GLP-1 receptor agonist-based and cardiovascular risk: a review of mechanisms

Cardiovascular outcome trials (CVOTs) in people living with T2DM and obesity have confirmed the cardiovascular benefits of glucagon-like peptide 1 receptor agonists (GLP-1RA), including reduced cardiovascular mortality, lower rates of myocardial infarction, and lower rates of stroke. The cardiovascular benefits observed following GLP-1RA treatment could be secondary to improvements in glycemia, blood pressure, postprandial lipidemia, and inflammation. Yet, the GLP-1R is also expressed in the heart and vasculature, suggesting that GLP-1R agonism may impact the cardiovascular system. The emergence of GLP-1RA combined with glucose-dependant insulinotropic polypeptide (GIP) and glucagon (GCG) receptor agonists has shown promising results as new weight loss medications. Dual-agonist and tri-agonist therapies have demonstrated superior outcomes in weight loss, lowered blood sugar and lipid levels, restoration of tissue function, and enhancement of overall substrate metabolism compared to using GLP-1R agonists alone. However, the precise mechanisms underlying their cardiovascular benefits remain to be fully elucidated. This review aims to summarize the findings from CVOTs of GLP-1RAs, explore the latest data on dual and triagonist therapies, and delve into potential mechanisms contributing to their cardioprotective effects. It also addresses current gaps in understanding and areas for further research.