Gastrointestinal and Hepatobiliary Safety of Glucagon-like Peptide-1 Receptor Agonists in Patients with Type 2 Diabetes

INTRODUCTION: To evaluate the long-term gastrointestinal and hepatobiliary safety of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in patients with type 2 diabetes mellitus (T2DM), compared to other oral antidiabetic medications. METHODS: A retrospective cohort study using the TriNetX network was conducted between 2010–2020. After 1:1 propensity score matching, 230,415 patients were included in each group (GLP-1 RAs vs. oral anti-DMs). Hazard ratios (HRs) for gastrointestinal (GI) and hepatobiliary outcomes were assessed over 5 years. RESULTS: Among 230,415 matched patients per group, GLP-1 RA use was associated with a higher risk of gastroparesis (HR=1.591, p<0.001) and intussusception (HR=1.383, p=0.025) compared to oral antidiabetic therapy. There were no significant differences in acute pancreatitis, cholecystitis, or cholecystectomy rates between groups. Conversely, GLP-1 RA therapy was not associated with increased incidence of gastrointestinal cancers. Lower hazard ratios were observed for pancreatic (HR=0.897, p=0.038), gastric (HR=0.838, p=0.034), esophageal (HR=0.741, p=0.001), and colorectal cancer (HR=0.870, p=0.001), though causality cannot be inferred. No significant differences were observed in biliary cancer or hepatocellular carcinoma. DISCUSSION: In this large real-world cohort study, GLP-1 RA therapy was not associated with increased risk of most serious GI or hepatobiliary outcomes compared to other oral diabetes medications. These findings support the overall GI and hepatobiliary safety of GLP-1 RAs in patients with type 2 diabetes, while underscoring the need for vigilance regarding gastroparesis and intussusception in susceptible individuals. Longer-term studies are warranted to fully evaluate cancer risk.