Inadequately controlled type 2 diabetes and hypercortisolism: improved glycemia with mifepristone treatment
Year: 2025
Type: other
Abstract: Objective: In many individuals, type 2 diabetes (T2D) remains poorly controlled despite taking multiple glucose-lowering therapies. Several studies have demonstrated that endogenous hypercortisolism is prevalent among these individuals. We tested whether cortisol-directed therapy improves their glycemic control. Research Design and Methods: In this prospective, multi-center, double-blind study (NCT05772169), 136 individuals with T2D (hemoglobin A1c [HbA1c] 7.5% to 11.5% [58 to 102 mmol/mol] on multiple medications) and hypercortisolism (by dexamethasone suppression test) were randomized 2:1 to the glucocorticoid-receptor antagonist mifepristone (300 mg to 900 mg once daily; n=91) or placebo (n=45) for 24 weeks, stratified by presence/absence of an adrenal imaging abnormality. The primary endpoint was the change in HbA1c. Secondary endpoints included changes in glucose-lowering medications, weight, and waist circumference and safety. Results: Baseline HbA1c in the study cohort was 8.55% (69.9 mmol/mol). At 24 weeks, the least-squares mean (LSM) difference from placebo in HbA1c was -1.32% (95% CI, -1.81 to 0.83; P<0.001). Participants receiving mifepristone experienced reductions in body weight and waist circumference (placebo-adjusted LSM differences of 5.12 kg; 95% CI, 8.20 to -2.03 and -5.1 cm; 95% CI, 8.23 to -1.99, respectively). On mifepristone, 46% of participants discontinued therapy, compared to 18% on placebo. Adverse events with mifepristone (>10% of participants) included hypokalemia, fatigue, nausea, vomiting, headache, peripheral edema, diarrhea, and dizziness, consistent with mifepristone’s known tolerability profile. Increases in blood pressure also occurred. Conclusions: In individuals with inadequately controlled T2D and hypercortisolism, cortisol-directed medical therapy with mifepristone reduced HbA1c with a manageable tolerability profile.
Authors: Ralph A. DeFronzo, Vivian Fonseca, Vanita R. Aroda, Richard J. Auchus, Timothy Bailey, Irina Bancos, Robert S. Busch, John B. Buse, Elena A. Christofides, Bradley Eilerman, James W. Findling, Yehuda Handelsman, Steven E. Kahn, Harold J. Miller, Jonathan G. Ownby, John C. Parker, Athena Philis-Tsimikas, Richard Pratley, Julio Rosenstock, Michael H. Shanik, Lance A. Sloan, Guillermo Umpierrez, Samir Shambharkar, Iulia Cristina Tudor, Tina K. Schlafly, Daniel Einhorn
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W4411527802