Aims: We investigated the associations between obesity, cardiorenal events, and benefits of dapagliflozin in patients with type 2 diabetes mellitus (T2DM)., Methods and Results: DECLARE-TIMI 58 randomized patients with T2DM and either atherosclerotic cardiovascular (CV) disease or multiple risk factors to dapagliflozin vs. placebo. Patients were stratified by body mass index (BMI, kg/m2): normal (18.5 to <25), overweight (25 to <30), moderately obese (30 to <35), severely obese (35 to <40), and very-severely obese (≥40). Outcomes analysed were CV death, hospitalization for heart failure (HHF), renal-specific composite outcome, and atrial fibrillation or flutter (AF/AFL). Of 17 134 patients, 9.0% had a normal BMI, 31.5% were overweight, 32.4% were moderately, 17.2% severely, and 9.8% were very-severely obese. Higher BMI was associated with a higher adjusted risk of HHF and AF/AFL (hazard ratio 1.30 and 1.28, respectively, per 5 kg/m2; P < 0.001 for all). Dapagliflozin reduced body weight by similar relative amounts consistently across BMI categories (percent difference: -1.9 to -2.4%). Although relative risk reductions in CV and renal-specific composite outcomes with dapagliflozin did not significantly differ across the range of BMI (P for interaction ≥0.20 for all outcomes), obese patients (BMI ≥ 30 kg/m2) tended to derive greater absolute risk reduction in HHF and AF/AFL (P for interaction 0.02 and 0.09, respectively) than non-obese patients., Conclusions: In DECLARE-TIMI 58, patients with T2DM and higher BMI were more likely to have HHF and AF/AFL. Whereas relative risk reductions in CV and renal outcomes with dapagliflozin were generally consistent across the range of BMI, absolute risk reduction in obesity-related outcomes including HHF and AF/AFL tended to be larger in obese patients with T2DM., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01730534., Competing Interests: Conflict of interest: K.O. reports a grant from JSPS Overseas Research Fellowships. I.R. reports advisory board fees from AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme, Novo Nordisk, Inc., and Sanofi, consultant fees from AstraZeneca, Insuline Medical, Medial EarlySign Ltd, CamerEyes Ltd, Exscopia, Orgenesis Ltd, BOL Pharma, Glucome Ltd, DarioHealth, Diabot, Concenter BioPharma, and CuraLife Ltd, speaker’s bureau fee from AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme, Novo Nordisk, Inc., and Sanofi, and has stocks of Glucome Ltd, Orgenesis Ltd, DarioHealth, CamerEyes Ltd, Diabot, and BOL Pharma. A.C. reports grants and personal fees from AstraZeneca and Novo Nordisk and personal fees from Abbott, Eli Lilly, Sanofi, Boehringer Ingelheim, Merck Sharp & Dohme, Medial Early-Sign, and GlucoMe. J.K. and S.A.M. report research grant support through Brigham and Women’s Hospital from Abbott Laboratories, Amgen, AstraZeneca, Critical Diagnostics, Daiichi Sankyo, Eisai, Genzyme, Gilead, GlaxoSmithKline, Intarcia, Janssen Research and Development, The Medicines Company, MedImmune, Merck, Novartis, Poxel, Pfizer, Roche Diagnostics, and Takeda. D.L.B. discloses the following relationships—advisory board: Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Janssen, Level Ex, Medscape Cardiology, MyoKardia, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences; board of directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; chair: American Heart Association Quality Oversight Committee; data monitoring committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), Population Health Research Institute; honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); others: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); research funding: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Lexicon, Lilly, Medtronic, MyoKardia, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi, Synaptic, The Medicines Company, 89Bio; royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); site co-investigator: Abbott, Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Svelte; trustee: American College of Cardiology; unfunded research: FlowCo, Merck, Takeda. L.A.L. reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, and Sanofi; personal fees from Lexicon, Merck and Servier; and grants from GlaxoSmithKline. D.K.M. reports personal fees from Lilly US, AstraZeneca, Sanofi, Janssen, Boehringer Ingelheim, Merck & Co, Novo Nordisk, Lexicon, Eisai, GlaxoSmithKline, CSL Behring and Esperion and consultancy for Afimmune, AstraZeneca, Sanofi, Lilly US, Boehringer Ingelheim, Merck & Co, Pfizer, Novo Nordisk, Applied Therapeutics, and Metavant. J.P.H.W. reports grants, personal fees, and consultancy fees from AstraZeneca, personal fees and consultancy fees from Boehringer Ingelheim, personal fees and consultancy fees from Lilly, grants, personal fees, and consultancy fees from Novo Nordisk, personal fees and consultancy fees from Janssen, personal fees and consultancy fees from Napp, personal fees and consultancy fees Mundipharma, personal fees and consultancy fees from Sanofi, grants, personal fees, and consultancy fees from Takeda, and consultancy fees from Rhythm Pharmaceuticals and Wilmington Healthcare outside the submitted work. K.S.P. reports nothing to disclose. A.G. reports grants, personal fees, and non-financial support from Amgen, Inc., personal fees and non-financial support from Servier, during the conduct of the study, personal fees from Novartis, personal fees from AstraZeneca, and personal fees from Bayer outside the submitted work. R.D. reports personal fees and other from AstraZeneca during the conduct of the study, personal fees from SANOFI, grants from AMARIN, and personal fees from Eli Lilly outside this work. J.S. reports nothing to disclose. I.A.M.G.-N. is an employee and shareholder of AstraZeneca, Gothenburg, Sweden. O.M. reports grants and personal fees from BOL Pharma, AstraZeneca, Bristol-Myers Squibb, Novo Nordisk, Eli Lilly, Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim, Jansen, and Novartis. M.S.S. reports Research grant support through Brigham and Women’s Hospital from: Amgen; AstraZeneca; Bayer; Daiichi Sankyo; Eisai; Intarcia; Janssen Research and Development; Medicines Company; MedImmune; Merck; Novartis; Pfizer; Quark Pharmaceuticals; Takeda. Consulting for: Althera; Amgen; Anthos Therapeutics; AstraZeneca; Bristol-Myers Squibb; CVS Caremark; DalCor; Dr Reddy’s Laboratories; Dyrnamix; Esperion; IFM Therapeutics; Intarcia; Janssen Research and Development; Medicines Company; MedImmune; Merck; Novartis. Research grant support through Brigham and Women’s Hospital from: Amgen; AstraZeneca; Bayer; Daiichi Sankyo; Eisai; Intarcia; Janssen Research and Development; Medicines Company; MedImmune; Merck; Novartis; Pfizer; Quark Pharmaceuticals; Takeda. Consulting for: Althera; Amgen; Anthos Therapeutics; AstraZeneca; Bristol-Myers Squibb; CVS Caremark; DalCor; Dr Reddy’s Laboratories; Dyrnamix; Esperion; IFM Therapeutics; Intarcia; Janssen Research and Development; Medicines Company; MedImmune; Merck; Novartis. S.D.W. reports grants from AstraZeneca, Bristol-Myers Squibb, Sanofi Aventis, and Amgen; grants and personal fees from Arena, Daiichi Sankyo, Eisai, Eli Lilly, and Janssen; grants and consulting fees from Merck (additionally his spouse is employed by Merck); and personal fees from Aegerion, Allergan, AngelMed, Boehringer Ingelheim, Boston Clinical Research Institute, Icon Clinical, Lexicon, St Jude Medical, Xoma, Servier, AstraZeneca, and Bristol-Myers Squibb., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)