Ralph A. DeFronzo, MD: Noxious Nine and Mifepristone for Hypercortisolism in T2D

In this expert interview at the 22nd Annual World Congress Insulin Resistance Diabetes & Cardiovascular Disease (WCIRDC), Ralph DeFronzo, MD, a professor of medicine and chief of the diabetes division at UT Health San Antonio, discussed the evolution of his influential concept, the Ominous Octet, which outlines the multiple defects contributing to type 2 diabetes (T2D), to the Noxious Nine.

Initially introduced in 1987 as the "triumvirate," focusing on insulin resistance in the liver and muscle and beta-cell dysfunction, the model expanded in 2008 to include five additional key players: obesity, the gastrointestinal tract, excess glucagon secretion, the kidney, and the brain, all of which exacerbate insulin resistance and beta-cell failure.

DeFronzo then shifted focus to a novel discovery about hypercortisolism in patients with difficult-to-control T2D, a condition in which the adrenal glands secrete excess cortisol, aggravating many of the defects in the ominous octet. The CATALYST study revealed that approximately 24% of these patients have elevated cortisol levels, which significantly contribute to their poor glycemic control. Treatment with mifepristone (Korlym), a glucocorticoid receptor blocker, led to a surprising 1.5% reduction in HbA1c, compared with 0.15% for placebo (placebo-adjusted reduction, 1.32%; P <.0001). In addition, mifepristone achieved a notable decrease in medication requirements, showcasing a promising new therapeutic avenue for this previously under-recognized cause of diabetes.

DeFronzo emphasized the importance of educating clinicians about hypercortisolism as a contributing factor in hard-to-treat diabetes, intending to integrate the Noxious Nine into clinical practice to improve patient outcomes. These findings represented a significant breakthrough in the understanding and management of complex T2D cases, with an FDA-approved treatment available for affected patients.

Relevant disclosures for DeFronzo include Corcept Therapeutics, AstraZeneca, Novo Nordisk, Alynylam Pharmaceuticals, and others.

References

1. _{DeFronzo R. Noxious Nine. Presented at the 22nd Annual World Congress Insulin Resistance Diabetes & Cardiovascular Disease (WCIRDC). Los Angeles, California. December 12-14, 2024.}
2. _{Iapoce C. Mifepristone Notably Reduces HbA1c in Treatment Phase of Catalyst Trial. HCP Live. December 12, 2024. Accessed December 13, 2024. https://www.hcplive.com/view/mifepristone-notably-reduces-hba1c-in-treatment-phase-of-catalyst-trial.}