Exploring the Potential Effect of GLP1R Agonism on Common Ageing-Related Diseases via Glucose Reduction: A Mendelian Randomization Study

Abstracts Background Glucagon-like peptide-1 receptor agonists (GLP1RAs) are widely used in manageing type 2 diabetes mellitus and weight control. Their potential in treating ageing-related diseases has been gaining attention in recent years. However, the long-term effects of GLP1RAs on these diseases have yet to be fully revealed. Methods Using genetic variant in the GLP1R gene to model the long-term effects of GLP1RAs, this Mendelian randomization (MR) study systematically explored potential causal associations between GLP1R agonism and 12 ageing-related diseases and indicators. Genetic summary datasets used in this study were obtained from previous genome-wide association studies. Results The primary MR analysis results suggested that GLP1R agonism was potentially positively causally associated with appendicular lean mass (Beta = 0.246, 95% CI = 0.096 - 0.396), whole body fat-free mass (Beta = 0.202, 95% CI = 0.048 - 0.355), and lung function (FVC) (Beta = 0.179, 95% CI = 0.152 - 0.205) (p < 0.05). Additionally, a potential negative causal association was observed with myocardial infarction (OR = 0.430, 95% CI = 0.249 - 0.745) (p < 0.05). Conclusion The present MR study provides exploratory evidence suggesting potential causal associations between GLP1R agonism and appendicular lean mass, whole-body fat-free mass, lung function (FVC), and myocardial infarction. Given the exploratory nature of these findings and the limitations of the MR methodology, further research is needed to validate these results and investigate the underlying biological mechanisms.