New FDA Guidance on T2D Trial Design Provides Flexibility

John B. Buse, MD, PhD; Mark Harmel, MPH


July 20, 2021

This transcript has been edited for clarity.

The story of cardiovascular outcomes in diabetes is a fascinating one. There were new developments in the regulatory landscape that really drove the past 10 years of history.

If you go way back to the first big clinical trial in diabetes — the UGDP [University Group Diabetes Program] study — there was an indication of cardiovascular harms with sulfonylureas that resulted in black box warnings for many, many years.

When thiazolidinediones were approved, they had the promise of reducing cardiovascular events because they attacked insulin resistance, which was linked to cardiovascular disease. When there were some emerging potential cardiovascular issues — rosiglitazone being associated with an increase in LDL cholesterol — it set the stage for more inquiry. Then, there was the drug muraglitazar, whose application was withdrawn because it had been associated with excess cardiovascular events.

This is the landscape in which the FDA, in 2008, mandated cardiovascular outcome trials in diabetes. As we started to do those trials, it started out kind of boring, with the DPP-4 inhibitors showing "safety" but not really any efficacy. Then we had the absolutely revolutionary results of the GLP-1 receptor agonists and the SGLT2 inhibitors that have really reset the landscape of diabetes management and extended these therapies to other indications, such as obesity, chronic kidney disease, and heart failure.

The 2020 draft guidance from the FDA provides a lot more flexibility. The guidance is around specific numbers of people that need to be exposed over specific durations of time and providing assurance regarding cardiovascular safety because of the prior concerns — but not a mandate for a specific multi-thousand patient cardiovascular outcome trial. That provides a lot of flexibility to address diabetes in novel populations: youth, pregnancy, the advanced elderly, and in specific areas like dementing illnesses, cancer biology, liver disease, etc.

This new flexibility allows a company to develop a program that highlights the unique benefits of their drug, which is going to be absolutely essential to have a successful diabetes drug in the future.

John B. Buse, MD, PhD, is a professor and chief of the division of endocrinology at the University of North Carolina at Chapel Hill, where he also serves as director of the Diabetes Care Center and director of the NC Translational and Clinical Sciences Institute. His clinical and research interests are in the prevention and treatment of diabetes and its complications. He has authored more than 300 publications and has received numerous awards and honors.

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