Semaglutide vs tirzepatide: what the head-to-head trial shows

In the one large randomized trial that put the two molecules against each other, tirzepatide produced a mean weight change of -20.2% at 72 weeks, against -13.7% for semaglutide. That is SURMOUNT-5, published in the New England Journal of Medicine in 2025. The gap is 6.5 percentage points, it was statistically significant (P<0.001), and it is the best direct evidence we found. It also comes with caveats worth knowing before you repeat the number.

What did SURMOUNT-5 actually test?

SURMOUNT-5 was a phase 3b, open-label trial. A total of 751 adults with obesity but without type 2 diabetes were randomly assigned 1:1 to the maximum tolerated dose of tirzepatide or the maximum tolerated dose of semaglutide, given once weekly for 72 weeks. The primary endpoint was the percent change in body weight from baseline to week 72.

Waist circumference followed the same pattern: -18.4 cm with tirzepatide and -13.0 cm with semaglutide. The tirzepatide group was also more likely to reach weight reductions of at least 10%, 15%, 20% and 25%. In both arms the most common adverse events were gastrointestinal, mostly mild to moderate, and clustered in the dose-escalation period.

The design choice matters. Comparing maximum tolerated doses asks which drug does more when each is pushed as far as a participant can manage, which is a fairer question than comparing one fixed dose against another. It also means the arms were not identical in dose exposure, so the result describes each drug used at its practical ceiling rather than a matched pair of settings. The paper's abstract reports funding by Eli Lilly and registers the trial as NCT05822830, so the protocol can be checked against what was published.

How do the two drugs look in their own pivotal trials?

Before SURMOUNT-5, people compared the two by lining up their separate placebo-controlled trials. The table shows those results next to the head-to-head. Read the first two rows with care: they come from different trials, different populations and different years.

Why does a head-to-head trial matter more than comparing two separate ones?

STEP 1 and SURMOUNT-1 enrolled different people, ran for different lengths of time and were designed by different sponsors. Both used an analysis that counts participants regardless of whether they stayed on treatment, which is the right choice for realism, but small differences in baseline weight, sex mix and dropout can still move the averages. Subtracting one trial's number from the other's would produce a comparison no one actually tested.

SURMOUNT-5 removes that problem by randomizing one population to both drugs. The fact that the gap in the separate trials (-14.9% vs -20.9%) and the gap in the direct trial (-13.7% vs -20.2%) point the same way, and are of similar size, makes the result more believable than either comparison alone.

What should you discount?

• The trial was open-label, so participants and investigators knew which drug was in use. Weight is an objective measure, but behavior and dropout are not.
• Eli Lilly, which makes tirzepatide, funded it. That does not invalidate the result. It is a reason to want an independent replication, and we are not aware of one at the time of writing.
• Each arm used the maximum tolerated dose, so the semaglutide arm includes people on a lower dose than the highest one studied in STEP 1.
• Seventy-two weeks says little about what happens after treatment stops, and weight change is not the same as outcomes such as cardiovascular events. SURMOUNT-5 did not compare those.

What about tolerability?

Gastrointestinal events dominated in both arms of SURMOUNT-5. For context from the placebo-controlled trials: in STEP 1, 4.5% of semaglutide participants stopped treatment because of gastrointestinal events versus 0.8% on placebo. In SURMOUNT-1, adverse events led to discontinuation in 4.3%, 7.1% and 6.2% of the three tirzepatide groups versus 2.6% on placebo. Those percentages come from different trials, so they should not be ranked against each other.

How does this relate to research-grade material?

Both molecules are approved prescription products. The FDA approved Zepbound (tirzepatide) for chronic weight management on November 8, 2023, and it approved Wegovy (semaglutide) for the same purpose in 2021. The trial results above describe those approved products, made and controlled to pharmaceutical standards, and they say nothing about the quality of any research-grade vial.

The FDA's page on unapproved GLP-1 drugs, dated October 1, 2026, warns against products falsely labeled as being for research purposes or not for human consumption that are sold for human use. Research-grade compounds on this site are discussed as laboratory materials only. If you are looking for weight management, a physician can tell you what is appropriate for you.

Bottom line

On the best evidence available, tirzepatide outperformed semaglutide on weight change over 72 weeks in adults without diabetes, by a margin large enough that the open-label design is unlikely to explain it away. What remains unknown is durability, independent replication and long-term outcomes. For the compound profiles, see tirzepatide and semaglutide. For vial sizes and cost per milligram of the research-grade versions, the price comparison table lays them out side by side.