Efficacy and Safety of Semaglutide 2.4 mg for Weight Management: A Systematic Review of the STEP Program
Background
Obesity remains a major global health challenge, affecting over 650 million adults worldwide. The glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide, originally developed for type 2 diabetes, has shown substantial efficacy in weight management. The Semaglutide Treatment Effect in People with Obesity (STEP) program comprises multiple phase 3 randomized controlled trials evaluating semaglutide 2.4 mg administered subcutaneously once weekly.
Methods
We performed a systematic review following PRISMA guidelines. Electronic databases including PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched from inception through December 2025. Eligible studies were randomized controlled trials comparing semaglutide 2.4 mg with placebo in adults with a body mass index (BMI) of 30 or greater, or 27 or greater with at least one weight-related comorbidity. The primary outcome was percentage change in body weight from baseline.
Results
Seven randomized controlled trials from the STEP program met inclusion criteria, enrolling a total of 10,561 participants. Mean baseline BMI ranged from 35.7 to 38.5. At 68 weeks, semaglutide 2.4 mg reduced body weight by a mean of 14.9% (95% CI, -16.2 to -13.6) compared with 2.4% for placebo. In STEP 1 (n=1,961), participants without diabetes lost 14.9% of body weight versus 2.4% with placebo. STEP 3, which combined semaglutide with intensive behavioral therapy, achieved 16.0% weight loss. Gastrointestinal adverse events, primarily nausea, diarrhea, and vomiting, occurred in 74.2% of semaglutide-treated participants versus 47.9% with placebo, though most were mild to moderate in severity and transient.
Conclusions
Semaglutide 2.4 mg once weekly, as evaluated across the STEP clinical trial program, produces substantial and sustained weight reduction in adults with obesity, regardless of diabetes status. The benefit-risk profile supports its use as a pharmacological adjunct to lifestyle intervention in eligible patients.
Semaglutide 2.4 mg once weekly demonstrates clinically significant weight reduction of 12-17% from baseline across diverse patient populations, with gastrointestinal adverse events being the most common treatment-related side effects.