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

This study integrated longitudinal cohort and Mendelian randomization analyses to explore antidiabetic drug effects on gastrointestinal health. Different medications, combinations, and sequences showed distinct effects on gastrointestinal diseases. Mendelian randomization supported potential causal associations between drug targets and gastrointestinal disorders. These findings highlight gastrointestinal safety and personalized strategies for diabetic patients. Abbreviations: TZDs, thiazolidinediones; AGI, alpha glucosidase inhibitors; GLP-1RA, glucagon-like peptide-1 receptor agonists; DPP-4i, dipeptidyl peptidase-4 inhibitors; MASLD, metabolic dysfunction-associated steatotic liver disease • This study uncovered complex associations of antidiabetic drugs with diverse gastrointestinal diseases • Insulin use exhibited a decreased risk of diverticular disease among patients with type 2 diabetes. • Sulfonylurea use exhibited a decreased risk of colorectal cancer in type 2 diabetes patients. • Metformin combined with sulfonylureas showed decreased colorectal cancer risk in type 2 diabetes patients. • These insights are vital for optimizing diabetes treatment and preventing gastrointestinal comorbidities. 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. This study aimed to explore the impact of antidiabetic drug use, combination therapy, and medication sequence on the risk of gastrointestinal disorders. 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. 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). 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.