Mifepristone: glucocorticoid receptor blockade
Mifepristone is a glucocorticoid receptor (GR2) antagonist, recently FDA-approved to treat hyperglycemia in adult patients with Cushing’s syndrome who have failed surgery or are not surgical candidates. Regulatory approval was based on a 24-week open-label trial studying 50 Cushing’s patients (43 with CD) and associated type 2 diabetes mellitus/impaired glucose tolerance (DM/IGT), or hypertension [74]. At the end of the treatment period, 15/25 patients (60 %) in the DM/IGT group achieved ≥25 % reductions in glucose AUC0–120 min. Patients also exhibited reductions in HbA1c and fasting plasma glucose levels, as well as reduced body weight and waist circumference, improvements in clinical status and quality of life.
With GR2 receptor blockade, ACTH and cortisol will likely increase, potentially resulting in hypokalemia, increased blood pressure, edema, or alkalosis through activation of mineralocorticoid receptors [75]. Other potential adverse reactions include adrenal insufficiency (AI) and endometrial thickening with vaginal bleeding—both requiring close monitoring and treatment [76, 77]. As there is no biochemical marker to follow (cortisol values are not reliable), treatment efficacy and potential adrenal insufficiency must be gauged through changes in clinical signs and symptoms [77]. Mifepristone is also a potent antagonist of progesterone, thus premenopausal women must be tested for pregnancy before administration. Caution is also warranted in combination with drugs metabolized by CYP3A or CYP2C (e.g., simvastatin, cyclosporine, fentanyl, ciprofloxacin, NSAIDs, warfarin).