18+ · Research use only
Semaglutide · Phase 3 · Completed
STEP 4
In STEP 4, a phase 3 trial of semaglutide in adults with BMI of at least 30 (or 27 or greater with at least 1 weight-related comorbidity) without diabetes, who reached the 2.4 mg maintenance dose during a 20-week run-in (n=803), mean body weight changed by -7.9% on continued 2.4 mg, weeks 20 to 68 over 68 weeks, against +6.9% on switched to placebo (treatment-policy estimand; Rubino D et al. JAMA 2021 (STEP 4)).
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Updated 24 September 2026
Results
Side effects reported
In STEP 4, discontinuation because of adverse events was 2.4% on continued 2.4 mg, weeks 20 to 68, against 2.2% on switched to placebo. The most frequently reported adverse events were gastrointestinal adverse events in 41.9% on continued 2.4 mg, weeks 20 to 68 against 26.1% on switched to placebo, diarrhoea in 14.4% on continued 2.4 mg, weeks 20 to 68 against 7.1% on switched to placebo, nausea in 14.0% on continued 2.4 mg, weeks 20 to 68 against 4.9% on switched to placebo and constipation in 11.6% on continued 2.4 mg, weeks 20 to 68 against 6.3% on switched to placebo.
| Event | Continued 2.4 mg, weeks 20 to 68 | Switched to placebo |
|---|---|---|
| Discontinuation for adverse events | 2.4% | 2.2% |
| Gastrointestinal adverse events | 41.9% | 26.1% |
| Diarrhoea | 14.4% | 7.1% |
| Nausea | 14.0% | 4.9% |
| Constipation | 11.6% | 6.3% |
| Vomiting | 10.3% | 3.0% |
Design
Trial design and sources
- Compound
- Semaglutide
- Phase
- 3
- Population
- Adults with BMI of at least 30 (or 27 or greater with at least 1 weight-related comorbidity) without diabetes, who reached the 2.4 mg maintenance dose during a 20-week run-in
- Participants randomised
- 803
- Duration
- 68 weeks
- Primary endpoint
- Percent change in body weight from week 20 to week 68
- Estimand
- treatment-policy
- Read out
- 1 April 2021
Withdrawal design: all participants took semaglutide for a 20-week run-in, then were randomised to continue or switch to placebo. The switch-to-placebo arm regained weight. The abstract gives gastrointestinal events as 49.1%; the results text and Table 3 give 41.9%.
Questions
STEP 4, answered
What did STEP 4 find?
In STEP 4, a phase 3 trial of semaglutide in adults with BMI of at least 30 (or 27 or greater with at least 1 weight-related comorbidity) without diabetes, who reached the 2.4 mg maintenance dose during a 20-week run-in (n=803), mean body weight changed by -7.9% on continued 2.4 mg, weeks 20 to 68 over 68 weeks, against +6.9% on switched to placebo (treatment-policy estimand; Rubino D et al. JAMA 2021 (STEP 4)).
What side effects were reported in STEP 4?
In STEP 4, discontinuation because of adverse events was 2.4% on continued 2.4 mg, weeks 20 to 68, against 2.2% on switched to placebo. The most frequently reported adverse events were gastrointestinal adverse events in 41.9% on continued 2.4 mg, weeks 20 to 68 against 26.1% on switched to placebo, diarrhoea in 14.4% on continued 2.4 mg, weeks 20 to 68 against 7.1% on switched to placebo, nausea in 14.0% on continued 2.4 mg, weeks 20 to 68 against 4.9% on switched to placebo and constipation in 11.6% on continued 2.4 mg, weeks 20 to 68 against 6.3% on switched to placebo.
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