SURPASS-2 Trial Summary: Tirzepatide vs Semaglutide in T2DM

Design

Open-label, randomized, phase 3 trial enrolling 1,879 adults with type 2 diabetes inadequately controlled on metformin alone (baseline HbA1c 7.0-10.5%). Participants were randomized 1:1:1:1 to once-weekly tirzepatide at 5 mg, 10 mg, or 15 mg, or once-weekly semaglutide 1 mg (the maximum approved dose for diabetes at the time of study). The semaglutide arm served as an active comparator rather than a placebo control, making this the first head-to-head trial of a dual GIP/GLP-1 receptor agonist against the established GLP-1 receptor agonist market leader. Treatment duration was 40 weeks, with semaglutide titrated per its approved label schedule and tirzepatide escalated from 2.5 mg through the target dose over 4-week intervals.

Primary result

All three tirzepatide doses demonstrated superior HbA1c reduction compared with semaglutide 1 mg. Mean HbA1c reductions were -2.01% (tirzepatide 5 mg), -2.24% (tirzepatide 10 mg), and -2.30% (tirzepatide 15 mg) versus -1.86% (semaglutide 1 mg). The estimated treatment differences versus semaglutide were -0.15 percentage points for the 5 mg dose, -0.39 for the 10 mg dose, and -0.45 for the 15 mg dose. Non-inferiority and superiority were demonstrated for all three tirzepatide doses against semaglutide for HbA1c reduction.

Secondary outcomes

Weight loss was substantially greater with tirzepatide across all doses: -7.6 kg (5 mg), -9.3 kg (10 mg), and -11.2 kg (15 mg) versus -5.7 kg (semaglutide 1 mg). The percentage of patients achieving HbA1c below 7.0% was 82-92% across tirzepatide doses versus 79% with semaglutide. The proportion achieving HbA1c below 5.7% (the normal range) was 27-46% with tirzepatide versus 19% with semaglutide — a notable finding suggesting that tirzepatide enables near-normalization of glycemia in a substantial proportion of patients with established T2DM. Fasting serum insulin and HOMA-IR (a measure of insulin resistance) improved to a greater degree with tirzepatide, consistent with the hypothesis that dual GIP/GLP-1 agonism improves insulin sensitivity through mechanisms beyond weight loss alone.

Adverse events

Gastrointestinal adverse events were the most common with both treatments. Nausea occurred in 17-22% of tirzepatide-treated participants versus 18% of semaglutide-treated participants. Diarrhea rates were 13-16% versus 12%, and vomiting 6-10% versus 8%. The GI adverse event profile was broadly comparable between the two treatments, though tirzepatide 15 mg had numerically higher rates of nausea and vomiting than semaglutide. Discontinuation due to adverse events was 3-7% across tirzepatide doses versus 4% with semaglutide. Hypoglycemia was infrequent in all groups (below 1% clinically significant hypoglycemia), consistent with the glucose-dependent mechanism of both agents.

Interpretation

SURPASS-2 established tirzepatide as the first incretin-based therapy to demonstrate superiority over semaglutide 1 mg in both glycemic control and weight loss. The dual GIP/GLP-1 mechanism appears to provide additive metabolic benefits beyond GLP-1 receptor agonism alone. The magnitude of HbA1c reduction with tirzepatide 10 mg and 15 mg — bringing nearly half of treated patients into the normal glycemic range — represented a new benchmark for injectable diabetes therapy. The trial's open-label design is a limitation (participants knew which drug they received), and the semaglutide comparator was 1 mg rather than the higher 2 mg dose that would later be studied. These results contributed to FDA approval of tirzepatide (Mounjaro) for type 2 diabetes in May 2022.