Comparative Effectiveness: Semaglutide vs. Tirzepatide in Head-to-Head Trials
SURMOUNT-5 is the only randomized head-to-head trial: -20.2% vs. -13.7% body weight at 72 weeks favoring tirzepatide. The full results table, the cardiovascular evidence gap, and what comparative effectiveness means for clinical decision-making.
Semaglutide and tirzepatide have been compared indirectly via their respective clinical trial programs — the STEP series for semaglutide and the SURMOUNT series for tirzepatide — but only one head-to-head randomized trial has reported primary results: SURMOUNT-5, published in early 2025. Here's what the direct comparison data shows, and what the trial's design decisions mean for interpretation.
SURMOUNT-5 Design
SURMOUNT-5 enrolled 751 adults with obesity (BMI ≥30 kg/m² or ≥27 with a weight-related comorbidity) without type 2 diabetes. Participants were randomized to tirzepatide 15mg weekly or semaglutide 2.4mg weekly for 72 weeks. The primary endpoint was percent change in body weight from baseline to 72 weeks.
The trial was designed and funded by Eli Lilly, the manufacturer of tirzepatide (Zepbound). This is standard for pharmaceutical comparative effectiveness trials and should be noted when evaluating the results, though the primary endpoint is objective (body weight) and less susceptible to reporting bias than subjective outcomes.
Primary and Secondary Results
| Endpoint | Tirzepatide 15mg | Semaglutide 2.4mg | Difference (95% CI) |
|---|---|---|---|
| Mean weight change (%) | -20.2% | -13.7% | -6.5% (-7.9 to -5.0) |
| ≥5% weight loss | 93.0% | 83.3% | p<0.001 |
| ≥15% weight loss | 64.3% | 40.7% | p<0.001 |
| ≥20% weight loss | 42.6% | 22.9% | p<0.001 |
| Waist circumference change | -18.4 cm | -13.0 cm | p<0.001 |
Safety Comparison
| Safety Metric | Tirzepatide | Semaglutide |
|---|---|---|
| Any GI adverse event | 71.7% | 69.4% |
| Discontinuation — GI | 4.3% | 5.6% |
| Serious adverse events | 6.4% | 7.1% |
GI adverse event profiles were similar between arms. Tirzepatide had a non-significantly lower discontinuation rate due to GI events — consistent with the hypothesis that GIP co-agonism reduces GLP-1R-mediated nausea, though this remains mechanistically unproven.
SURMOUNT-5 compares weight loss outcomes, not cardiovascular outcomes. Semaglutide's cardiovascular benefit in SELECT (20% reduction in MACE) was demonstrated in a dedicated CVOT. Tirzepatide's SURPASS-CVOT, examining cardiovascular outcomes in patients with type 2 diabetes, completed enrollment in 2023 with results expected 2025–2026. A tirzepatide CVOT in obesity without diabetes (analogous to SELECT) has been announced but not yet completed. For patients with established cardiovascular disease making treatment decisions, the cardiovascular evidence base is currently stronger for semaglutide.
Implications for Clinical Decision-Making
For weight loss as the primary treatment goal: the SURMOUNT-5 data provides direct trial support for tirzepatide's superior efficacy. For patients with obesity and established cardiovascular disease: the semaglutide cardiovascular outcomes data remains the more established evidence base. For patients who tolerated one drug poorly: cross-agent tolerability cannot be predicted from trial data — some patients who cannot tolerate one GLP-1 agent tolerate the other.
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Sources
- Jastreboff AM, et al. "Tirzepatide vs. Semaglutide in Adults with Obesity (SURMOUNT-5)." NEJM. 2025.
- Lincoff AM, et al. "Semaglutide and Cardiovascular Outcomes in Obesity Without Diabetes (SELECT)." NEJM. 2023.
- Eliaschewitz FG, et al. "Design and baseline characteristics of the SURPASS-CVOT trial." Am Heart J. 2021.