Effect of Dapagliflozin on Worsening Heart Failure and Cardiovascular Death in Patients with Heart Failure with and Without Diabetes

Mark C. Petrie, Subodh Verma, Kieran F. Docherty, Silvio E. Inzucchi, Inder Anand, Jan Bělohlávek, Michael Böhm, Chern En Chiang, Vijay K. Chopra, Rudolf A. De Boer, Akshay S. Desai, Mirta Diez, Jaroslaw Drozdz, Andre Dukát, Junbo Ge, Jonathan Howlett, Tzvetana Katova, Masafumi Kitakaze, Charlotta E.A. Ljungman, Béla MerkelyJose C. Nicolau, Eileen O'Meara, Pham Nguyen Vinh, Morten Schou, Sergey Tereshchenko, Lars Køber, Mikhail N. Kosiborod, Anna Maria Langkilde, Felipe A. Martinez, Piotr Ponikowski, Marc S. Sabatine, Mikaela Sjöstrand, Scott D. Solomon, Per Johanson, Peter J. Greasley, David Boulton, Olof Bengtsson, Pardeep S. Jhund, John J.V. McMurray*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

349 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1353-1368
Number of pages16
JournalJAMA - Journal of the American Medical Association
Volume323
Issue number14
DOIs
Publication statusPublished - 14 Apr 2020
Externally publishedYes

Bibliographical note

Funding Information:
Funding/Support: This study was funded by

Funding Information:
and Bayer; personal fees from Otsuka, Alnylam, and Akcea; grants from Medtronic; and serving on the medical advisory board for Caridiol outside the submitted work. Dr Katova reported receiving personal fees from AstraZeneca during the conduct of the study. Dr Kitakaze reported receiving grants and personal fees from AstraZeneca during the conduct of the study and grants from the Japanese government, the Japan Heart Foundation, and the Japan Agency for Medical Research and Development; grants and personal fees from Asteras, Sanofi, Pfizer, Ono, Novartis, Tanabe-Mitubishi, and Takeda; and personal fees from Daiichi-sankyo, Bayer, Bheringer, Kowa, Sawai, Merck Sharp & Dohme, Shionogi, Kureha, Japan Medical Data, Taisho-Toyama, and Toa Eiyo outside the submitted work. Dr Ljungman reported receiving personal fees and financial reimbursement to the institution from AstraZeneca during the conduct of the study and personal fees from Novartis and Pfizer outside the submitted work. Dr Merkely reported receiving personal fees from AstraZeneca and Servier outside the submitted work. Dr Nicolau reported receiving grants from AstraZeneca during the conduct of the study and personal fees from Amgen, Daiichi-Sankyo, and Servier; grants from AstraZeneca, Bristol-Meyers-Squibb, CLS Behring, Dalcor, Jansen, Novo Nordisk, and Vifor; and grants and personal fees from Bayer, Novartis, and Sanofi outside the submitted work. Dr O'Meara reported consultation and speaker fees being paid to the Montreal Heart Institute Research Center from Amgen, Merck, and Novartis; receiving consultation and speaker fees from AstraZeneca, Bayer, and Boehringer Ingelheim; serving on a steering committee and as a national leader for clinical studies with fees paid to Montreal Heart Institute Research Center from American Regent, AstraZeneca, Cytokinetics, Merck, and Novartis; and clinical trial participation from Amgen, Abbott, American Regent, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Eidos, Novartis, Merck, Pfizer, and Sanofi. Dr Schou reported receiving personal fees and nonfinancial support from AstraZeneca and personal fees from Novo Nordisk and Bohringer Ingelheim outside the submitted work. Dr Tereschchenko reported receiving personal fees from AstraZeneca during the conduct of the study and personal fees from AstraZeneca, Boehringer Ingelheim, Novartis, Servier, and Amgen outside the submitted work. Dr Køber reported receiving grants from AstraZeneca to the institution for participation in Dapa-HF steering committee during the conduct of the study and personal fees from speakers honorarium from AstraZeneca and Novartis outside the submitted work. Dr Kosiborod reported receiving grants and personal fees from AstraZeneca and Boehringer Inelheim and personal fees from Sanofi, Amgen, Novo Nordisk, Merck, Eisai, Janssen, Bayer, GlaxoSmithKline, Glytec, Intarcia, Novartis, Applied Therapeutics, Amarin, and Eli Lilly outside the submitted work. Dr Langkilde reported receiving being a full-time employee of and shareholder in AstraZeneca during the conduct of the study. Dr Martinez reported receiving personal fees from AstraZeneca during the conduct of the study. Dr Ponikowski reported receiving personal fees and fees to his institution from participation as an investigator in clinical trials from AstraZeneca during the conduct of the study and from Boehringer Ingelheim, Servier, Novartis, Berlin-Chemie, Bayer, Renal Guard Solutions, Pfizer,

