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NCT Number: NCT07361874

IMPACT-MACS: Adrenalectomy vs Semaglutide for Metabolic Outcomes 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

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Key information

Conditions

Mild Autonomous Cortisol Secretion (MACS) ACTH Syndrome, Ectopic Adrenal Gland Diseases Adrenal incidentaloma Adrenocortical Hyperfunction Autonomous Cortisol Secretion (ACS) Body Weight Body Weight Changes Cushing Syndrome Endocrine System Diseases Glucose Metabolism Disorders Hyperinsulinism Insulin Resistance Metabolic Diseases Mild Autonomous Cortisol Excess Neoplasms Nutritional and Metabolic Diseases Paraneoplastic Endocrine Syndromes Paraneoplastic Syndromes Pathological Conditions, Signs and Symptoms Signs and Symptoms Subclinical Cushing's Weight Loss

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

University of Texas Southwestern Medical Center

Dallas, Texas, 75390, United States

Location status: Recruiting

Location contact

Oksana Hamidi, DO, MSCS

CONTACT

[email protected]

2146456397

Oksana Hamidi, DO, MSCS

PRINCIPAL_INVESTIGATOR

CONTACT

[email protected]

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Intervention 1: Adrenalectomy

Procedure

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: Semaglutide

Drug

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.

Primary outcomes

  1. Change in Insulin Sensitivity (M-value), mg/kg/min

    Time frame: Baseline to Week 26

    Hyperinsulinemic-euglycemic clamp

Secondary outcomes

  1. Change in fasting plasma glucose, mg/dL

    Time frame: Baseline to Week 26

  2. Change in hemoglobin A1C, %

    Time frame: Baseline to Week 26

    fasting blood test

  3. Change in fasting insulin, µU/mL

    Time frame: Baseline to Week 26

    Fasting blood test

  4. Change in glucagon, pg/mL

    Time frame: Baseline to Week 26

    Fasting blood test

  5. Change in c-peptide, nmol/L

    Time frame: Baseline to Week 26

    Fasting blood test

  6. Change in IGF-1, ng/mL

    Time frame: Baseline to Week 26

    Fasting blood glucose

  7. Change in IGF-II, ng/mL

    Time frame: Baseline to Week 26

    Fasting blood test

  8. Change in IGFBP-1, ng/mL

    Time frame: Baseline to Week 26

    Fasting blood test

  9. Change in leptin, ng/mL

    Time frame: Baseline to Week 26

    Fasting blood glucose

  10. Change in adiponectin, μg/mL

    Time frame: Baseline to Week 26

    Fasting blood test

  11. % of patients with normal dexamethasone suppression test, %

    Time frame: Baseline to Week 26

    1-mg dexamethasone suppression test

  12. Change in steroid profile, ng/24h

    Time frame: Baseline to Week 26

    25-steroid profiling in the 24-hour urine, reported as aggregate

  13. Mean change in systolic BP, mmHg

    Time frame: Baseline to Week 26

    24-hour Ambulatory BP

  14. Mean change in diastolic BP, mmHg

    Time frame: Baseline to Week 26

    24-hour Ambulatory BP

  15. Change in cholesterol, mg/dL

    Time frame: Baseline to Week 26

    Fasting blood test

  16. Change in Free Fatty Acids, mmol/L

    Time frame: Baseline to Week 26Baseline to Week 26

    Fasting blood test

  17. Change in C-reactive protein, pg/mL

    Time frame: Baseline to Week 26

    Fasting blood test

  18. Change in TNF-alpha, pg/mL

    Time frame: Baseline to Week 26

    Fasting blood glucose

  19. Change in Interleukin-1, pg/mL

    Time frame: Baseline to Week 26

    Fasting blood test

  20. Change in Interleukin-6, pg/mL

    Time frame: Baseline to Week 26

    Fasting blood test

  21. Change in body weight, kg

    Time frame: Baseline to Week 26

    electronic scale

  22. Change in BMI, kg/m2

    Time frame: Baseline to Week 26

    calculated from weight and height

  23. Change in waist circumference, cm

    Time frame: Baseline to Week 26

    Tape measure

  24. Change in fat area, cm2

    Time frame: Baseline to Week 26

    Limited unenhanced CT

  25. Change in muscle area, cm2

    Time frame: Baseline to Week 26

    Limited unenhanced CT

  26. Change in bone mineral density, mg/cm³

    Time frame: Baseline to Week 26

    Limited unenhanced CT

  27. Change in chair rise test, stands/30s

    Time frame: Baseline to Week 26

    Time test, number of stands from chair in 30 seconds

  28. Change in Hand Grip Strength, kg

    Time frame: Baseline to Week 26

    Dynamometer

  29. Change in overall quality of life, score

    Time frame: 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.

  30. Change in disease-specific QoL, score

    Time frame: 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.

  31. Change in mood, score

    Time frame: 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.

  32. Change in cognition, seconds

    Time frame: 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.

  33. Change in sleep, score

    Time frame: 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.

  34. Change in frailty, score

    Time frame: 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.

  35. Change in eating behavior, score

    Time frame: 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.

  36. Adverse Events and Serious Adverse Events

    Time frame: Baseline through Week 30

Study contacts

Contact information is provided by the study sponsor or research team.

Oksana Hamidi, DO, MSCS

CONTACT

[email protected]

214-645-6397

Sponsors and collaborators

Lead sponsor

University of Texas Southwestern Medical Center

Other

Collaborators

  • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Registry information

Official study title

IMPACT-MACS Study: Investigating the Mechanisms, Pathophysiology, and Cardiometabolic Treatment in Mild Autonomous Cortisol Secretion

Acronym: IMPACT-MACS

Important dates

Study start
2026
Primary completion
2030
Study completion
2030
First posted
Jan 23, 2026
Registry last updated
Mar 27, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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