Comparative effectiveness of tirzepatide and semaglutide for obesity management in US clinical practice: a 6-month retrospective cohort study.

PURPOSE: The SURMOUNT-5 trial demonstrated greater weight reduction with tirzepatide vs. semaglutide in adults with obesity without diabetes. This study compared real-world weight reduction and cardiometabolic parameters associated with tirzepatide and semaglutide for obesity management. METHODS: A retrospective cohort study was conducted using Truveta de-identified US electronic health record data. Adults with obesity or overweight and ≥ 1 obesity-related complication, without diabetes, who initiated tirzepatide or semaglutide December 2023–June 2024 and adhered to treatment, were followed for 6 months. Primary outcome was percentage weight change from baseline. Secondary outcomes included weight-reduction targets and changes in body mass index (BMI) and cardiometabolic parameters. Primary analysis employed propensity-score weighted regression. Sensitivity analyses included modified intention-to-treat. RESULTS: Among 2,396 on-treatment patients (1,003 tirzepatide; 1,393 semaglutide), greater 6-month mean percentage weight reduction was observed with tirzepatide (–11.15% vs. −8.83%; adjusted difference −2.32%-points [95% CI: −3.17, −1.48]). Higher proportions of tirzepatide-treated patients achieved 5%, 10%, 15%, and 20% weight-reduction targets. Greater reductions in BMI, blood pressure, and haemoglobin A1c were observed with tirzepatide. More patients received higher doses of semaglutide (≥ 1.7 mg; 67.7%) vs. tirzepatide (≥ 10 mg; 42.4%). Sensitivity analysis findings were consistent. CONCLUSIONS: Consistent with clinical trials, real-world tirzepatide treatment was associated with greater 6-month weight reduction and more frequent achievement of weight-reduction targets and improvements in select cardiometabolic parameters than semaglutide among adults with obesity without diabetes. This early emergence of tirzepatide’s comparative advantage over semaglutide was observed despite more semaglutide-treated patients receiving higher doses than tirzepatide-treated patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40618-025-02792-1.