Avivit Cahn1, Itamar Raz1, Marc Bonaca2, Ofri Mosenzon1, Sabina A Murphy2, Ilan Yanuv1, Aliza Rozenberg1, John P H Wilding3, Deepak L Bhatt2, Darren K McGuire4, Ingrid A M Gause-Nilsson5, Martin Fredriksson5, Peter A Johansson5, Gyorgy Jermendy6, Samy Hadjadj7, Anna Maria Langkilde5, Marc S Sabatine2, Stephen D Wiviott2, Lawrence A Leiter8. 1. Diabetes Unit, Department of Endocinology and Metabolism, Hadassah Medical Center, Hebrew University of Jerusalem, Faculty of Medicine, Jerusalem, Israel. 2. TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. 3. Institute of Ageing and Chronic Disease, Faculty of Health and Life Science, University of Liverpool, Liverpool, UK. 4. Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Centre, Dallas, Texas. 5. BioPharmaceuticals R&D, Gothenburg, Sweden. 6. 3rd Medical Department, Bajcsy-Zsilinszky Teaching Hospital, Budapest, Hungary. 7. L'institut du thorax, INSERM, CNRS, UNIV Nantes, CHU Nantes, Department of Endocrinology, Diabetes and Nutrition, Nantes, France. 8. Li Ka Shing Knowledge Institute, Department of Medicine, St Michael's Hospital, University of Toronto, Toronto, Canada.
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.
RCT Entities:
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.
Authors: Cristóbal Morales; Juan Francisco Merino-Torres; Paloma Moreno-Moreno; María Lainez; Iñigo Tejado; Alfredo Yoldi; Sonsoles Gutiérrez Medina; Alfonso Soto; Manuel A Botana; Virginia Bellido; Irene Caballero Journal: Drugs Context Date: 2022-02-17
Authors: Michelle L O'Donoghue; Eri T Kato; Ofri Mosenzon; Sabina A Murphy; Avivit Cahn; Marisol Herrera; Tsvetalina Tankova; Alena Šmahelová; Piera Merlini; Ingrid Gause-Nilsson; Anna Maria Langkilde; Darren K McGuire; John P H Wilding; Larry A Leiter; Deepak L Bhatt; Itamar Raz; Marc S Sabatine; Stephen D Wiviott Journal: Diabetologia Date: 2021-02-20 Impact factor: 10.122