18+ · Research Use Only · Not for Human Consumption

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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Results

STEP 4: mean percent change in body weight by armSTEP 4 treatment-policy estimandContinued 2.4 mg, weeks 20 to 68-7.9%Switched to placebo+6.9%
Mean percent change in body weight by arm, as each source reports it. Bars from different trials are not a head-to-head comparison: populations, durations and estimands differ.

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.

EventContinued 2.4 mg, weeks 20 to 68Switched to placebo
Discontinuation for adverse events2.4%2.2%
Gastrointestinal adverse events41.9%26.1%
Diarrhoea14.4%7.1%
Nausea14.0%4.9%
Constipation11.6%6.3%
Vomiting10.3%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%.

  • Rubino D et al. JAMA 2021 (STEP 4) open · checked 23 September 2026
  • ClinicalTrials.gov NCT03548987 open · checked 23 September 2026
  • Registry: NCT03548987

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.