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
- PMID: 40884036
- DOI: 10.1161/CIRCULATIONAHA.125.076575
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
Abstract
Background: SGLT2 (sodium-glucose cotransporter-2) inhibitors reduce the risk of cardiovascular death or worsening heart failure (HF) in outpatients with HF. Data on initiation in patients hospitalized for HF are limited.
Methods: We conducted a randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of in-hospital initiation of dapagliflozin (10 mg daily) in patients hospitalized for HF. The primary efficacy outcome was a composite of time to cardiovascular death or worsening HF through 2 months. Key safety outcomes included symptomatic hypotension and worsening kidney function. A prespecified meta-analysis of randomized trials evaluating initiation of SGLT2 inhibitors in patients hospitalized for HF was performed.
Results: Of 2401 patients (median age, 69 [Q1-Q3, 58-77] years, 815 [33.9%] women, 448 [18.7%] Black race, 1717 [71.5%] left ventricular ejection fraction ≤40%, 1074 [44.7%] newly diagnosed HF) randomized between September 2020 and March 2025, 1218 were assigned to dapagliflozin and 1183 to placebo. The primary outcome occurred in 133 patients (10.9%) in the dapagliflozin group and 150 (12.7%) in the placebo group (hazard ratio [HR], 0.86 [95% CI, 0.68-1.08]; P=0.20). A worsening HF event occurred in 115 (9.4%) and 122 (10.3%) patients in the dapagliflozin and placebo groups, respectively (HR, 0.91 [95% CI, 0.71-1.18]). Cardiovascular death occurred in 30 (2.5%) and 37 (3.1%) patients (HR, 0.78 [95% CI, 0.48-1.27]), and death from any cause occurred in 36 (3.0%) and 53 (4.5%) patients in the dapagliflozin and placebo groups, respectively (HR, 0.66 [95% CI, 0.43-1.00]). The rates of symptomatic hypotension were 3.6% and 2.2%, and the rates of worsening kidney function were 5.9% and 4.7% with dapagliflozin and placebo, respectively. In a meta-analysis of patients hospitalized for HF, SGLT2 inhibitors reduced the early risk of cardiovascular death or worsening HF (HR, 0.71 [95% CI, 0.54-0.93] P=0.012) and of all-cause death (HR, 0.57 [95% CI, 0.41-0.80]; P=0.001).
Conclusions: In this trial, in-hospital initiation of dapagliflozin did not significantly reduce the risk of cardiovascular death or worsening HF through 2 months in hospitalized HF patients. However, the totality of randomized clinical trial data suggests that in-hospital initiation of SGLT2 inhibitors may reduce the early risk of cardiovascular death or worsening HF and of all-cause mortality.
Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04363697.
Keywords: hospitalization; randomized clinical trial; sodium-glucose cotransporter 2 inhibitors; worsening heart failure..
Conflict of interest statement
Dr Berg, Dr Patel, Dr Haller, Ms Cange, Mr Palazzolo, Dr Bellavia, Ms Kuder, Dr Ruff, Dr O’Donoghue, Ms Murphy, and Dr Sabatine are members of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott; Abiomed, Inc; Amgen; Anthos Therapeutics; ARCA Biopharma, Inc; AstraZeneca; Boehringer Ingelheim; Cleerly, Inc; Daiichi-Sankyo; Ionis Pharmaceuticals, Inc; Janssen Research and Development, LLC; MedImmune; Merck; Novartis; Pfizer; Regeneron Pharmaceuticals, Inc; Roche; Saghmos Therapeutics, Inc; Softcell Medical Limited; The Medicines Company; Verve Therapeutics, Inc; and Zora Biosciences. Dr Berg has received institutional research grant support through Brigham and Women’s Hospital from AstraZeneca, Merck, and Pfizer; consulting fees from AstraZeneca, Pfizer, Mobility Bio, and Youngene Therapeutics; and honoraria from the Metabolic Endocrine Education Foundation, Pri-Med, and USV Private Limited and has served on clinical end point committees for studies sponsored by Beckman Coulter, CeleCor Therapeutics, Kowa Pharmaceuticals, Novo Nordisk, and Tosoh Biosciences. Dr Patel is supported by a K12TR004381 award through Harvard Catalyst, The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health), and has received consultant advisory fees from Janssen. Dr Haller is funded by the Deutsche Forschungsgemeinschaft (German Research Foundation, 10086/1-1) and has received travel grants from the German Center of Cardiovascular Research and project grants from the German Heart Foundation. Dr Bellavia has received consultancy fees from Arboretum LifeSciences and MarvelBiome and honoraria from Columbia University and BioEpiEdu. Dr Desai has received institutional research grants from Abbott, Alnylam Pharmaceuticals, AstraZeneca, Bayer, Novartis, and Pfizer and personal consulting fees from Abbott, Alnylam Pharmaceuticals, AstraZeneca, Bayer, Biofourmis, Boston Scientific, Endotronix, GlaxoSmithKline, iRhythm Technologies, Medpace, Medtronic, Merck, Novartis, Parexel, Porter