Regulatory Approach to Medications for Type 2 Diabetes: Past, Present, and Future
Regulatory requirements for the approval of new antihyperglycemic medications have evolved substantially over the past decade and a half. The use of hemoglobin A1c reduction is the established measure of efficacy for new antihyperglycemic medications and is unlikely to change for the foreseeable future. In 2008 the US Food and Drug Administration (FDA) adopted guidance requiring manufacturers to demonstrate that new drugs were not associated with an increased risk of adverse cardiovascular outcomes. This requirement led to the conduct of more than 20 large, randomized, placebo-controlled cardiovascular outcome trials, with several sodium glucose cotransporter-2 inhibitor and glucagon-like peptide-1 receptor agonist medications demonstrating important reductions in major adverse cardiovascular events, hospitalization for heart failure, and/or kidney disease while improving glycemic control. While the most recent FDA guidance, issued in 2020, has eliminated the requirement for large phase 4 outcome trials to demonstrate cardiovascular safety for all newly approved drugs, clinicians and their patients with type 2 diabetes and cardiovascular disease are likely to demand evidence of cardiovascular, kidney, or other nonglycemic benefit to adopt novel antihyperglycemic drugs in clinical practice. Spurred on by the 21st Century Cures Act passed by the US Congress, the FDA is exploring the use of real-world evidence to assess the safety of novel medications. Whether these methods prove to be robust and reliable enough to assess efficacy will depend on an array of factors, including the disease of interest and the accepted efficacy endpoint(s).
