Mild Autonomous Cortisol Secretion (MACS)IMPACT-MACSNCT07361874
IMPACT-MACS: Adrenalectomy vs Semaglutide for Metabolic Outcomes in Mild Autonomous Cortisol Secretion
A study testing Intervention 1: Adrenalectomy and Intervention 2: Semaglutide in people with Mild Autonomous Cortisol Secretion (MACS) and Autonomous Cortisol Secretion (ACS), run by University of Texas Southwestern Medical Center at 1 site in United States.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Mild Autonomous Cortisol Secretion (MACS), Autonomous Cortisol Secretion (ACS), Subclinical Cushing's
- What is being tested?
- Intervention 1: Adrenalectomy and Intervention 2: Semaglutide
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 75 participants
- Where
- 1 siteUnited States
- Study dates
- 5 Mar 2026to 31 May 2030
- Phase
- Interventional
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 10Show fewer
- Pregnancy, breastfeeding
- Contraindication to semaglutide
- Contraindication to surgery delay
- Chronic glucocorticoid use
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
University of Texas Southwestern Medical Center
Dallas, Texas, 75390
Oksana Hamidi, DO, MSCS, 2146456397, oksana.hamidi@utsouthwestern.edu
oksana.hamidi@utsouthwestern.edu
About this study
Official title: 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:
Read more
- Does adrenalectomy or semaglutide improve insulin resistance more in people with MACS?
- How do these treatments change cortisol patterns and other cardiometabolic risk factors?
- Do people with MACS respond differently to semaglutide compared to matched adults without MACS?
Participants will:
- Receive either adrenalectomy or semaglutide if they have MACS, or semaglutide if they are matched controls
- Complete clinic visits and phone visits over about 26-30 weeks
- 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
Read the 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:
- a randomized controlled trial comparing adrenalectomy to semaglutide in MACS, and
- 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.
- Conditions
- Mild Autonomous Cortisol Secretion (MACS), Autonomous Cortisol Secretion (ACS), Subclinical Cushing's, Mild Autonomous Cortisol Excess
- Being tested
- Intervention 1: Adrenalectomy, Intervention 2: Semaglutide
- 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
- Medical subject headings
- Adrenal incidentaloma, ACTH Syndrome, Ectopic, Cushing Syndrome, Weight Loss, Insulin Resistance
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Intervention 1: AdrenalectomyProcedure or surgery
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.
Intervention 2: SemaglutideDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| Arm 1: Adrenalectomy (MACS) | Active comparator | 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. Receives: Procedure: Intervention 1: Adrenalectomy |
| Arm 2: Semaglutide (MACS) | Active comparator | 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. Receives: Drug: Intervention 2: Semaglutide |
| Arm 3: Semaglutide (Matched Controls) | Active comparator | 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. Receives: Drug: Intervention 2: Semaglutide |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Insulin Sensitivity (M-value), mg/kg/min
Hyperinsulinemic-euglycemic clamp
Measured: Baseline to Week 26
Secondary outcomes (36)
Change in fasting plasma glucose, mg/dL
Measured: Baseline to Week 26
Change in hemoglobin A1C, %
fasting blood test
Measured: Baseline to Week 26
Change in fasting insulin, µU/mL
Fasting blood test
Measured: Baseline to Week 26
Change in glucagon, pg/mL
Fasting blood test
Measured: Baseline to Week 26
Change in c-peptide, nmol/L
Fasting blood test
Measured: Baseline to Week 26
Change in IGF-1, ng/mL
Fasting blood glucose
Measured: Baseline to Week 26
Change in IGF-II, ng/mL
Fasting blood test
Measured: Baseline to Week 26
Change in IGFBP-1, ng/mL
Fasting blood test
Measured: Baseline to Week 26
Change in leptin, ng/mL
Fasting blood glucose
Measured: Baseline to Week 26
Change in adiponectin, μg/mL
Fasting blood test
Measured: Baseline to Week 26
% of patients with normal dexamethasone suppression test, %
1-mg dexamethasone suppression test
Measured: Baseline to Week 26
Change in steroid profile, ng/24h
25-steroid profiling in the 24-hour urine, reported as aggregate
Measured: Baseline to Week 26
Mean change in systolic BP, mmHg
24-hour Ambulatory BP
Measured: Baseline to Week 26
Mean change in diastolic BP, mmHg
24-hour Ambulatory BP
Measured: Baseline to Week 26
Change in cholesterol, mg/dL
Fasting blood test
Measured: Baseline to Week 26
Change in Free Fatty Acids, mmol/L
Fasting blood test
Measured: Baseline to Week 26Baseline to Week 26
Change in C-reactive protein, pg/mL
Fasting blood test
Measured: Baseline to Week 26
Change in TNF-alpha, pg/mL
Fasting blood glucose
Measured: Baseline to Week 26
Change in Interleukin-1, pg/mL
Fasting blood test
Measured: Baseline to Week 26
Change in Interleukin-6, pg/mL
Fasting blood test
Measured: Baseline to Week 26
Change in body weight, kg
electronic scale
Measured: Baseline to Week 26
Change in BMI, kg/m2
calculated from weight and height
Measured: Baseline to Week 26
Change in waist circumference, cm
Tape measure
Measured: Baseline to Week 26
Change in fat area, cm2
Limited unenhanced CT
Measured: Baseline to Week 26
Change in muscle area, cm2
Limited unenhanced CT
Measured: Baseline to Week 26
Change in bone mineral density, mg/cm³
Limited unenhanced CT
Measured: Baseline to Week 26
Change in chair rise test, stands/30s
Time test, number of stands from chair in 30 seconds
Measured: Baseline to Week 26
Change in Hand Grip Strength, kg
Dynamometer
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Baseline to Week 26
Adverse Events and Serious Adverse Events
Measured: Baseline through Week 30
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Jan 2026
- Study start5 Mar 2026
- Primary completion31 May 2030 (estimated)
- Study completion31 May 2030 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (8)Papers the sponsor has linked to this study.
