SURPASS-5

Background

Adults with type 2 diabetes on basal insulin frequently remain above HbA1c targets. SURPASS-5 was designed to evaluate Tirzepatide as an add-on to titrated insulin glargine, addressing the basal-insulin-inadequate segment that SURPASS-3 and SURPASS-4 did not cover. ^[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, 10 or 15 mg or placebo, each administered subcutaneously once weekly for 40 weeks, all arms with titrated insulin glargine and stable metformin where applicable.

Population

475 adults with type 2 diabetes and HbA1c 7.0–10.5% on titrated insulin glargine ± metformin.

Intervention

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

Comparator

Matching placebo added to titrated insulin glargine.

Primary endpoints

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

Secondary endpoints

Change in body weight, insulin dose, hypoglycaemia rates, proportion achieving HbA1c <7% and <5.7%, and safety.

Key findings

• Mean HbA1c reduction was approximately −2.11% (5 mg), −2.24% (10 mg) and −2.34% (15 mg) with Tirzepatide versus approximately −0.86% with placebo.
• Body-weight reduction with Tirzepatide contrasted with modest weight gain in the placebo-plus-insulin arm.
• Basal insulin dose requirements were lower with Tirzepatide than with placebo.
• Gastrointestinal adverse events were the dominant tolerability finding.

Mechanistic significance

• Demonstrates additive glycaemic and body-weight effect of dual GIP/GLP-1 receptor agonism on top of a titrated basal insulin backbone.
• Supports the pharmacological hypothesis that incretin-mediated glucose-dependent insulin secretion and central appetite modulation act on axes distinct from exogenous basal insulin.

Limitations

Research context

SURPASS-5 completes the core SURPASS Phase 3 programme by covering the basal-insulin-inadequate segment and complements SURPASS-3 (vs basal insulin) and SURPASS-4 (elevated CV risk).