IMPACT-MACS: Adrenalectomy vs Semaglutide for Metabolic Outcomes in Mild Autonomous Cortisol Secretion

IMPACT-MACS Study: Investigating the Mechanisms, Pathophysiology, and Cardiometabolic Treatment in Mild Autonomous Cortisol Secretion

The goal of this study is to learn how two treatments-adrenalectomy (surgical removal of an adrenal gland) and semaglutide (a medication used for weight management)-affect insulin resistance and cortisol regulation in adults with mild autonomous cortisol secretion (MACS). The study will also learn how these treatments impact body composition, blood pressure, cholesterol, inflammation, muscle strength, and quality of life.

The main questions the study aims to answer are:

1. Does adrenalectomy or semaglutide improve insulin resistance more in people with MACS?
2. How do these treatments change cortisol patterns and other cardiometabolic risk factors?
3. Do people with MACS respond differently to semaglutide compared to matched adults without MACS?

Participants will:

1. Receive either adrenalectomy or semaglutide if they have MACS, or semaglutide if they are matched controls
2. Complete clinic visits and phone visits over about 26-30 weeks
3. Undergo metabolic testing such as blood tests, urine steroid profiling, body composition scans, blood pressure monitoring, muscle strength testing, and questionnaires about health and well-being

This single-center, prospective, interventional study evaluates metabolic responses to surgical versus medical treatment in adults with mild autonomous cortisol secretion (MACS). The study includes:

1. a randomized controlled trial comparing adrenalectomy to semaglutide in MACS, and
2. a parallel matched case-control comparison evaluating semaglutide effects in MACS versus matched controls without adrenal tumors.

The primary objective is to compare changes in insulin sensitivity measured by hyperinsulinemic-euglycemic clamp (M-value) from baseline to week 26. Secondary outcomes include cortisol dynamics, steroid profiling, cardiometabolic biomarkers, body composition, blood pressure, muscle strength, and patient-reported quality of life.

Semaglutide is administered within its FDA-approved indication for weight management; adrenalectomy is standard of care. No investigational drugs or devices are used, and no IND is required.

Inclusion Criteria:

• Adults ≥18 years
• MACS groups: adrenal adenoma + DST cortisol >1.8 µg/dL + no overt Cushing + eligible for adrenalectomy
• Willingness to postpone surgery 6 months if randomized
• Controls: no adrenal abnormalities + normal DST + BMI ≥27 + ≥2 cardiometabolic conditions
• Stable medication doses for ≥4 weeks
• Negative pregnancy test if applicable

Exclusion Criteria:

• Prior GLP-1 RA within 90 days
• Weight change >5 kg in past 90 days
• Prior obesity/diabetes surgery
• Type 1 diabetes or other diabetes types
• Severe organ disease
• Recent pancreatitis
• Pregnancy, breastfeeding
• Contraindication to semaglutide
• Contraindication to surgery delay
• Chronic glucocorticoid use