- Other trials for Mild Autonomous Cortisol Secretion (MACS)Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- 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.
- Masking
- None (open label)
- Enrolment
- 75 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Texas Southwestern Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Oksana Hamidi, DO, MSCS, University of Texas Southwestern Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07361874
- Sponsor's protocol ID
- STU20251717
- Other IDs
- 1K23DK142038-01A1
- Acronym
- IMPACT-MACS
- Status last verified
- Mar 2026
- First submitted
- 20 Jan 2026
- Last updated
- 27 Mar 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: De-identified individual participant data (IPD) from the IMPACT-MACS study will be shared in accordance with NIH Data Management and Sharing Policy. Shared IPD will include primary and secondary outcome data such as insulin sensitivity (M-value), hormonal and cardiometabolic biomarkers, body composition measures, ambulatory blood pressure data, physical function tests, patient-reported outcomes, and adverse events. No genetic data will be shared. IPD will become available at the time of primary publication or by the end of the award period, expected by Q2 2030. Data will be accessible to qualified investigators for biomedical research through the NIDDK Central Repository, with requests managed under a Data Use Agreement. IRB approval or exemption is required, and data may not be used for ancestry or non-biomedical research.
Publications
Yozamp N, Vaidya A. Assessment of mild autonomous cortisol secretion among incidentally discovered adrenal masses. Best Pract Res Clin Endocrinol Metab. 2021 Jan;35(1):101491. doi: 10.1016/j.beem.2021.101491. Epub 2021 Feb 6.
PubMed 33593680Bancos I, Prete A. Approach to the Patient With Adrenal Incidentaloma. J Clin Endocrinol Metab. 2021 Oct 21;106(11):3331-3353. doi: 10.1210/clinem/dgab512.
PubMed 34260734Prete A, Subramanian A, Bancos I, Chortis V, Tsagarakis S, Lang K, Macech M, Delivanis DA, Pupovac ID, Reimondo G, Marina LV, Deutschbein T, Balomenaki M, O'Reilly MW, Gilligan LC, Jenkinson C, Bednarczuk T, Zhang CD, Dusek T, Diamantopoulos A, Asia M, Kondracka A, Li D, Masjkur JR, Quinkler M, Ueland GA, Dennedy MC, Beuschlein F, Tabarin A, Fassnacht M, Ivovic M, Terzolo M, Kastelan D, Young WF Jr, Manolopoulos KN, Ambroziak U, Vassiliadi DA, Taylor AE, Sitch AJ, Nirantharakumar K, Arlt W; ENSAT EURINE-ACT Investigators*; ENSAT EURINE-ACT Investigators. Cardiometabolic Disease Burden and Steroid Excretion in Benign Adrenal Tumors : A Cross-Sectional Multicenter Study. Ann Intern Med. 2022 Mar;175(3):325-334. doi: 10.7326/M21-1737. Epub 2022 Jan 4.
PubMed 34978855Ebbehoj A, Li D, Kaur RJ, Zhang C, Singh S, Li T, Atkinson E, Achenbach S, Khosla S, Arlt W, Young WF, Rocca WA, Bancos I. Epidemiology of adrenal tumours in Olmsted County, Minnesota, USA: a population-based cohort study. Lancet Diabetes Endocrinol. 2020 Nov;8(11):894-902. doi: 10.1016/S2213-8587(20)30314-4.
PubMed 33065059Fassnacht M, Tsagarakis S, Terzolo M, Tabarin A, Sahdev A, Newell-Price J, Pelsma I, Marina L, Lorenz K, Bancos I, Arlt W, Dekkers OM. European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2023 Jul 20;189(1):G1-G42. doi: 10.1093/ejendo/lvad066.
PubMed 37318239Kolanska K, Owecki M, Nikisch E, Sowinski J. High prevalence of obesity in patients with non-functioning adrenal incidentalomas. Neuro Endocrinol Lett. 2010;31(3):418-22.
PubMed 20588242Reimondo G, Castellano E, Grosso M, Priotto R, Puglisi S, Pia A, Pellegrino M, Borretta G, Terzolo M. Adrenal Incidentalomas are Tied to Increased Risk of Diabetes: Findings from a Prospective Study. J Clin Endocrinol Metab. 2020 Apr 1;105(4):dgz284. doi: 10.1210/clinem/dgz284.
PubMed 31900474Bovio S, Cataldi A, Reimondo G, Sperone P, Novello S, Berruti A, Borasio P, Fava C, Dogliotti L, Scagliotti GV, Angeli A, Terzolo M. Prevalence of adrenal incidentaloma in a contemporary computerized tomography series. J Endocrinol Invest. 2006 Apr;29(4):298-302. doi: 10.1007/BF03344099.
PubMed 16699294