Impact of Regulatory Guidance on Evaluating Cardiovascular Risk of New Glucose-Lowering Therapies to Treat Type 2 Diabetes Mellitus: Lessons Learned and Future Directions.

Responding to concerns about the potential for increased risk of adverse cardiovascular (CV) outcomes, specifically myocardial infarction, associated with certain glucose-lowering therapies, the U.S. 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 primarily granted regulatory approval 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 CV outcomes. The 2008 guidance aimed to ensure CV safety of new glucose-lowering therapies to treat patients with type 2 diabetes mellitus. This resulted in a plethora of new CV outcome trials, most designed primarily as placebo-controlled noninferiority trials, but with many also powered for superiority. Several of these outcome trials demonstrated CV benefits of the newer agents, resulting in the first-ever CV 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 CV outcome trials. The group made several recommendations for future regulatory guidance and for CV outcome trials regarding 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, 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.