IMPACT-MACS Study: Investigating the Mechanisms, Pathophysiology, and Cardiometabolic Treatment in Mild Autonomous Cortisol Secretion
Summary
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
Detailed 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.
Arms & interventions
- ProcedureIntervention 1: Adrenalectomy
Surgical removal of one adrenal gland performed by an endocrine surgeon following institutional standard-of-care practices. Includes postoperative monitoring for adrenal insufficiency and routine clinical follow-up.
- DrugIntervention 2: Semaglutide
Once-weekly subcutaneous semaglutide administered according to FDA-approved titration for chronic weight management (0.25 mg to 2.4 mg weekly as tolerated). Participants receive training on injection technique, dose escalation, and safety monitoring.
Outcome measures
Primary
Change in Insulin Sensitivity (M-value), mg/kg/min
Hyperinsulinemic-euglycemic clamp
Time frame: Baseline to Week 26
Secondary
Change in fasting plasma glucose, mg/dL
Time frame: Baseline to Week 26
Change in hemoglobin A1C, %
Time frame: Baseline to Week 26
Change in fasting insulin, µU/mL
Time frame: Baseline to Week 26
Change in glucagon, pg/mL
Time frame: Baseline to Week 26
Change in c-peptide, nmol/L
Time frame: Baseline to Week 26
Change in IGF-1, ng/mL
Time frame: Baseline to Week 26
Change in IGF-II, ng/mL
Time frame: Baseline to Week 26
Change in IGFBP-1, ng/mL
Time frame: Baseline to Week 26
Change in leptin, ng/mL
Time frame: Baseline to Week 26
Change in adiponectin, μg/mL
Time frame: Baseline to Week 26
% of patients with normal dexamethasone suppression test, %
Time frame: Baseline to Week 26
Change in steroid profile, ng/24h
Time frame: Baseline to Week 26
Mean change in systolic BP, mmHg
Time frame: Baseline to Week 26
Mean change in diastolic BP, mmHg
Time frame: Baseline to Week 26
Change in cholesterol, mg/dL
Time frame: Baseline to Week 26
Change in Free Fatty Acids, mmol/L
Time frame: Baseline to Week 26Baseline to Week 26
Change in C-reactive protein, pg/mL
Time frame: Baseline to Week 26
Change in TNF-alpha, pg/mL
Time frame: Baseline to Week 26
Change in Interleukin-1, pg/mL
Time frame: Baseline to Week 26
Change in Interleukin-6, pg/mL
Time frame: Baseline to Week 26
Change in body weight, kg
Time frame: Baseline to Week 26
Change in BMI, kg/m2
Time frame: Baseline to Week 26
Change in waist circumference, cm
Time frame: Baseline to Week 26
Change in fat area, cm2
Time frame: Baseline to Week 26
Change in muscle area, cm2
Time frame: Baseline to Week 26
Change in bone mineral density, mg/cm³
Time frame: Baseline to Week 26
Change in chair rise test, stands/30s
Time frame: Baseline to Week 26
Change in Hand Grip Strength, kg
Time frame: Baseline to Week 26
Change in overall quality of life, score
Time frame: Baseline to Week 26
Change in disease-specific QoL, score
Time frame: Baseline to Week 26
Change in mood, score
Time frame: Baseline to Week 26
Change in cognition, seconds
Time frame: Baseline to Week 26
Change in sleep, score
Time frame: Baseline to Week 26
Change in frailty, score
Time frame: Baseline to Week 26
Change in eating behavior, score
Time frame: Baseline to Week 26
Adverse Events and Serious Adverse Events
Time frame: Baseline through Week 30
Eligibility criteria
Study locations (1)
University of Texas Southwestern Medical Center
Dallas, Texas, 75390
References
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