Genetically proxied GLP-1 receptor agonism was linked to lower paralytic ileus risk but not to most other gastrointestinal events.
Evidence
Drug-target across 24 gastrointestinal disorders was supplemented by UK Biobank polygenic-score Cox analysis and mediation testing for paralytic ileus.
Caveat
The UK Biobank Cox analysis supported the direction but was not statistically significant, and genetic proxies mimic lifelong GLP1R expression rather than actual treatment exposure.
Simplified
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 (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.
Key numbers
−1.474
Log Odds Ratio for Paralytic Ileus
Causal association determined through analysis.
1.58%
Mediation Effect of HbA1c
Mediation analysis indicated low contribution of HbA1c to the protective effect.
0.52%
Mediation Effect of BMI
Mediation analysis showed BMI's minimal contribution to the protective effect.
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