Once-weekly semaglutide 7·2 mg in adults with obesity (STEP UP): a randomised, controlled, phase 3b trial

Background

Once-weekly subcutaneous semaglutide 2·4 mg is approved for weight management in people with obesity and related complications; however, some individuals do not reach their therapeutic goals with this dose. We aimed to test the efficacy and safety of a higher dose of semaglutide (7·2 mg) in people with obesity.

Methods

STEP UP was a phase 3b, randomised, double-blind, placebo-controlled and active-controlled trial conducted across 95 hospitals, specialist clinics, and medical centres in 11 countries in adults with BMI 30 kg/m² or greater, without diabetes. Participants were randomly assigned (5:1:1) to receive once-weekly subcutaneous semaglutide 7·2 mg, 2·4 mg, or placebo, with a lifestyle intervention, for 72 weeks. Coprimary endpoints were percentage change in bodyweight and the proportion of participants with a bodyweight reduction of 5% or greater for semaglutide 7·2 mg versus placebo from baseline to week 72 (treatment policy estimand). Confirmatory secondary endpoints were percentage change in bodyweight with 7·2 mg versus 2·4 mg, change in waist circumference (cm), and proportion of participants with bodyweight reductions of 10% or greater, 15% or greater, 20% or greater, and 25% or greater versus placebo, and 20% or greater and 25% or greater versus 2·4 mg. Safety was assessed in all participants who received at least one dose of the trial product. This trial is registered with ClinicalTrials.gov (NCT05646706) and is now completed.

Findings

Between Jan 1, 2023, and Nov 26, 2024, 1407 participants were randomly assigned to semaglutide 7·2 mg (n=1005), semaglutide 2·4 mg (n=201), or placebo (n=201). 1037 (73·7%) of 1407 participants were female, the mean age was 47 (SD 12) years, mean bodyweight was 113·0 (24·1) kg, and mean BMI was 39·9 (7·1) kg/m². The mean change in bodyweight was greater with semaglutide 7·2 mg versus 2·4 mg (–18·7% [SE 0·4] vs –15·6% [0·7]; estimated treatment difference [ETD] –3·1% [95% CI –4·7 to –1·6]; p<0·0001) and with semaglutide 7·2 mg versus placebo (–18·7% [0·4] vs –3·9% [0·6]; –14·8% [–16·2 to –13·4]; p<0·0001). Participants in the semaglutide 7·2 mg group were more likely than those in the placebo group to reach bodyweight reductions of 5% or greater (odds ratio 12·1 [95% CI 8·3 to 17·6]; p<0·0001), 10% or greater (14·5 [9·6 to 21·9]; p<0·0001), 15% or greater (20·3 [11·2 to 36·8]; p<0·0001), 20% or greater (27·3 [10·9 to 68·0]; p<0·0001), and 25% or greater (127·4 [36·8 to 441·4]; p<0·0001); and more likely than those in the 2·4 mg group to reach bodyweight reductions of 20% or greater (1·8 [1·3 to 2·4]; p=0·0006) and 25% or greater (2·4 [1·6 to 3·5]; p<0·0001). Improvements in waist circumference were observed with semaglutide 7·2 mg versus placebo (ETD –11·7 cm [95% CI –13·0 to –10·4]; p<0·0001). Gastrointestinal adverse events were more common with semaglutide 7·2 mg (711 [70·8%] of 1004) versus 2·4 mg (123 [61·2%] of 201) or placebo (86 [42·8%] of 201), as was dysaesthesia (230 [22·9%], 12 [6·0%], and one [0·5%], respectively). Serious adverse events were reported by 68 (6·8%) of 1004 participants with semaglutide 7·2 mg, 22 (10·9%) of 201 with semaglutide 2·4 mg, and 11 (5·5%) of 201 with placebo.

Interpretation

Semaglutide 7·2 mg was superior to placebo and 2·4 mg for bodyweight reduction in adults with obesity, while retaining a favourable risk–benefit profile.

Funding

Novo Nordisk.

Translations

For the German and Greek translations of the abstract see Supplementary Materials section.