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Semaglutide: group average over time
| Week | Treatment avg (kg) | Interval | Placebo avg |
|---|---|---|---|
| 68 | 85.1 | — | 97.6 |
Study population
Adults 18 years or older with BMI ≥30 kg/m², or BMI ≥27 kg/m² plus at least one weight-related comorbidity (hypertension, dyslipidaemia, obstructive sleep apnoea or cardiovascular disease), and a history of at least one unsuccessful dietary effort to lose weight. Excluded HbA1c ≥48 mmol/mol (6.5%) — i.e. diabetes — and a self-reported weight change over 5 kg within 90 days of screening. Randomized 2:1 to semaglutide 2.4 mg (1306) or placebo (655); 129 sites in 16 countries.
Sample size: 1961
Dose: Once-weekly subcutaneous semaglutide 2.4 mg (escalated from 0.25 mg through 0.5, 1.0 and 1.7 mg at 4-week intervals, maintenance dose reached at week 16) versus matching placebo, each as an adjunct to a reduced-calorie diet and increased physical activity.
Primary endpoint: Coprimary endpoints: percentage change in body weight from baseline to week 68, and the proportion achieving a body-weight reduction of at least 5%. The primary estimand assessed effects regardless of treatment discontinuation or rescue interventions (treatment-policy estimand).
Safety
- Nausea and diarrhea were the most common adverse events with semaglutide; they were typically transient and mild to moderate in severity and subsided with time (NEJM).
- More participants discontinued treatment because of gastrointestinal events on semaglutide than on placebo: 59 (4.5%) vs 5 (0.8%) (NEJM).
- Deaths during the trial: 1 in the semaglutide group and 1 in the placebo group (registry participant flow). The registry does not attribute a cause to either death.
- The registry posts serious adverse events by MedDRA 22 term under systematic assessment (149 terms listed); neither the abstract nor the registry summary supplies a single overall serious-adverse-event rate.
- Trial completed as planned: 1240 of 1306 semaglutide and 609 of 655 placebo participants finished; withdrawals by participant 26 vs 17 and lost to follow-up 39 vs 28 (registry participant flow).
Published abstract
Background: Obesity is a global health challenge with few pharmacologic options. Whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed.
Methods: In this double-blind trial, we enrolled 1961 adults with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or greater (≥27 in persons with ≥1 weight-related coexisting condition), who did not have diabetes, and randomly assigned them, in a 2:1 ratio, to 68 weeks of treatment with once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo, plus lifestyle intervention. The coprimary end points were the percentage change in body weight and weight reduction of at least 5%. The primary estimand (a precise description of the treatment effect reflecting the objective of the clinical trial) assessed effects regardless of treatment discontinuation or rescue interventions.
Results: The mean change in body weight from baseline to week 68 was -14.9% in the semaglutide group as compared with -2.4% with placebo, for an estimated treatment difference of -12.4 percentage points (95% confidence interval [CI], -13.4 to -11.5; P<0.001). More participants in the semaglutide group than in the placebo group achieved weight reductions of 5% or more (1047 participants [86.4%] vs. 182 [31.5%]), 10% or more (838 [69.1%] vs. 69 [12.0%]), and 15% or more (612 [50.5%] vs. 28 [4.9%]) at week 68 (P<0.001 for all three comparisons of odds). The change in body weight from baseline to week 68 was -15.3 kg in the semaglutide group as compared with -2.6 kg in the placebo group (estimated treatment difference, -12.7 kg; 95% CI, -13.7 to -11.7). Participants who received semaglutide had a greater improvement with respect to cardiometabolic risk factors and a greater increase in participant-reported physical functioning from baseline than those who received placebo. Nausea and diarrhea were the most common adverse events with semaglutide; they were typically transient and mild-to-moderate in severity and subsided with time. More participants in the semaglutide group than in the placebo group discontinued treatment owing to gastrointestinal events (59 [4.5%] vs. 5 [0.8%]).
Conclusions: In participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight. (Funded by Novo Nordisk; STEP 1 ClinicalTrials.gov number, NCT03548935).
Abstract reproduced verbatim via PubMed. © Massachusetts Medical Society.
Source: Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, McGowan BM, Rosenstock J, Tran MTD, Wadden TA, Wharton S, Yokote K, Zeuthen N, Kushner RF; STEP 1 Study Group. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021;384(11):989-1002. doi:10.1056/NEJMoa2032183. Epub 2021 Feb 10. PMID: 33567185. Read the paper (NCT03548935, published 2021-02-10) · Reviewed by Avi Shaw, MD on 2026-10-11
RetaRevolution · Study snapshot
-14.9% group average at week 68
Semaglutide · STEP 1: Effect and Safety of Semaglutide 2.4 mg Once-weekly in Subjects With Overweight or Obesity (NEJM 2021) · placebo -2.4%
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