Background Both tirzepatide and semaglutide have been shown to reduce weight for patients with overweight or obesity in randomized controlled trials (RCTs). While tirzepatide appears to provide greater weight loss than semaglutide in this population, head-to-head RCTs are not yet available. Accordingly, we sought to compare on-treatment weight loss in a real-world setting for adults with overweight or obesity initiated on tirzepatide or semaglutide.

Methods Adults with overweight or obesity first dispensed semaglutide or tirzepatide between May 2022 and September 2023 were identified from Truveta Data, a large electronic health record (EHR) dataset linked with comprehensive pharmacy dispensing data. The study cohort was restricted to patients with no prior GLP-1 RA use, who initiated a formulation of semaglutide or tirzepatide labelled for type 2 diabetes mellitus (T2D) (a proxy for dose), received regular care in the previous year, had a GLP-1 RA prescription written in the 60 days prior to initiation, and had an available baseline weight. On treatment weight changes in a propensity score matched population were compared for outcomes of time to 5%, 10%, and 15% weight loss, and percentage change in weight by 3, 6, and 12 months. For all outcomes, we conducted subgroup analyses stratified by T2D (on-label users) and sensitivity analyses using inverse probability of treatment weighting.

Results A total of 41,223 patients met our cohort definition (semaglutide: 32,030; tirzepatide: 9,193). Propensity score matching produced an analytic cohort of 18,386 patients with good balance on all baseline covariates. At treatment initiation, the mean(SD) age was 52.0 (12.9) years, 70.5% of patients were female, 51.7% had T2D, and mean(SD) weight was 110 (25.7) kg. A larger proportion of patients on tirzepatide, compared to semaglutide, achieved weight reductions ≥5% (81.8% vs. 64.6%), ≥10% (62.1% vs. 38.0%), and ≥15% (42.3% vs 19.3%) within 1 year on treatment, yielding hazard ratios of 1.76 (1.68 - 1.85) for 5%, 2.42 (2.25 - 2.59) for 10%, and 3.04 (2.73 - 3.38) for 15% weight loss. Patients on tirzepatide experienced larger changes in percentage of body weight lost at 3 months on treatment (difference [95% CI]) (−2.3% [-2.5%, -2.2%]), 6 months on treatment (−4.3% [-4.6%, -3.9%]), and 12 months on treatment (−7.2% [-8.3%, -6.2%]). Hazards for all gastrointestinal (GI) adverse events were similar between groups.

Conclusion In a real-world population of US adults with overweight or obesity initiated on tirzepatide or semaglutide formulations labelled for T2D, patients on tirzepatide were significantly more likely to achieve 5%, 10% and 15% weight loss and experience larger reductions in weight at 3, 6, and 12 months. Findings were robust to analytic choice and consistent among populations stratified by T2D. Future work is needed to understand whether these findings result in a differential impact on other outcomes, including rates of adverse cardiovascular events.

All authors except TJ Gluckman are employees of Truveta, Inc.

This study did not receive any funding.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Normalized electronic health record data are de-identified by expert determination under the HIPAA Privacy Rule before being made available to researchers. In accordance with 46.101 Protection of Human Subjects, our study did not require Institutional Review Board approval because it used only deidentified medical records. All data used in this study are publicly available to all Truveta subscribers and may be accessed at studio.truveta.com.

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The data used in this study are available to all Truveta subscribers and may be accessed at studio.truveta.com.