Aims/hypothesis: Adrenal incidentaloma (AI) are very common, but optimal management of patients with AI and low-grade excess cortisol secretion is not established. Uncontrolled studies reporting outcomes of adrenalectomy suggest improvements in cardiovascular risk, but all are subject to selection bias, and it is unclear if benefits are due to removal of excess cortisol. We reasoned that short-term use of mifepristone, a rapidly-acting glucocorticoid receptor (GR) antagonist, could improve GR-mediated cardiovascular and metabolic risk, with the ultimate aim of devising a individualised means of selecting those most likely to benefit from surgical intervention.
Methods: In a prospective open label pilot study, six patients with mild cortisol excess from adrenal incidentalomas (mean serum cortisol post 1 mg ONDST was 79.8 nmol/l) were treated with mifepristone 200 mg twice/day for up to 8 weeks. Primary end-points were 2-h glucose from OGTT and resting/24-h BP at 4 weeks. Secondary end-points included insulin sensitivity, fasting and AUC insulin and glucose at 4 weeks, resting/24-h BP at 8 weeks, serum 0900 h ACTH/cortisol and salivary 0900/2300 h cortisol at 4 and 8 weeks, lipids and bone markers at 8 weeks.
Results: All subjects showed clear biochemical evidence of GR antagonism, with significant elevations of serum and salivary cortisol, and plasma ACTH. As a group, at 4 weeks, there was a significant improvement in all indices of insulin sensitivity/resistance including HOMA-IR (3.16 vs 2.3; P=0.05), HOMA-%β (147.6 vs 91.67; P=0.03) and Matsuda index (3.31 vs 4.98; P=0.03). In one subject, however, there was no improvement. There were no significant changes in resting/24 h BP, mean serum osteocalcin levels and urine NTX/Creat.
Conclusions/interpretation: Short-term GR antagonism with mifepristone improves insulin sensitivity in some, but not all, patients with mild cortisol excess. Larger studies are needed, but our data suggest that GR antagonism may form the basis of a clinical tool to stratify patients for intervention in an individualised manner.