Weight Changes With Tirzepatide and Concomitant Weight-Inducing Medications: Post Hoc Analysis of Randomized Clinical Trials.

IMPORTANCE: Given the common use of weight-inducing (WI) medications, it is crucial to understand the potential association of these medications with the effectiveness of obesity treatments. OBJECTIVE: To assess the association between tirzepatide and weight reduction among participants with overweight or obesity who initiated WI medications during the SURMOUNT-1, -3, and -4 trials. DESIGN, SETTING, AND PARTICIPANTS: This post hoc analysis of the phase 3 randomized clinical trials SURMOUNT-1 (December 4, 2019, to April 1, 2022), SURMOUNT-3 (March 29, 2021, to May 12, 2023), and SURMOUNT-4 (March 29, 2021, to May 18, 2023) assessed the association between tirzepatide and weight reduction among participants taking concomitant WI medications. Randomized participants (lead-in and randomized treatment period data) who started taking 1 or more WI medications for 3 or more months (≥1 week for oral corticosteroids) during the trial were included in the analysis. Statistical analysis was performed from July to December 2025 in the modified intent-to-treat population. MAIN OUTCOMES AND MEASURES: WI medication use was summarized for all treatment arms from weeks 0 to 72 (SURMOUNT-1 and SURMOUNT-3) or weeks 0 to 88 (SURMOUNT-4). A mixed model of repeated measures was used to assess percentage change in weight from week 0 to week 72 or week 88 in the efficacy analysis sets (excluding off-treatment data), with 1 or more postbaseline weight measures. RESULTS: This post hoc analysis comprised the WI medication subgroups of SURMOUNT-1 participants (N = 442; mean [SD] age, 48.0 [12.5] years; 325 women [73.5%]; mean [SD] body weight, 105.9 [22.4] kg), SURMOUNT-3 participants (N = 100; mean [SD] age, 49.5 [12.0] years; 75 women [75.0%]; mean [SD] body weight, 102.7 [23.5] kg), and SURMOUNT-4 participants (N = 134; mean [SD] age, 51.8 [11.9] years; 91 women [67.9%]; mean [SD] body weight, 111.8 [23.7] kg). Approximately one-fifth of participants used 1 or more WI medications (SURMOUNT-1, 17.4% [442 of 2539]; SURMOUNT-3, 17.3% [100 of 579]; and SURMOUNT-4, 20.0% [134 of 670]). Among them, 72.9% in SURMOUNT-1 (322 of 442), 68.0% in SURMOUNT-3 (68 of 100), and 64.9% in SURMOUNT-4 (87 of 134) were taking 1 nonsteroid WI medication, with 2.0% in SURMOUNT-1 (9 of 442), 3.0% in SURMOUNT-3 (3 of 100), and 2.2% in SURMOUNT-4 (3 of 134) using 3 or more medications. The mean (SD) duration of treatment with nonsteroid WI medications was 50.9 (28.8) weeks in SURMOUNT-1, 50.9 (29.3) weeks in SURMOUNT-3, and 58.1 (34.9) weeks in SURMOUNT-4. The mean percentage weight change compared with placebo from randomization to 72 weeks for those treated with tirzepatide and using WI medication was -13.3% (95% CI, -16.0% to -10.7%) for 5 mg to -21.3% (95% CI, -23.9% to -18.7%) for 15 mg in SURMOUNT-1 and -26.1% (95% CI, -30.0% to -22.3%) for the maximum tolerated dose in SURMOUNT-3, and from randomization to 88 weeks, it was -18.6% (95% CI, -20.9% to -16.3%) for the maximum tolerated dose in SURMOUNT-4. CONCLUSIONS AND RELEVANCE: In this post hoc analysis of 3 randomized clinical trials for participants taking at least 1 concomitant WI medication, tirzepatide treatment was associated with weight loss comparable with the primary study results. These findings suggest that people with overweight or obesity who require treatment with WI medications may be able to achieve clinically meaningful weight reduction with tirzepatide. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT04184622, NCT04657016, NCT04660643.