NCT07361874

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. 1.Does adrenalectomy or semaglutide improve insulin resistance more in people with MACS?
  2. 2.How do these treatments change cortisol patterns and other cardiometabolic risk factors?
  3. 3.Do people with MACS respond differently to semaglutide compared to matched adults without MACS?
  4. 4.Receive either adrenalectomy or semaglutide if they have MACS, or semaglutide if they are matched controls
  5. 5.Complete clinic visits and phone visits over about 26-30 weeks
  6. 6.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

Trial Health

77
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
75

participants targeted

Target at P50-P75 for not_applicable

Timeline
50mo left

Started Mar 2026

Longer than P75 for not_applicable

Geographic Reach
1 country

1 active site

Status
recruiting

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Progress4%
Mar 2026May 2030

First Submitted

Initial submission to the registry

January 20, 2026

Completed
3 days until next milestone

First Posted

Study publicly available on registry

January 23, 2026

Completed
1 month until next milestone

Study Start

First participant enrolled

March 5, 2026

Completed
4.2 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

May 31, 2030

Expected
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

May 31, 2030

Last Updated

March 27, 2026

Status Verified

March 1, 2026

Enrollment Period

4.2 years

First QC Date

January 20, 2026

Last Update Submit

March 25, 2026

Conditions

Mild Autonomous Cortisol Secretion (MACS)Autonomous Cortisol Secretion (ACS)Subclinical Cushing'sMild Autonomous Cortisol Excess

Keywords

Mild Autonomous Cortisol SecretionMACSAdrenal incidentalomaAdrenal adenomaSubclinical CushingHypercortisolismCortisol dysregulationAdrenalectomySemaglutideWeight lossBody compositionInsulin resistanceGLP-1 receptor agonistHyperinsulinemic-euglycemic clampCortisol dynamicsVisceral fatcardiometabolic riskrandomized controlled trial

Outcome Measures

Primary Outcomes (1)

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

    Hyperinsulinemic-euglycemic clamp

    Baseline to Week 26

Secondary Outcomes (36)

  • Change in fasting plasma glucose, mg/dL

    Baseline to Week 26

  • Change in hemoglobin A1C, %

    Baseline to Week 26

  • Change in fasting insulin, µU/mL

    Baseline to Week 26

  • Change in glucagon, pg/mL

    Baseline to Week 26

  • Change in c-peptide, nmol/L

    Baseline to Week 26

  • +31 more secondary outcomes

Study Arms (3)

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.

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.

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.

Drug: Intervention 2: Semaglutide

Interventions

Intervention 1: AdrenalectomyPROCEDURE

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.

Arm 1: Adrenalectomy (MACS)
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.

Arm 2: Semaglutide (MACS)Arm 3: Semaglutide (Matched Controls)

Eligibility Criteria

Age18 Years+
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • 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

You may not qualify if:

  • 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

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

University of Texas Southwestern Medical Center

Dallas, Texas, 75390, United States

RECRUITING

Related Publications (8)

  • 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.

    PMID: 33593680BACKGROUND

  • 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.

    PMID: 34260734BACKGROUND

  • 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.

    PMID: 34978855BACKGROUND

  • 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.

    PMID: 33065059BACKGROUND

  • 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.

    PMID: 37318239BACKGROUND

  • 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.

    PMID: 20588242BACKGROUND

  • 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.

    PMID: 31900474BACKGROUND

  • 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.

    PMID: 16699294BACKGROUND

Related Links

MeSH Terms

Conditions

Adrenal incidentalomaACTH Syndrome, EctopicCushing SyndromeWeight LossInsulin Resistance

Condition Hierarchy (Ancestors)

Paraneoplastic Endocrine SyndromesParaneoplastic SyndromesNeoplasmsAdrenocortical HyperfunctionAdrenal Gland DiseasesEndocrine System DiseasesBody Weight ChangesBody WeightSigns and SymptomsPathological Conditions, Signs and SymptomsHyperinsulinismGlucose Metabolism DisordersMetabolic DiseasesNutritional and Metabolic Diseases

Central Study Contacts

Oksana Hamidi, DO, MSCS

CONTACT

214-645-6397oksana.hamidi@utsouthwestern.edu

Study Design

Study Type
interventional
Phase
not applicable
Allocation
RANDOMIZED
Masking
NONE
Purpose
TREATMENT
Intervention Model
PARALLEL
Model Details: 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.
Sponsor Type
OTHER
Responsible Party
PRINCIPAL INVESTIGATOR
PI Title
Associate Professor

Study Record Dates

First Submitted

January 20, 2026

First Posted

January 23, 2026

Study Start

March 5, 2026

Primary Completion (Estimated)

May 31, 2030

Study Completion (Estimated)

May 31, 2030

Last Updated

March 27, 2026

Record last verified: 2026-03

Data Sharing

IPD Sharing
Will share

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.

Shared Documents
STUDY PROTOCOL, SAP, CSR, ANALYTIC CODE
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.
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.
More information

Locations

US(1)