Genetic evidence for a causal protective effect of GLP-1 receptor agonists on paralytic ileus but not on other gastrointestinal events

The association between glucagon-like peptide-1 receptor agonists (GLP-1RAs) and gastrointestinal events remains controversial in observational studies. To address this, our study employed drug-target Mendelian randomization (MR) to investigate the causal relationship between GLP-1RAs and 24 gastrointestinal disorders, supplemented by sensitivity analyses, Cox proportional hazards regression analysis and mediation testing. Using single-nucleotide polymorphisms significantly associated with GLP1R gene expression as instrumental variables, we mimicked the lifelong pharmacological effects of GLP-1RAs. The significant causal association was further examined by the association study using weighted polygenic scores (PGSs) for GLP1R expression by the Cox proportional hazards regression model in UK Biobank (UKB). Our results revealed that genetically proxied GLP-1RA effects were significantly associated with a lower risk of paralytic ileus (log(OR) = -1.474, 95% CI = (-2.164, -0.784), P = 2.86 × 10-5). The direction of the association was further supported by Cox proportional hazards model using PGSs in the UKB, though the association did not reach significance (P > .05). According to two-step mediation analysis, glycated hemoglobin A1c and body mass index only mediated 1.58% and 0.52% of the protective effect of GLP-1RAs on paralytic ileus. Unlike observational studies, our MR analysis found no causal links between GLP-1R expression and the other gastrointestinal events including cholelithiasis, pancreatitis and so on. By overcoming confounding biases inherent in observational research, this study provides genetic evidence supporting the causal protective effect of GLP-1 receptor agonists on paralytic ileus and highlights the need to reevaluate GLP-1RA-associated gastrointestinal risks in clinical contexts.