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Randomized Controlled Trial
. 2025 Jul;27(7):3757-3765.
doi: 10.1111/dom.16401. Epub 2025 May 5.

Tirzepatide 10 and 15 mg versus semaglutide 2.4 mg in people with obesity or overweight with type 2 diabetes: An indirect treatment comparison

Emily R Hankosky  1 , Xuanyao He  1 , Raleigh Malik  1 , Julia Fraseur Brumm  1 , Fangyu Wang  1 , Anthony Niemeyer  1 , Xiaotian M Zhang  1 , W Timothy Garvey  2
Affiliations
Randomized Controlled Trial

Tirzepatide 10 and 15 mg versus semaglutide 2.4 mg in people with obesity or overweight with type 2 diabetes: An indirect treatment comparison

Emily R Hankosky et al. Diabetes Obes Metab. 2025 Jul.

Abstract

Aims: Tirzepatide and semaglutide demonstrated clinically meaningful weight reduction in people with obesity or overweight and type 2 diabetes (T2D) in SURMOUNT-2 and STEP 2 clinical trials, respectively. In the absence of head-to-head trials, this study compared the efficacy of tirzepatide 10 and 15 mg with semaglutide 2.4 mg using an indirect treatment comparison.

Materials and methods: Mean percent change in weight from baseline, weight reduction ≥5% and mean change in glycated haemoglobin (HbA1c [%]) were compared between tirzepatide 10/15 mg (week 72, SURMOUNT-2) and semaglutide 2.4 mg (week 68, STEP 2) applying the Bucher method to the efficacy estimand. Sensitivity analyses included the use of matching-adjusted indirect comparison, treatment regimen estimand and comparing study outcomes at 68 weeks.

Results: Tirzepatide 10 and 15 mg were associated with significantly greater mean percent weight reductions versus semaglutide (mean difference, 10 mg: 2.57%; 15 mg: 4.79%, p < 0.01). Tirzepatide 15 mg had significantly higher odds of achieving ≥5% weight reduction (odds ratio 15 mg: 1.76, 95% CI 1.04-2.97, p = 0.035; odds ratio 10 mg: 1.24, 95% CI 0.75-2.04, p = 0.407), and both tirzepatide doses were associated with significantly greater reductions in HbA1c (%) levels (mean difference, 10 mg: 0.47%; 15 mg: 0.56%, p < 0.001) than semaglutide. Sensitivity analyses were generally consistent with the primary analysis, exceptions including when power was reduced in the matching-adjusted indirect comparison analyses and in the categorical weight reduction outcome.

Conclusions: This analysis suggested greater reductions in bodyweight and HbA1c (%) levels associated with tirzepatide 10 and 15 mg than with semaglutide 2.4 mg in people with obesity or overweight and T2D.

Keywords: indirect treatment comparison; obesity; semaglutide; tirzepatide; type 2 diabetes; weight reduction.

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Conflict of interest statement

Emily R. Hankosky, Xuanyao He, Julia Fraseur Brumm, Fangyu Wang, Anthony Niemeyer and Xiaotian Michelle Zhang are employees and stockholders of Eli Lilly and Company, Indianapolis, United States. Raleigh Malik was an employee of Eli Lilly and Company at the time of the study. W. Timothy Garvey has served as a consultant on advisory boards for Boehringer Ingelheim, Eli Lilly and Company, Novo Nordisk, Pfizer, Fractyl Health, Alnylam Pharmaceuticals, Inogen, Zealand, Carmot/Roche, Regeneron and Merck, and as a site principal investigator for multi‐centred clinical trials sponsored by his university and funded by Novo Nordisk, Eli Lilly and Company, Epitomee, Neurovalens and Pfizer.

Figures

FIGURE 1
FIGURE 1
Network diagram for the indirect treatment comparison.
FIGURE 2
FIGURE 2
Comparison of tirzepatide versus semaglutide for mean percent change from baseline in bodyweight and ≥5% bodyweight reduction from baseline. Indirect treatment comparison of tirzepatide 10 and 15 mg versus semaglutide 2.4 mg for (A) mean percent change from baseline in bodyweight, and (B) odds of participants achieving ≥5% bodyweight reduction from baseline (primary and sensitivity analyses; see Supplementary Table 2 for details). All outcomes and methodological choices from the primary analysis were kept constant for the sensitivity analyses except: Sensitivity analysis 1: comparison of treatment regimen estimand (tirzepatide) or treatment policy estimand (semaglutide) Sensitivity analysis 2: comparing endpoints at 68 weeks for both medications. Sensitivity analysis 3: matching‐adjusted indirect comparison adjusting for ethnicity, sex, baseline HbA1c (%) and treatment with sodium‐glucose co‐transporter 2 inhibitors. Sensitivity analysis 4: matching‐adjusted indirect comparison adjusting for sex, baseline HbA1c and treatment with sodium‐glucose co‐transporter 2 inhibitors. Mean difference <0 favours tirzepatide (panel A); OR >1 favours tirzepatide (panel B). CI, confidence interval; OR, odds ratio.
FIGURE 3
FIGURE 3
Comparison of tirzepatide versus semaglutide for mean change in HbA1c (%). Indirect treatment comparison of tirzepatide 10 and 15 mg versus semaglutide 2.4 mg for mean change in HbA1c (primary and sensitivity analyses; see Supplementary Table 2 for details). All outcomes and methodological choices from the primary analysis were kept constant for the sensitivity analyses except: Sensitivity analysis 1: comparison of treatment regimen estimand (tirzepatide) or treatment policy estimand (semaglutide). Sensitivity analysis 2: comparing endpoints at 68 weeks for both medications. Sensitivity analysis 3: matching‐adjusted indirect comparison adjusting for ethnicity, sex, baseline HbA1c (%) and treatment with sodium‐glucose co‐transporter 2 inhibitors. Sensitivity analysis 4: matching‐adjusted indirect comparison adjusting for sex, baseline HbA1c and treatment with sodium‐glucose co‐transporter 2 inhibitors. Mean difference <0 favours tirzepatide. CI, confidence interval; HbA1c (%), glycated haemoglobin.
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