SURPASS-2

Background

Semaglutide 1 mg once weekly was, at the time, a leading GLP-1 receptor agonist for glycaemic control in type 2 diabetes. SURPASS-2 was designed as the direct randomised head-to-head comparison of Tirzepatide with Semaglutide 1 mg on background metformin. ^[1]

Study design

Randomised, open-label, active-controlled, four-arm parallel-group Phase 3 trial. Participants were randomised 1:1:1:1 to Tirzepatide 5 mg, Tirzepatide 10 mg, Tirzepatide 15 mg or Semaglutide 1 mg, each administered subcutaneously once weekly for 40 weeks alongside stable metformin.

Population

1,879 adults with type 2 diabetes and HbA1c 7.0–10.5% on metformin (≥1500 mg/day).

Intervention

Once-weekly subcutaneous Tirzepatide titrated to 5, 10 or 15 mg.

Comparator

Once-weekly subcutaneous Semaglutide titrated to 1 mg.

Primary endpoints

Mean change in HbA1c from baseline to week 40, tested for non-inferiority and superiority of each Tirzepatide dose vs Semaglutide 1 mg.

Secondary endpoints

Body-weight reduction, proportions achieving HbA1c targets (<7%, <5.7%), fasting glucose, insulin resistance markers, safety and tolerability.

Key findings

• Mean HbA1c reduction from baseline was approximately −2.01% (5 mg), −2.24% (10 mg) and −2.30% (15 mg) with Tirzepatide versus approximately −1.86% with Semaglutide 1 mg.
• All three Tirzepatide doses met non-inferiority and superiority criteria vs Semaglutide 1 mg for HbA1c reduction.
• Mean body-weight reduction was approximately −7.6 kg (5 mg), −9.3 kg (10 mg) and −11.2 kg (15 mg) with Tirzepatide versus approximately −5.7 kg with Semaglutide 1 mg.
• Gastrointestinal adverse events were the dominant tolerability finding across both compounds, predominantly during dose titration.

Mechanistic significance

• Consistent with the hypothesis that dual GIP/GLP-1 receptor agonism produces a broader incretin response than mono-GLP-1 receptor agonism.
• Provides the first direct randomised comparison against Semaglutide and remains a reference dataset for subsequent triple-agonist (Retatrutide) contextualisation.

Limitations

Research context

SURPASS-2 is the anchor head-to-head trial for Tirzepatide vs Semaglutide in type 2 diabetes and is the reference used across the incretin literature when contextualising later dual and triple-agonist trials.