Comparative Observation of Metabolic and Pharmacologic Adipose Remodeling With Enhanced Incretin AgonisTs (COMPARE-AT)

May 10, 2026 updated by: Feng-Chih Kuo, Tri-Service General Hospital

Comparative Adipose Tissue and Cardiometabolic System Remodeling by Tirzepatide and Semaglutide: an AI-integrated Multimodal Metabolomics and Translational Mechanistic Study

This randomized, open label, head to head clinical trial directly compares tirzepatide and semaglutide in adults with obesity and metabolic syndrome (N=120, age 20-65, 1:1 randomization). Participants undergo deep phenotyping at baseline, 6 months, and 12 months, including DXA (regional fat, lean mass, and BMD), MRI PDFF (liver fat), 7 site skinfold thickness, grip strength, fasting biochemistry, and AI processed 12 lead ECGs. Centralized biobanking of serum, plasma, and PBMCs enables targeted and discovery multi omic analyses.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

This study is a single-center, randomized, open-label, active-comparator trial designed to characterize the differential effects of tirzepatide and semaglutide on adipose tissue biology and cardiometabolic remodeling over 12 months in adults with obesity and metabolic syndrome. The trial integrates pharmacologic weight-loss therapy with multimodal phenotyping to quantify changes across body composition, hepatic steatosis, metabolic biomarkers, functional strength, and AI-derived electrophysiologic signatures.

The scientific premise is that incretin-based therapies may produce qualitatively distinct patterns of fat loss, ectopic fat mobilization, and cardiometabolic improvement. Tirzepatide, a dual GIP/GLP-1 receptor agonist, may induce greater reductions in visceral adiposity and hepatic fat compared with GLP-1 receptor agonism alone. This trial is designed to directly compare these mechanistic profiles using harmonized imaging, biochemical, and digital phenotyping platforms.

Participants are randomized 1:1 to tirzepatide or semaglutide using a computer-generated permuted block scheme stratified by sex and baseline BMI category. Both interventions follow standard titration schedules and are paired with structured lifestyle counseling to ensure comparable background care. Study visits occur at baseline, 3, 6, and 12 months, with deep phenotyping at baseline, 6, and 12 months.

The phenotyping framework emphasizes regional adiposity, lean mass preservation, hepatic steatosis, and cardiometabolic risk signatures. Whole-body DXA provides quantification of total and regional fat and lean mass, enabling derivation of fat-to-lean mass loss ratios and redistribution indices. Abdominal MRI with proton density fat fraction (PDFF) quantifies liver fat content and abdominal fat compartments. Functional and behavioral assessments-including grip strength and the Chinese version of the Weight-Related Eating Questionnaire-characterize changes in physical function and eating behavior patterns over time.

Fasting biochemical panels measure glycemic indices, lipid metabolism, inflammation, renal and hepatic function, and cardiometabolic biomarkers. Standard 12-lead ECGs are processed through a validated AI pipeline to generate electrophysiologic risk features (e.g., predicted ASCVD risk, ECG-derived heart age), which serve as exploratory digital biomarkers.

A centralized biobanking program supports mechanistic analyses. Serum, plasma, and PBMCs collected at each deep-phenotyping visit are stored under standardized SOPs for targeted and discovery-based metabolomic, proteomic, epigenetic and transcriptomic analyses. These biospecimens will enable downstream investigation of molecular pathways underlying differential treatment responses.

Together, this integrated platform allows for a comprehensive comparison of tirzepatide and semaglutide across structural, metabolic, functional, and molecular domains, providing mechanistic insight into how incretin-based therapies remodel adipose tissue and cardiometabolic physiology.

Study Type

Interventional

Enrollment (Estimated)

120

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Taiwan
      • Taipei, Taiwan, 114202
        • Recruiting
        • Tri-Service General Hospital
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Age 20-65 years.
  • BMI ≥27 kg/m² with metabolic syndrome (ATP III or IDF criteria).
  • Stable background medications (antihypertensives, statins, etc.) for ≥3 months.
  • Able and willing to provide informed consent and comply with study procedures.

Exclusion Criteria:

