The Head-to-Head, and What It Settles

This is the trial everyone wanted. Seven hundred and fifty-one adults with obesity and without diabetes, randomized to tirzepatide or semaglutide, each at the highest dose they could tolerate, for 72 weeks. Tirzepatide produced 20.2% weight loss against 13.7%.^[1] On weight, the question is settled. On several other questions this register has covered, the answer runs the other way.

Why this comparison is fair

Most claimed comparisons between these two drugs are not comparisons at all — they set one trial’s headline beside another’s, which measures the trials as much as the drugs. This is different. Same participants, same period, same protocol, randomized against each other.

It also avoids the criticism that sank an earlier comparison. Both arms ran to their own maximum tolerated dose: tirzepatide at 10 or 15 mg, semaglutide at 1.7 or 2.4 mg. Semaglutide 2.4 mg is its full weight-management dose, so nobody was held back. That is exactly the objection we raised about a different analysis, where tirzepatide’s full range was set against semaglutide at the 1 mg diabetes dose — a composite is only its components.

Both differences reached P<0.001. Gastrointestinal effects dominated in both arms, mostly mild to moderate, mostly during dose escalation.

The design flaw that is worth naming

This is unavoidable to a degree, since the two drugs titrate differently and blinding would require elaborate dummy injections. It is still the reason a 6.5 percentage point gap should be read as approximately right rather than precisely measured.

The trial was funded by Eli Lilly, which makes tirzepatide. That is normal for a phase 3b head-to-head and it is worth stating in a trial where the sponsor’s drug won.

What 'better' does not follow from

Tirzepatide removes more weight. Whether it is the better drug depends on which outcome you are buying, and on several of them this corpus has found a different answer — including from this very trial.

The drug that removes more weight is not the drug with the outcome evidence.

That is not a reason to prefer semaglutide either. It is a reason to notice that “which is better” contains a hidden clause — better at what — and that the honest answer changes depending on how it is filled in.

How to actually use this

• If the goal is the largest weight reduction, this trial answers it directly and in tirzepatide’s favor.
• If the goal is cardiovascular risk with established disease, semaglutide has outcome trials behind it that tirzepatide does not yet have.
• Tolerability is individual and not settled by a group mean. The drug you can stay on beats the drug you stop — and slower titration has randomized evidence behind it, in five clicks.
• Cost, coverage and supply decide this for most people more often than either trial does.

For each drug’s own record on its own terms, see the tirzepatide timeline and the semaglutide timeline.