STEP-5

Background

Weight regain typically follows initial pharmacological or behavioural weight loss. STEP-5 was designed to characterise the durability of Semaglutide 2.4 mg over two years — approximately twice the duration of the pivotal STEP-1 trial. ^[1]

Study design

Randomised, double-blind, placebo-controlled parallel-group Phase 3 trial. Participants were randomly assigned 1:1 to once-weekly subcutaneous Semaglutide 2.4 mg or matching placebo for 104 weeks, both plus lifestyle intervention.

Population

304 adults with a body-mass index of at least 30, or at least 27 with a weight-related coexisting condition, without diabetes.

Intervention

Once-weekly subcutaneous Semaglutide titrated to 2.4 mg for 104 weeks plus lifestyle intervention.

Comparator

Matching placebo plus the same lifestyle intervention.

Primary endpoints

Co-primary endpoints were percent change in body weight from baseline to week 104 and the proportion achieving ≥5% weight reduction.

Secondary endpoints

Proportions achieving ≥10%, ≥15% and ≥20% weight reduction; change in waist circumference, systolic blood pressure, HbA1c, glycaemic transition status and patient-reported outcomes.

Key findings

• Mean change in body weight from baseline to week 104 was approximately −15.2% with Semaglutide 2.4 mg versus approximately −2.6% with placebo.
• Weight-loss trajectories appeared to reach a plateau by approximately week 60 and were maintained through week 104 with continued treatment.
• Transition from prediabetes to normoglycaemia was more frequent with Semaglutide than with placebo.

Mechanistic significance

• Supports the interpretation that GLP-1 receptor agonist–mediated weight change reaches a steady state maintained by continued dosing, consistent with STEP-4 maintenance dynamics.
• Provides two-year durability evidence relevant to the design of long-term cardiometabolic trials such as SELECT.

Limitations

Research context

STEP-5 is the longest-duration randomised placebo-controlled Semaglutide 2.4 mg weight-management trial in the public literature. It anchors durability discussion across the incretin agonist class and complements STEP-4 withdrawal data.