Antidiabetic drug effects on gastrointestinal health: convergent evidence from a longitudinal cohort and Mendelian randomization study

INTRODUCTION: The global prevalence of diabetes continues to rise, and long-term use of anti-diabetic drugs has thus become a cornerstone of clinical management for most patients. OBJECTIVES: This study aimed to explore the impact of antidiabetic drug use, combination therapy, and medication sequence on the risk of gastrointestinal disorders. METHODS: This study included 27,784 type 2 diabetes patients at baseline in the UK Biobank. Multivariate Cox models were employed to explore the associations between antidiabetic drugs (metformin, sulfonylureas, thiazolidinediones, alpha glucosidase inhibitors (AGI), glucagon-like peptide-1 receptor agonists (GLP-1RA), and insulin) and the incidence of gastrointestinal disorders. We leveraged the summary statistics from the FinnGen study and genome-wide association studies to perform drug-target Mendelian randomization (MR) analyses, validating the observed associations. RESULTS: During a median follow-up period of 15.2 years, sulfonylurea users had a lower risk of colorectal cancer (CRC) (HR: 0.76, 95% CI: 0.62-0.94) than nonsulfonylurea users. Insulin users had a decreased risk of diverticular disease (HR: 0.75, 95% CI: 0.68-0.83) compared with noninsulin users. In addition, metformin combined with sulfonylureas was associated with decreased CRC risk (HR: 0.61, 95% CI: 0.46-0.82), while postmetformin use of DPP-4i with sulfonylureas or GLP-1RA was related to higher acute pancreatitis risk. In two-sample MR, genetically predicted sulfonylureas targeting INS were associated with a reduced risk of CRC (OR: 0.56, 95% CI: 0.35-0.88), and insulin targeting LRP2 was associated with a reduced risk of diverticular disease (OR: 0.89, 95% CI: 0.80-0.98). CONCLUSION: Our study indicates that antidiabetic regimens, including combination therapies and treatment sequences, are clinically important for preventing gastrointestinal morbidity in type 2 diabetes patients. This underscores the need for personalized treatment to prevent gastrointestinal comorbidities.