MADRID —– SGLT2 inhibitors can be added to the list of guideline-directed medical therapies for heart failure that are best initiated before hospital discharge, according to a meta-analysis of randomized trials.

This meta-analysis included data from DAPA ACT HF-TIMI 68, the most recently completed trial of dapagliflozin in patients hospitalized for heart failure. Although this trial missed its primary composite endpoint of a reduction in cardiovascular death or worsening heart failure at 2 months, the preplanned meta-analysis showed significant improvements in outcome, including a reduction in all-cause death, according to David D. Berg, MD, MPH, of Brigham and Women’s Hospital in Boston.

The investigator-initiated, multinational randomized DAPA ACT HF-TIMI 68 trial adds SGLT2 inhibitors to the list of guideline-directed medical therapies for heart failure that should be started in the hospital, said Berg, who served as principal investigator for the trial.

Early Start of SGLT2 Inhibitors Begets Early Benefit

“The totality of the randomized trial data suggests that starting an SGLT2 inhibitor during heart failure hospitalization reduces risk for cardiovascular death or worsening heart failure and all-cause mortality, even in the early post-discharge period,” Berg said.

The DAPA ACT HF-TIMI 68 trial was presented at European Society of Cardiology (ESC) Congress 2025 and was published simultaneously in Circulation.

In this trial, Berg and colleagues randomly assigned 2401 patients with heart failure, of whom about 45% were newly diagnosed, to 10 mg of dapagliflozin or placebo at least for 24 hours, but no longer than 14 days, after hospitalization. Initially, the trial required a left ventricular ejection fraction (LVEF) of < 40% but was amended when the EMPEROR trial with empagliflozin showed benefit in ambulatory heart failure patients with mildly reduced LVEF.

The primary endpoint of DAPA ACT HF-TIMI 68 was a composite of cardiovascular death or worsening heart failure during the first 2 months of follow-up. This study was the last in a series of randomized trials evaluating in-hospital initiation of SGLT2 inhibitors in patients with heart failure.

A primary outcome event occurred within 2 months in 10.9% of those assigned dapagliflozin and 12.7% of those assigned placebo. The relative risk reduction was not significant (hazard ratio [HR], 0.86; 95% CI 0.68-1.08). The relative risk reductions in each component of the primary endpoint, cardiovascular death (HR, 0.78; 95% CI, 0.48-1.27) and worsening heart failure (HR, 0.91; 95% CI, 0.71-1.18), were also not significant.

The lower rate of all-cause death in the dapagliflozin group generated a relative risk reduction that approached but did not meet the conventional definition of statistical significance (3.0% vs 4.5%; HR, 0.66; 95% CI, 0.43-1.00).

The preplanned meta-analysis of three trials, of which DAPA ACT HF-TIMI 68 is the latest, included the placebo-controlled EMPULSE trial with empagliflozin and the placebo-controlled SOLOIST-WHF with sotagliflozin. However, researchers restricted the data from SOLOIST-WHF, which enrolled patients with heart failure and diabetes, to the 49% of patients randomized before hospital discharge.

Reduction in All-Cause Death Is Highly Significant

In this collective population of 3527 patients, researchers assessed outcomes of patients from DAPA ACT HF-TIMI 68 at 60 days in the context of the 90-day outcomes of the other two trials. For cardiovascular death or worsening heart failure, the 29% risk reduction for in-hospital start of the SGLT2 inhibitor did reach statistical significance (HR, 0.71; P = .012). The 43% reduction in all-cause mortality at this time was also highly significant (HR, 0.57; P = .001).

“There was no between-trial heterogeneity of treatment effect for either outcome,” Berg reported.

After a series of placebo-controlled trials, such as DAPA-HF, showed a reduction in cardiovascular events in patients with or without diabetes, SGLT2 inhibitor therapy was added to guideline-directed medical therapy for patients with reduced left ventricular function. Subsequently, a series of placebo-controlled trials, starting with EMPEROR-Preserved, also showed risk reductions in patients with LVEF > 40%.

In DAPA ACT HF-TIMI 68, about 30% of patients had a LVEF > 40%, known as mildly impaired ventricular function or heart failure with preserved ejection fraction (HFpEF). When these two groups were compared in the meta-analysis, the advantage of SGLT2 inhibition compared with placebo was “directionally consistent,” according to Biykem Bozkurt, MD, PhD, senior dean of faculty at Baylor College of Medicine in Houston.

The totality of the data from the meta-analysis shows “SGLT2 inhibition is safe and effective across the spectrum of heart failure, including when it is initiated in the hospital,” said Bozkurt, who was invited by ESC to discuss the study.

While the safety in this study is consistent with extensive placebo-controlled trials with SGLT2 inhibitors across numerous heart failure populations, Bozkurt also believes that the evidence of an early reduction in heart failure-related events with administering the drug in the hospital is compelling. She pointed out that a signal of early benefit was consistent across all three trials in the meta-analysis.

In her opinion, two factors hobbled the DAPA ACT HF-TIMI 68 trial: an event rate that was lower than expected in the placebo group and a 2-month follow-up that was likely too short to demonstrate a significant advantage for the in-hospital start of the SGLT2 inhibitor.

“There was also an early benefit in both SOLOIST-WHF and EMPULSE, but statistical significance would probably not have been met if these trials were stopped at 2 months,” Bozkurt said.

New Data Reinforce Early Start of Guideline-Directed Medical Therapy

A 2024 expert consensus pathway published by the American College of Cardiology emphasized the value of early initiation and rapid uptitration of all guideline-directed therapies for the optimal protection against progression in heart failure with reduced ejection fraction. Although the expert consensus recommendations acknowledged that it might not be feasible to initiate all guideline-directed therapies prior to discharge, the authors implied that the disease-modifying activity of these drugs make an early start attractive.

The main message of the meta-analysis of in-hospital initiation of SGLT2 inhibitors is that the advantage of an early relative to a delayed start was associated with an improvement in outcomes, even within a few months, according to Filippo Crea, MD, PhD, director of the Department of Cardiovascular Sciences at Catholic University, Rome, Italy.

“I think this supports the idea that all drugs indicated for heart failure should be started early including at the time of first hospitalization,” Crea said.

Berg agreed.

“These results certainly support this message,” he said.

Berg reported financial relationships with AstraZeneca, Merck, Mobility Bio, Pfizer, and Youngene Therapeutics. Bozkurt reported financial relationships with Abbott, Abiomed, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardurion, Cytokinetics, Daiichi Sankyo, Johnson & Johnson, Lantheus, Liva Nova, Merck, Regeneron, Renovacor, Respicardia/Zoll, Roche, Sanofi-Aventis, and Vifor. Crea reported no potential conflicts of interest.