STEP 1: trial summary, limitations and UK relevance

Key findings

STEP-1 established semaglutide 2.4 mg weekly as a substantially more effective weight-management therapy than placebo across 68 weeks in adults with overweight or obesity without diabetes. It set the foundational efficacy anchor for the Wegovy marketing authorisation. Weight-loss trajectories continued to increase throughout titration and into the maintenance phase — a pattern with implications for how long a course of therapy should run before assessing response. Body-composition and metabolic-parameter secondary endpoints improved alongside the primary weight endpoint. The published mean percent body-weight reduction with semaglutide was reported in NEJM 2021 (Wilding et al.); readers should consult the primary publication for exact figures. Cardiovascular outcomes were not addressed by STEP-1 — see SELECT for the CV benefit signal in overweight/obesity + established CVD.

Safety summary

GI adverse events (nausea, diarrhoea, constipation, vomiting) were the most common reported side effects, concentrated in the titration phase. Gallbladder-related events were reported more frequently with semaglutide than placebo.

Limitations

• 68-week duration cannot establish long-term safety or durability after discontinuation.
• Non-diabetic population — does not directly establish glycaemic outcomes.

UK relevance

Foundational evidence for the MHRA's licensing of semaglutide 2.4 mg (Wegovy) for chronic weight management in adults with obesity or overweight with comorbidities.