Once-weekly semaglutide 7·2 mg in adults with obesity and type 2 diabetes (STEP UP T2D): a randomised, controlled, phase 3b trial.

BACKGROUND: Semaglutide 2·4 mg is approved for weight management in adults with obesity or overweight in the presence of at least one obesity-related complication; however, many people with obesity and type 2 diabetes do not reach their bodyweight reduction goals with this dose. We aimed to investigate the efficacy and safety of a new 7·2 mg maintenance dose of once-weekly subcutaneous semaglutide in people with obesity and type 2 diabetes. METHODS: STEP UP T2D was a randomised, phase 3b, double-blind controlled, three-arm, parallel-group trial conducted at 68 hospitals, specialist clinics, and medical centres in Bulgaria, Canada, Hungary, Poland, Portugal, Slovakia, South Africa, and the USA. Adults aged 18 years or older (BMI ≥30·0 kg/m, HbA7·0-10·0% [53-86 mmol/mol]) were randomly assigned (3:1:1) to receive once-weekly subcutaneous semaglutide 7·2 mg, 2·4 mg, or placebo, alongside a lifestyle intervention, for 72 weeks. Coprimary endpoints were the percentage change in bodyweight and the proportion of participants reaching a bodyweight reduction of 5% or greater with semaglutide 7·2 mg versus placebo. Confirmatory secondary endpoints were the proportion of participants reaching a bodyweight reduction of 10% or greater, 15% or greater, and 20% or greater, and changes in waist circumference (cm) and HbA(%) with semaglutide 7·2 mg versus placebo. Efficacy was assessed in all randomly assigned participants, and safety was assessed in all randomly assigned participants who received at least one dose of the trial product. This trial is registered with ClinicalTrials.gov (NCT05649137) and is now closed and completed. FINDINGS: Between Jan 4 and May 4, 2023, 512 participants were randomly assigned to receive semaglutide 7·2 mg (n=307), semaglutide 2·4 mg (n=103), or placebo (n=102). 265 (51·8%) of 512 participants were female, the mean age was 56 (SD 10) years, mean bodyweight was 110·1 (22·9) kg, mean BMI was 38·6 (7·1) kg/m, and mean HbAwas 8·1% (0·9). Compared with placebo, semaglutide 7·2 mg led to greater reductions in mean bodyweight (-13·2% vs -3·9%; estimated treatment difference [ETD] -9·3% [95% CI -11·0 to -7·7]; p<0·0001); more participants reaching bodyweight reductions of 5% or greater (odds ratio 10·0 [95% CI 6·0 to 16·9]; p<0·0001), 10% or greater (11·3 [5·9 to 21·4]; p<0·0001), 15% or greater (8·1 [3·7 to 17·7]; p<0·0001), and 20% or greater (12·3 [3·0 to 51·0]; p=0·0006); and reduced waist circumference (ETD -6·5 cm [95% CI -9·0 to -4·1]; p<0·0001) and HbA(ETD -1·5% [95% CI -1·8 to -1·2]; p<0·0001). Level 2-3 hypoglycaemia risk was low and comparable between semaglutide doses and placebo. Gastrointestinal events were reported by 163 (53·1%) of 307 participants with semaglutide 7·2 mg, 53 (51·5%) of 103 participants with semaglutide 2·4 mg, 26 (25·5%) of 102 participants with placebo; and serious adverse events were reported by 28 (9·1%) participants with semaglutide 7·2 mg, nine (8·7%) participants with semaglutide 2·4 mg, and nine (8·8%) participants with placebo. Dysaesthesia was more common with semaglutide 7·2 mg (58 [18·9%] of 307) versus 2·4 mg (five [4·9%] of 103) and placebo (none). INTERPRETATION: Among people with obesity and type 2 diabetes, semaglutide 7·2 mg was superior to placebo in reducing bodyweight, waist circumference, and HbA. Safety and tolerability were comparable between semaglutide 7·2 mg and 2·4 mg, except for the imbalance in dysaesthesia. FUNDING: Novo Nordisk. TRANSLATIONS: For the Bulgarian, Hungarian and Polish translations of the abstract see Supplementary Materials section.