STEP 1 trial reports 14.9% average weight loss with semaglutide 2.4 mg

The New England Journal of Medicine published the STEP 1 trial on Feb. 10, 2021, reporting that adults with overweight or obesity who took once-weekly semaglutide 2.4 mg lost an average of 14.9% of their body weight over 68 weeks, compared with 2.4% for those on placebo ^[1].

The trial enrolled 1,961 adults without diabetes who had 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 ^[1]. Participants were randomly assigned in a 2:1 ratio to semaglutide or placebo injections, both given alongside a lifestyle program that included counseling every four weeks, a 500-calorie daily deficit and a target of 150 minutes of physical activity per week ^[1]. Treatment started at 0.25 mg and increased every four weeks, reaching the 2.4 mg maintenance dose by week 16 ^[1]. The trial ran at 129 sites in 16 countries, and participants were enrolled between June and November 2018 ^[1].

The average change in body weight from the start of the trial to week 68 was −14.9% with semaglutide versus −2.4% with placebo, an estimated difference of −12.4 percentage points (95% confidence interval, −13.4 to −11.5; P<0.001) ^[1]. Measured in kilograms, that was a loss of 15.3 kg versus 2.6 kg, a difference of 12.7 kg (95% CI, −13.7 to −11.7) ^[1].

More participants on semaglutide reached common weight-loss thresholds. Of those taking the drug, 86.4% lost at least 5% of body weight, compared with 31.5% on placebo; 69.1% versus 12.0% lost at least 10%; and 50.5% versus 4.9% lost at least 15% ^[1]. Participants who received semaglutide also had greater improvement in cardiometabolic risk factors and a larger increase in self-reported physical functioning than those on placebo ^[1].

Nausea and diarrhea were the most common side effects with semaglutide, and were typically transient and mild to moderate, subsiding over time ^[1]. More participants in the semaglutide group stopped treatment because of gastrointestinal events: 59 people, or 4.5%, versus 5 people, or 0.8%, on placebo ^[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 ^[1]. Novo Nordisk funded the trial, registered as NCT03548935 ^[1].

Semaglutide is sold under several brand names, including Ozempic and Rybelsus, with the 2.4 mg weight-management dose marketed as Wegovy ^[2][3]. Ozempic's diabetes doses of roughly 0.5 mg to 1.0 mg weekly were designed and tested for blood sugar control rather than maximum weight loss, and are associated with about 5% to 7% weight reduction in diabetes trials ^[3]. Citing the 14.9% figure as Ozempic's weight-loss result is a common error ^[3].

Why it matters for patients

Before this trial, prescription weight-loss options were limited by modest effectiveness, safety concerns and cost, and clinical guidelines suggested adding medication mainly for adults with a BMI of 30 or higher, or 27 or higher with related conditions ^[1]. A 14.9% average loss changed what a single medication was expected to achieve, and it gave patients and clinicians a set of clear benchmarks: about 9 in 10 participants on the drug lost at least 5% of body weight, and about half lost at least 15% ^[1].

The comparison group matters too. People on placebo, who received the same diet and exercise counseling, lost an average of 2.4% of body weight, or 2.6 kg, showing how much of the result came from the drug rather than lifestyle support alone ^[1]. The tolerability data also give a realistic picture: gastrointestinal side effects were common, and about 1 in 22 participants on semaglutide stopped because of them ^[1].

The trial excluded people with diabetes, so its results do not directly describe that group ^[1]. And because the same molecule is sold at different doses for different conditions, which product a person is prescribed, and whether insurance covers it, can depend on the diagnosis on the prescription rather than on the molecule itself; coverage for off-label weight-loss use is uncommon ^[3].

What happens next

Later studies extended the comparison. Tirzepatide, a GLP-1 and GIP dual agonist sold as Mounjaro for diabetes and Zepbound for weight management, produced 20.9% mean weight loss at 72 weeks at its 15 mg dose in the SURMOUNT-1 obesity trial ^[3]. In SURPASS-2, a head-to-head trial in 1,879 adults with type 2 diabetes over 40 weeks, tirzepatide 15 mg produced 5.5 kg more weight loss than semaglutide 1.0 mg, the diabetes dose rather than the 2.4 mg weight-loss dose ^[3]. A head-to-head trial in an obesity population using equal doses has not been completed as of 2026, according to that comparison ^[3]. Semaglutide's SELECT cardiovascular trial in 2023 reported a 20% reduction in major cardiovascular events ^[3].