Semaglutide vs. Tirzepatide: What the Trials Actually Found

The trial that actually compared them

SURMOUNT-5 is the reason this comparison is different from every other one on this site. It randomized 751 adults with obesity and without type 2 diabetes, 1:1, to the maximum tolerated dose of tirzepatide — 10 mg or 15 mg — or the maximum tolerated dose of semaglutide — 1.7 mg or 2.4 mg — once weekly for 72 weeks. The primary endpoint was percent weight change at week 72. Tirzepatide reached −20.2% and semaglutide −13.7%, a difference the trial reported as significant, and waist circumference fell 18.4 cm against 13.0 cm ¹. Participants on tirzepatide were also more likely to reach reductions of at least 10%, 15%, 20% and 25% ¹.

That is a real, randomized, within-one-trial comparison, and it is the strongest evidence anyone can point to on this question. Two things bound it. It was open-label, so everyone knew which drug they were on — the trial states this in its own design, and a weight endpoint measured in unblinded participants is not the same instrument as one measured under a blind. And it assigned dose ceilings rather than fixed doses, so the finding is about each drug used up to its tolerated limit as those limits stood in the protocol, not about two specific milligram amounts.

What the diabetes comparison adds

SURPASS-2 ran the same kind of comparison in a different disease. It randomized 1,879 adults with type 2 diabetes 1:1:1:1 to tirzepatide at 5 mg, 10 mg or 15 mg, or to semaglutide at 1 mg, open-label, for 40 weeks. The primary endpoint was glycated hemoglobin, which fell 2.01, 2.24 and 2.30 percentage points on the three tirzepatide doses against 1.86 on semaglutide; tirzepatide was noninferior and superior at every dose ². Weight was a secondary endpoint, and the treatment differences were 1.9 kg, 3.6 kg and 5.5 kg in tirzepatide's favor ².

Note what the comparator was. Semaglutide 1 mg is the diabetes dose, not the obesity dose. A trial that pits three tirzepatide doses against a single low semaglutide dose answers a question about those assignments, and the honest reading of the 5.5 kg gap is that it is the gap between 15 mg of one drug and 1 mg of the other.

The dose neither comparison tested

Semaglutide's label has moved since both head-to-head trials were designed. As of August 2026 the Wegovy label describes a route to a maximum of 7.2 mg once weekly for adults who tolerate 2.4 mg for at least four weeks and for whom further weight reduction is clinically indicated. SURMOUNT-5 capped semaglutide at 2.4 mg. SURPASS-2 capped it at 1 mg. Neither randomized 7.2 mg against anything made by anyone else.

What exists for that dose is a placebo-controlled trial. STEP UP randomized 1,407 participants 5:1:1 to semaglutide 7.2 mg, 2.4 mg or placebo for 72 weeks and reported −18.7%, −15.6% and −3.9% ⁵. Set that 18.7% next to tirzepatide's 20.2% from SURMOUNT-5 and you are comparing two different trials, two different populations and two different comparators — the exact move this table's duration, sample size and phase columns exist to make visible. The higher dose also cost something measurable: gastrointestinal events were reported by 70.8% of participants on 7.2 mg against 61.2% on 2.4 mg, and an altered-skin-sensation side effect by 230 of 1,004 participants on 7.2 mg against 12 of 201 on 2.4 mg ⁵.

What each drug did on its own

The two placebo-controlled headline trials are still worth reading, because they are larger and blinded where the comparisons are not. STEP 1 randomized 1,961 adults without diabetes 2:1 to semaglutide 2.4 mg or placebo for 68 weeks and reported −14.9% against −2.4%, with 50.5% of the semaglutide group losing at least 15% of body weight against 4.9% on placebo ³. SURMOUNT-1 randomized 2,539 adults to three tirzepatide doses or placebo for 72 weeks and reported −15.0%, −19.5% and −20.9% against −3.1%, with 57% of the 15 mg group losing at least 20% against 3% on placebo ⁴.

The number that travels from that second trial is 20.9%, and it is a dose arm rather than a trial average: on the published 1:1:1:1 randomization the 15 mg group is roughly 635 of the 2,539 participants. The 5 mg arm of the same trial reached 15.0%, which is close to what semaglutide reached in STEP 1 — a reminder that "which drug" and "which dose" are two different questions.

Both are approved, for different things

Approval is a separate axis from effect size, and the two labels do not cover the same ground. As of August 2026 the Zepbound label covers weight reduction and long-term weight maintenance, plus moderate-to-severe obstructive sleep apnea in adults with obesity, and the Mounjaro label covers glycemic control in type 2 diabetes. Neither carries a cardiovascular risk-reduction indication. The Wegovy injection label carries three: reducing major adverse cardiovascular events in adults with established cardiovascular disease and obesity or overweight, weight reduction and maintenance, and noncirrhotic metabolic dysfunction-associated steatohepatitis with moderate to advanced fibrosis — the last of those under accelerated approval.

So a reader whose priority is a cardiovascular indication and a reader whose priority is sleep apnea are looking at different drugs, and neither is answered by the 20.2% figure. Which one fits a given person is a prescribing decision made by someone who can see their history. This page reports what was measured; it does not recommend.

The bottom line

On weight, in adults with obesity and without diabetes, over 72 weeks, at each drug's tolerated ceiling as those trials defined it, tirzepatide produced more weight loss than semaglutide, and it did so inside one randomized trial rather than across two. That is a genuine finding and it should not be talked down. What it does not establish is a general ranking: it did not test semaglutide's highest labeled dose, it was not blinded, it measured one endpoint in one population, and it says nothing about which drug's approved indications match a particular reader. For the compound that posted a larger phase 2 number than either of these and still has no approval, see retatrutide vs. tirzepatide.