Mifepristone in Hypercortisolism: Mechanism, Metabolic Benefits, and Management Challenges

In this segment, Richard Auchus, MD, introduces mifepristone as a cornerstone medical therapy for Cushing syndrome and, increasingly, for hypercortisolism in difficult-to-control diabetes. Mifepristone (RU-486) is characterized as a potent oral glucocorticoid receptor antagonist that also blocks the progesterone receptor. Initially studied in the SEISMIC trial for overt Cushing syndrome, mifepristone is now leveraged in contexts like CATALYST where cortisol excess contributes to refractory metabolic disease. Dr Auchus notes that typical dosing ranges from 300 to 1200 mg once daily, with the drug acting primarily by blocking cortisol action at the receptor level rather than reducing cortisol production.

Clinical data from SEISMIC demonstrated robust metabolic benefits: approximately 7% weight loss over 6 months, reductions in waist circumference and body fat, and substantial improvement in glycemic control. The primary endpoints of improved glucose area under the curve on oral glucose tolerance testing and reduction in hemoglobin A1c were met, with early and clinically meaningful changes. In CATALYST, mifepristone similarly produced an A1c reduction of about 1.5 percentage points, meeting thresholds typically required for FDA approval of glucose-lowering agents. Ralph DeFronzo, MD, further underscores that patients achieved approximately 40% reductions in basal insulin requirements and significant decreases in prandial insulin, suggesting that the A1c improvement may understate the true therapeutic impact.

The faculty also review important safety and tolerability concerns. Because mifepristone blocks glucocorticoid receptors at the pituitary and peripheral tissues, serum cortisol levels often rise in compensation and can activate mineralocorticoid receptors, leading to hypertension and hypokalemia. In blinded trials such as CATALYST, investigators could not readily pre-empt these issues, leading to more frequent episodes of hypokalemia and blood pressure elevation than would be expected in open-label practice. Patients commonly experience a glucocorticoid withdrawal syndrome—fatigue, myalgias, and anorexia—analogous to postoperative recovery in surgically cured Cushing syndrome. Dr Auchus emphasizes that in routine clinical care, these effects can be mitigated by anticipatory monitoring, early use of spironolactone, potassium supplementation, and patient counseling, but they may challenge primary care clinicians less familiar with the drug’s nuances.