Impact of semaglutide on lipid profiles in overweight and obese non-diabetic adults: A systematic review and meta-analysis of randomized controlled trials

Semaglutide, a glucagon-like peptide-1 receptor agonist, is known for weight reduction and glycemic control and is approved to lower major cardiovascular event risk in adults with overweight or obesity. While individual trials have explored its effects on lipid profiles in non-diabetic adults with overweight or obesity, a comprehensive pooled analysis has been lacking. Dyslipidemia, a key modifiable cardiovascular risk factor, prompted this meta-analysis—the first to evaluate semaglutide 2.4 mg's impact on total cholesterol, low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides in this population. A systematic search identified four randomized controlled trials evaluating semaglutide 2.4 mg over 68 weeks or more in non-diabetic adults with overweight or obesity. A random-effects meta-analysis was conducted to calculate pooled mean differences (MDs) and 95 % confidence intervals (CIs) for lipid parameters, taking into account study heterogeneity. Semaglutide significantly reduced total cholesterol (MD: 6.39 mg/dL, 95 % CI: 9.25 to −3.53, p < 0.01), LDL-C (MD: 6.01 mg/dL, 95 % CI: 10.17 to −1.85, p < 0.01), VLDL-C (MD: 10.67 mg/dL, 95 % CI: 17.79 to −3.54, p < 0.01), and triglycerides (MD: 14.75 mg/dL, 95 % CI: 21.30 to −8.19, p < 0.01), while slightly increasing HDL-C (MD: +1.82 mg/dL, 95 % CI: 0.90 to 2.74, p < 0.01). Semaglutide 2.4 mg weekly improves lipid profiles in non-diabetic adults with overweight or obesity, suggesting metabolic benefits beyond weight loss. These findings highlight a potential mechanism for semaglutide cardiovascular risk reduction, given the link between improved lipid profiles and lower cardiovascular risk. Trial registration: PROSPERO registration: CRD42025100858.