occurred in 3% of patients receiving dapagliflozin and 4.5% receiving placebo (HR, 0.66; 95% CI, 0.43-1). Rates of symptomatic hypotension were 3.6% and 2.2%, respectively, and rates of worsening kidney function were 5.9% and 4.7%, respectively.1

A prespecified meta-analysis was conducted, including 2 other SGLT2i trials – specifically, empagliflozin and sotagliflozin – to assess in-hospital initiation in a total of 3527 patients hospitalized for HF. SGLT2is reduced early risks of cardiovascular death or worsening HF (HR, 0.71; 95% CI, 0.54-0.93; P = .012) and all-cause mortality (HR, 0.57; 95% CI, 0.41-0.8; P = .001).1

“In-hospital initiation of dapagliflozin did not significantly reduce the risk of cardiovascular death or worsening HF over the first 2 months in DAPA ACT HF-TIMI 68,” Berg said. “However, the totality of trial data suggests that in-hospital initiation of an SGLT2i reduces the early risk of cardiovascular death or worsening HF and all-cause mortality.”1

References

1. 1: European Society of Cardiology. Evidence appears supportive for the initiation of SGLT2 inhibitors in patients hospitalized for heart failure. August 30, 2025. Accessed September 4, 2025. https://www.escardio.org/The-ESC/Press-Office/Press-releases/Evidence-appears-supportive-for-the-initiation-of-SGLT2-inhibitors-in-patients-hospitalised-for-heart-failure

2. 2: Berg DD, Patel SM, Haller PM, et al. Dapagliflozin in Patients Hospitalized for Heart Failure: Primary Results of the DAPA ACT HF-TIMI 68 Randomized Clinical Trial and Meta-Analysis of Sodium-Glucose Cotransporter-2 Inhibitors in Patients Hospitalized for Heart Failure. Circulation. Published online August 29, 2025. doi:10.1161/CIRCULATIONAHA.125.076575