Health, Regeneron, River 2 Renal, Roche, Veristat, Verily, and Zydus. Dr Inzucchi has received honoraria for consulting or clinical trial committee work from AstraZeneca, Boehringer Ingelheim, Corcept, Novo Nordisk, Pfizer, and Bayer and has given lectures sponsored by AstraZeneca and Boehringer Ingelheim. Dr McMurray has received payments to Glasgow University for clinical trials and other research projects from the National Institutes of Health National Heart, Lung, and Blood Institute, AstraZeneca, Bayer, Cardurion, Cytokinetics, Novartis, and Roche; personal consultancy fees from AnaCardio, AstraZeneca, Bayer, Cardurion, Cytokinetics, Novartis, River BioMedics, Biohaven Pharmaceuticals, RyCarma Therapeutics, Inc, Regeneron, and DalCor Pharmaceuticals; and personal lecture fees from Alkem Metabolics, AstraZeneca, Canadian Medical and Surgical Knowledge Translation Research Group, Centrix Healthcare, Emcure Pharmaceuticals, Eris Lifesciences, Hikma Pharmaceuticals, Imagica Health, Intas Pharmaceuticals, J.B. Chemicals and Pharmaceuticals, Lupin Pharmaceuticals, ProAdWise Communications, Radcliffe Cardiology, Sun Pharmaceuticals, Translational Medicine Academy, and Hilton Pharmaceuticals. He serves on the data safety monitoring board of WCG Clinical Services, and he is a director at Global Clinical Trial Partners (which provides clinical trial services such as end point committees and educational programs). Dr O’Meara holds the Montreal Heart Institute Carolyn and Richard J. Renaud chair for research in heart failure, with fees paid through her institution for this chair and fora Canadian Heart Function Alliance team grant, funded by the Canadian Institutes of Health Research (steering committee member), and involvement as a steering committee member for DAPA ACT HF-TIMI 68 (TIMI Study Group and AstraZeneca), GARDEN-TIMI 74 (TIMI Study Group and Pfizer), HEART-FID (American Regent), CARDINAL-HF (Cardurion), HERMES (National Lead Investigator, Novo Nordisk), and BalancedD-HF (NLI, AstraZeneca). She has received consulting fees from AstraZeneca, Boehringer Ingelheim, Bayer, Novartis, and Novo Nordisk and speaker fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Novo Nordisk, and Pfizer. Dr Verma has received research grants or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, the Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Janssen, Novartis, Novo Nordisk, Pfizer, PhaseBio, S&L Solutions Event Management, and Sanofi. Dr Bělohlávek has received lecture honoraria from Novartis, AstraZeneca, Boehringer Ingelheim, Getinge, Abiomed, and Resuscitec. Dr Drożdż has received research grants from AstraZeneca and lecture fees from Celon Pharma, Merck, Novo Nordisk, and Servier Poland. Dr Merkely has received payments for lectures or studies from Boehringer Ingelheim, Daiichi Sankyo, the Duke Clinical Research Institute, and Novartis and reports grants through his institution from Biotronik, Boehringer Ingelheim, the Duke Clinical Research Institute, Eli Lilly, and Novartis. Dr Ogunniyi has received institutional research grant support from AstraZeneca and Pfizer and serves on a clinical trial steering committee for Novartis. Dr Izzo reports payments from AstraZeneca, Cardurion, Mineralys, and Brigham and Women’s Hospital. Dr Ruff has received research grant support through his institution from Anthos, AstraZeneca, Daiichi Sankyo, Janssen, and Novartis and honoraria for scientific advisory boards and consulting from Anthos, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Janssen, and Pfizer. Dr O’Donoghue reports grants to the TIMI Study Group through her institution from Amgen, AstraZeneca, Novartis, Merck, and Janssen Medicines Company; consulting or DSMB fees from Amgen, Novartis, Janssen, AstraZeneca, and CRICO; and honoraria from Medscape Cardiology. Dr Sabatine has received research grant support through Brigham and Women’s Hospital from Abbott; Amgen; Anthos Therapeutics, Inc; AstraZeneca; Boehringer Ingelheim; Daiichi-Sankyo; Ionis; Marea; Merck; Novartis; Pfizer; Saghmos Therapeutics; and Verve Therapeutics and consulting fees from Amgen; AMPEL BioSolutions; Anthos Therapeutics, Inc; AstraZeneca; Beren Therapeutics; Boehringer Ingelheim; CCRN; Dr Reddy’s Laboratories; General Medicines; Merck; NATF; Novo Nordisk; and Precision BioSciences. Dr Wiviott has received research grants from Amgen, AstraZeneca, Janssen, Merck, and Pfizer; consulting fees from Icon, Novo Nordisk, and Verian; and speaking honoraria from Harvard Medical School. As of June 16, 2025, Dr Wiviott is employed by AstraZeneca. Dr Wiviott’s wife, Dr Caroline Fox, has been employed by Vertex Pharmaceuticals and Pfizer.
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