Once-Weekly Semaglutide in Adults with Overweight or Obesity
Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, McGowan BM, Rosenstock J, +6 more
New England Journal of Medicine (2021) · n=1961
Mean body-weight change at week 68 was -14.9% on semaglutide versus -2.4% on placebo, with 86.4% of treated participants achieving at least 5% weight loss — the trial that anchored the cultural moment around GLP-1 agonists for obesity.
This is the pivotal STEP 1 trial, the largest randomized placebo-controlled study of semaglutide for chronic weight management at the time of publication and the trial behind Wegovy's FDA approval for obesity. Investigators randomized 1,961 adults with BMI ≥30 (or ≥27 with at least one weight-related comorbidity), without diabetes, in a 2:1 ratio to once-weekly subcutaneous semaglutide 2.4 mg or placebo, plus lifestyle intervention, for 68 weeks. The primary endpoints were percentage change in body weight and the proportion of participants achieving ≥5% weight loss. At week 68, mean body weight changed by -14.9% on semaglutide versus -2.4% on placebo, a 12.4-percentage-point treatment difference. Achievement rates: 86.4% reached ≥5% loss on semaglutide vs 31.5% on placebo; 69.1% vs 12.0% reached ≥10%; 50.5% vs 4.9% reached ≥15%. Mean absolute weight change was -15.3 kg vs -2.6 kg. Cardiometabolic risk factors and physical functioning improved more on semaglutide. Nausea and diarrhea were the most common adverse events; 4.5% of semaglutide recipients discontinued for GI reasons versus 0.8% on placebo.
The trial was 68 weeks; durability beyond that point in this population is studied in the STEP 1 extension and STEP 4 trials, both of which show meaningful weight regain after discontinuation. The 2:1 randomization favoring semaglutide is unusual and slightly compresses the placebo arm's statistical power on secondary endpoints. The primary endpoint is body weight, not lean-mass-adjusted weight; published body-composition substudies with semaglutide vary widely on what fraction of weight loss is fat versus lean mass. The trial population was predominantly White (~75%) and excluded people with type 2 diabetes — both of which are known semaglutide indications. Industry sponsorship by Novo Nordisk is disclosed; the published analysis is consistent with the regulatory-grade primary outcome but should be read alongside the broader STEP program before drawing applied conclusions.