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

The University of Texas System (UT)

Status: Not yet enrolling

Conditions: Mild Autonomous Cortisol Excess; Subclinical Cushing's; Mild Autonomous Cortisol Secretion (MACS); Autonomous Cortisol Secretion (ACS)

Treatments: Procedure: Intervention 1: Adrenalectomy; Drug: Intervention 2: Semaglutide

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT07361874

STU20251717

1K23DK142038-01A1 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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

Full description

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.

Enrollment: 75 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

---

75 participants in 3 patient groups

Arm 1: Adrenalectomy (MACS)

Active Comparator group

Description:

Adults with mild autonomous cortisol secretion (MACS) who are clinically eligible for adrenalectomy undergo unilateral adrenalectomy as part of standard care. Participants complete all metabolic assessments before and after treatment.

Treatment:

Procedure: Intervention 1: Adrenalectomy

Arm 2: Semaglutide (MACS)

Active Comparator group

Description:

Adults with MACS receive once-weekly semaglutide for 26 weeks using FDA-approved weight-management dosing. Participants undergo the same assessments as the surgery group.

Treatment:

Drug: Intervention 2: Semaglutide

Arm 3: Semaglutide (Matched Controls)

Active Comparator group

Description:

Matched adults without adrenal tumors receive semaglutide using the same dosing schedule as MACS participants. This arm allows comparison of semaglutide responses between individuals with and without cortisol dysregulation.

Treatment:

Drug: Intervention 2: Semaglutide