Importance: Additional treatments are needed for heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter 2 (SGLT2) inhibitors may be an effective treatment for patients with HFrEF, even those without diabetes. Objective: To evaluate the effects of dapagliflozin in patients with HFrEF with and without diabetes. Design, Setting, and Participants: Exploratory analysis of a phase 3 randomized trial conducted at 410 sites in 20 countries. Patients with New York Heart Association classification II to IV with an ejection fraction less than or equal to 40% and elevated plasma N-terminal pro B-type natriuretic peptide were enrolled between February 15, 2017, and August 17, 2018, with final follow-up on June 6, 2019. Interventions: Addition of once-daily 10 mg of dapagliflozin or placebo to recommended therapy. Main Outcomes and Measures: The primary outcome was the composite of an episode of worsening heart failure or cardiovascular death. This outcome was analyzed by baseline diabetes status and, in patients without diabetes, by glycated hemoglobin level less than 5.7% vs greater than or equal to 5.7%. Results: Among 4744 patients randomized (mean age, 66 years; 1109 [23%] women; 2605 [55%] without diabetes), 4742 completed the trial. Among participants without diabetes, the primary outcome occurred in 171 of 1298 (13.2%) in the dapagliflozin group and 231 of 1307 (17.7%) in the placebo group (hazard ratio, 0.73 [95% CI, 0.60-0.88]). In patients with diabetes, the primary outcome occurred in 215 of 1075 (20.0%) in the dapagliflozin group and 271 of 1064 (25.5%) in the placebo group (hazard ratio, 0.75 [95% CI, 0.63-0.90]) (P value for interaction = .80). Among patients without diabetes and a glycated hemoglobin level less than 5.7%, the primary outcome occurred in 53 of 438 patients (12.1%) in the dapagliflozin group and 71 of 419 (16.9%) in the placebo group (hazard ratio, 0.67 [95% CI, 0.47-0.96]). In patients with a glycated hemoglobin of at least 5.7%, the primary outcome occurred in 118 of 860 patients (13.7%) in the dapagliflozin group and 160 of 888 (18.0%) in the placebo group (hazard ratio, 0.74 [95% CI, 0.59-0.94]) (P value for interaction = .72). Volume depletion was reported as an adverse event in 7.3% of patients in the dapagliflozin group and 6.1% in the placebo group among patients without diabetes and in 7.8% of patients in the dapagliflozin group and 7.8% in the placebo group among patients with diabetes. A kidney adverse event was reported in 4.8% of patients in the dapagliflozin group and 6.0% in the placebo group among patients without diabetes and in 8.5% of patients in the dapagliflozin group and 8.7% in the placebo group among patients with diabetes. Conclusions and Relevance: In this exploratory analysis of a randomized trial of patients with HFrEF, dapagliflozin compared with placebo, when added to recommended therapy, significantly reduced the risk of worsening heart failure or cardiovascular death independently of diabetes status. Trial Registration: ClinicalTrials.gov Identifier: NCT03036124.

2nd Department of Internal Medicine Cardiovascular Medicine General Teaching Hospital 1st Faculty of Medicine Charles University Prague Czech Republic

5th Department of Internal Medicine Comenius University in Bratislava Bratislava Slovakia

British Heart Foundation Cardiovascular Research Centre University of Glasgow Glasgow United Kingdom

Cardiovascular Division Brigham and Women's Hospital Boston Massachusetts

Cardiovascular Division of Medicine National Cerebral and Cardiovascular Center Osaka Japan

Center for Heart Diseases University Hospital Wroclaw Medical University Wroclaw Poland

Clinic of Cardiology National Cardiology Hospital Sofia Bulgaria

Clinical Pharmacology and Safety Sciences BioPharmaceuticals R and D AstraZeneca Gaithersburg Maryland

Department Cardiology Medical University of Lodz Lodz Poland

Department of Cardiology Copenhagen University Hospital Copenhagen Denmark

Department of Cardiology Gentofte University Hospital Copenhagen Copenhagen Denmark

Department of Cardiology Medanta Gurgaon Haryana India

Department of Cardiology Montreal Heart Institute Montreal Ontario Canada

Department of Cardiology University Medical Center Groningen University of Groningen Groningen the Netherlands

Department of Cardiology University of Minnesota Minneapolis

Department of Internal Medicine Tan Tao University Tan Duc Vietnam

Department of Medicine Saarland University Hospital Homburg Saar Germany

Department of Myocardial Disease and Heart Failure National Medical Research Center of Cardiology Moscow Russia

Division of Cardiac Surgery St Michael's Hospital University of Toronto Toronto Ontario Canada

Division of Cardiology Instituto Cardiovascular de Buenos Aires Buenos Aires Argentina

Division of Cardiology Taipei Veterans General Hospital Taipei Taiwan National Yang Ming University Taipei Taiwan

Early Discovery and Development Cardiovascular Renal and Metabolism BioPharmaceuticals R and D AstraZeneca Gothenburg Sweden

Heart and Vascular Center Semmelweis University Budapest Hungary

Institute of Medicine Department of Molecular and Clinical Medicine Cardiology Sahlgrenska Academy University of Gothenburg Gothenburg Sweden

Instituto do Coracao Hospital das Clínicas Faculdade de Medicina Universidade de São Paulo São Paulo Brazil

Late Stage Development Cardiovascular Renal and Metabolism BioPharmaceuticals R and D AstraZeneca Gothenburg Sweden

Libin Cardiovascular Institute Cumming School of Medicine University of Calgary Calgary Alberta Canada

Section of Endocrinology Yale University School of Medicine New Haven Connecticut

Shanghai Institute of Cardiovascular Disease Department of Cardiology Zhongshan Hospital Fudan University Shanghai China

St Luke's Mid America Heart Institute University of Missouri Kansas City Kansas City

Universidad Nacional de Córdoba Córdoba Argentina

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