Autonomous Cortisol Secretion (ACS), Mild Autonomous Cortisol Excess, Mild Autonomous Cortisol Secretion (MACS), Subclinical Cushing's
Conditions
Keywords
Mild Autonomous Cortisol Secretion, MACS, Adrenal incidentaloma, Adrenal adenoma, Subclinical Cushing, Hypercortisolism, Cortisol dysregulation, Adrenalectomy, Semaglutide, Weight loss, Body composition, Insulin resistance, GLP-1 receptor agonist, Hyperinsulinemic-euglycemic clamp, Cortisol dynamics, Visceral fat, cardiometabolic risk, randomized controlled trial
Brief 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.
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.
Sponsors
University of Texas Southwestern Medical Center
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This study includes two coordinated components. First, a randomized controlled trial in adults with mild autonomous cortisol secretion (MACS) who are eligible for adrenalectomy. Participants are randomized 1:1 to adrenalectomy or semaglutide for 26 weeks, stratified by post-DST cortisol and sex. This evaluates surgical versus medical effects on insulin sensitivity and cortisol regulation. Second, a matched case-control comparison in adults without adrenal tumors who receive semaglutide using the same schedule. Controls are matched 1:1 by age, sex, BMI, and diabetes status to isolate disease-specific metabolic responses. Both components follow identical assessments in an open-label, parallel-assignment design without crossover, enabling evaluation of treatment modality in MACS and differential response to semaglutide.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Insulin Sensitivity (M-value), mg/kg/min | Baseline to Week 26 | Hyperinsulinemic-euglycemic clamp |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in fasting plasma glucose, mg/dL | Baseline to Week 26 | — |
| Change in hemoglobin A1C, % | Baseline to Week 26 | fasting blood test |
| Change in fasting insulin, µU/mL | Baseline to Week 26 | Fasting blood test |
| Change in glucagon, pg/mL | Baseline to Week 26 | Fasting blood test |
| Change in c-peptide, nmol/L | Baseline to Week 26 | Fasting blood test |
| Change in IGF-1, ng/mL | Baseline to Week 26 | Fasting blood glucose |
| Change in IGF-II, ng/mL | Baseline to Week 26 | Fasting blood test |
| Change in IGFBP-1, ng/mL | Baseline to Week 26 | Fasting blood test |
| Change in leptin, ng/mL | Baseline to Week 26 | Fasting blood glucose |
| Change in adiponectin, μg/mL | Baseline to Week 26 | Fasting blood test |
| % of patients with normal dexamethasone suppression test, % | Baseline to Week 26 | 1-mg dexamethasone suppression test |
| Change in steroid profile, ng/24h | Baseline to Week 26 | 25-steroid profiling in the 24-hour urine, reported as aggregate |
| Mean change in systolic BP, mmHg | Baseline to Week 26 | 24-hour Ambulatory BP |
| Mean change in diastolic BP, mmHg | Baseline to Week 26 | 24-hour Ambulatory BP |
| Change in cholesterol, mg/dL | Baseline to Week 26 | Fasting blood test |
| Change in Free Fatty Acids, mmol/L | Baseline to Week 26Baseline to Week 26 | Fasting blood test |
| Change in C-reactive protein, pg/mL | Baseline to Week 26 | Fasting blood test |
| Change in TNF-alpha, pg/mL | Baseline to Week 26 | Fasting blood glucose |
| Change in Interleukin-1, pg/mL | Baseline to Week 26 | Fasting blood test |
| Change in Interleukin-6, pg/mL | Baseline to Week 26 | Fasting blood test |
| Change in body weight, kg | Baseline to Week 26 | electronic scale |
| Change in BMI, kg/m2 | Baseline to Week 26 | calculated from weight and height |
| Change in waist circumference, cm | Baseline to Week 26 | Tape measure |
| Change in fat area, cm2 | Baseline to Week 26 | Limited unenhanced CT |
| Change in muscle area, cm2 | Baseline to Week 26 | Limited unenhanced CT |
| Change in bone mineral density, mg/cm³ | Baseline to Week 26 | Limited unenhanced CT |
| Change in chair rise test, stands/30s | Baseline to Week 26 | Time test, number of stands from chair in 30 seconds |
| Change in Hand Grip Strength, kg | Baseline to Week 26 | Dynamometer |
| Change in overall quality of life, score | Baseline to Week 26 | 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. |
| Change in disease-specific QoL, score | Baseline to Week 26 | 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. |
| Change in mood, score | Baseline to Week 26 | 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. |
| Change in cognition, seconds | Baseline to Week 26 | 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. |
| Change in sleep, score | Baseline to Week 26 | 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. |
| Change in frailty, score | Baseline to Week 26 | 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. |
| Change in eating behavior, score | Baseline to Week 26 | 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. |
| Adverse Events and Serious Adverse Events | Baseline through Week 30 | — |
Countries
United States
Contacts
CONTACTOksana Hamidi, DO, MSCS
Outcome results
None listed