Trial summary

SURPASS-2: tirzepatide against semaglutide

The first trial to put the two medications in the same room. It is quoted constantly as evidence about weight, and weight was not what it was built to measure.

Participants

1,879 randomized

Duration

40 weeks

Comparator

Semaglutide 1 mg once weekly

Published

New England Journal of Medicine, 2021

Registration

NCT03987919

PubMed

PMID 34170647

Who was in the trial

Adults with type 2 diabetes. Mean baseline glycated hemoglobin was 8.28%, mean age 56.6 years and mean weight 93.7 kg.

Everybody enrolled had type 2 diabetes, which is the single most important fact about how this trial is usually cited. The weight figures below were measured in that population, and the corpus’s own trials in people without diabetes report much larger reductions over longer periods. A reader without diabetes should not read these weight numbers as their own.

How it was run

Phase 3, open-label, 40 weeks. Participants were assigned 1:1:1:1 to tirzepatide 5 mg, 10 mg or 15 mg, or to semaglutide 1 mg, once weekly.

Change in glycated hemoglobin from baseline to week 40. The trial was designed to test noninferiority against semaglutide first.

The trial was open-label, meaning participants and investigators knew which medication was being given, and it compared against semaglutide at 1 mg — the dose licensed for type 2 diabetes, not the 2.4 mg dose used for weight. That choice was appropriate for a diabetes trial and it is exactly what makes the weight comparison here incomplete.

What it found

Glycated hemoglobin fell by 2.01, 2.24 and 2.30 percentage points on tirzepatide 5, 10 and 15 mg against 1.86 points on semaglutide 1 mg, over 40 weeks in 1,879 participants. Tirzepatide was noninferior and then superior at every dose; the differences against semaglutide were -0.15, -0.39 and -0.45 percentage points.

Weight was a secondary endpoint. Participants on tirzepatide lost more than those on semaglutide by an estimated 1.9 kg, 3.6 kg and 5.5 kg at 5, 10 and 15 mg. Those are differences between the two arms, not total weight lost, and they were measured in people with diabetes at 40 weeks.

What was reported about tolerability

The most common adverse events in both arms were gastrointestinal and primarily mild to moderate: nausea in 17 to 22% of the tirzepatide groups and 18% of the semaglutide group, diarrhea in 13 to 16% and 12%, vomiting in 6 to 10% and 8%. Serious adverse events were reported in 5 to 7% of tirzepatide participants and 3% of semaglutide participants.

Hypoglycemia below 54 mg per deciliter was reported in 0.6%, 0.2% and 1.7% of the tirzepatide groups and 0.4% of the semaglutide group. This is a report of what the trial recorded, not a safety comparison and not medical advice.

Reading this alongside the price index

Nothing in SURPASS-2 was a compounded preparation, and nothing in it was priced. If the question is which of the two medications produces more weight loss in people without diabetes, SURPASS-2 is the wrong trial to answer it with — the comparison page sets it beside the trial that was designed for that question.