Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of anti-diabetic medications initially approved for the management of type 2 diabetes (T2DM). The drug class includes medications such as liraglutide, exenatide, dulaglutide, semaglutide, and tirzepatide. Semaglutide, dulaglutide, and tirzepatide are newer GLP-1-based medications that are longer acting due to the addition of heavy chain fragments, allowing for weekly dosing, in contrast to earlier agents like liraglutide, which requires once-daily injections (Almandoz et al., 2020; Cerillo and Parmar, 2025). This extended dosing interval improves compliance and increases utilization of these medications for diabetes management. In addition to lowering blood glucose, GLP-1 receptor agonists have been associated with several beneficial effects, including reductions in body weight, improvements in blood pressure, and favorable changes in lipid metabolism, all of which may contribute to lowering overall cardiometabolic risk (Brandfon et al., 2023; Cerillo and Parmar, 2025; Drucker, 2024; Wong et al., 2025).

Semaglutide is a widely used medication approved not only for glycemic control but also for weight reduction in individuals who are overweight or obese. Clinical trials have demonstrated that semaglutide achieves approximately 14 % weight reduction in overweight or obese adults without diabetes (Wilding et al., 2021). This weight reduction is clinically beneficial in reducing the risk of associated conditions such as cardiovascular disease, type 2 diabetes, and non-alcoholic fatty liver disease. In 2024, semaglutide received FDA approval to reduce the risk of major cardiovascular events, including death, heart attack, or stroke, in adults with known heart disease and either obesity or overweight. The approved dosing for semaglutide, for both weight reduction and cardiovascular risk reduction, is 2.4 mg administered subcutaneously once weekly (Lincoff et al., 2023).

Although randomized clinical trials (RCTs) have investigated semaglutide effects on lipid parameters—total cholesterol, LDL-C, HDL-C, triglycerides, and VLDL-C—in non-diabetic adults with overweight or obesity, results have been inconsistent due to differences in study designs, treatment durations, baseline metabolic profiles, and concurrent lifestyle interventions This variability, coupled with emerging evidence of semaglutide cardiovascular benefits in non-diabetic individuals, highlights the need for a systematic evaluation of its impact on lipid profiles, which are key biomarkers of cardiovascular health.

To isolate the lipid effects of semaglutide, we excluded patients with diabetes, as glycemic variability and more severe baseline dyslipidemia can confound the results (Al-Mrabeh et al., 2020; Gan et al., 2023; Parhofer, 2015). By focusing on non-diabetic individuals with overweight or obesity, we aimed to identify the direct metabolic effects of semaglutide without the influence of diabetes-related variables. Cardiovascular disease risk remains significantly elevated in individuals with obesity, even in the absence of diabetes. Excess adipose tissue, particularly visceral fat, induces a chronic pro-inflammatory state and promotes insulin resistance, contributing to endothelial dysfunction and atherogenesis. These changes accelerate the development of cardiovascular disease (Ormazabal et al., 2018). If semaglutide is found to improve lipid profiles, it could represent an additional strategy for reducing cardiometabolic risk in this population.

This meta-analysis aims to synthesize RCT evidence to evaluate the effect of subcutaneous semaglutide 2.4 mg on lipid profiles, including total cholesterol, LDL-C, HDL-C, triglycerides, and VLDL-C, in non-diabetic adults with overweight or obesity, providing insights into its role in cardiometabolic risk management.