Effect of Metyrapone on Cardiovascular Risk Factors in Patients With Adrenal Incidentalomas and Cushing's Syndrome

Drug interventional, controlled, randomized open-label, parallel-group, multicenter (3 centers in total), interventional study in patients with bilateral adrenal incidentalomas associated with SCS.

The study has 3 phases: run-in (phase 1), randomization (phase 2), and interventional phase (phase 3).

Phase 1. During run-in, patients will receive standardized antihypertensive therapy, as provided in the normal course of care and in accordance with current European guidelines. Four classes of antihypertensives will be used: Angiotensin-Converting Enzyme inhibitors (ACEi) or angiotesnine receptor antagonists (ARBs), calcium channel blockers, thiazide diuretics, and beta-blockers with vasodilator properties (Carvedilol or Nebivolol). Treatment will be chosen according to the recommendations of European guidelines and the patient's clinical condition. Patients will be evaluated monthly to check BP and to identify the lowest effective dose of antihypertensive to maintain BP <130/85 mmHg. BP will be measured during medical visits. Home PA monitoring will also be performed during the 7 days before each medical visit. Echocardiogram, electrocardiogram, 24-hour Holter PA, carotid echodoppler, albumin/creatinine ratio, and indices of glucose and lipid metabolism will also be performed, according to the normal procedures of routine clinical practice performed in patients with this problem. The run-in period will be prolonged until pressor values are stabilized (BP >100/60 mmHg and <130/85 mmHg, under minimal effective dose of antihypertensive therapy), with a minimum duration of 2 months and a maximum of 6 months. If stabilization of blood pressure values (according to the criteria outlined above) is not obtained by the sixth month after enrollment, the run-in period may be extended to a maximum of 10 months. If stabilization of the pressor values (according to the criteria outlined above) is not obtained by that time, the patient will be excluded from the study.

Phase 2. After run-in, patients will be randomized (1:1) to treatment with Metirapone (Group A) or observation (Group B) by computer-generated random sequence.

Phase 3. During the interventional phase, patients (Group A and Group B) will be seen every 4 weeks (+/- 7 days). In addition, patients receiving Metirapone (Group A) will be evaluated every 7 days (+/- 2 days) during the first month to titrate Metirapone according to cortisol and cortisone values, monitor electrolytes, and analyze potential side effects. In some patients, titration of Metirapone up to the maximum tolerated dose (and in any case no more than 750 mg/day) may be prolonged beyond 4 weeks. In this case, weekly visits will continue until the maximum tolerated dose is reached (and in any case no more than 750 mg/day) for a period of up to 4 months, after which the achieved dose of Metirapone will be maintained. Patients assigned to Metirapone treatment will not be allowed to take Paracetamol, Phenytoin and estrogen during the interventional phase. Ambulatory and home PA will be assessed monthly to optimize antihypertensive treatment to maintain PA values <130/85 mmHg. Hypotension (BP <100/60 mmHg) will be treated with modification of antihypertensive therapy. At the end of the interventional phase, cardiovascular and metabolic reevaluation will be performed.

Blood samples for serum and plasma collection will be collected after fasting from the previous evening, before randomization and at the end of the study. Saliva samples will be collected during the entire day before blood collection at 10 predetermined times. Blood samples will be collected monthly in patients treated with Metirapone. Serum and saliva will be used for steroid profiles by LC-MS/MS. The following steroids will be measured: cortisol, 21-desoxycortisol, 11-DF, 17-hydroxyprogesterone (17OHP), Delta4-androstenedione, DHEA, testosterone, progesterone, cortisone, DOC and corticosterone. Cortisol, cortisone, 17OHP, Delta4-androstenedione, DHEA and testosterone will be measured in saliva. Waist circumference and body mass index will be assessed at each visit.

Within 6 months after completion of the study, an abdominal CT scan will be repeated. This investigation will be performed as part of the patients' normal course of care, which involves performing follow-up abdomen CT scans periodically (every 18-36 months).