SURPASS-2

SURPASS-2 was the first trial to put tirzepatide directly against semaglutide, and it did so in type 2 diabetes rather than obesity. Adults with inadequately controlled type 2 diabetes on metformin were randomized to tirzepatide 5, 10 or 15 mg weekly, or to semaglutide 1 mg weekly — the standard Ozempic diabetes dose at the time. Frías and colleagues published the 40-week results in the New England Journal of Medicine in 2021.

On the primary endpoint, HbA1c, tirzepatide beat semaglutide at every dose. Estimated mean reductions were 2.01, 2.24 and 2.30 percentage points for tirzepatide 5, 10 and 15 mg, versus 1.86 for semaglutide. Tirzepatide was both noninferior and superior at all three doses, though the margin at 5 mg was small (0.15 percentage points).

Weight moved further apart. Tirzepatide produced greater reductions than semaglutide by an estimated 1.9 kg, 3.6 kg and 5.5 kg at the three doses respectively. Side effects were the familiar gastrointestinal set in both arms — nausea in 17–22% on tirzepatide and 18% on semaglutide, with similar patterns for diarrhea and vomiting.

The caveat that gets dropped when this trial is quoted: semaglutide was tested at 1 mg, not the 2 mg diabetes dose or the 2.4 mg weight-management dose that came later. A fairer weight comparison arrived with SURMOUNT-5, which ran both drugs at their maximum tolerated doses in obesity without diabetes and still favored tirzepatide, by about 6.5 percentage points.

Worth asking your clinician: whether your target is primarily glucose or primarily weight, since the two drugs separate more on one than the other; whether your insurance covers the diabetes-labeled or weight-labeled product; and what dose you can realistically tolerate. Our SURPASS-2 deep dive and diabetes head-to-head comparison go further.