The causal relationship between anti-diabetic drugs and gastrointestinal disorders: a drug-targeted mendelian randomization study

Abstract

Background: The incidence of diabetic gastrointestinal diseases is increasing year by year. This study aimed to investigate the causal relationship between antidiabetic medications and gastrointestinal disorders, with the goal of reducing the incidence of diabetes-related gastrointestinal diseases and exploring the potential repurposing of antidiabetic drugs.

Methods: We employed a two-sample Mendelian randomization (TSMR) design to investigate the causal association between antidiabetic medications and gastrointestinal disorders, including gastroesophageal reflux disease (GERD), gastric ulcer (GU), chronic gastritis, acute gastritis, Helicobacter pylori infection, gastric cancer (GC), functional dyspepsia (FD), irritable bowel syndrome (IBS), ulcerative colitis (UC), Crohn's disease (CD), diverticulosis, and colorectal cancer (CRC). To identify potential inhibitors of antidiabetic drug targets, we collected single-nucleotide polymorphisms (SNPs) associated with metformin, GLP-1 receptor agonists, SGLT2 inhibitors, DPP-4 inhibitors, insulin, and its analogs, thiazolidinediones, sulfonylureas, and alpha-glucosidase inhibitors from published genome-wide association study statistics. We then conducted a drug-target Mendelian randomization (MR) analysis using inverse variance weighting (IVW) as the primary analytical method to assess the impact of these inhibitors on gastrointestinal disorders. Additionally, diabetes was selected as a positive control.

Results: Sulfonylureas were found to significantly reduce the risk of CD (IVW: OR [95% CI] = 0.986 [0.978, 0.995], p = 1.99 × 10^{- 3}), GERD (IVW: OR [95% CI] = 0.649 [0.452, 0.932], p = 1.90 × 10^{- 2}), and chronic gastritis (IVW: OR [95% CI] = 0.991 [0.982, 0.999], p = 4.50 × 10^{- 2}). However, they were associated with an increased risk of GU development (IVW: OR [95%CI] = 2 0.761 [1.259, 6.057], p = 1 0.12 × 10^{- 2}).

Conclusions: The results indicated that sulfonylureas had a positive effect on the prevention of CD, GERD, and chronic gastritis but a negative effect on the development of gastric ulcers. However, our research found no causal evidence for the impact of metformin, GLP-1 agonists, SGLT2 inhibitors, DPP 4 inhibitors, insulin and its analogs, thiazolidinediones, or alpha-glucosidase inhibitors on gastrointestinal diseases.

Keywords: Antidiabetic drugs; Diabetes; Drug targets; Gastrointestinal diseases; Mendelian randomization study.

Fig. 1

This is a flowchart of the study design and the MR Analysis process The causal relationship between antidiabetic drugs and gastrointestinal disorders was assessed by a two-sample MR analysis dealing with exposure and outcome data. Three core assumptions were met: (1) IVs and exposure (antidiabetic drugs) are strongly correlated; (2) there is no correlation between IVs and confounders; and (3) there is no direct correlation between IVs and outcomes, and their effect on outcomes can only be reflected by the degree of exposure

Fig. 2

Relationship between GLP-1 receptor agonists, sulfonylureas and diabetes mellitus nsnp (number of single nucleotide polymorphisms), OR (odds ratio), CI (confidence interval)

Fig. 3

The relationship between GLP-1 receptor agonists and gastrointestinal disorders nsnp (number of single nucleotide polymorphisms), OR (odds ratio), CI (confidence interval), GERD: Gastroesophageal reflux disease;; GC: Gastric cancer; functional dyspepsia (FD); IBS: Irritable bowel syndrome; UC: Ulcerative colitis; CD: Crohn’s Disease; CRC: Colorectal cancer

Fig. 4

The relationship between Sulfonylureas and gastrointestinal disorders nsnp (number of single nucleotide polymorphisms), OR (odds ratio), CI (confidence interval), GERD: Gastroesophageal reflux disease; GC: Gastric cancer; functional dyspepsia (FD); IBS: Irritable bowel syndrome; UC: Ulcerative colitis; CD: Crohn’s Disease; CRC: Colorectal cancer