Funding Information:
receiving lecture fees from AstraZeneca and Eli Lilly during the conduct of the study and personal fees from Novo Nordisk, AstraZeneca, NAPP Pharmaceuticals, Takeda Pharmaceutical, Alnylam, Bayer, Resverlogix, and Cardiorentis and grants and personal fees from Boehringer Ingelheim and Novartis outside the submitted work. Dr Verma reported receiving personal fees from AstraZeneca, Sun Pharmaceuticals, and Toronto Knowledge Translation Working Group during the conduct of the study and grants and personal fees from Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, and Merck; grants from Bristol-Myers Squibb; and personal fees from Eli Lilly, Janssen, Novartis, Novo Nordisk, Sanofi outside the submitted work. Dr Docherty reported his employer, the University of Glasgow, being paid by AstraZeneca (sponsor of DAPA-HF) for his involvement in the DAPA-HF trial and receiving personal fees from Eli Lilly outside the submitted work. Dr Inzucchi reported receiving personal fees from AstraZeneca during the conduct of the study and personal fees from AstraZeneca, Boehringer Ingelheim, Merck, VTV Therapeutics, Sanofi/Lexicon, and Novo Nordisk outside the submitted work. Dr Anand reported receiving personal fees from AstraZeneca during the conduct of the study and personal fees from Amgen, ARCA, Boston Scientific Corporation, Boehringer Ingelheim, LivaNova, and Zensun outside the submitted work. Dr Belohlavek reported receiving personal fees from AstraZeneca during the conduct of the study and grants from the Ministry of Health/ Grant Agency for Health Research of the Czech Republic and personal fees from Novartis, Boehringer Ingelheim, Amgen, Medpace, and Pfizer outside the submitted work. Dr Boehm reported receiving personal fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Servier, Medtronic, Vifor, and Novartis outside the submitted work. Dr Chiang reported receiving honorarium for lectures from AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Merck Sharp & Dohme, Novartis, Pfizer, and Sanofi. Dr de Boer reported receiving grants from Abbott, Bristol-Myers Squibb, and Novo Nordisk; personal fees from Abbott; and grants and personal fees from Novartis, Roche, and AstraZeneca outside the submitted work. Dr Desai reported receiving personal fees from Abbott, Biofourmis, Boston Scientific, Boehringer Ingelheim, Merck, Regeneron, and Relypsa and grants and personal fees from AstraZeneca, Alnylam, and Novartis outside the submitted work. Dr Diez reported receiving personal fees from AstraZeneca during the conduct of the study. Dr Howlett reported receiving grants and personal fees from AstraZeneca Canada and Boerhinger Ingelheim/Eli Lilly during the conduct of the study and grants and personal fees from Servier Canada, Novartis, Pfizer,

Funding Information:
Respicardia, Cardiorentis, and Cibiem; grants, personal fees, and fees to his institution from Impulse Dynamics; and fees to his institution from Vifor, Corvia, and Revamp Medical outside the submitted work. Dr Sabatine reported receiving grants and personal fees from AstraZeneca during the conduct of the study; grants and personal fees from Amgen, Intarcia, Janssen Research and Development, Medicines Company, MedImmune, Merck, and Novartis; personal fees from Anthos Therapeutics, Bristol-Myers Squibb, CVS Caremark, DalCor, Dyrnamix, Esperion, IFM Therapeutics, Ionis; and grants from Daiichi-Sankyo, Bayer, Pfizer, Poxel, Eisai, GlaxoSmithKline, Quark Pharmaceuticals, and Takeda outside the submitted work; and is a member of the TIMI Study Group, which has also received institutional research grant support through Brigham and Women's Hospital from Abbott, Aralez, Roche, and Zora Biosciences. Dr Sjöstrand reported receiving personal fees from and being a full-time employee and shareholder of AstraZeneca outside the submitted work. Dr Solomon reported receiving grants from AstraZeneca during the conduct of the study and grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol-Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Sanofi Pasteur, and Theracos and personal fees from Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Bristol-Myers Squibb, Cardior, Corvia, Cytokinetics, Daiichi-Sankyo, Gilead, GlaxoSmithKline, Ironwood, Merck, Myokardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, and Tenaya outside the submitted work. Dr Johanson reported receiving personal fees from AstraZeneca during the conduct of the study and outside the submitted work. Dr Greasley reported being an employee of and shareholder in AstraZeneca. Dr Boulton reported being an employee of and shareholder in AstraZeneca outside the submitted work. Dr Bengtsson reported receiving personal fees from AstraZeneca outside the submitted work. Dr Jhund reported his employer being paid by AstraZeneca for his time working on the study and receiving personal fees from and his employer being paid by Novartis; grants and personal fees from Boehringer Ingelheim; personal fees from Cytokinetics and Vifor Pharma outside the submitted work; and being the director of Global Clinical Trials Partners Ltd. Dr McMurray reported receiving grants and his employer being paid by AstraZeneca, Theracos, and GlaxoSmithKline during the conduct of the study and grants and his employer being paid by Novartis, Amgen, Bristol-Myers Squibb, Bayer, Abbvie, Dal-Cor, Kidney Research UK, and Cardurion and grants from British Heart Foundation outside the submitted work. No other disclosures were reported.

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