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

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

National Yang Ming University Taipei Taiwan

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

JAMA. 2020 Apr 14;323(14):1349-1350. doi: 10.1001/jama.2020.1905. PubMed

JAMA. 2021 Apr 6;325(13):1335. doi: 10.1001/jama.2021.2802. PubMed

Zobrazit více v PubMed

Meng W, Ellsworth BA, Nirschl AA, et al. . Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. J Med Chem. 2008;51(5):1145-1149. doi:10.1021/jm701272q PubMed DOI

Pfister M, Whaley JM, Zhang L, List JF. Inhibition of SGLT2: a novel strategy for treatment of type 2 diabetes mellitus. Clin Pharmacol Ther. 2011;89(4):621-625. doi:10.1038/clpt.2011.16 PubMed DOI

Thomas MC, Cherney DZI. The actions of SGLT2 inhibitors on metabolism, renal function and blood pressure. Diabetologia. 2018;61(10):2098-2107. doi:10.1007/s00125-018-4669-0 PubMed DOI

Zinman B, Wanner C, Lachin JM, et al. ; EMPA-REG OUTCOME Investigators . Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128. doi:10.1056/NEJMoa1504720 PubMed DOI

Neal B, Perkovic V, Mahaffey KW, et al. ; CANVAS Program Collaborative Group . Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-657. doi:10.1056/NEJMoa1611925 PubMed DOI

Wiviott SD, Raz I, Bonaca MP, et al. ; DECLARE–TIMI 58 Investigators . Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347-357. doi:10.1056/NEJMoa1812389 PubMed DOI

Fitchett D, Zinman B, Wanner C, et al. ; EMPA-REG OUTCOME trial investigators . Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME trial. Eur Heart J. 2016;37(19):1526-1534. doi:10.1093/eurheartj/ehv728 PubMed DOI PMC

Inzucchi SE, Zinman B, Fitchett D, et al. . How does empagliflozin reduce cardiovascular mortality? insights from a mediation analysis of the EMPA-REG OUTCOME trial. Diabetes Care. 2018;41(2):356-363. doi:10.2337/dc17-1096 PubMed DOI

Yurista SR, Silljé HHW, Oberdorf-Maass SU, et al. . Sodium-glucose co-transporter 2 inhibition with empagliflozin improves cardiac function in non-diabetic rats with left ventricular dysfunction after myocardial infarction. Eur J Heart Fail. 2019;21(7):862-873. doi:10.1002/ejhf.1473 PubMed DOI

Garg V, Verma S, Connelly K. Mechanistic insights regarding the role of SGLT2 inhibitors and GLP1 agonist drugs on cardiovascular disease in diabetes. Prog Cardiovasc Dis 2019;62(4):349-357. doi:10.1016/j.pcad.2019.07.005 PubMed DOI

Santos-Gallego CG, Requena-Ibanez JA, San Antonio R, et al. . Empagliflozin ameliorates adverse left ventricular remodeling in nondiabetic heart failure by enhancing myocardial energetics. J Am Coll Cardiol. 2019;73(15):1931-1944. doi:10.1016/j.jacc.2019.01.056 PubMed DOI

McMurray JJV, DeMets DL, Inzucchi SE, et al. ; DAPA-HF Committees and Investigators . A trial to evaluate the effect of the sodium-glucose co-transporter 2 inhibitor dapagliflozin on morbidity and mortality in patients with heart failure and reduced left ventricular ejection fraction (DAPA-HF). Eur J Heart Fail. 2019;21(5):665-675. doi:10.1002/ejhf.1432 PubMed DOI PMC

McMurray JJV, Solomon SD, Inzucchi SE, et al. ; DAPA-HF Trial Committees and Investigators . Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995-2008. doi:10.1056/NEJMoa1911303 PubMed DOI

US Department of Health and Human Services Guidance for Industry: Diabetes Mellitus—Evaluating Cardiovascular Risk in New Antidiabetic Therapies to treat Type 2 Diabetes US Food and Drug Administration; 2008. Accessed December 3, 2019. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/diabetes-mellitus-evaluating-cardiovascular-risk-new-antidiabetic-therapies-treat-type-2-diabetes

Collection of Race and Ethnicity Data in Clinical Trials: Guidance for Industry and Food and Drug Administration Staff US Food and Drug Administration; 2016. Accessed December 3, 2019. https://www.fda.gov/media/75453/download

Hicks KA, Mahaffey KW, Mehran R, et al. ; Standardized Data Collection for Cardiovascular Trials Initiative (SCTI) . 2017 Cardiovascular and stroke endpoint definitions for clinical trials. J Am Coll Cardiol. 2018;71(9):1021-1034. doi:10.1016/j.jacc.2017.12.048 PubMed DOI

