Semaglutide vs tirzepatide: what the head-to-head trial actually showed

The short answer

In the only large randomized trial that compared the two medicines directly, SURMOUNT-5, people taking tirzepatide lost more weight on average than people taking semaglutide: 20.2% versus 13.7% of body weight after 72 weeks. The trial enrolled 751 adults with obesity and no type 2 diabetes.

That is a meaningful difference, but it is an average across a group. Individual responses varied in both arms, and the trial does not tell any one person which medicine will work better for them. The choice between approved medicines belongs to a prescriber who knows the patient's history.

How the two molecules differ

Semaglutide activates one receptor: the GLP-1 receptor. GLP-1 is a gut hormone involved in insulin release, stomach emptying and appetite signalling. Semaglutide is approved under the brand names Ozempic (type 2 diabetes), Wegovy (weight management) and Rybelsus (oral, diabetes). In December 2025 the FDA also approved an oral 25 mg Wegovy tablet for weight management.

Tirzepatide activates two receptors: GLP-1 and GIP, a second gut hormone. It is approved as Mounjaro for type 2 diabetes and Zepbound for weight management. The dual action is the main hypothesis for why tirzepatide produced larger average weight loss, although the trials were not designed to prove the mechanism.

SURMOUNT-5 in numbers

Participants were randomized 1:1 to the maximum tolerated dose of tirzepatide (10 or 15 mg weekly) or semaglutide (1.7 or 2.4 mg weekly), alongside lifestyle advice. Results were published in the New England Journal of Medicine in 2025.

Average weight change at week 72 was −20.2% with tirzepatide and −13.7% with semaglutide. Waist circumference fell by 18.4 cm and 13.0 cm respectively. Both differences were statistically significant.

The trial was sponsored by Eli Lilly, the maker of tirzepatide, and was open-label: participants knew which medicine they were receiving. Those design features do not invalidate the results, but they are worth knowing when you read headlines about it.

What the earlier placebo trials found

Before the direct comparison, each medicine was tested against placebo. In STEP 1, 1,961 adults received semaglutide 2.4 mg or placebo for 68 weeks; average weight loss was 14.9% versus 2.4%. In SURMOUNT-1, 2,539 adults received tirzepatide 5, 10 or 15 mg or placebo for 72 weeks; average weight loss was 15.0%, 19.5% and 20.9% versus 3.1%.

Cross-trial comparisons are weak evidence because populations and methods differ. That is exactly why SURMOUNT-5 matters: it removed most of those differences by testing both medicines in the same study.

Side effects and tolerability

For both medicines the most common adverse events are gastrointestinal: nausea, diarrhoea, vomiting and constipation, usually during dose escalation. In SURMOUNT-5, discontinuation because of gastrointestinal events was reported in 5.6% of the semaglutide group and 2.7% of the tirzepatide group.

A 2025 meta-analysis of placebo-controlled trials found that both medicines increase gastrointestinal adverse events compared with placebo. Approved product labels list further warnings, including pancreatitis, gallbladder disease and a boxed warning about thyroid C-cell tumours seen in rodents. The label for the exact product and market is the authoritative source.

Where semaglutide has data tirzepatide does not (yet)

Weight loss is not the only outcome that matters. In the SELECT trial, 17,604 adults with overweight or obesity and established cardiovascular disease, but without diabetes, had 20% fewer major cardiovascular events on semaglutide 2.4 mg than on placebo. That result supports an approved cardiovascular indication for Wegovy.

Outcome trials for tirzepatide are ongoing or newer. When comparing the two, look at which outcomes have actually been proven, not just which medicine produced the larger number on the scale.

Approved medicine, compounded version or research product

Results from SURMOUNT-5, STEP 1 and SURMOUNT-1 apply to the approved medicines manufactured and tested in those trials. The FDA has warned about counterfeit Ozempic in the US supply chain and about fraudulent compounded semaglutide and tirzepatide with false label information.

A product that shares a substance name with an approved medicine does not inherit its clinical evidence, safety data or legal status. See our guides on research products versus approved medicines and on reading a certificate of analysis before drawing conclusions from a name alone.