Semaglutide 2.4 mg produced 14.9% average weight loss in 68-week trial

Adults with overweight or obesity who took semaglutide 2.4 mg once a week lost an average of 14.9% of their body weight over 68 weeks, compared with 2.4% for those taking a placebo, according to results published in the New England Journal of Medicine ^[1].

The trial, called STEP 1, enrolled 1,961 adults without diabetes at 129 sites in 16 countries across Asia, Europe, North America and South America. Participants had to have a body-mass index of 30 or higher, or 27 or higher with at least one weight-related condition such as high blood pressure, abnormal cholesterol, obstructive sleep apnea or cardiovascular disease. People with diabetes, a glycated hemoglobin level of 6.5% or higher, a history of chronic pancreatitis, previous obesity surgery or recent use of a weight-loss drug could not take part ^[1].

Everyone in the trial also received lifestyle support: counseling every four weeks, a diet designed for a 500-calorie daily deficit and a goal of 150 minutes of physical activity a week ^[1]. Participants were assigned in a 2-to-1 ratio to semaglutide or placebo and treated for 68 weeks, followed by a seven-week period with no drug and no lifestyle intervention. Semaglutide began at 0.25 mg weekly for four weeks and was raised every four weeks to reach 2.4 mg by week 16; lower maintenance doses were allowed if side effects were unacceptable ^[1]. At the time of the trial, the paper notes, semaglutide was approved at doses up to 1 mg weekly for type 2 diabetes and for lowering cardiovascular risk in people with type 2 diabetes and cardiovascular disease ^[1].

The average weight change was −14.9% with semaglutide versus −2.4% with placebo, an estimated treatment difference of −12.4 percentage points (95% confidence interval, −13.4 to −11.5; P<0.001). Measured in kilograms, the change was −15.3 kg versus −2.6 kg, a difference of −12.7 kg (95% CI, −13.7 to −11.7) ^[1].

Those averages covered a wide range of individual results. Of the 1,306 people assigned to semaglutide, 1,047 (86.4%) lost at least 5% of their body weight, 838 (69.1%) lost at least 10% and 612 (50.5%) lost at least 15%. In the placebo group of 655, the corresponding counts were 182 (31.5%), 69 (12.0%) and 28 (4.9%) (P<0.001 for all three comparisons) ^[1].

Nausea and diarrhea were the most common side effects with semaglutide and were typically short-lived and mild to moderate, subsiding over time. More people stopped treatment because of gastrointestinal events in the semaglutide group — 59, or 4.5% — than in the placebo group — 5, or 0.8% ^[1]. Overall, 94.3% of participants completed the trial, 91.2% had a body-weight measurement at week 68 and 81.1% adhered to treatment. Seven people in the semaglutide group and 13 in the placebo group received rescue interventions such as bariatric surgery or another weight-loss medication ^[1]. Participants on semaglutide also had greater improvement in cardiometabolic risk factors and in self-reported physical functioning ^[1].

Why it matters for patients

The trial describes what a GLP-1 medicine at a weight-management dose did over roughly 16 months in a carefully selected group, which is different from what any single person should expect. The mean is not a prediction: about one in seven people on semaglutide did not reach 5% weight loss, and roughly three in ten did not reach 10% ^[1].

Two details shape how the results apply. First, the trial excluded people with diabetes, so these figures do not describe that group ^[1]. Second, everyone received diet and exercise counseling throughout, so the results reflect the drug plus that support, not the drug alone ^[1].

The results also cover only the treatment period. Weight change after the drug was stopped has not been reported here, even though the trial design included a seven-week period without treatment ^[1]. Whether weight is regained after stopping, and how quickly, is not established by this paper.

The trial was funded by Novo Nordisk, the maker of semaglutide, which designed the trial and oversaw its conduct, including site monitoring and data analysis ^[1].

What happens next

STEP 1 is one trial in the larger phase 3 STEP program, which was set up to test semaglutide 2.4 mg in people with overweight or obesity, with or without weight-related complications ^[1]. The trial is registered as NCT03548935 ^[1]. Results from the other STEP trials and any longer-term follow-up have not been described here.