| Autor: |
Sharma A; Division of Cardiology, McGill University Health Centre, Montreal, QC, Canada (A.S.).; Division of Cardiovascular Medicine, Stanford University School of Medicine, CA (A.S.)., Pagidipati NJ; Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC (N.J.P., J.B.G., M.T.R., C.G.)., Califf RM; Verily Life Sciences and Duke University School of Medicine, Durham, NC (R.M.C.)., McGuire DK; UT Southwestern, Dallas (D.K.M.)., Green JB; Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC (N.J.P., J.B.G., M.T.R., C.G.)., Demets D; University of Wisconsin, Madison (D.D.)., George JT; Boehringer-Ingelheim International, Ingelheim am Rhein, Germany (J.T.G.)., Gerstein HC; McMaster University, Hamilton, ON, Canada (H.C.G.)., Hobbs T; Novo Nordisk, Plainsboro, NJ (T.H.)., Holman RR; Diabetes Trials Unit, University of Oxford, UK (R.R.H.)., Lawson FC; Sanofi US, Bridgewater, NJ (F.C.L.)., Leiter LA; University of Toronto, ON, Canada (L.A.L.)., Pfeffer MA; Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (M.A.P.)., Reusch J; University of Colorado School of Medicine, Denver (J.R.)., Riesmeyer JS; Eli Lilly & Co, Indianapolis, IN (J.S.R.)., Roe MT; Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC (N.J.P., J.B.G., M.T.R., C.G.)., Rosenberg Y; National Heart, Lung, and Blood Institute, Bethesda, MD (Y.R.)., Temple R; Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD (R.T.)., Wiviott S; TIMI Study Group, Harvard Medical School, Boston, MA (S.W.)., McMurray J; University of Glasgow, Scotland, UK (J.M.)., Granger C; Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC (N.J.P., J.B.G., M.T.R., C.G.). |
| Abstrakt: |
Responding to concerns about the potential for increased risk of adverse cardiovascular outcomes, specifically myocardial infarction, associated with certain glucose-lowering therapies, the US Food and Drug Administration and the Committee for Medicinal Products for Human Use of the European Medicines Agency issued guidance to the pharmaceutical industry in 2008. Glucose-lowering therapies were granted regulatory approval primarily from smaller studies that have demonstrated reductions in glycated hemoglobin concentration. Such studies were overall underpowered and of insufficient duration to show any effect on cardiovascular outcomes. The 2008 guidance aimed to ensure the cardiovascular safety of new glucose-lowering therapies to treat patients with type 2 diabetes mellitus. This resulted in a plethora of new cardiovascular outcome trials, most designed primarily as placebo-controlled noninferiority trials, but with many also powered for superiority. Several of these outcome trials demonstrated cardiovascular benefits of the newer agents, resulting in the first-ever cardiovascular protection indications for glucose-lowering therapies. Determining whether the guidance continues to have value in its current form is critically important as we move forward after the first decade of implementation. In February 2018, a think tank comprising representatives from academia, industry, and regulatory agencies convened to consider the guidance in light of the findings of the completed cardiovascular outcome trials. The group made several recommendations for future regulatory guidance and for cardiovascular outcome trials of glucose-lowering therapies. These recommendations include requiring only the 1.3 noninferiority margin for regulatory approval, conducting trials for longer durations, considering studying glucose-lowering therapies as first-line management of type 2 diabetes mellitus, considering heart failure or kidney outcomes within the primary outcome, considering head-to-head active comparator trials, increasing the diversity of patients enrolled, evaluating strategies to streamline registries and the study of unselected populations, and identifying ways to improve translation of trial results to general practice. |
