SURMOUNT-5: Tirzepatide Beats Semaglutide Head-to-Head (What the Data Show)

The headline numbers

The gap was about 6.5 percentage points, or roughly 7.8 kg more weight lost on average. Nearly a third of tirzepatide users reached at least 25% weight loss, roughly double the semaglutide rate. Waist reduction and other cardiometabolic markers also favored tirzepatide.

Full results

Why tirzepatide pulled ahead

Tirzepatide is a dual GIP/GLP-1 receptor agonist, while semaglutide acts on GLP-1 alone. Researchers noted the result was consistent with each drug’s separate prior trials. Both had broadly similar safety, with gastrointestinal effects most common; notably, GI-related discontinuations were lower with tirzepatide, suggesting the larger weight loss did not come at the cost of worse tolerability in this study.

How the trial was designed

SURMOUNT-5 was a randomized, open-label phase 3b trial. Participants received the maximum tolerated dose of tirzepatide (10 or 15 mg) or semaglutide (1.7 or 2.4 mg) once weekly for 72 weeks. Comparing each drug at its top tolerated dose is what makes the result a fair, direct test rather than a mismatched comparison. The findings closely tracked what each drug had shown independently, which strengthens confidence in the conclusion.

Caveats worth noting

A few limitations matter. The trial was open-label, so participants knew which drug they received. It enrolled a higher share of men than most obesity trials, and men lost slightly less weight in both groups, which may have modestly lowered the overall figures. And it studied FDA-approved products, not compounded versions. None of this undercuts the headline, but individual results still depend on tolerability, cost, and adherence, so semaglutide remains a strong option for many patients.

What it means for patients

For many people, tirzepatide offers a larger average weight-loss ceiling, but semaglutide is still highly effective, and choice depends on tolerability, cost, coverage, and clinical history. A new oral GLP-1 pill now adds a third option. See our semaglutide vs tirzepatide decision guide to weigh the trade-offs.

Cost and access context

Efficacy is only one input. Both drugs are FDA-approved but coverage varies widely, and manufacturer self-pay programs have narrowed the gap with compounded routes. The newer oral semaglutide pill and the oral orforglipron pill add lower-friction options that trade some efficacy for convenience and, often, lower monthly cost with coverage. When SURMOUNT-5 shows tirzepatide ahead on weight loss, that advantage still has to be weighed against what each option actually costs you and how consistently you can stay on it, since an interrupted course tends to give back progress.

Where compounded tirzepatide fits

SURMOUNT-5 studied FDA-approved tirzepatide, not compounded versions. Compounded tirzepatide is not FDA-approved and now depends on patient-specific compounding with a documented clinical need, so its availability is narrower than during the shortage. The trial’s results describe the branded molecule’s performance under controlled conditions; they should not be read as a guarantee for a compounded product that may differ in concentration or formulation. Anyone weighing compounded tirzepatide should factor that distinction in alongside the head-to-head efficacy data.

Frequently asked questions

Which drug won SURMOUNT-5?

Tirzepatide. Participants lost 20.2% of body weight on average versus 13.7% with semaglutide at 72 weeks — superior on the primary and all key secondary endpoints.

How big was the difference?

About 6.5 percentage points, or roughly 7.8 kg more on average. And 31.6% of tirzepatide users reached at least 25% weight loss versus 16.1% on semaglutide.

Was it a fair comparison?

Yes — a randomized head-to-head trial of 751 adults using each drug at its maximum tolerated dose, published in NEJM.

Does this apply to compounded tirzepatide?

The trial studied FDA-approved tirzepatide (Zepbound). Compounded tirzepatide is not FDA-approved and was not the product tested.