STEP-4

Background

Sustained weight loss requires either indefinite pharmacotherapy or durable non-pharmacological change. STEP-4 was designed to characterise weight-loss maintenance and post-withdrawal weight regain with Semaglutide 2.4 mg, a question left open by STEP-1 through STEP-3. ^[1]

Study design

Two-part Phase 3 trial. All participants received once-weekly subcutaneous Semaglutide 2.4 mg for 20 weeks (open-label lead-in with dose titration). Responders tolerating the maintenance dose were then randomised 2:1 to continue Semaglutide 2.4 mg or switch to matching placebo for a further 48 weeks, both arms with continued lifestyle intervention.

Population

803 adults with a body-mass index of at least 30, or at least 27 with a weight-related coexisting condition, without diabetes, who completed the 20-week run-in and tolerated the 2.4 mg maintenance dose.

Intervention

Continuation of once-weekly subcutaneous Semaglutide 2.4 mg for 48 weeks post-randomisation plus lifestyle intervention.

Comparator

Switch to matching placebo once weekly for 48 weeks plus lifestyle intervention.

Primary endpoints

Percent change in body weight from randomisation (week 20) to week 68.

Secondary endpoints

Change in waist circumference, systolic blood pressure, HbA1c, patient-reported outcomes, and proportions maintaining ≥5%, ≥10% and ≥15% weight reduction from baseline.

Key findings

• Participants continuing Semaglutide achieved further weight loss during the randomised period; participants switched to placebo regained a substantial fraction of run-in weight loss.
• The between-group difference at week 68 was approximately 14 percentage points of body weight, favouring continued Semaglutide.
• Cardiometabolic parameters that improved during the run-in returned toward baseline in the placebo-switch arm.

Mechanistic significance

• Consistent with GLP-1 receptor agonist mechanism as an ongoing pharmacological modulator of appetite rather than a driver of durable neuro-behavioural change persisting after withdrawal.
• Frames long-term dosing considerations as a central research question, contextualising STEP-5 and SELECT.

Limitations

Research context

STEP-4 is the canonical maintenance/withdrawal trial for Semaglutide 2.4 mg. It informs interpretation of long-term trials (STEP-5) and cardiovascular outcomes trials (SELECT) and shapes the research question of chronic incretin therapy across the incretin agonist class.