SURPASS-1

Background

Dual GIP/GLP-1 receptor agonism was hypothesised to widen the incretin response beyond GLP-1 mono-agonism. SURPASS-1 was the first Phase 3 monotherapy trial for Tirzepatide and the first Phase 3 monotherapy trial in the dual-agonist class. ^[1]

Study design

Randomised, double-blind, placebo-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 matching placebo, each administered subcutaneously once weekly for 40 weeks.

Population

478 adults with type 2 diabetes and inadequate glycaemic control (HbA1c 7.0–9.5%) on diet and exercise alone, without concomitant glucose-lowering medication.

Intervention

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

Comparator

Matching placebo administered subcutaneously once weekly.

Primary endpoints

Mean change in HbA1c from baseline to week 40 (each Tirzepatide dose versus placebo).

Secondary endpoints

Change in body weight, proportion achieving HbA1c targets (<7%, <6.5%, <5.7%), fasting glucose, waist circumference and safety.

Key findings

• Mean HbA1c reduction from baseline was approximately −1.87% (5 mg), −1.89% (10 mg) and −2.07% (15 mg) with Tirzepatide versus +0.04% with placebo.
• Mean body-weight reduction was approximately −7.0 kg (5 mg), −7.8 kg (10 mg) and −9.5 kg (15 mg) with Tirzepatide versus −0.7 kg with placebo.
• The majority of Tirzepatide-treated participants achieved HbA1c <7% and a substantial proportion achieved <5.7%.
• Gastrointestinal adverse events (nausea, diarrhoea, vomiting) were the most common tolerability finding, predominantly during titration.

Mechanistic significance

• Consistent with the hypothesis that GIPR co-agonism broadens the incretin response and augments GLP-1R–mediated effects on glycaemic control and body weight.
• Established a monotherapy dose-response reference for subsequent SURPASS and SURMOUNT trials.

Limitations

Research context

SURPASS-1 anchors the SURPASS programme and framed subsequent active-controlled trials (SURPASS-2 against Semaglutide, SURPASS-3 against insulin degludec, SURPASS-4 against insulin glargine, SURPASS-5 as add-on to basal insulin).