Obesity and Metabolic Syndrome
Conditions
Keywords
tirzepatide, semaglutide, obesity, metabolic syndrome, multi omic
Brief summary
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.
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.
Interventions
DRUGTirzepatide 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.
DRUGSemaglutide 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.
Sponsors
Tri-Service General Hospital
National Science and Technology Council, Taiwan
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to 65 Years
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percent change in total body weight from baseline to 6 months. | Baseline to 6 months |
| Total fat to lean mass loss ratio (DXA derived) from baseline to 6 months. | Baseline to 6 months |
| Change in metabolic syndrome severity Z score from baseline to 6 months. | Baseline to 6 months. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in waist circumference (cm) | Baseline to 6 months and 12 months | — |
| Change in waist-to-hip ratio (unitless ratio) | Baseline to 6 months and 12 months. | — |
| Change in regional fat mass measured by DXA (grams) | Baseline to 6 months and 12 months. | — |
| Change in regional lean mass measured by DXA (grams) | Baseline to 6 months and 12 months | — |
| Change in 7-site skinfold thickness (mm) | Baseline to 6 months and 12 months. | — |
| Change in liver fat content measured by MRI-PDFF (percentage, %PDFF) | Baseline to 6 months and 12 months | — |
| Change in abdominal visceral fat volume (mL) | Baseline to 6 months and 12 months | — |
| Change in abdominal subcutaneous fat volume (mL) | Baseline to 6 months and 12 months | — |
| Change in systolic and diastolic blood pressure (mmHg) | Baseline to 6 months and 12 months | — |
| Change in fasting lipid profile (mg/dL) | Baseline to 6 months and 12 months | Lipid profile includes total cholesterol, LDL-C, HDL-C and Triglycerides |
| Change in fasting glucose (mg/dL) | Baseline to 6 and 12 months | — |
| Change in hsCRP (mg/L) | Baseline to 6 and 12 months | — |
| Change in insulin sensitivity (HOMA-IR, unitless) | Baseline to 6 and 12 months | — |
| Change in β-cell function (HOMA-β, percentage, %) | Baseline to 6 and 12 months | — |
| Change in AI-ECG predicted ASCVD risk score (percentage, %) | Baseline to 6 and 12 months | — |
| Change in ECG-derived heart age (years) | Baseline to 6 and 12 months | — |
| Change in AI-ECG diabetes risk index (HbA1c, percentage, %) | Baseline to 6 and 12 months | — |
| Change in estimated 10-year ASCVD risk (percentage, %) | Baseline to 6 and 12 months | — |
| Change in bone mineral density (g/cm²) | Baseline to 6 and 12 months | — |
| Change in serum P1NP (ng/mL) | Baseline to 6 and 12 months | — |
| Change in serum CTX-1 (ng/mL) | Baseline to 6 and 12 months | — |
| Change in fasting plasma metabolomics profile (relative abundance units) | Baseline to 6 and 12 months | — |
| Change in fasting plasma proteomics profile (relative abundance units) | Baseline to 6 and 12 months | — |
| Change in microRNA expression signatures (normalized expression units) | Baseline to 6 and 12 months | — |
| Change in RNA-seq transcriptomic signatures (normalized counts, e.g., TPM) | Baseline to 6 and 12 months | — |
| Change in epigenetic methylation signatures (Methylation, percentage, %) | Baseline to 6 and 12 months | — |
| Change in depressive symptoms (scale score) | Baseline to 6 and 12 months | Instrument: e.g., PHQ-9 |
| Change in sleep quality (scale score) | Baseline to 6 and 12 months | Instrument: e.g., PSQI |
| Change in quality of life (scale score) | Baseline to 6 and 12 months | Instrument: e.g., EQ-5D or SF-36 |
| Change in eating behavior (WREQ-C total and subscale scores) | Baseline to 3, 6, and 12 months | — |
Countries
Taiwan
Contacts
CONTACTFeng-Chih Kuo, M.D., Ph.D.
STUDY_DIRECTORFeng-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.
Outcome results
None listed