Tirzepatide and Semaglutide Head-to-Head Trial to Compare Metabolic and Adipose Remodeling

The global prevalence of obesity and type 2 diabetes continues to rise, necessitating more effective pharmacotherapeutic strategies. Incretin-based therapies, particularly GLP-1 receptor agonists like semaglutide, have revolutionized treatment. However, tirzepatide, a dual GIP/GLP-1 receptor agonist, offers a distinct mechanism. Despite their widespread use, direct comparative data on their specific impacts on metabolic health and adipose tissue remodeling remain limited. This study aims to fill this critical gap by providing a head-to-head comparison, elucidating the nuanced benefits of dual versus single incretin agonism beyond just weight loss.

This randomized, open-label, head-to-head clinical trial will enroll N=120 adults (age 20-65) with obesity and metabolic syndrome, randomized 1:1 to receive either tirzepatide or semaglutide. Participants will undergo comprehensive deep phenotyping at baseline, 6 months, and 12 months. Assessments include DXA for regional fat, lean mass, and bone mineral density (BMD), MRI PDFF for liver fat quantification, 7-site skinfold thickness measurements, and grip strength. Fasting biochemistry panels and AI-processed 12-lead ECGs will also be performed. Centralized biobanking of serum, plasma, and peripheral blood mononuclear cells (PBMCs) will facilitate targeted and discovery multi-omic analyses to explore underlying biological mechanisms.