The DAPA ACT HF-TIMI 68 trial has provided new insights into the timing of SGLT2 inhibitor initiation for heart failure patients, despite failing to meet its primary endpoint. Presented at the European Society of Cardiology Congress 2025 in Madrid, the study evaluated the safety and efficacy of starting dapagliflozin during acute heart failure hospitalization in 2,401 patients across 210 sites.
Trial Design and Patient Population
The randomized, placebo-controlled trial enrolled patients with a median age of 69 years, 34% of whom were women, hospitalized for acute heart failure. Most participants (72%) had an LVEF of 40% or less, and for 45%, the hospitalization represented their first presentation of heart failure. Patients received either dapagliflozin 10 mg daily or placebo and were well-treated with guideline-directed medical therapy including beta-blockers, renin-angiotensin-aldosterone-system inhibitors, mineralocorticoid receptor antagonists, and loop diuretics.
Primary Results Fall Short of Significance
The primary endpoint—a composite of cardiovascular death or worsening heart failure through 60 days—occurred in 10.9% of patients treated with dapagliflozin compared to 12.7% of those receiving placebo (HR 0.86; 95% CI 0.68-1.08). While the results showed trends toward benefit, they did not reach statistical significance. The trial also demonstrated nonsignificant trends toward reductions in both individual components of the primary endpoint, as well as in all-cause death and a composite of cardiovascular death or rehospitalization for heart failure.
David Berg, MD, principal investigator from Brigham and Women's Hospital, attributed the neutral results to the trial being underpowered due to "the combined effects of a short follow-up and a lower-than-expected number of events."
Safety Profile Remains Consistent
Dapagliflozin demonstrated a safety profile consistent with the known characteristics of SGLT2 inhibitors. Compared with placebo, the drug was associated with higher rates of symptomatic hypotension (3.6% vs 2.2%) and worsening kidney function (5.9% vs 4.7%) but showed no increase in major hypoglycemia (0.2% vs 0.3%). Notably, there were no cases of diabetic ketoacidosis in the trial, and the rate of adverse events leading to study drug discontinuation was similar between groups (4.8% with dapagliflozin vs 4.7% with placebo).
Meta-Analysis Provides Broader Perspective
To address the limitations of the individual trial, researchers conducted a prespecified meta-analysis combining DAPA ACT HF-TIMI 68 results with data from EMPULSE (empagliflozin) and the in-hospital cohort of SOLOIST-WHF (sotagliflozin). This broader analysis revealed significant benefits of early SGLT2 inhibitor treatment, showing reduced risks of cardiovascular death or worsening heart failure (HR 0.71; 95% CI 0.54-0.93) and all-cause mortality (HR 0.57; 95% CI 0.41-0.80).
"The totality of randomized trial data really suggests that starting SGLT2 inhibitors during heart failure hospitalization reduces the early risk of cardiovascular death or worsening heart failure and all-cause mortality in the early postdischarge period," Berg stated during the press conference.
Expert Consensus Supports Early Initiation
Despite the primary trial's neutral results, experts at the congress endorsed the early initiation of SGLT2 inhibitors during heart failure hospitalization. Filippo Crea, MD, PhD, from Catholic University in Rome, emphasized that there is already convincing evidence supporting the initiation of all four pillars of guideline-directed medical therapy, including SGLT2 inhibitors, during heart failure hospitalization.
Biykem Bozkurt, MD, PhD, from Baylor College of Medicine, who served as the study discussant, reinforced that the findings validate the safety of in-hospital SGLT2 inhibitor initiation. "The totality of evidence indicates that the therapy is safe and effective across the spectrum of heart failure, including when initiated during hospitalization, and the clinicians should not be dissuaded from starting SGLT2 therapy in hospitalized patients when the patient is stabilized," she concluded.
Addressing an Important Unmet Need
The research addresses a significant clinical challenge, as patients hospitalized with heart failure face high risks of death and adverse outcomes during admission and shortly after discharge. The incidence of acute heart failure continues to rise, representing a substantial financial burden on healthcare systems due to hospitalization costs and frequent readmissions. Current treatment relies primarily on loop diuretics for symptom relief, but the lack of evidence-based therapies for acute heart failure represents an important unmet medical need.
