SURPASS-3

Background

Basal insulin remains a standard add-on option when oral glucose-lowering therapy is insufficient. SURPASS-3 was designed to compare Tirzepatide against a titrated basal insulin (insulin degludec) as add-on therapy in adults with type 2 diabetes on metformin ± SGLT2 inhibitor. ^[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, 10 mg or 15 mg once weekly or once-daily insulin degludec titrated to a fasting self-monitored blood glucose target, for 52 weeks alongside stable background therapy.

Population

1,444 adults with type 2 diabetes and HbA1c 7.0–10.5% on metformin (with or without an SGLT2 inhibitor).

Intervention

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

Comparator

Once-daily subcutaneous insulin degludec titrated by protocol.

Primary endpoints

Mean change in HbA1c from baseline to week 52.

Secondary endpoints

Change in body weight, proportions achieving HbA1c <7% and <5.7%, hypoglycaemia rates, fasting glucose, safety and tolerability.

Key findings

• Mean HbA1c reduction from baseline was approximately −1.93% (5 mg), −2.20% (10 mg) and −2.37% (15 mg) with Tirzepatide versus approximately −1.34% with insulin degludec.
• Body-weight change diverged sharply: weight reduction with Tirzepatide versus weight gain with insulin degludec.
• Rates of clinically significant hypoglycaemia were lower with Tirzepatide than with insulin degludec.
• Gastrointestinal adverse events were the dominant tolerability finding with Tirzepatide.

Mechanistic significance

• Illustrates the clinical distinction between glucose-dependent incretin action (Tirzepatide) and non–glucose-dependent basal insulin, particularly with respect to hypoglycaemia and body-weight trajectory.
• Supports the pharmacological rationale for dual GIP/GLP-1 receptor agonism as an alternative to basal insulin escalation in appropriate research populations.

Limitations

Research context

SURPASS-3 sits alongside SURPASS-4 (vs insulin glargine, high-CV-risk) and SURPASS-5 (add-on to basal insulin) as the SURPASS trials against or with basal insulin.