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Inadequately Controlled Type 2 Diabetes and Hypercortisolism: Improved Glycemia With Mifepristone Treatment
Ralph A DeFronzo1, Vivian Fonseca2, Vanita R Aroda3
1University of Texas Health Science Center at San Antonio and Texas Diabetes Institute, San Antonio, TX.
Diabetes Care
|June 23, 2025
Summary
Cortisol-directed therapy with mifepristone significantly improved glycemic control in patients with type 2 diabetes and hypercortisolism. This treatment reduced hemoglobin A1c levels and other metabolic markers, offering a new therapeutic option.
Area of Science:
- Endocrinology
- Metabolic Diseases
- Pharmacology
Background:
- Type 2 diabetes (T2D) often remains poorly controlled despite multiple therapies.
- Endogenous hypercortisolism is prevalent in individuals with uncontrolled T2D.
- Investigating cortisol's role is crucial for improving glycemic management.
Purpose of the Study:
- To evaluate the efficacy of cortisol-directed therapy in improving glycemic control in T2D patients with hypercortisolism.
- To assess the impact of mifepristone on hemoglobin A1c (HbA1c), weight, and waist circumference.
- To determine the safety and tolerability profile of mifepristone in this patient population.
Main Methods:
- Prospective, multicenter, double-blind study involving 136 individuals with T2D and hypercortisolism.
- Randomization of participants to mifepristone (glucocorticoid receptor antagonist) or placebo for 24 weeks.
- Primary endpoint: change in HbA1c; secondary endpoints: changes in weight, waist circumference, and safety.
Main Results:
- Mifepristone significantly reduced HbA1c by -1.32% compared to placebo (P < 0.001).
- Participants on mifepristone experienced significant reductions in body weight (-5.12 kg) and waist circumference (-5.1 cm).
- Higher discontinuation rates (46%) in the mifepristone group due to adverse events like hypokalemia and fatigue.
Conclusions:
- Cortisol-directed therapy with mifepristone is effective in reducing HbA1c in T2D patients with hypercortisolism.
- The treatment offers benefits in weight and waist circumference reduction.
- Mifepristone presents a manageable, albeit notable, tolerability profile requiring careful monitoring.
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