Semaglutide vs Tirzepatide for Weight Loss in Adults With Overweight or Obesity

Abstract

Importance: Although tirzepatide and semaglutide were shown to reduce weight in randomized clinical trials, data from head-to-head comparisons in populations with overweight or obesity are not yet available.

Objective: To compare on-treatment weight loss and rates of gastrointestinal adverse events (AEs) among adults with overweight or obesity receiving tirzepatide or semaglutide labeled for type 2 diabetes (T2D) in a clinical setting.

Design, setting, and participants: In this cohort study, adults with overweight or obesity receiving semaglutide or tirzepatide between May 2022 and September 2023 were identified using electronic health record (EHR) data linked to dispensing information from a collective of US health care systems. On-treatment weight outcomes through November 3, 2023, were assessed. Adults with overweight or obesity and regular care in the year before initiation, no prior glucagon-like peptide 1 receptor agonist receptor agonist use, a prescription within 60 days prior to initiation, and an available baseline weight were identified. The analysis was completed on April 3, 2024.

Exposures: Tirzepatide or semaglutide in formulations labeled for T2D, on or off label.

Main outcomes and measures: On-treatment weight change in a propensity score-matched population, assessed as hazard of achieving 5% or greater, 10% or greater, and 15% or greater weight loss, and percentage change in weight at 3, 6, and 12 months. Hazards of gastrointestinal AEs were compared.

Results: Among 41 222 adults meeting the study criteria (semaglutide, 32 029; tirzepatide, 9193), 18 386 remained after propensity score matching. The mean (SD) age was 52.0 (12.9) years, 12 970 were female (70.5%), 14 182 were white (77.1%), 2171 Black (11.8%), 354 Asian (1.9%), 1679 were of other or unknown race, and 9563 (52.0%) had T2D. The mean (SD) baseline weight was 110 (25.8) kg. Follow-up was ended by discontinuation for 5140 patients (55.9%) receiving tirzepatide and 4823 (52.5%) receiving semaglutide. Patients receiving tirzepatide were significantly more likely to achieve weight loss (≥5%; hazard ratio [HR], 1.76, 95% CI, 1.68, 1.84; ≥10%; HR, 2.54; 95% CI, 2.37, 2.73; and ≥15%; HR, 3.24; 95% CI, 2.91, 3.61). On-treatment changes in weight were larger for patients receiving tirzepatide at 3 months (difference, -2.4%; 95% CI -2.5% to -2.2%), 6 months (difference, -4.3%; 95% CI, -4.7% to -4.0%), and 12 months (difference, -6.9%; 95% CI, -7.9% to -5.8%). Rates of gastrointestinal AEs were similar between groups.

Conclusions and relevance: In this population of adults with overweight or obesity, use of tirzepatide was associated with significantly greater weight loss than semaglutide. Future study is needed to understand differences in other important outcomes.

Figure 1.. Study Flow Diagram

A complete negative history of glucagon-like peptide 1 receptor agonist (GLP-1 RA) dispensing was required before the index date. Other exclusions include missing sex and no follow-up time. GLP-1 RA refers to both GLP-1 RA and GLP-1 RA/gastric inhibitory polypeptide agonist medications. ^aIndex event: first GLP-1 dispensed between May 2022 to September 2023.

Figure 2.. Event Probabilities for 5% or Greater, 10% or Greater, and 15% or Greater Weight Reduction Among Propensity-Score Matched Patients on Treatment

The y-axis represents the event probability (1-survival probability [eg, probability of being event-free]).

Figure 3.. Mean Percentage Change in Body Weight at 3, 6, and 12 Months Receiving Treatment for the Overall Population, Those With Type 2 Diabetes (T2D), and Those Without T2D

Bars represent mean changes in body weight from baseline to the time point among the propensity score matched population of patients still receiving treatment. The whiskers represent 95% CIs.

Figure 4.. Treatment Effects Comparing Tirzepatide to Semaglutide for All Patients, Patients With Type 2 Diabetes (T2D), and Patients Without T2D

Points represent point estimates; the whiskers represent 95% CIs. Panels A-C contain hazard ratios for achieving 5% or greater, 10% or greater, and 15% or greater weight loss for patients receiving tirzepatide vs semaglutide among propensity score matched populations. Hazard ratios greater than 1 indicate higher likelihood of reaching weight loss threshold with tirzepatide. Panels D-F contain absolute differences in body weight change at 3 months, 6 months, and 12 months for patients receiving tirzepatide vs semaglutide among propensity score matched populations still receiving treatment at the time point. Negative differences indicate greater weight loss with tirzepatide.