@article{e45981aa36d845dd9f81236b1f5cdab3,
title = "Safety of dapagliflozin in a broad population of patients with type 2 diabetes: Analyses from the DECLARE-TIMI 58 study",
abstract = "Aims: To evaluate comprehensively the safety of dapagliflozin in patients with type 2 diabetes (T2DM), with emphasis placed on potential safety concerns related to the sodium-glucose co-transporter-2 inhibitor class. Methods: In the Dapagliflozin Effect on Cardiovascular Events – Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) study, 17 160 patients with T2DM were randomized to dapagliflozin or placebo and followed for a median of 4.2 years. Safety was evaluated in 17 143 patients receiving at least one dose of study drug. Results: Acute kidney injury occurred less frequently with dapagliflozin, and adverse events suggestive of volume depletion were balanced between treatment groups, both irrespective of baseline estimated glomerular filtration rate, blood pressure, diuretic or loop diuretic use (interaction P values >0.05). Fractures and malignancies were balanced between the groups, irrespective of sex, diabetes duration or smoking (interaction P values >0.05) and fewer cases of bladder cancer occurred in the dapagliflozin versus the placebo group. Diabetic ketoacidosis was very rare, but more frequent with dapagliflozin versus placebo (27 vs. 12 patients with events; P = 0.02), yet signs, symptoms and contributing factors were similar in the two groups. Major hypoglycaemia occurred less frequently with dapagliflozin versus placebo, regardless of baseline use of either insulin or sulphonylureas (interaction P values >0.05). There were more adverse events of genital infections leading to discontinuation of study drug in the dapagliflozin versus the placebo group, but serious genital infections were few and balanced between treatment groups. Urinary tract infections, acute pyelonephritis and urosepsis were also balanced between treatment groups. Conclusions: Dapagliflozin was well tolerated. The long duration and large number of patient-years in DECLARE-TIMI 58 comprehensively addressed previous safety questions, confirming the robust safety profile of dapagliflozin.",
keywords = "SGLT2 inhibitor, acute kidney injury, dapagliflozin, diabetic ketoacidosis, fractures, genital infections, hypoglycemia, malignancy, safety, urinary tract infections, volume depletion",
author = "Avivit Cahn and Itamar Raz and Marc Bonaca and Ofri Mosenzon and Murphy, {Sabina A.} and Ilan Yanuv and Aliza Rozenberg and Wilding, {John P.H.} and Bhatt, {Deepak L.} and McGuire, {Darren K.} and Gause-Nilsson, {Ingrid A.M.} and Martin Fredriksson and Johansson, {Peter A.} and Gyorgy Jermendy and Samy Hadjadj and Langkilde, {Anna Maria} and Sabatine, {Marc S.} and Wiviott, {Stephen D.} and Leiter, {Lawrence A.}",
note = "Funding Information: A.C. reports grants and personal fees from AstraZeneca and Novo Nordisk and personal fees from Eli Lilly, Medial EarlySign, Abbott, Gefen Medical, Sanofi, Boehringer Ingelheim, Merck Sharp & Dohme and GlucoMe. I.R. reports personal fees from AstraZeneca, Bristol‐Myers Squibb, Boehringer Ingelheim, Concenter BioPharma and Silkim, Eli Lilly, Merck‐Sharp & Dohme, Novo Nordisk, Orgenesis, Pfizer, Sanofi, SmartZyme‐Innovation, Panaxia, FuturRx, Insuline Medical, Medial EarlySign, CameraEyes, Exscopia, Dermal Biomics, Johnson & Johnson, Novartis, Teva, GlucoMe and DarioHealth. O.M. reports grants and personal fees from AstraZeneca, Bristol‐Myers Squibb and Novo Nordisk and personal fees from Eli Lilly, Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim, Johnson & Johnson and 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. S.A.M. reports research grant support through Brigham and Women's Hospital from Abbott, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., Daiichi‐Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, The Medicines Company, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda and Zora Biosciences. A.R. and I.Y. declare no competing interests. J.P.H.W., outside the submitted work, has grants, personal fees for lectures and consultancy fees (paid to