STEP-2

Background

STEP-1 established the pivotal placebo-controlled evidence for Semaglutide 2.4 mg in adults without diabetes. STEP-2 was designed to evaluate the same regimen in adults with overweight or obesity and inadequately controlled type 2 diabetes, and to isolate the incremental effect of 2.4 mg over the licensed 1.0 mg glycaemic dose. ^[1]

Study design

Randomised, double-blind, placebo-controlled, three-arm parallel-group Phase 3 trial. Participants were randomised 1:1:1 to Semaglutide 2.4 mg, Semaglutide 1.0 mg or matching placebo, each administered subcutaneously once weekly for 68 weeks, alongside a lifestyle intervention.

Population

1,210 adults with a body-mass index of at least 27, type 2 diabetes and HbA1c 7–10%, treated with diet and exercise alone or with up to three oral glucose-lowering agents.

Intervention

Once-weekly subcutaneous Semaglutide titrated to a maintenance dose of 2.4 mg, plus a lifestyle intervention.

Comparator

Semaglutide 1.0 mg once weekly (active reference to the licensed glycaemic dose) and matching placebo once weekly, both with the same lifestyle intervention.

Primary endpoints

Percent change in body weight from baseline to week 68 (Semaglutide 2.4 mg versus placebo).

Secondary endpoints

Proportions achieving ≥5% and ≥10% weight reduction, change in HbA1c, fasting plasma glucose, waist circumference, systolic blood pressure and patient-reported outcomes.

Key findings

• Semaglutide 2.4 mg produced approximately −9.6% mean weight change from baseline to week 68 versus approximately −3.4% with placebo.
• Semaglutide 1.0 mg produced intermediate weight change and comparable glycaemic effect to previously reported SUSTAIN trials.
• HbA1c reductions with both Semaglutide doses were substantially greater than placebo.
• Gastrointestinal adverse events were the most common tolerability findings and predominated during dose titration.

Mechanistic significance

• Demonstrates that GLP-1 receptor agonist–mediated weight change is preserved but attenuated in the type 2 diabetes population relative to non-diabetic adults, consistent with observations across the incretin literature.
• Separates the dose-response contribution of Semaglutide above the licensed glycaemic dose.

Limitations

Research context

STEP-2 sits between STEP-1 (obesity without diabetes) and the SURPASS programme (which used Tirzepatide in type 2 diabetes) as the anchor Semaglutide 2.4 mg dataset in the T2D-obesity intersection.