Inadequately controlled type 2 diabetes and hypercortisolism: improved glycemia with mifepristone treatment

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.