SURMOUNT-5

Most obesity drug trials compare a drug with placebo, which tells you whether it works but not how it stacks up against the alternative you are actually choosing between. SURMOUNT-5 did the harder thing: it put tirzepatide and semaglutide head to head in the same trial, in adults with obesity and without diabetes, for 72 weeks. Aronne and colleagues published the results in the New England Journal of Medicine in 2025.

751 participants were randomized. At week 72, mean body weight fell 20.2% on tirzepatide versus 13.7% on semaglutide — a gap of about 6.5 percentage points. Waist circumference fell 18.4 cm versus 13.0 cm. Participants on tirzepatide were more likely to hit every weight-loss threshold measured: at least 10%, 15%, 20% and 25%. For someone starting at 250 pounds, those averages are roughly 51 pounds versus 34.

Side effects looked similar in kind if not in degree. Gastrointestinal complaints dominated in both groups, most were mild to moderate, and most clustered during dose escalation rather than at maintenance.

Two caveats keep this honest. Both drugs were titrated to their maximum tolerated dose, so the comparison is best-case versus best-case, not the doses most people end up on. And an average gap says nothing about you specifically — plenty of people lose more on semaglutide than the tirzepatide average, and tolerability, insurance coverage and injection-device preference all reasonably outweigh 6.5 percentage points. Zepbound and Wegovy are also priced and covered differently.

Worth asking your clinician: whether you can realistically reach the maintenance dose these results depend on, what the plan is if side effects cap you lower, and which of the two your insurance actually covers this plan year. Our SURMOUNT-5 deep dive, SURPASS-2 head-to-head in diabetes, and brand-switch dose equivalence calculator cover the switching question.