Effects of Metyrapone in Patients with Mild Hypercortisolism

Background: Mild Hypercotisolism (mH) is associated with increased cardiometabolic risk despite limited clinical signs. Surgery is the first-line treatment, with medical therapies reserved when surgery is not feasible. However, data on its efficacy in mH, particularly for blood pressure (BP) control, remain limited. The aim of the present study was to evaluate the impact of low-dose evening metyrapone on 24-hour ambulatory BP, glucose metabolism, and cortisol circadian rhythm in patients with mH. Methods: In this prospective, single-center observational study (NCT05255900), 20 patients with mH were treated with evening metyrapone (250-500 mg/day) for 24 weeks. Inclusion criteria included cortisol >1.8 µg/dL after 1 mg dexamethasone suppression, <2 specific Cushing syndrome related symptoms (i.e. easy bruising, facial plethora, proximal myopathy, purple striae) and presence of hypertension or glucose metabolism impairment. BP control, glucometabolic profile, and salivary cortisol rhythms were assessed at baseline, 12, and 24 weeks. Results: At 24 weeks, 40% of patients (8/20) achieved a predefined clinically significant BP improvement (≥5 mmHg reduction in mean 24-h systolic BP without therapy escalation). This effect was more pronounced in patients with elevated baseline systolic BP. Glucometabolic control improved in 4 patients, notably in those with type 2 diabetes, with a reduction in HbA1c ≥0.5% in two patients without changes in antidiabetic therapy. Metyrapone was well tolerated, with no adverse events or adrenal insufficiency reported. Conclusions: Low-dose evening metyrapone appears to be a safe and potentially effective option for improving BP control in patients with mH, especially those with higher baseline systolic pressure.