Weight Loss Dynamics and Health Burden Changes with Tirzepatide versus Semaglutide

Abstract Background Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for obesity and type 2 diabetes, yet substantial variability in weight-loss response remains poorly understood. Methods We conducted a retrospective cohort study using de-identified electronic health records and performed 1:1 propensity matching on age, sex, type 2 diabetes status, baseline BMI and weight, index year, and follow-up duration. The matched cohorts included 10,339 tirzepatide-treated and 10,339 semaglutide-treated patients. Patients were categorized by maximum weight loss over two years into five response groups. Adverse events were identified through AI-enabled curation of clinical notes. Weight-loss trajectories, demographic patterns, adverse-event profiles, and pre- to post-treatment disease-prevalence changes were compared across drugs. Results Patients treated with tirzepatide lost more weight than those treated with semaglutide (mean reduction, 14.7% vs. 10.8%; p<0.001). High-response rates (≥15% weight loss in year 1) were nearly doubled with tirzepatide (42.6% vs. 21.6%; p<0.001), accompanied by faster monthly weight-loss velocity (2.54% vs. 2.18%). AI-enabled curation showed that tirzepatide was associated with lower prevalence of gastrointestinal and systemic adverse events. For both tirzepatide and semaglutide, women were more represented among high responders than the minimal weight-loss group (<5% weight loss) and White patients were more represented among high responders, whereas Black and Hispanic patients were more represented among the minimal weight loss group. Conclusions In this large, propensity-matched real-world cohort, tirzepatide was associated with greater and faster weight loss than semaglutide. Marked demographic disparities highlight the need for precision approaches to obesity treatment.