Long-Term Efficacy and Safety of Once-Weekly Semaglutide for Weight Loss in Patients Without Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Semaglutide, a glucagon-like peptide-1 receptor agonist, has demonstrated clinically important weight loss effects in patients with type 2 diabetes. However, its effects on sustained weight loss among individuals without diabetes remains unclear. Our objective was to examine the long-term efficacy and safety of semaglutide use for weight loss among individuals with overweight/obesity and without diabetes. MEDLINE, Embase, and the Cochrane Libraries were systematically searched to identify randomized controlled trials (RCTs) that randomized participants with overweight/obesity but without diabetes to once-weekly 2.4 mg subcutaneous semaglutide versus placebo with follow-up of at least 68 weeks. The primary outcome was change in relative body weight from baseline to longest follow-up. Random-effects models with inverse variance weighting were used to estimate weighted mean differences (WMDs) and relative risks (RRs) with 95% confidence intervals (CIs). A total of 4 RCTs (n=3,087) were included. Of the 3 trials which provided BMI by category (n=2,783), 94.0% of participants had a baseline BMI ≥30 kg/m2. Compared to placebo, use of semaglutide was associated with substantial decreases in long-term relative (WMD: -12.1%; 95% CI -13.5, -10.7) and absolute body weight (WMD: -12.3 kg; 95% CI -13.6, -11.0). At longest follow-up, 33.4% of participants randomized to semaglutide achieved ≥20% weight loss compared to 2.2% with placebo (RR: 15.08; 95% CI 9.31, 24.43). The risk of gastrointestinal adverse events was higher among semaglutide participants than placebo (RR: 1:47; 95% CI 1.28, 1.68); however, the majority of these events were transient, mild-to-moderate in severity, and did not require treatment discontinuation. In conclusion, semaglutide is efficacious for sustained weight loss among individuals with overweight/obesity and without diabetes.