The question people ask most often about these two drugs — which one works better — has a direct answer, and has had one since July 2025. In SURMOUNT-5, a trial that gave 751 adults either tirzepatide or semaglutide and followed them for 72 weeks, tirzepatide produced an average weight reduction of 20.2% against semaglutide’s 13.7%. That is a gap of roughly six and a half percentage points, and it is not close. Two features of how the trial was run should shape how much weight you put on it.
What the trial did
Participants were adults with obesity but without type 2 diabetes, randomly assigned one-to-one to the maximum tolerated dose of either drug, injected once weekly for 72 weeks. Maximum tolerated matters: this was not a fixed-dose comparison but each drug at the most a participant could take, which is closer to how they are actually prescribed.
The primary result was a least-squares mean weight change of −20.2% (95% confidence interval −21.4 to −19.1) for tirzepatide and −13.7% (CI −14.9 to −12.6) for semaglutide, p < 0.001. Those intervals do not overlap, which is what makes the difference convincing rather than suggestive. Waist circumference fell 18.4 cm against 13.0 cm. Participants on tirzepatide were also more likely to reach every weight-loss threshold the trial measured — 10%, 15%, 20% and 25%.
Side effects were gastrointestinal in both groups, mostly mild to moderate, and concentrated during dose escalation rather than spread across the 72 weeks.
The two caveats
It was open-label. Participants and investigators both knew which drug was being taken. For an outcome like body weight, that is not a trivial detail: someone who knows they were assigned the newer drug reputed to work better may eat and move differently than someone who knows they were not. Blinding exists to remove exactly that, and this trial did not have it. The effect size is large enough that expectation alone is unlikely to explain all of it, but it can plausibly explain some.
It was funded by Eli Lilly, which makes tirzepatide — the drug that won. Industry funding is normal in Phase 3 work and does not invalidate a result. It does mean the trial that most favours one manufacturer’s product was designed and paid for by that manufacturer, and that is worth stating plainly rather than leaving in a footnote.
What it does not settle
Everyone in this trial had obesity without type 2 diabetes. People with diabetes lose less weight on these drugs, so the figures do not transfer to them. The trial measured weight and waist, not heart attacks, strokes or deaths — whether the extra weight loss produces better long-term health is a separate question requiring separate trials. And 72 weeks is not a lifetime; these are medicines many people take indefinitely, and weight regain after stopping is well documented for both.
The practical translation is narrower than the headline. If effectiveness is the only consideration, this trial favours tirzepatide clearly. Cost is a second consideration and it does not point the same way — Zepbound runs $449 a month at maintenance against $349 for the standard Wegovy pen, as our pricing breakdown sets out. Whether roughly six percentage points of additional weight loss is worth $1,200 a year is a question the trial does not attempt to answer.
