Effects of Osilodrostat on the corticosteroid metabolome in patients with mild autonomous cortisol excess (the OSI-CORT study)

The adrenals are glands located on top of the kidneys that produce a variety of hormones, including the stress hormone cortisol. Up to 10 out of 100 adults have a benign lump in their adrenal glands called an “adrenal incidentaloma”. When doctors find an incidentaloma, they do some tests to check if it produces excess cortisol, which can cause diabetes, high blood pressure and abnormal amounts of lipids in the blood. We found that about half of adrenal incidentalomas produce excess cortisol, a condition called “mild autonomous cortisol excess” (MACE). Therefore, MACE comes with an increased risk of diabetes and heart disease. The only established treatment for MACE is surgery (removal of the adrenal tumour). However, surgery is an invasive procedure and carries risk. Osilodrostat is a daily oral treatment for patients with clinically overt and severe cortisol excess (a condition known as Cushing’s syndrome), which prevents the adrenal glands from producing too much cortisol. We hypothesise that osilodrostat, given at doses much lower than those recommended in Cushing’s syndrome, is a potential therapy to reduce comorbidities of patients with MACE and avoid surgery. In this study, we would test if very low doses of osilodrostat are effective in significantly reducing the amounts of cortisol produced by adrenal incidentalomas in patients with MACE. We would start by giving a very small dose of osilodrostat to participants with MACE for 4 weeks. We would assess cortisol production in the urine, blood, and saliva at the beginning and at the end of the study. If we find out that this small dose is not sufficient in lowering cortisol production, we would test progressively higher doses of osilodrostat until we find the minimum effective dose.