Advances in Weight-Loss-Independent Cardiovascular Protective Mechanisms of GLP-1 Receptor Agonists

The comorbidity burden of obesity and cardiovascular disease (CVD) is escalating globally. Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been consistently demonstrated to reduce the risk of major adverse cardiovascular events (MACE) significantly, it remains unclear whether their cardiovascular benefits are entirely mediated by weight loss. This review synthesizes current clinical evidence supporting the weight-loss-independent cardiovascular protection of GLP-1RAs in patients with obesity and CVD, with a focus on the underlying molecular mechanisms, thereby providing a foundation for future mechanistic research and precise clinical application. Analysis of major cardiovascular outcome trials (CVOTs), including LEADER, SUSTAIN-6, and SELECT, and their prespecified subgroup analyses reveals that GLP-1RAs exhibit consistent cardiovascular benefits across different baseline body mass index (BMI) subgroups. Exploratory mediation analyses suggest that 35%-55% of these benefits may not be explained by weight loss; however, these estimates depend on model assumptions and do not establish a causal pathway. Mechanistic studies support that GLP-1RAs exert cardiovascular protection through multiple weight-loss-independent pathways, including preservation of endothelial function, anti-atherosclerotic effects, preclinically supported direct myocardial protection with ongoing disputes regarding human translation, anti-inflammation and immunomodulatory effects, and improved microcirculatory perfusion. In conclusion, GLP-1RAs have demonstrated cardiovascular protective effects in patients with obesity and CVD, and a proportion of these benefits may be attributable to mechanisms beyond weight reduction. Future rigorously designed clinical trials are warranted to further validate these pathways, clarify the tissue-specific functions of GLP-1 receptors, and identify novel molecular targets.