Two randomized trials have put tirzepatide and semaglutide side by side. In both, tirzepatide produced more weight loss. The size of that gap depends on who was in the trial and which semaglutide dose they got. Both trials were open-label, and both were paid for by the company that makes tirzepatide.
Both drugs are peptides, short chains of amino acids made to act like gut hormones. If that term is new, the plain version is in what peptides are. Semaglutide acts on one receptor, GLP-1. Tirzepatide acts on two, GLP-1 and GIP.
SURMOUNT-5: the obesity trial
SURMOUNT-5 enrolled 751 adults with obesity who did not have type 2 diabetes [1]. They were randomized 1:1 to the highest dose they could tolerate of either drug. For tirzepatide that meant 10 mg or 15 mg a week. For semaglutide it meant 1.7 mg or 2.4 mg a week. Treatment lasted 72 weeks.
The mean weight change was −20.2% on tirzepatide (95% CI, −21.4 to −19.1) and −13.7% on semaglutide (95% CI, −14.9 to −12.6). Waist circumference fell by 18.4 cm against 13.0 cm. People on tirzepatide were also more likely to reach each of the 10%, 15%, 20% and 25% weight-loss thresholds.
The authors report that stomach and bowel symptoms were the most common adverse events in both groups. Most were mild to moderate and came during dose escalation. The abstract does not give per-drug rates for these events, so none are quoted here.
SURPASS-2: the diabetes trial
SURPASS-2 randomized 1,879 adults with type 2 diabetes to tirzepatide 5, 10 or 15 mg, or semaglutide 1 mg, once weekly for 40 weeks [2]. Semaglutide 1 mg is a diabetes dose. It is lower than the 2.4 mg used for weight management, which matters for the weight results.
The primary outcome was HbA1c, a three-month blood sugar average. It fell by 2.01, 2.24 and 2.30 percentage points on the three tirzepatide doses, against 1.86 on semaglutide. Every tirzepatide dose met the trial’s tests for noninferiority and superiority.
Weight fell more on tirzepatide too. The estimated extra loss against semaglutide was 1.9 kg, 3.6 kg and 5.5 kg for the 5, 10 and 15 mg doses.
Side effects were similar in kind. Nausea was reported by 17 to 22% on tirzepatide and 18% on semaglutide. Diarrhea was 13 to 16% against 12%, and vomiting 6 to 10% against 8%. Serious adverse events were reported in 5 to 7% on tirzepatide and 3% on semaglutide.
Blood sugar in people without diabetes
A post hoc analysis looked at the 425 SURMOUNT-5 participants who had prediabetes at the start [3]. By week 72, 89.9% of those on tirzepatide had returned to normal blood sugar, against 76.2% on semaglutide. HbA1c fell 0.60% against 0.48%.
Post hoc means the question was asked after the trial ended. It can suggest a difference but was not what the trial was designed to test. It is also sponsor-funded, like the main trial.
What the trials do not answer
Neither trial compared heart attacks, strokes or deaths. Neither ran past 72 weeks. Neither compared the drugs at the same price, or in compounded form. The results apply to the branded doses used in the trials, given with dose escalation.
The trials also tell you nothing about the many peptides sold for weight loss outside this pair. That evidence is much thinner, and what exists beyond these two drugs is covered separately. For how this site reads trial numbers, see the methodology.