Almost every comparison of these two drugs is stitched together from separate trials run years apart. SURMOUNT-5 put them in the same room, at the same time, at their top doses.
SURMOUNT-5 was a phase 3b randomized head-to-head trial run across 32 sites in the United States and Puerto Rico between April 2023 and November 2024. It enrolled 751 adults with a BMI of at least 30, or at least 27 with one or more weight-related complication, and no type 2 diabetes. Mean age was 45. Roughly 35% of participants were men, which is a higher share than most obesity trials.
Participants were randomized to weekly tirzepatide or weekly semaglutide for 72 weeks, each titrated to the maximum tolerated dose — 10mg or 15mg for tirzepatide, 1.7mg or 2.4mg for semaglutide. Those are the highest approved doses of Zepbound and Wegovy respectively, so this was a fair top-of-label comparison rather than one drug being handicapped.
Why a direct comparison matters. Cross-trial arithmetic is unreliable. STEP 1 and SURMOUNT-1 enrolled different populations in different years under different protocols, so subtracting one result from the other does not give you a real difference between the drugs. Randomizing the same pool of people to both arms does.
The primary endpoint was percent change in body weight at week 72. Waist circumference and the proportion of people reaching specific weight-loss thresholds were among the secondary endpoints.
Tirzepatide won on the primary endpoint, and it was not close. A 6.5 percentage-point gap in mean weight change, with p<0.001. The waist circumference difference ran in the same direction and reached the same level of statistical significance — worth noting, because waist measurement tracks visceral fat more closely than the scale does.
The threshold numbers tell a sharper story than the averages. Nearly a third of the tirzepatide group lost a quarter of their body weight or more, roughly double the semaglutide share. Averages compress that kind of tail. If your prescriber is weighing which drug to try, the odds of landing in the deep end of the response curve are part of the picture.
Side effects were mostly a dose-escalation phenomenon. Most adverse events were mild to moderate and clustered during titration in both arms. Gastrointestinal side effects severe enough to end treatment were about twice as common on semaglutide, 5.6% versus 2.7% — a reminder that "more weight loss" and "harder to tolerate" did not travel together here.
One finding nobody expected. Weight loss was lower in men than in women in both treatment groups, by roughly six percent. The investigators think the unusually high proportion of male participants may be why overall results came in slightly below earlier trials of the same drugs. An accompanying NEJM editorial called it a genuine open question about what tissue is actually being lost, and why that might differ by sex.
In 751 adults with obesity and no diabetes, 72 weeks of maximum-tolerated tirzepatide produced −20.2% mean body weight change versus −13.7% on semaglutide — 22.8kg against 15.0kg — with fewer treatment discontinuations from GI side effects.
Sources: Aronne LJ, Horn DB, le Roux CW, et al. Tirzepatide as compared with semaglutide for the treatment of obesity. New England Journal of Medicine, 2025;393(1):26-36 (doi:10.1056/NEJMoa2416394) · American College of Cardiology journal scan, Jul 10 2025. NEJM full text · ACC summary.
Both arms took 72 weekly injections to get there. Neither result is a property of the molecule alone — it is the molecule plus roughly a year and a half of not missing doses. Trial participants had study staff, scheduled visits and reminder calls. Outside a trial, that scaffolding is whatever you build yourself.
Bigger numbers do not make a drug the right one for you. Coverage, cost, supply, prior response and tolerance all sit outside this trial. Semaglutide still produced a 13.7% mean reduction, which was a landmark result when STEP 1 reported it. SURMOUNT-5 raises the ceiling; it does not make the other option a failure.
Track the escalation weeks specifically. Adverse events concentrated during titration in both groups, and GI symptoms were the main reason people quit. Notes on what you felt in the seven days after each step up are far more useful to a prescriber deciding whether to hold a dose than a general sense that the month was rough.
Read the entry criteria before applying the result. Everyone in SURMOUNT-5 had obesity or overweight with a complication, and nobody had type 2 diabetes. Weight-loss results in people with diabetes have consistently run lower for both drugs, so these figures are not a forecast for that group.
This article summarizes published clinical trial results and a professional-society trial summary for general education. It is not medical advice. Individual results vary, and any decision about starting, switching, adjusting, or stopping any GLP-1 or GIP/GLP-1 medication should be made with a prescriber.