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

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:

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

Study Overview

• Status: Recruiting
• Conditions: Autonomous Cortisol Secretion (ACS); Mild Autonomous Cortisol Excess; Subclinical Cushing's; Mild Autonomous Cortisol Secretion (MACS)
• Intervention / Treatment: Procedure: Intervention 1: Adrenalectomy; Drug: Intervention 2: Semaglutide

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.

• Study Type: Interventional
• Enrollment (Estimated): 75
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Oksana Hamidi, DO, MSCS; Phone Number: 214-645-6397; Email: oksana.hamidi@utsouthwestern.edu

Study Locations

• United States
  • Texas
    • Dallas, Texas, United States, 75390
      • Recruiting
      • University of Texas Southwestern Medical Center
      • Contact: Email: oksana.hamidi@utsouthwestern.edu
      • Principal Investigator: Oksana Hamidi, DO, MSCS
      • Contact: Oksana Hamidi, DO, MSCS; Phone Number: 2146456397; Email: oksana.hamidi@utsouthwestern.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm 1: Adrenalectomy (MACS); 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.	Procedure: Intervention 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.
Active Comparator: Arm 2: Semaglutide (MACS); 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.	Drug: Intervention 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.
Active Comparator: Arm 3: Semaglutide (Matched Controls); 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.	Drug: Intervention 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Insulin Sensitivity (M-value), mg/kg/min	Hyperinsulinemic-euglycemic clamp	Baseline to Week 26

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in fasting plasma glucose, mg/dL		Baseline to Week 26
Change in hemoglobin A1C, %	fasting blood test	Baseline to Week 26
Change in fasting insulin, µU/mL	Fasting blood test	Baseline to Week 26
Change in glucagon, pg/mL	Fasting blood test	Baseline to Week 26
Change in c-peptide, nmol/L	Fasting blood test	Baseline to Week 26
Change in IGF-1, ng/mL	Fasting blood glucose	Baseline to Week 26
Change in IGF-II, ng/mL	Fasting blood test	Baseline to Week 26
Change in IGFBP-1, ng/mL	Fasting blood test	Baseline to Week 26
Change in leptin, ng/mL	Fasting blood glucose	Baseline to Week 26
Change in adiponectin, μg/mL	Fasting blood test	Baseline to Week 26
% of patients with normal dexamethasone suppression test, %	1-mg dexamethasone suppression test	Baseline to Week 26
Change in steroid profile, ng/24h	25-steroid profiling in the 24-hour urine, reported as aggregate	Baseline to Week 26
Mean change in systolic BP, mmHg	24-hour Ambulatory BP	Baseline to Week 26
Mean change in diastolic BP, mmHg	24-hour Ambulatory BP	Baseline to Week 26
Change in cholesterol, mg/dL	Fasting blood test	Baseline to Week 26
Change in Free Fatty Acids, mmol/L	Fasting blood test	Baseline to Week 26Baseline to Week 26
Change in C-reactive protein, pg/mL	Fasting blood test	Baseline to Week 26
Change in TNF-alpha, pg/mL	Fasting blood glucose	Baseline to Week 26
Change in Interleukin-1, pg/mL	Fasting blood test	Baseline to Week 26
Change in Interleukin-6, pg/mL	Fasting blood test	Baseline to Week 26
Change in body weight, kg	electronic scale	Baseline to Week 26
Change in BMI, kg/m2	calculated from weight and height	Baseline to Week 26
Change in waist circumference, cm	Tape measure	Baseline to Week 26
Change in fat area, cm2	Limited unenhanced CT	Baseline to Week 26
Change in muscle area, cm2	Limited unenhanced CT	Baseline to Week 26
Change in bone mineral density, mg/cm³	Limited unenhanced CT	Baseline to Week 26
Change in chair rise test, stands/30s	Time test, number of stands from chair in 30 seconds	Baseline to Week 26
Change in Hand Grip Strength, kg	Dynamometer	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.	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.	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.	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.	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.	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.	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.	Baseline to Week 26
Adverse Events and Serious Adverse Events		Baseline through Week 30

Collaborators and Investigators

• Sponsor: University of Texas Southwestern Medical Center
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Publications and helpful links

General Publications

• Ebbehoj 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.
• 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.
• Bancos 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.
• Prete 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.
• Fassnacht 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.
• Kolanska 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.
• Reimondo 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.
• Bovio 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.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): March 5, 2026
• Primary Completion (Estimated): May 31, 2030
• Study Completion (Estimated): May 31, 2030

Study Registration Dates

• First Submitted: January 20, 2026
• First Submitted That Met QC Criteria: January 21, 2026
• First Posted (Actual): January 23, 2026

Study Record Updates

• Last Update Posted (Actual): March 27, 2026
• Last Update Submitted That Met QC Criteria: March 25, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: randomized controlled trial; Insulin resistance; Semaglutide; Weight loss; Body composition; cardiometabolic risk; Visceral fat; Hypercortisolism; GLP-1 receptor agonist; MACS; Adrenal adenoma; Adrenalectomy; Adrenal incidentaloma; Mild Autonomous Cortisol Secretion; Subclinical Cushing; Cortisol dysregulation; Hyperinsulinemic-euglycemic clamp; Cortisol dynamics
• Additional Relevant MeSH Terms: Endocrine System Diseases; Neoplasms; Metabolic Diseases; Body Weight; Body Weight Changes; Glucose Metabolism Disorders; Hyperinsulinism; Paraneoplastic Syndromes; Adrenal Gland Diseases; Adrenocortical Hyperfunction; Paraneoplastic Endocrine Syndromes; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Weight Loss; Insulin Resistance; Cushing Syndrome; ACTH Syndrome, Ectopic; Adrenal incidentaloma
• Other Study ID Numbers: STU20251717; 1K23DK142038-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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.

IPD Sharing Time Frame

Start Date:

Individual participant data (IPD) and supporting documents will become available at the time of primary results publication or by the end of the study award period, whichever occurs first. Availability is expected to begin by Q2 2030.

End Date:

IPD will remain available indefinitely through the NIDDK Central Repository, as long as the repository remains active and able to distribute the data under its Data Use Agreement procedures.

IPD Sharing Access Criteria

Individual participant data (IPD) and supporting materials will be available to qualified investigators conducting health-related, medical, or biomedical research. Requestors must submit a research proposal and obtain institutional IRB approval or exemption before access is granted.

Data will be shared in de-identified form through the NIDDK Central Repository, which manages requests under its governed Data Use Agreement (DUA) process. Approved investigators will be able to access the de-identified IPD, study protocol, and data dictionary through the repository's secure system. No identifiable information or genetic data will be shared.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No