The design and rationale for the Dapagliflozin Effect on Cardiovascular Events (DECLARE)–TIMI 58 Trial - 11/06/18
, Itamar Raz b, Marc P Bonaca a, Ofri Mosenzon b, Eri T Kato c, Avivit Cahn b, Michael G Silverman d, Sameer Bansilal e, Deepak L Bhatt a, Lawrence A. Leiter g, Darren K. McGuire i, John PH Wilding h, Ingrid AM Gause-Nilsson f, Anna Maria Langkilde f, Peter A. Johansson f, Marc S. Sabatine aAbstract |
Background |
Dapagliflozin is a sodium-glucose co-transporter-2 (SGLT-2) inhibitor that reduces blood glucose in patients with type 2 diabetes mellitus (T2DM) by promoting glycosuria via inhibiting urinary glucose reabsorption. In addition to improving blood glucose control, treatment with dapagliflozin results in glucose-induced osmotic diuresis, weight loss, and blood pressure lowering. Previous trials of SGLT-2 inhibitors showed reductions in cardiovascular (CV) events, including CV death and hospitalization for heart failure, and ischemic events in patients with atherosclerotic cardiovascular disease (ASCVD).
Research design and methods |
DECLARE–TIMI 58 (NCT01730534) is a phase 3b randomized, double-blind, placebo-controlled trial designed to evaluate the CV safety and efficacy of dapagliflozin that has completed randomization of 17,160 patients with T2DM and a history of either established ASCVD (n=6,971) or multiple risk factors for ASCVD (n=10,189). Patients were randomized in a 1:1 fashion to dapagliflozin 10 mg or matching placebo. The primary safety outcome is the time to the first event of the composite of CV death, myocardial infarction, or ischemic stroke (major adverse cardiovascular events; MACEs). The co-primary efficacy outcomes are the composite of CV death, myocardial infarction, or ischemic stroke and the composite of CV death or hospitalization for heart failure. This event-driven trial will continue until at least 1,390 subjects have a MACE outcome, thereby providing >99% power to test for the primary outcome of safety of dapagliflozin measured by rejecting the hypothesis that the upper bound of the CI >1.3 for the primary outcome of MACE, as well as 85% power to detect a 15% relative risk reduction in MACE and an estimated 87% power to detect a 20% reduction in the composite of CV death or hospitalization for heart failure at a 1-sided α level of .0231.
Conclusion |
The DECLARE–TIMI 58 trial is testing the hypotheses that dapagliflozin is safe (does not increase) and may reduce the occurrence of major CV events. DECLARE–TIMI 58 is the largest study to address this question with an SGLT-2 inhibitor in patients with T2DM and with established CV disease and without CV disease but with multiple risk factors.
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| RCT# NCT01730534 |
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| Disclosures: Dr Wiviott reports grants and personal fees from AstraZeneca, grants and personal fees from Bristol Myers Squibb, grants and personal fees from Eisai, grants and personal fees from Merck, personal fees from Aegerion, personal fees from Angelmed, personal fees from Xoma, personal fees from ICON Clinical, personal fees from Boston Clinical Research Institute, grants and personal fees from Eli Lilly/Daiichi Sankyo, grants from Sanofi-Aventis, other from Merck Research Laboratory, personal fees from Boehringer Ingelheim, grants and personal fees from Amgen, personal fees from Allergan, grants and personal fees from Janssen, grants from Arena, and personal fees from St Jude Medical and Lexicon outside the submitted work. Dr Wiviott's wife is an employee of Merck. Dr. Raz discloses the following relationships: Advisory Board: AstraZeneca, Boehringer Ingelheim, Concenter BioPharma/Silkim Ltd, Eli Lilly and Company, Merck Sharp & Dohme, Novo Nordisk, Inc., Orgenesis, Pfizer, Sanofi, SmartZyme Innovation Ltd, Panaxia; Consultant: AstraZeneca/Bristol-Myers Squibb, Diabetes Medical Center, FuturRx Ltd, Insuline Medical, Medial EarlySign Ltd, CamerEyes, Exscopia, Dermal Biomics Inc; Speaker’s Bureau: AstraZeneca/Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly and Company, Johnson & Johnson, Merck Sharp & Dohme Limited, Novartis Pharma AG, Novo Nordisk, Inc., Sanofi, Teva; Stock/Shareholder: Glucome Ltd, Insuline Medical, Orgenesis, DarioHealth, CamerEyes. Dr. Bonaca reports grant support to BWH from AstraZeneca, MedImmune, and Merck; Consulting for Aralez, AstraZeneca, Merck and Bayer Dr Bhatt discloses the following relationships: Advisory Board: Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Cleveland Clinic, Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine, Population Health Research Institute; honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology Today's Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); research funding:Abbott, Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Ironwood, Ischemix, Lilly, Medtronic, Pfizer, Regeneron, Roche, Sanofi Aventis, The Medicines Company; royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald's Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, St. Jude Medical (now Abbott); Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, PLx Pharma, Takeda. Dr Leiter has received research funding from, has provided CME on behalf of, and/or has acted as an advisor to AstraZeneca, Boehringer Ingelheim, Eli Lilly, GSK, Janssen, Merck, Novo Nordisk, Sanofi, Servier. J. P. H. Wilding has received lecture fees from Astellas, AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Novo Nordisk, Orexigen, Sanofi; consultancy (Institutional) from AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, and Orexigen; and grants to institution from Takeda, Novo Nordisk and AstraZeneca. Dr Cahn discloses the following relationships: Advisory Board: Novo Nordisk, Eli Lilly, Sanofi, Boehringer Ingelheim, AstraZeneca; research grant support through Hadassah Hebrew University Hospital: AstraZeneca; Speaker's Bureau: AstraZeneca, Novo Nordisk, Eli Lilly, Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim. Stock/shareholder: Glucome Ltd. Dr Nilsson, Dr Langkilde, and Dr Johansson are employees and shareholders of AstraZeneca. Dr Darren K. McGuire discloses the following relationships: honoraria for clinical trials leadership: AstraZeneca, Sanofi Aventis, Janssen, Boehringer Ingelheim, Merck & Co, Novo Nordisk, Lexicon, Eisai, GlaxoSmithKline, Esperion; honoraria for consultancy: AstraZeneca, Sanofi Aventis, Lilly US, Boehringer Ingelheim, Merck & Co, Pfizer, Novo Nordisk. Dr Bansilal is an and employee of Bayer US LLC and reports prior consulting fees from Janssen and AstraZeneca and research grant from AstraZeneca. Dr Kato discloses the following relationships: honoraria from AstraZeneca, Bristol-Myers Squibb, Daiichi-Sankyo, Ono Pharmaceutical, and Mitsubishi Tanabe Pharma. Dr Bonaca discloses the following relationships: research grant support to Brigham and Women's Hospital from AstraZeneca, MedImmune, Merck; consulting for Aralez, AstraZeneca, Bayer, Johnson and Johnson, and Merck Dr Mosenzon discloses the following: Advisory Board: Novo Nordisk, Eli Lilly, sanofi, Merck Sharp & Dohme, Boehringer Ingelheim, Jansen and Jansen, Novartis, AstraZeneca; grants paid to institution as study physician by AstraZeneca and Bristol-Myers Squibb; research grant support through Hadassah Hebrew University Hospital: Novo Nordisk; Speaker's Bureau: AstraZeneca and Bristol-Myers Squibb, Novo Nordisk, Eli Lilly, Sanofi, Novartis, Merck Sharp & Dohme, Boehringer Ingelheim. |
Vol 200
P. 83-89 - juin 2018 Retour au numéro
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