Semaglutide for obesity: four STEPs forward, but more to come

Semaglutide 2·4 mg once weekly, an anti-obesity medication now submitted to regulators across the USA and Europe, is generating much excitement and attention about the amount of weight loss it produced in the phase 3 studies. Five phase 3 STEP (Semaglutide Treatment Effect in People with obesity) trials have now been completed, 1 Kushner RF Calanna S Davies M et al. Semaglutide 2.4 mg for the treatment of obesity: key elements of the step trials 1 to 5. Obesity (Silver Spring). 2020; 28: 1050-1061 Crossref PubMed Scopus (36) Google Scholar and four have been published. 2 Wilding JPH Batterham RL Calanna S et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021; 384: 989 Crossref PubMed Scopus (120) Google Scholar , 3 Davies M Færch L Kleist Jeppesen O et al. Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomized, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet. 2021; 397: 971-984 Summary Full Text Full Text PDF PubMed Scopus (27) Google Scholar , 4 Wadden TA Bailey TS Billings LK et al. Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: the STEP 3 randomized clinical trial. JAMA. 2021; (published online Feb 24.)https://doi.org/10.1001/jama.2021.1831 Crossref Scopus (35) Google Scholar , 5 Rubino D Abrahamsson N Davies M et al. Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: the STEP 4 randomized clinical trial. JAMA. 2021; (published online March 23.)https://doi.org/10.1001/jama.2021.3224 Crossref Scopus (19) Google Scholar Reasons for the enthusiastic reception of these findings relate primarily to weight loss efficacy, but within the context of confidence in the safety profile of semaglutide given the wide experience with this molecule and drug class (ie, GLP-1 receptor agonists). The table describes the weight loss observed with semaglutide in the first four published phase 3 studies and their characteristics. TableCharacteristics of four published phase 3 trials of semaglutide 2·4 mg weekly for obesity STEP 1 (Wilding et al, 2021)2 Wilding JPH Batterham RL Calanna S et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021; 384: 989 Crossref PubMed Scopus (120) Google Scholar STEP 2 (Davies et al, 2021)3 Davies M Færch L Kleist Jeppesen O et al. Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomized, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet. 2021; 397: 971-984 Summary Full Text Full Text PDF PubMed Scopus (27) Google Scholar STEP 3 (Wadden et al, 2021)4 Wadden TA Bailey TS Billings LK et al. Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: the STEP 3 randomized clinical trial. JAMA. 2021; (published online Feb 24.)https://doi.org/10.1001/jama.2021.1831 Crossref Scopus (35) Google Scholar STEP 4 (Rubino et al, 2021)5 Rubino D Abrahamsson N Davies M et al. Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: the STEP 4 randomized clinical trial. JAMA. 2021; (published online March 23.)https://doi.org/10.1001/jama.2021.3224 Crossref Scopus (19) Google Scholar Population 1961 adults with BMI >30 kg/m2 or >27 kg/m2 with >1 weight-related comorbidity 1595 adults with BMI >27 kg/m2 with type 2 diabetes 611 adults with BMI >30 kg/m2 or >27 kg/m2 with >1 weight-related comorbidity 902 adults with BMI >30 kg/m2 or >27 kg/m2 with >1 weight-related comorbidity entered 20-week run-in; 806 who reached 2·4 mg dose semaglutide entered randomisation Randomisation scheme Randomised 2:1 to semaglutide 2·4 mg vs placebo Randomised 1:1:1 to semaglutide 2·4 mg vs semaglutide 1·0 mg vs placebo Randomised 2:1 to semaglutide 2·4 mg vs placebo Randomised 2:1 to continued semaglutide 2·4 mg vs placebo Background treatment Both groups received lifestyle intervention All groups received lifestyle intervention Both groups received low-calorie diet for 8 weeks and intensive behavioural therapy (ie, 30 counselling visits) Both groups received lifestyle intervention Mean change in bodyweight at week 68 Semaglutide 2·4 mg −14·9% −9·6% * Mean change in bodyweight at week 68 was −6·99% for semaglutide 1·0 mg weekly. −16·0% −7·9% from week 20; −17·4% from baseline Placebo −2·4% −3·4% −5·7% +6·9% from week 20; −5·9% from baseline Proportion of participants with >5% weight loss at week 68 Semaglutide 2·4 mg 86·4% 68·8% 86·6% 88·7% Placebo 31·5% 28·5% 47·6% 47·6% * Mean change in bodyweight at week 68 was −6·99% for semaglutide 1·0 mg weekly. Open table in a new tab