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Nwachukwu, Nwachukwu O., Balogun, Favour O., Ogunlade, Akinwale F., Bob-Ume, Nwamaka C., Olukorode, John O., Ayobami-Ojo, Petra S., Oloyede, Praise O., Omiko, Raymond A., Falade, David M., Omotoso, Esther O., Olabode, Deborah M., Mamudu, Akhere, Ajani, Opemipo O., Ogunnoiki, Samuel O., Samuel-Ogunnoiki, Precious M., Fakah, Hilda N., Francis, Gbone A., Oludahunsi, Oluwatobi, Adekoya, Yemisi M. and Chigbo, Chisom G. (2026) The impact of Glucagon-like peptide-1 (GLP-1) receptor agonists on lipid metabolism: a new avenue for cardiovascular disease prevention - a meta-analysis of randomized control trials. Postgraduate Medical Journal, 102 (Supple). i5-i6. ISSN 1469-0756
Background:
Cardiovascular disease is a leading cause of death globally, with type 2 diabetes mellitus increasing the risk. Lipid dysregulation, particularly increased LDL cholesterol and triglyceride concentrations, drives atherosclerosis, a primary driver of cardiovascular disease. Glucagon-like peptide-1 receptor agonists, initially designed for glucose control in type 2 diabetes mellitus, show potential in reducing cardiovascular risk factors, including lipid abnormalities. However, their impact on lipid metabolism remains unclear.
Aim:
This systematic review and meta-analysis aims to evaluate the effects of GLP-1 receptor agonists on lipid metabolism and cardiovascular outcomes, and to determine the potential mechanisms by which GLP-1 receptor agonists affect cardiovascular risk factors, whether or not these are directly linked to lipid metabolism. Glucagon-like peptide-1 receptor agonists liraglutide, semaglutide and exanetide were investigated.
Methods:
This systematic review and meta-analysis of randomized controlled trials was conducted in accordance with PRISMA guidelines. PubMed, Scopus and Cochrane Library were searched from 2000 to 2025 for randomized controlled trials evaluating liraglutide, semaglutide or exenatide in adults with type 2 diabetes and reporting lipid concentrations and/or major adverse cardiovascular events. The inclusion criteria were participants aged ≥18 years with or without type 2 diabetes, obesity and other comorbidities, reported in a randomized control trial (with placebo or antidiabetic or lipid-lowering drugs in the control arm), and the end points/outcomes of the trial, including cardiovascular events and lipid profiles, with a follow-up period of at least six weeks. English language articles only were considered, with full-text and open access. The exclusion criteria were case reports, case series, observational studies, proposed or ongoing clinical trials, letters to the editors, commentaries, diagnostic studies, narrative and systematic reviews and meta-analyses, studies performed on animals, cross-over trials, and post hoc analysis. Studies without a control arm, studies with GLP-1 receptor agonists in combination with other therapies as intervention, studies that included participants with gestational diabetes, studies that included participants already on other oral hypoglycaemic agents or insulin, or who had suffered cardiovascular events (acute myocardial infarction, angina, transient ischaemic attack, or stroke) within the last 30–60 days. Two reviewers (Akhere Mamudu and Praise O. Oloyede) independently extracted data. Risk of bias was assessed using the Cochrane Risk of Bias Tool. Pooled mean differences for lipid outcomes and hazard ratios for cardiovascular outcomes were calculated using RevMan software. Heterogeneity was assessed using the I2 statistic. A fixed-effects model was applied where heterogeneity was low (I2 < 50%) and a random-effects model where heterogeneity was substantial.
Results:
Systematic searches were performed according to PRISMA guidelines across three databases (PubMed/MEDLINE, Cochrane Library, and Scopus) using predefined search terms. Six hundred and seventy-two articles were identified. After applying exclusion and inclusion requirements, the number was reduced to 50 articles based on title selection. Twenty articles were chosen according to the relevance of their abstract. Lastly, five studies [1–5], whose full texts met the eligibility criteria, were included in the final review, comprising 18 227 participants. Meta-analysis demonstrated no statistically significant pooled reduction by liraglutide, semaglutide or exenatide in LDL cholesterol concentration (mean deviation = 0.03 mmol/L; P = 0.86) or triglyceride concentration (mean deviation = 0.11 mmol/L; P = 0.76). Glucagon-like peptide-1 receptor agonists were associated with cardiovascular safety across the five studies. Pooled analysis of major adverse cardiovascular events demonstrated a reduction favouring GLP-1 receptor agonists (hazard ratio = 0.89; 95% CI: 0.82–0.97; P = 0.009; I2 = 0%). Subgroup data from individual trials showed cardiovascular superiority for semaglutide and liraglutide, while exenatide demonstrated non-inferiority.
Conclusions:
Glucagon-like peptide-1 receptor agonists confer cardiovascular protection in patients with type 2 diabetes mellitus; however, pooled analysis does not demonstrate a consistent lipid-mediated effect. Cardiovascular benefits appear multifactorial (via their effect on glycaemic control plus inflammation) rather than primarily driven by direct lipid modulation. Although the pooled analysis showed no statistically significant changes in triglyceride, LDL cholesterol, HDL cholesterol, or total cholesterol concentrations, a major decline in adverse cardiovascular events was found. These findings suggest that the cardiovascular benefits of GLP-1 receptor agonists are potentially mediated by mechanisms independent of direct lipid modification, underscoring the complexity of their role in preventing cardiovascular disease.
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