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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
75
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.
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.
University of Texas Southwestern Medical Center
Dallas, Texas, United States
Change in Insulin Sensitivity (M-value), mg/kg/min
Hyperinsulinemic-euglycemic clamp
Time frame: Baseline to Week 26
Change in fasting plasma glucose, mg/dL
Time frame: Baseline to Week 26
Change in hemoglobin A1C, %
fasting blood test
Time frame: Baseline to Week 26
Change in fasting insulin, µU/mL
Fasting blood test
Time frame: Baseline to Week 26
Change in glucagon, pg/mL
Fasting blood test
Time frame: Baseline to Week 26
Change in c-peptide, nmol/L
Fasting blood test
Time frame: Baseline to Week 26
Change in IGF-1, ng/mL
Fasting blood glucose
Time frame: Baseline to Week 26
Change in IGF-II, ng/mL
Fasting blood test
Time frame: Baseline to Week 26
Change in IGFBP-1, ng/mL
Fasting blood test
Time frame: Baseline to Week 26
Change in leptin, ng/mL
Fasting blood glucose
Time frame: Baseline to Week 26
Change in adiponectin, μg/mL
Fasting blood test
Time frame: Baseline to Week 26
% of patients with normal dexamethasone suppression test, %
1-mg dexamethasone suppression test
Time frame: Baseline to Week 26
Change in steroid profile, ng/24h
25-steroid profiling in the 24-hour urine, reported as aggregate
Time frame: Baseline to Week 26
Mean change in systolic BP, mmHg
24-hour Ambulatory BP
Time frame: Baseline to Week 26
Mean change in diastolic BP, mmHg
24-hour Ambulatory BP
Time frame: Baseline to Week 26
Change in cholesterol, mg/dL
Fasting blood test
Time frame: Baseline to Week 26
Change in Free Fatty Acids, mmol/L
Fasting blood test
Time frame: Baseline to Week 26Baseline to Week 26
Change in C-reactive protein, pg/mL
Fasting blood test
Time frame: Baseline to Week 26
Change in TNF-alpha, pg/mL
Fasting blood glucose
Time frame: Baseline to Week 26
Change in Interleukin-1, pg/mL
Fasting blood test
Time frame: Baseline to Week 26
Change in Interleukin-6, pg/mL
Fasting blood test
Time frame: Baseline to Week 26
Change in body weight, kg
electronic scale
Time frame: Baseline to Week 26
Change in BMI, kg/m2
calculated from weight and height
Time frame: Baseline to Week 26
Change in waist circumference, cm
Tape measure
Time frame: Baseline to Week 26
Change in fat area, cm2
Limited unenhanced CT
Time frame: Baseline to Week 26
Change in muscle area, cm2
Limited unenhanced CT
Time frame: Baseline to Week 26
Change in bone mineral density, mg/cm³
Limited unenhanced CT
Time frame: Baseline to Week 26
Change in chair rise test, stands/30s
Time test, number of stands from chair in 30 seconds
Time frame: Baseline to Week 26
Change in Hand Grip Strength, kg
Dynamometer
Time frame: Baseline to Week 26
Change in overall quality of life, score
PROMIS Global Health Questionnaire, domain-specific scales; The Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health v1.2 Questionnaire assesses overall health-related quality of life across multiple domains, including physical health, mental health, social functioning, fatigue, and general well-being. It yields two standardized T-score summary measures (Global Physical Health and Global Mental Health). Score Range: T-scores typically range from 20 to 80. Interpretation: Higher T-scores indicate better health-related quality of life. Assessment Method: Self-report questionnaire; estimated completion time 2-5 minutes.
Time frame: Baseline to Week 26
Change in disease-specific QoL, score
Cushing Quality of Life Questionnaire (CushingQoL) Description: The Cushing Quality of Life Questionnaire (CushingQoL) is a disease-specific tool assessing health-related quality of life in individuals with hypercortisolism. It contains 12 items scored on a 5-point Likert scale. Score Range: 12 (minimum) to 60 (maximum). Interpretation: Higher scores indicate better quality of life; lower scores indicate poorer quality of life. Domains: Sleep disturbances, mood, physical appearance, social interaction, health concerns. Assessment Method: Self-administered; estimated completion time \~5 minutes.
Time frame: Baseline to Week 26
Change in mood, score
PROMIS Depression Short Form \& PROMIS Anxiety Short Form Description: The PROMIS Depression Short Form and PROMIS Anxiety Short Form measure depressive and anxiety symptoms over the past seven days, assessing emotional distress, negative affect, and somatic symptoms. Responses are on a 5-point Likert scale ("Never" to "Always"), converted to standardized T-scores. Score Range: T-scores typically range from 20 to 80. Interpretation: Higher scores indicate worse depressive or anxiety symptoms. Assessment Method: Self-report questionnaires; estimated completion time 2-4 minutes each.
Time frame: Baseline to Week 26
Change in cognition, seconds
Trail Making Test - Part A and Part B (TMT-A and TMT-B) Description: The Trail Making Test Parts A and B assess visual attention, processing speed, cognitive flexibility, and executive function. Part A requires sequential connection of numbers; Part B requires alternating between numbers and letters. Score Range: 0 to 300 seconds (maximum test time). Interpretation: Higher (longer) completion times indicate worse cognitive performance. Assessment Method: Performance-based timed test administered by study personnel; expected duration \~5 minutes.
Time frame: Baseline to Week 26
Change in sleep, score
PROMIS Sleep Disturbance Short Form Description: The PROMIS Sleep Disturbance Short Form evaluates sleep quality, difficulty initiating and maintaining sleep, and overall sleep problems over the past seven days. Scores are converted into standardized T-scores. Score Range: T-scores typically range from 20 to 80. Interpretation: Higher scores indicate worse sleep disturbance. Assessment Method: Self-administered; estimated completion time 2-4 minutes.
Time frame: Baseline to Week 26
Change in frailty, score
FRAIL Scale (Fatigue, Resistance, Ambulation, Illnesses, Loss of Weight) Description: The FRAIL Scale is a validated screening instrument assessing functional decline and physiological frailty. It consists of five yes/no items: fatigue, resistance, ambulation, illnesses, and weight loss. Score Range: 0 (minimum) to 5 (maximum). Interpretation: Higher scores indicate greater frailty. Frailty Categories: 0: Robust 1-2: Pre-frail 3-5: Frail Assessment Method: Administered by study personnel; duration \~1 minute.
Time frame: Baseline to Week 26
Change in eating behavior, score
Eating Behavior and Appetite Questionnaire (EBAQ) Description: The Eating Behavior and Appetite Questionnaire (EBAQ) evaluates hunger, satiety, food cravings, and changes in appetite and eating behavior. It generates domain-specific and total scores. Score Range: Varies by version; treated as continuous scores with defined minimum and maximum values per subscale. Interpretation: Higher scores indicate greater appetite or more pronounced eating-behavior disturbances. Assessment Method: Self-administered; estimated completion time 3-5 minutes.
Time frame: Baseline to Week 26
Adverse Events and Serious Adverse Events
Time frame: Baseline through Week 30
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