STEP-3

Background

Lifestyle intervention intensity affects the observed pharmacological effect of weight-management drugs. STEP-3 was designed to quantify the incremental effect of Semaglutide 2.4 mg on top of a demanding, high-contact behavioural programme with a low-calorie meal-replacement run-in. ^[1]

Study design

Randomised, double-blind, placebo-controlled parallel-group Phase 3 trial. Participants were randomised 2:1 to Semaglutide 2.4 mg or matching placebo, both plus intensive behavioural therapy (30 counselling visits) and an initial 8-week 1,000–1,200 kcal/day meal-replacement diet transitioning to a hypocaloric diet.

Population

611 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, plus IBT and low-calorie diet.

Comparator

Matching placebo, plus the same IBT and low-calorie diet.

Primary endpoints

Percent change in body weight from baseline to week 68 and proportion of participants achieving ≥5% weight reduction.

Secondary endpoints

Proportions achieving ≥10% and ≥15% weight reduction; change in waist circumference, systolic blood pressure, HbA1c, fasting plasma glucose and patient-reported outcomes.

Key findings

• Mean change in body weight was approximately −16.0% with Semaglutide 2.4 mg versus approximately −5.7% with placebo at week 68.
• The placebo-plus-IBT arm achieved larger weight change than placebo arms in trials without intensive lifestyle intervention, isolating the added pharmacological effect of Semaglutide.
• Gastrointestinal adverse events remained the dominant tolerability finding.

Mechanistic significance

• Provides evidence that pharmacological suppression of appetite via GLP-1 receptor agonism is additive to, rather than replaced by, intensive behavioural intervention.
• Illustrates the ceiling of behavioural intervention alone in short-to-medium-term weight-management trials.

Limitations

Research context

STEP-3 complements STEP-1 (routine lifestyle counselling) and STEP-5 (long-term extension) by testing the pharmacological effect at the top of the behavioural-intervention spectrum.