Research brief · 2026-09-09
Semaglutide vs Tirzepatide: What Do Head-to-Head Trials Show?
Semaglutide and tirzepatide are both prescription medications approved for type 2 diabetes and chronic weight management. Semaglutide acts on the GLP-1 receptor; tirzepatide acts on both the GLP-1 and GIP receptors. For years the only way to compare them was to line up their separate placebo-controlled trials, a method that cannot account for differences in who was enrolled or how each trial was run.
Those indirect comparisons pointed one way. In STEP 1, published in the New England Journal of Medicine in 2021, semaglutide produced an average weight change of minus 14.9 percent over 68 weeks against minus 2.4 percent for placebo. In SURMOUNT-1, in the same journal in 2022, the highest tirzepatide dose produced minus 20.9 percent over 72 weeks against minus 3.1 percent. Different trials, different populations, so a real answer needed a direct test.
SURMOUNT-5 provided it. Published by Aronne and colleagues in the New England Journal of Medicine in 2025, it randomised 751 adults with obesity, but without diabetes, to the maximum tolerated dose of either drug for 72 weeks. Tirzepatide produced an average weight change of minus 20.2 percent versus minus 13.7 percent for semaglutide. Waist circumference fell 18.4 centimetres versus 13.0. People on tirzepatide were more likely to reach each weight-loss threshold the trial measured. The most common side effects in both arms were gastrointestinal, mostly mild to moderate and concentrated during dose escalation.
That is genuine head-to-head evidence, and it confirmed what the indirect comparisons had suggested. But it is one trial, over one time window, in one population, and it was open-label, meaning participants and investigators knew which drug had been assigned. For body weight that matters less than it would for a subjective outcome, but it could plausibly affect adherence, reported side effects and dropout.
The bigger limit is what the trial was not built to test. No study has compared semaglutide and tirzepatide on heart attacks, strokes, kidney outcomes or survival. Semaglutide's cardiovascular trial was placebo-controlled; tirzepatide's ongoing SURPASS-CVOT compares it against a different active drug in people with diabetes, so the two cannot be stacked against each other. A larger drop on the scale is not automatically a larger health benefit. Which medication, if either, is right for a given person is a decision for that person and their physician.
Sources
- Aronne LJ, et al. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity (SURMOUNT-5)
- New England Journal of Medicine 2025
- Wilding JPH, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP 1)
- New England Journal of Medicine 2021
- Jastreboff AM, et al. Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1)
- New England Journal of Medicine 2022
- Nicholls SJ, et al. Comparison of tirzepatide and dulaglutide on major adverse cardiovascular events: SURPASS-CVOT design and baseline characteristics
- American Heart Journal 2023
Peptide Proof reports what studies found. We do not give medical advice, dosing guidance, or treatment recommendations.