OBJECTIVE: To analyze the impact of adding saxagliptin versus placebo on the risk for hypoglycemia and to identify predictors of any and major hypoglycemia in patients with type 2 diabetes included in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) study. RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes (n = 16,492) were randomized to saxagliptin or placebo and followed for a median of 2.1 years. Associations between any hypoglycemia (symptomatic or glucose measurement <54 mg/dL) or major hypoglycemia (requiring extended assistance) and patient characteristics overall and by treatment allocation were studied. RESULTS: At least one hypoglycemic event was reported in 16.6% of patients, and 1.9% reported at least one major event. Patients allocated to saxagliptin versusplacebo experienced higher rates of any (hazard ratio [HR] 1.16 [95% CI 1.08, 1.25]; P < 0.001) or major (HR 1.26 [1.01, 1.58]; P = 0.038) hypoglycemia. Hypoglycemia rates (any or major) were increased with saxagliptin in patients taking sulfonylureas (SURs) but not in those taking insulin. Rates were increased with saxagliptin in those with baseline HbA1c ≤7.0% and not in those with baseline HbA1c >7.0%. Multivariate analysis of the overall population revealed that independent predictors of any hypoglycemia were as follows: allocation to saxagliptin, long duration of diabetes, increased updated HbA1c, macroalbuminuria, moderate renal failure, SUR use, and insulin use. Predictors of major hypoglycemia were allocation to saxagliptin, advanced age, black race, reduced BMI, long duration of diabetes, declining renal function, microalbuminuria, and use of short-acting insulin. Among SURs, glibenclamide was associated with increased risk of major but not any hypoglycemia. CONCLUSIONS: The identification of patients at risk for hypoglycemia can guide physicians to better tailor antidiabetic therapy.
Bibliographical noteFunding Information:
The SAVOR-TIMI 53 trial was funded by AstraZeneca and Bristol-Myers Squibb. A.C. reports receipt of consulting fees and payment for lectures from AstraZeneca, Boehringer Ingelheim, Elli Lilly and Company, Merck Sharp & Dohme, Novartis, Novo Nordisk, and Sanofi. I.R. has served on the advisory board for AstraZeneca/BristolMeyers Squibb, Eli Lilly and Company, Medscape LLC, Merck Sharp & Dohme, Novo Nordisk, Sanofi, Orgenesis, SmartZyme Innovation Ltd., and LabStyle Innovations Corp.; has been a consultant for AstraZeneca/Bristol-Meyers Squibb, Insuline Medical, Gili Medical, KAMADA, and FutuRx; has served on the speaker's bureau for AstraZeneca/Bristol-Meyers Squibb, Eli Lilly and Company, Johnson & Johnson, Merck Sharp & Dohme, Novartis, Novo Nordisk, Sanofi, and Teva; and is a stock-/shareholder of Insuline Medical, LabStyle Innovations Corp., SmartZyme Innovation Ltd., Orgenesis, and GlucoMe. O.M. has served on the advisory board for Novo Nordisk, Eli Lilly and Company, Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim, Janssen, Novartis, and AstraZeneca; had grants paid to their institution as a study physician by AstraZeneca and Bristol-Myers Squibb; has received research grant support through Hadassah Hebrew University Hospital-Novo Nordisk; and has served on the speaker's bureau for AstraZeneca, Bristol-Myers Squibb, Novo Nordisk, Eli Lilly and Company, Sanofi, Novartis, Merck Sharp & Dohme, and Boehringer Ingelheim. G.L. has received speaker's honoraria from Novartis, Novo Nordisk, Eli Lilly and Company, and Sanofi and has attended advisory board meetings for Sanofi and AstraZeneca. N.I., M.S., and C.S. are employees of AstraZeneca. B.H. is an employee of MedImmune, a subsidiary of AstraZeneca. B.M.S. has received research grants via the TIMI Study and Brigham and Women's Hospital from AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Gilead, Eisai, and Merck Sharp & Dohme and consulting fees from AstraZeneca, Biogen Idec, Boehringer Ingelheim, Boston Clinical Research Institute, Bristol-Myers Squibb, Covance, Dr. Reddy's Laboratory, Eisai, Elsevier Practice Update Cardiology, Forest Laboratory, GE Healthcare, Gilead, GlaxoSmithKline, Lexicon, Merck Sharp & Dohme, St. Jude Medical, and the University of Calgary. D.L.B. has served on the advisory board for Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; has served on the board of directors for Boston VA Research Institute and Society of Cardiovascular Patient Care; has been the chair of the American Heart Association Quality Oversight Committee; has served on the data monitoring committee for the Duke Clinical Research Institute, the Harvard Clinical Research Institute, the Mayo Clinic, and the Population Health Research Institute; has received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org), Belvoir Publications (Editor in Chief, Harvard Heart Letter), the Duke Clinical Research Institute (clinical trial steering committees), the Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (editor inchief, Journal of Invasive Cardiology), the Journal of the American College of Cardiology (guest editor and associate editor), the Population Health Research Institute (clinical trial steering committee), Slack Publications (chief medical editor, Cardiology Today's Intervention), the Society of Cardiovascular Patient Care (secretary/treasurer), WebMD (continuing medical education steering committees), Clinical Cardiology (deputy editor), NCDR-ACTION Registry Steering Committee (vice chair), and VA CART Research and Publications Committee (chair); has received research funding from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Medtronic, Pfizer, Roche, Sanofi, and The Medicines Company; has received royalties from Elsevier (editor, Cardiovascular Intervention: A Companion to Braunwald's Heart Disease); has served as site co-investigator for Biotronik, Boston Scientific, and St. Jude Medical; is atrustee of the American College of Cardiology; and has performed unfunded research for FlowCo, PLx Pharma, and Takeda. E.B. has received research grants via the TIMI Study Group and Brigham and Women's Hospital from Merck Sharp & Dohme, Daiichi Sankyo, GlaxoSmithKline, Bristol-Myers Squibb, Duke University, AstraZeneca, Johnson & Johnson, Sanofi, and Novartis; has received consulting fees from The Medicines Company, Sanofi, and Theravance Biopharma; and has received payment for lectures from Menarini Group, Bayer, and Medscape. No other potential conflicts of interest relevant to this article were reported.
© 2016 by the American Diabetes Association.