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

Official title

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

Overview

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

• 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.
• 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.

Primary outcome measures

• Change in Insulin Sensitivity (M-value), mg/kg/min [Time frame: Baseline to Week 26]

Secondary outcome measures (12)

• Change in fasting plasma glucose, mg/dL [Time frame: Baseline to Week 26]
• Change in hemoglobin A1C, % [Time frame: Baseline to Week 26]
• Change in fasting insulin, µU/mL [Time frame: Baseline to Week 26]
• Change in glucagon, pg/mL [Time frame: Baseline to Week 26]
• Change in c-peptide, nmol/L [Time frame: Baseline to Week 26]
• Change in IGF-1, ng/mL [Time frame: Baseline to Week 26]
• Change in IGF-II, ng/mL [Time frame: Baseline to Week 26]
• Change in IGFBP-1, ng/mL [Time frame: Baseline to Week 26]
• Change in leptin, ng/mL [Time frame: Baseline to Week 26]
• Change in adiponectin, μg/mL [Time frame: Baseline to Week 26]
• % of patients with normal dexamethasone suppression test, % [Time frame: Baseline to Week 26]
• Change in steroid profile, ng/24h [Time frame: Baseline to Week 26]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• University of Texas Southwestern Medical Center — Dallas

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. PMID 33593680
• 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 34260734
• 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 J PMID 34978855
• 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 33065059
• 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 37318239
• 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 20588242
• 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 31900474
• 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 16699294

Identifiers

NCT: NCT07361874 · STU20251717 · 1K23DK142038-01A1

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