Green CP, Porter CB, Bresnahan DR, Spertus JA. Development and evaluation of the Kansas City Cardiomyopathy Questionnaire: a new health status measure for heart failure. J Am Coll Cardiol. 2000;35(5):1245-1255. doi:10.1016/S0735-1097(00)00531-3 PubMed DOI

Lin DY, Wei LJ, Yang I, Ying Z. Semiparametric regression for the mean and rate functions of recurrent events. J R Stat Soc Series B Stat Methodol. 2000;62:711-730. doi:10.1111/1467-9868.00259 DOI

Wang D, Pocock S. A win ratio approach to comparing continuous non-normal outcomes in clinical trials. Pharm Stat. 2016;15(3):238-245. doi:10.1002/pst.1743 PubMed DOI

American Diabetes Association 2. Classification and diagnosis of diabetes: Standards of Medical Care in Diabetes-2019. Diabetes Care. 2019;42(suppl 1):S13-S28. doi:10.2337/dc19-S002 PubMed DOI

Chatterton H, Younger T, Fischer A, Khunti K; Programme Development Group . Risk identification and interventions to prevent type 2 diabetes in adults at high risk: summary of NICE guidance. BMJ. 2012;345:e4624. doi:10.1136/bmj.e4624 PubMed DOI

Hallow KM, Helmlinger G, Greasley PJ, McMurray JJV, Boulton DW. Why do SGLT2 inhibitors reduce heart failure hospitalization? a differential volume regulation hypothesis. Diabetes Obes Metab. 2018;20(3):479-487. doi:10.1111/dom.13126 PubMed DOI

McMurray J. EMPA-REG - the “diuretic hypothesis”. J Diabetes Complications. 2016;30(1):3-4. doi:10.1016/j.jdiacomp.2015.10.012 PubMed DOI

Devineni D, Vaccaro N, Polidori D, Rusch S, Wajs E. Effects of hydrochlorothiazide on the pharmacokinetics, pharmacodynamics, and tolerability of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in healthy participants. Clin Ther. 2014;36(5):698-710. doi:10.1016/j.clinthera.2014.02.022 PubMed DOI

Nassif ME, Windsor SL, Tang F, et al. . Dapagliflozin effects on biomarkers, symptoms, and functional status in patients with heart failure with reduced ejection fraction: the DEFINE-HF trial. Circulation. 2019;140(18):1463-1476. doi:10.1161/CIRCULATIONAHA.119.042929 PubMed DOI

Kosiborod M, Gause-Nilsson I, Xu J, Sonesson C, Johnsson E. Efficacy and safety of dapagliflozin in patients with type 2 diabetes and concomitant heart failure. J Diabetes Complications. 2017;31(7):1215-1221. doi:10.1016/j.jdiacomp.2017.02.001 PubMed DOI

Heerspink HJ, Perkins BA, Fitchett DH, Husain M, Cherney DZ. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation. 2016;134(10):752-772. doi:10.1161/CIRCULATIONAHA.116.021887 PubMed DOI

Kidokoro K, Cherney DZI, Bozovic A, et al. . Evaluation of glomerular hemodynamic function by empagliflozin in diabetic mice using in vivo imaging. Circulation. 2019;140(4):303-315. doi:10.1161/CIRCULATIONAHA.118.037418 PubMed DOI

Yanai H, Katsuyayama H. A possible mechanism for renoprotective effect of sodium-glucose cotransporter 2 inhibitor: elevation of erythropoietin production. J Clin Med Res. 2017;9(2):178-179. doi:10.14740/jocmr2857w PubMed DOI PMC

Wojcik C, Warden BA. Mechanisms and evidence for heart failure benefits from SGLT2 inhibitors. Curr Cardiol Rep. 2019;21(10):130. doi:10.1007/s11886-019-1219-4 PubMed DOI

Verma S, McMurray JJV. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia. 2018;61(10):2108-2117. doi:10.1007/s00125-018-4670-7 PubMed DOI

Verma S, Mazer CD, Yan AT, et al. ; EMPA-HEART CardioLink-6 Investigators . Effect of empagliflozin on left ventricular mass in patients with type 2 diabetes and coronary artery disease: the EMPA-HEART CardioLink-6 randomized clinical trial. Circulation. 2019;140:1693-1702. doi:10.1161/CIRCULATIONAHA.119.042375 PubMed DOI

Sodium Glucose Cotransporter-2 Inhibitors: Spotlight on Favorable Effects on Clinical Outcomes beyond Diabetes

Efficacy of dapagliflozin in heart failure with reduced ejection fraction according to body mass index

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ClinicalTrials.gov
NCT03036124