  • History of diabetes; history of pancreatitis; personal/family history of medullary thyroid carcinoma or MEN2.
  • eGFR <30 mL/min/1.73 m², decompensated liver disease, NYHA class III-IV heart failure.
  • Recent (<3 months) acute coronary syndrome, stroke, or coronary revascularization.
  • Current use of GLP 1RA, tirzepatide, or other incretin based therapies within 3 months.
  • Contraindications to MRI or DXA (e.g., metal implants incompatible with MRI, pregnancy).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Tirzepatide arm
starting at 2.5 mg weekly and escalated every month (5.0 mg, 7.5 mg to 10 mg) as tolerated
Drug: Tirzepatide with lifestyle modification
Starting at Tirzepatide 2.5 mg weekly and escalated as tolerated to 10 mg along with standardized lifestyle counseling by a dietitian (caloric deficit, physical activity guidance) and written materials.
Active Comparator: Semaglutide arm
starting at 0.25 mg weekly and escalated every month (0.5 mg, 1.0 mg, 1.7 mg to 2.4 mg) as tolerated
Drug: Semaglutide with lifestyle modification
Starting at Semaglutide 0.25 mg weekly and escalated as tolerated to 2.4 mg along with standardized lifestyle counseling by a dietitian (caloric deficit, physical activity guidance) and written materials.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Percent change in total body weight from baseline to 6 months.
Time Frame: Baseline to 6 months
Baseline to 6 months
Total fat to lean mass loss ratio (DXA derived) from baseline to 6 months.
Time Frame: Baseline to 6 months
Baseline to 6 months
Change in metabolic syndrome severity Z score from baseline to 6 months.
Time Frame: Baseline to 6 months.
Baseline to 6 months.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in waist circumference (cm)
Time Frame: Baseline to 6 months and 12 months
Baseline to 6 months and 12 months
Change in waist-to-hip ratio (unitless ratio)
Time Frame: Baseline to 6 months and 12 months.
Baseline to 6 months and 12 months.
Change in regional fat mass measured by DXA (grams)
Time Frame: Baseline to 6 months and 12 months.
Baseline to 6 months and 12 months.
Change in regional lean mass measured by DXA (grams)
Time Frame: Baseline to 6 months and 12 months
Baseline to 6 months and 12 months
Change in 7-site skinfold thickness (mm)
Time Frame: Baseline to 6 months and 12 months.
Baseline to 6 months and 12 months.
Change in liver fat content measured by MRI-PDFF (percentage, %PDFF)
Time Frame: Baseline to 6 months and 12 months
Baseline to 6 months and 12 months
Change in abdominal visceral fat volume (mL)
Time Frame: Baseline to 6 months and 12 months
Baseline to 6 months and 12 months
Change in abdominal subcutaneous fat volume (mL)
Time Frame: Baseline to 6 months and 12 months
Baseline to 6 months and 12 months
Change in systolic and diastolic blood pressure (mmHg)
Time Frame: Baseline to 6 months and 12 months
Baseline to 6 months and 12 months
Change in fasting lipid profile (mg/dL)
Time Frame: Baseline to 6 months and 12 months
Lipid profile includes total cholesterol, LDL-C, HDL-C and Triglycerides
Baseline to 6 months and 12 months
Change in fasting glucose (mg/dL)
Time Frame: Baseline to 6 and 12 months
Baseline to 6 and 12 months
Change in hsCRP (mg/L)
Time Frame: Baseline to 6 and 12 months
Baseline to 6 and 12 months
Change in insulin sensitivity (HOMA-IR, unitless)
Time Frame: Baseline to 6 and 12 months
Baseline to 6 and 12 months
Change in β-cell function (HOMA-β, percentage, %)
Time Frame: Baseline to 6 and 12 months
Baseline to 6 and 12 months
Change in AI-ECG predicted ASCVD risk score (percentage, %)
Time Frame: Baseline to 6 and 12 months
Baseline to 6 and 12 months
Change in ECG-derived heart age (years)
Time Frame: Baseline to 6 and 12 months
Baseline to 6 and 12 months
Change in AI-ECG diabetes risk index (HbA1c, percentage, %)
Time Frame: Baseline to 6 and 12 months
Baseline to 6 and 12 months
Change in estimated 10-year ASCVD risk (percentage, %)
Time Frame: Baseline to 6 and 12 months
Baseline to 6 and 12 months
Change in bone mineral density (g/cm²)
Time Frame: Baseline to 6 and 12 months
Baseline to 6 and 12 months
Change in serum P1NP (ng/mL)
Time Frame: Baseline to 6 and 12 months
Baseline to 6 and 12 months
Change in serum CTX-1 (ng/mL)
Time Frame: Baseline to 6 and 12 months
Baseline to 6 and 12 months
Change in fasting plasma metabolomics profile (relative abundance units)
Time Frame: Baseline to 6 and 12 months
Baseline to 6 and 12 months
Change in fasting plasma proteomics profile (relative abundance units)
Time Frame: Baseline to 6 and 12 months
Baseline to 6 and 12 months
Change in microRNA expression signatures (normalized expression units)
Time Frame: Baseline to 6 and 12 months
Baseline to 6 and 12 months
Change in RNA-seq transcriptomic signatures (normalized counts, e.g., TPM)
Time Frame: Baseline to 6 and 12 months
Baseline to 6 and 12 months
Change in epigenetic methylation signatures (Methylation, percentage, %)
Time Frame: Baseline to 6 and 12 months
Baseline to 6 and 12 months
Change in depressive symptoms (scale score)
Time Frame: Baseline to 6 and 12 months
Instrument: e.g., PHQ-9
Baseline to 6 and 12 months
Change in sleep quality (scale score)
Time Frame: Baseline to 6 and 12 months
Instrument: e.g., PSQI
Baseline to 6 and 12 months
Change in quality of life (scale score)
Time Frame: Baseline to 6 and 12 months
Instrument: e.g., EQ-5D or SF-36
Baseline to 6 and 12 months
Change in eating behavior (WREQ-C total and subscale scores)
Time Frame: Baseline to 3, 6, and 12 months
Baseline to 3, 6, and 12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Tri-Service General Hospital

Collaborators

National Science and Technology Council, Taiwan

Investigators

  • Study Director: Feng-Chih Kuo, M.D., Ph.D., Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 31, 2026

Primary Completion (Estimated)

September 30, 2028

Study Completion (Estimated)

September 30, 2029

Study Registration Dates

First Submitted

May 1, 2026

First Submitted That Met QC Criteria

May 10, 2026

First Posted (Actual)

May 15, 2026

Study Record Updates

Last Update Posted (Actual)

May 15, 2026

Last Update Submitted That Met QC Criteria

May 10, 2026

Last Verified

May 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • C202505161

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

It is still ongoing and can not be shared before the final analysis.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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