Ralph DeFronzo, MD is a Professor of Medicine and Chief, Diabetes Division at UT Health San Antonio.

Ralph DeFronzo, MD 

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

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 

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.

DeFronzo R. Noxious Nine. Presented at the 22nd Annual World Congress Insulin Resistance Diabetes & Cardiovascular Disease (WCIRDC). Los Angeles, California. December 12-14, 2024.

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.

Videos

Ralph DeFronzo, MD, discussed the evolution of his Ominous Octet concept to the Noxious Nine, highlighting the role of hypercortisolism in difficult-to-control type 2 diabetes (T2D). Initially focusing on insulin resistance and beta-cell dysfunction, the model expanded to include additional factors like obesity and excess glucagon secretion. The CATALYST study found that 24% of patients with challenging T2D have elevated cortisol levels, significantly impacting glycemic control. Mifepristone treatment showed a 1.5% reduction in HbA1c, suggesting a new therapeutic approach for these patients.

Ralph A. DeFronzo, MD discusses the Noxious Nine and the impact of hypercortisolism on difficult-to-control type 2 diabetes.








Reconsidering Standard of Care for Hypercortisolism

Video content above is prompted by the following:

For patients undergoing treatment for hypercortisolism, what are the long-term implications for glycemic control and overall health?

How might future findings from this study influence the standard of care for patients with difficult-to-control T2D?

Part 2 of this study is currently ongoing. In the meantime, how should clinicians be approaching patients who meet these criteria right now?

Panelists discuss how treating hypercortisolism in patients may have long-term effects on glycemic control and overall health, potentially influencing future standards of care for difficult-to-control Type 2 diabetes, while emphasizing the need for clinicians to carefully manage such patients as ongoing research continues.

Mifeprestone for Treatment of Hypercortisolism

•	Part 2 of the CATALYST study will assess the safety and efficacy of mifepristone treatment in patients with hypercortisolism who have difficult-to-control type 2 diabetes. Can you explain how mifepristone works to control hypercortisolism? For which patients would this treatment be appropriate?
•	The catalyst study also showed that a quarter of the patients with hypercortisolism had an adrenal tumor. What would be the best way to treat these patients?
•	Which patients would not be good candidates for surgery?

Experts discuss the CATALYST study's evaluation of mifepristone for hypercortisolism patients with hard-to-manage type 2 diabetes, its mechanism of action, suitable patient populations, treatment approaches for those with adrenal tumors, and factors determining surgical candidacy.

Spectrum of Hypercortisolism Presentations

Can you discuss the spectrum of hypercortisolism and its various clinical presentations, especially in T2D?

Based on the prevalence data from the CATALYST study, how should we approach screening of patients for hypercortisolism?

Are there specific subgroups of patients with T2D who may have a higher prevalence of hypercortisolism?

Can you talk about testing for hypercortisolism? What tests are recommended for screening and subsequent confirmation?

Can you explain the dexamethasone suppression test (DST) used in the CATALYST study?

Key opinion leaders explore the diverse clinical manifestations of hypercortisolism across its spectrum of presentations.

Ralph DeFronzo, MD

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