Dr. Javed Butler, Chair of Medicine at UMMC, served as lead author on a White Paper published in Circulation that explored to what extent persuasive treatment effects on nonprimary end points can be used to support FDA regulatory claims and guideline recommendations. The White Paper is a summary of a meeting at the FDA in March 2019 involving stakeholders across scientific disciplines, including clinical trialists, industry sponsors, regulators, representatives from professional societies and practicing cardiologists and endocrinologists. In 2008, the FDA recommended that sponsors of new antihyperglycemic drugs perform large-scale randomized trials to rule out unacceptable cardiovascular (CV) risk. Due to these recommendations, many global CVOT (cardiovascular outcome trials) were conducted to confirm CV safety, with 2 classes of diabetes medications showing superiority for the primary endpoint of major adverse cardiac events (glucagon-like peptide-1 receptor agonists and sodium glucose cotransporter 2 inhibitors). These findings led to FDA-approval of these medications for CV risk mitigation in patients with Type II diabetes.

However, there was no mention of heart failure (HF) in the FDA guidance since HF events were not included in primary CV outcomes of these trials and were mostly secondary or exploratory end points. This paper calls for a critical reappraisal of the relevance of nonprimary clinical trial end points in regulatory and clinical decision making. The authors recommended that future large-scale CVOTs of antihyperglycemic therapies include HF data points, specifically including patients with baseline HF at the start of a trial, characterization of HF, and consideration of HF events as a primary endpoint.

This White Paper is an important contribution to cardiovascular medicine and the regulation of medications in this field. Since the meeting in March, two approvals for SGLT2 inhibitors based on DECLARE and on CREDENCE trials have been given by the FDA for the management of cardio-renal complications of high-risk patients with diabetes.

Read the full paper here.