IDDF2024-ABS-0297 Repurposing antidiabetic drugs for inflammatory bowel disease: results from a two-sample mendelian randomization study

<h3>Background</h3> Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), poses a substantial disease burden worldwide. Recent studies have indicated that anti-diabetic drugs like metformin may attenuate intestinal inflammation. We aim to explore the repurposing potential of antidiabetic drugs in IBD prevention by assessing associations between genetic variation in antidiabetic drug target genes and IBD using Mendelian randomization (MR). <h3>Methods</h3> A two-sample MR design was applied to examine associations between genetic variations in 8 targets of 5 antidiabetic drug classes and IBD risk. Summary statistics were obtained from previous genome-wide association studies comprising 31,665 cases and 33,977 controls of European individuals. The effect of genetic variation in the drug targets on IBD risk was estimated by the Wald ratio test or inverse-variance weighted method. <h3>Results</h3> Genetic variation in metformin target (gene: <i>ETFDH</i>) was inversely correlated with overall IBD susceptibility (odds ratio [OR] = 0.953, 95% confidence interval [CI]: 0.911 to 0.998, <i>P</i> = 0.039). An association between genetic variations in the thiazolidinediones (TZD) target (<i>PPARG</i>) and a lower risk of CD was also observed (OR = 0.924, 95% CI: 0.858 to 0.995,<i> P</i> = 0.037). In contrast, genetic variation in the target of dipeptidyl peptidase 4 (DPP4) inhibitor was associated with a higher IBD risk (OR = 1.615, 95% CI: 1.051 to 2.483, <i>P</i> = 0.029), particularly for UC (OR = 1.514, 95% CI: 1.095 to 2.093,<i> P</i> = 0.012). These results were largely unchanged in the sensitivity analysis. Results regarding other metformin targets (gene: <i>PRKAB1</i> and<i> GPD2</i>), targets in glucagon−likepeptide1analogues (<i>GLP1R</i>), sodium−glucosecotransporter 2 inhibitor (<i>SLC5A2</i>), or sulfonylurea (<i>KCNJ11</i>) were inconclusive. <h3>Conclusions</h3> Our results suggest that genetic variation in the target of metformin and TZD was associated with a decreased risk of overall IBD and CD, respectively. In contrast, genetic variation in the DDP4 inhibitor target was linked to an elevated IBD risk, particularly for UC. The underlying mechanisms warrant further investigation.