his institution) from AstraZeneca and Novo Nordisk, personal fees for lectures and consultancy fees (paid to his institution) from Boehringer Ingelheim, Janssen, Lilly, Mundipharma, Napp, Sanofi and Takeda, and consultancy fees (paid to his institution) from Wilmington Healthcare. D.L.B. discloses the following relationships: Advisory Board: Cardax, Cereno Scientific, Elsevier Practice Update Cardiology, Medscape Cardiology, 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), 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, , ACC.org; Vice‐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, ), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, ), (Guest Editor; Associate Editor), Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Population Health Research Institute (for the CO.M.PASS operations committee, publications committee, steering committee, and USA national co‐leader, funded by Bayer), Slack Publications (Chief Medical Editor, ), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: (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, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lexicon, Lilly, Medtronic, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; Royalties: Elsevier (Editor, ); Site Co‐Investigator: Biotronik, Boston Scientific, CSI, St Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, Novo Nordisk, Takeda. D.K.M. discloses the following relationships: personal fees for clinical trial leadership from GlaxoSmithKline, Janssen, Lexicon AstraZeneca, Sanofi Aventis, Boehringer Ingelheim, Merck & Co, Pfizer, Novo Nordisk, Eisai Inc., Esperion, Lilly USA; and personal fees for consultancy from AstraZeneca, Lilly USA, Boehringer Ingelheim, Merck & Co, Novo Nordisk, Metavant, Applied Therapeutics, Sanofi Aventis, Afimmune. I.A.M.G.‐N., M.F., P.A.J. and A.M.L. are employees of AstraZeneca. S.H. has served as National Leader for France in the DECLARE‐TIMI study and as a consultant and/or on advisory panels for Astra Zeneca/ Bristol Myers Squibb/ Valbiotis, has received honoraria or speaking fees from Astra Zeneca, Abbott, Boehringer Ingelheim, Eli‐Lilly, Janssen, Merck Sharpe Dome, Novartis, Novo Nordisk, Sanofi, Servier and Takeda, has received research grants from Abbott, Dinno Sant{\'e} and Takeda, and has received travel grants from Janssen, Astra Zeneca/Bristol Myers Squibb, Merck Sharpe Dome, Servier and Sanofi. G.J. served as study investigator and national lead investigator for Hungary in the DECLARE‐TIMI 58 trial and received honoraria for speaking engagements and for participation in advisory board for AstraZeneca; outside the submitted work, has personal fees for lectures and consutancy fees from Novo Nordisk, Eli Lilly, Merck Sharp & Dohme, Boehringer Ingelheim, TEVA, Novartis, Sanofi‐Aventis, Servier, KRKA, 77 Electronics. M.S.S. reports research grant support through Brigham and Women's Hospital from Amgen, AstraZeneca, Bayer, Daiichi Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen Research and Development, The Medicines Company, MedImmune, Merck Sharp & Dohme, Novartis, Poxel, Pfizer, Quark, and Takeda and consulting fees from Alnylam, Anthos Therapeutics, Amgen, AstraZeneca, Bristol‐Myers Squibb, CVS Caremark, Dyrnamix, Esperion, IFM Therapeutics, Intarcia, Ionis, Janssen Research and Development, The Medicines Company, MedImmune, Merck Sharp & Dohme, and Novartis, 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. L.A.L. reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, and Sanofi; personal fees from Merck and Servier; and grants from GlaxoSmithKline. Clinical Trials and News Harvard Heart Letter Journal of Invasive Cardiology Journal of the American College of Cardiology Cardiology Today's Intervention Clinical Cardiology Cardiovascular Intervention: A Companion to Braunwald's Heart Disease Publisher Copyright: {\textcopyright} 2020 John Wiley & Sons Ltd",
year = "2020",
month = aug,
day = "1",
doi = "10.1111/dom.14041",
language = "English (US)",
volume = "22",
pages = "1357--1368",
journal = "Diabetes, Obesity and Metabolism",
issn = "1462-8902",
publisher = "Wiley-Blackwell",
number = "8",
}