What the head-to-head actually compared
There is one direct randomised comparison, SURPASS-2. Over 40 weeks in adults with type 2 diabetes, tirzepatide beat semaglutide on both A1c and body weight at all three of its doses.
The detail that gets lost every time this is quoted: the comparator was semaglutide 1 mg. That is the diabetes dose. The weight-management dose is 2.4 mg. So SURPASS-2 is strong evidence that tirzepatide is more potent, and it is not a comparison of the two drugs at their weight-management ceilings. Nobody has run that trial.
What the indirect comparison suggests
In STEP 1, semaglutide 2.4 mg produced a mean reduction of about 15% over 68 weeks. In SURMOUNT-1, tirzepatide 15 mg produced about 20.9% over 72 weeks.
Those are different trials with different populations and different durations, so this is a suggestive comparison rather than a decisive one. But it points the same direction as the head-to-head, which is about as much confidence as indirect comparison ever earns.
Where the choice is actually made
- Outcomes evidence. Semaglutide has SELECT, a cardiovascular outcomes trial in 17,604 adults without diabetes showing around a 20% relative reduction in major adverse cardiovascular events. Tirzepatide's outcomes record is younger. If your reason for taking one of these is cardiovascular as much as metabolic, that difference is the whole argument.
- Tolerability, which is individual and not predictable in advance. The person who cannot tolerate one sometimes does fine on the other, and no test tells you which in advance.
- Contraception. Tirzepatide can reduce the effectiveness of oral contraceptives, with labelled advice to use a barrier method for four weeks after starting and after each dose increase. This applies to tirzepatide and not to semaglutide, and it is routinely missed.
- Sleep apnoea. Tirzepatide carries a specific indication for moderate to severe obstructive sleep apnoea with obesity, built on its own trial.
- An oral option exists for semaglutide and not for tirzepatide, which matters for people who will not inject.
- Cost and availability, which differ by route, by insurance plan and by month, and in practice decide this more often than any trial does.
What should not decide it
The gap between the two headline percentages is smaller than the gap between a drug you stay on and one you stop. Adherence, tolerability and whether you can still afford it in month fourteen will move your outcome more than five percentage points of trial average.
Both of these work. The interesting question is almost never which is stronger.
Sources
- Frías et al., SURPASS-2, New England Journal of Medicine, 2021
- Wilding et al., STEP 1, New England Journal of Medicine, 2021
- Jastreboff et al., SURMOUNT-1, New England Journal of Medicine, 2022
- Lincoff et al., SELECT, New England Journal of Medicine, 2023
- Mounjaro and Zepbound prescribing information, Eli Lilly