STEP-1

Background

By 2020 no GLP-1 receptor agonist had been evaluated in a dedicated Phase 3 weight-management programme at doses higher than those used for glycaemic control in type 2 diabetes. STEP-1 was designed as the pivotal placebo-controlled trial for once-weekly Semaglutide 2.4 mg in adults with overweight or obesity without diabetes. ^[1]

Study design

Randomised, double-blind, placebo-controlled parallel-group Phase 3 trial. Participants were randomly assigned 2:1 to once-weekly subcutaneous Semaglutide 2.4 mg or matching placebo for 68 weeks, followed by a 7-week off-treatment follow-up. Both arms received a structured lifestyle intervention.

Population

1,961 adults aged 18 years or older with a body-mass index of at least 30, or at least 27 accompanied by a weight-related coexisting condition (such as hypertension or dyslipidaemia), and without type 2 diabetes.

Intervention

Once-weekly subcutaneous Semaglutide, titrated over 16 weeks to a maintenance dose of 2.4 mg, plus a lifestyle intervention comprising reduced-calorie diet (500 kcal/day deficit) and 150 minutes/week of physical activity guidance.

Comparator

Matching placebo administered subcutaneously once weekly, plus the same lifestyle intervention.

Primary endpoints

Co-primary endpoints were percent change in body weight from baseline to week 68 and the proportion of participants achieving weight reduction of 5% or greater. Analyses used a treatment-policy estimand for participants regardless of treatment adherence.

Secondary endpoints

Confirmatory secondary endpoints included proportions achieving ≥10% and ≥15% weight reduction, change in waist circumference, systolic blood pressure, HbA1c, fasting plasma glucose, and patient-reported outcomes including SF-36 physical function and IWQOL-Lite-CT scores.

Key findings

• Mean change in body weight from baseline to week 68 was approximately −14.9% with Semaglutide 2.4 mg versus approximately −2.4% with placebo.
• A markedly greater proportion of participants achieved ≥5%, ≥10% and ≥15% weight reduction with Semaglutide than with placebo.
• Improvements were reported in waist circumference, systolic blood pressure, HbA1c and fasting glucose relative to placebo.
• Gastrointestinal adverse events (nausea, diarrhoea, vomiting, constipation) were the most common tolerability issues, predominantly during dose titration.

Mechanistic significance

• Supports the hypothesis that sustained GLP-1 receptor agonism modulates central appetite circuitry and gastric emptying in a manner sufficient to drive substantial body-weight reduction in humans without diabetes.
• Demonstrated the pharmacological ceiling of a mono-GLP-1 receptor agonist at a higher-than-glycaemic dose — subsequently used as the reference for dual and triple incretin agonist comparisons.

Limitations

Research context

STEP-1 is the anchor trial of the STEP programme and framed the subsequent large cardiovascular outcomes trial in obesity without diabetes (SELECT). Its magnitude of weight reduction became the reference against which dual (Tirzepatide, SURPASS/SURMOUNT) and triple (Retatrutide) incretin-agonist trial results are contextualised.