Tirzepatide vs semaglutide: what the head-to-head trial showed

Until 2025, comparing tirzepatide with semaglutide meant comparing two separate placebo-controlled trials with different populations. SURMOUNT-5 removed that problem by randomising people to one drug or the other. Here is what it showed, and what it left open.

The trial

Phase 3b, randomised, open-label, 751 adults with obesity and without type 2 diabetes. Each participant was escalated to the maximum tolerated dose of their assigned drug: tirzepatide 10 or 15 mg weekly, or semaglutide 1.7 or 2.4 mg weekly, the two top doses of each label. Treatment ran 72 weeks. Primary endpoint: percent change in body weight. PubMed 40353578; N Engl J Med 2025;393:26-36.

The results

The difference in mean weight change is about 6.5 percentage points, with confidence intervals that do not overlap. Gastrointestinal adverse events were the most common in both groups, mostly mild to moderate, mostly during escalation; the abstract does not report a difference in tolerability between the drugs.

Set against the placebo-controlled trials, the tirzepatide figure is close to SURMOUNT-1's 15 mg arm (-20.9%, PubMed 35658024), which is reassuring about consistency.

The caveats

Open-label. Everyone knew which drug they were on. Weight is an objective measurement, which limits the damage, but expectations affect adherence and behaviour, and the study cannot exclude that.

No diabetes. SURMOUNT-2 showed tirzepatide produces smaller losses in people with type 2 diabetes (-12.8% and -14.7% at 10 and 15 mg). Semaglutide's own diabetes trials show the same pattern for that drug. SURMOUNT-5 does not tell you how the two compare in that population.

Maximum tolerated doses. The comparison is top dose against top dose. It says nothing about tirzepatide 5 mg against semaglutide 1 mg, or about any lower-dose strategy.

Funded by Lilly. As every SURMOUNT trial is. The results were published in a peer-reviewed journal with the confidence intervals above; funding is a fact to know, not a reason to discard the numbers.

How the two drugs differ on paper

Tirzepatide is a GIP and GLP-1 receptor agonist (Zepbound label section 11); semaglutide is a GLP-1 receptor agonist only. Both are weekly injections with half-lives measured in days. The escalation schedules differ in shape: tirzepatide climbs 2.5, 5, 7.5, 10, 12.5, 15 mg with at least four weeks per step, so the label-minimum route to the top dose is 20 weeks; the Wegovy label's route to 2.4 mg runs 0.25, 0.5, 1, 1.7, 2.4 mg at four weeks each, 16 weeks. The milligram numbers are not comparable between the drugs; they are different molecules with different potencies, which is why "15 mg versus 2.4 mg" is not a statement about strength.

Cost

Lilly's published self-pay prices for Zepbound vials and KwikPens as of December 1, 2025 run $299 to $449 per 28 days depending on strength; the cost page has the history. Semaglutide's manufacturer programmes are tracked on the sister site, Semaglutide Hub, and both brands' list prices, savings cards and compounded price ranges are compared with methodology on the network's GLP-1 Pricing Index. FormBlends' own GLP-1 cost report covers the same ground from the compounded side; note that compounded tirzepatide and semaglutide are not FDA approved and are not interchangeable with the brand products in this trial.

What to take from it

If the question is which drug produced more weight loss in a direct comparison in adults with obesity and no diabetes, the answer is tirzepatide, by about six and a half points of body weight over 72 weeks. If the question is which drug is right for you, the answer depends on tolerability, diabetes status, coverage, cost and what your prescriber has seen you tolerate, and none of that is in the trial. The SURMOUNT numbers page has every tirzepatide trial in one place for the next conversation.