Semaglutide vs tirzepatide: the head-to-head trials

Comparing STEP 1 with SURMOUNT-1 is tempting: -14.9% on semaglutide, -20.9% on tirzepatide. But they were different trials, run at different times, in different people, with different placebo results. The only clean comparison is a trial that randomises people to one drug or the other. There are two published so far for weight and glucose: SURPASS-2 in type 2 diabetes and SURMOUNT-5 in obesity. Both were funded by Eli Lilly, which makes tirzepatide.

The two trials side by side

SURMOUNT-5: weight

751 adults with obesity and no type 2 diabetes were randomised one to one. Each person climbed to the highest dose they tolerated: 10 or 15 mg of tirzepatide, 1.7 or 2.4 mg of semaglutide. At 72 weeks, mean weight change was -20.2% (95% CI -21.4 to -19.1) on tirzepatide and -13.7% (95% CI -14.9 to -12.6) on semaglutide, a gap of about 6.5 points. Tirzepatide users were more likely to reach every threshold the trial tested: 10, 15, 20 and 25 percent. Waist circumference fell 18.4 cm against 13.0 cm. The most common side effects in both arms were gastrointestinal, mostly mild to moderate and mostly during the climb.

Notice that semaglutide's -13.7% here is close to its -14.9% in STEP 1, and tirzepatide's -20.2% is close to its -20.9% in SURMOUNT-1. The head-to-head result is consistent with what the separate programmes suggested.

SURPASS-2: type 2 diabetes

1,879 people with type 2 diabetes, a mean HbA1c of 8.28% and a mean weight of 93.7 kg, were randomised to tirzepatide 5, 10 or 15 mg or semaglutide 1 mg for 40 weeks. HbA1c fell 2.01, 2.24 and 2.30 percentage points on the three tirzepatide doses and 1.86 points on semaglutide. All three tirzepatide doses were statistically superior. Weight loss was greater by 1.9, 3.6 and 5.5 kg. Side effects were similar in kind and rate: nausea in 17 to 22% on tirzepatide and 18% on semaglutide, diarrhoea 13 to 16% against 12%, vomiting 6 to 10% against 8%. Serious adverse events were reported in 5 to 7% on tirzepatide and 3% on semaglutide.

The obvious criticism: 1 mg was the top semaglutide dose for diabetes at the time, but not the top dose that exists. Ozempic has since gone to 2 mg, and Wegovy is 2.4 mg. SURPASS-2 compared tirzepatide at up to 15 mg with semaglutide well below its weight dose.

What head-to-head does tell you

• On average, in these populations, tirzepatide produced more weight loss. Randomisation removes the differences between trial populations that make cross-trial comparisons unreliable.
• The size of the gap. About 6.5 percentage points of body weight over 72 weeks at the highest tolerated doses. For a 100 kg person, roughly 20 kg against 14 kg.
• Tolerability looks broadly similar. Neither trial showed a large difference in gastrointestinal side effects between the drugs.

What it does not tell you

• Which drug you will respond to better. The ranges overlap heavily. Some people lose more on semaglutide than the average person on tirzepatide. The trial cannot predict your response.
• Anything about heart, kidney or death outcomes. Neither trial was built or powered for that. Semaglutide has the SELECT result in people with heart disease. Tirzepatide's cardiovascular outcomes evidence is a separate question, covered on the safety studies page.
• Anything about the higher semaglutide dose. SURMOUNT-5 used 2.4 mg. The 7.2 mg dose in STEP UP gave -18.7% in its own trial, but has not been compared directly with tirzepatide in a published randomised trial.
• Anything about compounded versions, which were not used.
• Cost, access or what your insurer covers. See GLP-1 costs.

Reading a sponsor's head-to-head

Both trials were planned and paid for by the maker of tirzepatide, and both were open label, so participants knew which drug they were on. Neither fact invalidates the results: the trials were registered in advance, used objective primary endpoints (a weighed body, a blood test), and the result matched what the separate programmes showed. But the choice of comparator dose is the sponsor's, and in SURPASS-2 that choice favoured tirzepatide. A fair summary is that tirzepatide is the stronger drug for weight on average, and semaglutide has the longer record and the outcomes trials. For the brand-by-brand practical comparison, see Ozempic vs Wegovy vs Mounjaro vs Zepbound, and for every trial in one place, the master table.

Switching between them

People do move from one drug to the other, for cost, supply or response. The labels for both say not to combine them. Switching is the prescriber's call, including the starting dose on the new drug. Logging the date and dose of the switch, alongside weight and side effects, is what lets you and the prescriber see whether it worked.

Trials report averages. Your own result is a line on a chart: the dose and the date you changed it, your weight, the side effects that came with each step and, if you have them, your labs. Peptide AI keeps those on one timeline, and the dose log and titration schedule are free. The free GLP-1 tracker page explains what it records, or download the app.