EXPLORING GASTROINTESTINAL AND HEPATOBILIARY ADVERSE EVENTS IN GLP-1 RECEPTOR AGONISTS THERAPY: A LARGE COHORT RETROSPECTIVE STUDY

Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are integral in managing type 2 diabetes. However, their long-term impact on gastrointestinal and hepatobiliary health remains uncertain. Addressing the gap in existing literature, our retrospective study, using a large cohort from the TriNetX database with a 5-year follow-up, investigates these potential adverse events, including the often-debated risk of GI cancers.

Methods: This retrospective study utilized data from the TriNetX database, analyzing a large cohort over five years. Propensity score matching (PSM) was employed to create six cohorts, each comparing oral semaglutide, injectable formulations of semaglutide, liraglutide, dulaglutide, exenatide, and lixisenatide against control group. We assessed the incidence of cholecystitis, choledocholithiasis, cholangitis, pancreatitis, gastroparesis, biliary and pancreatic cancer, and gastroesophageal reflux disease (GERD), using hazard ratios (HRs) and P values for statistical significance.

Results: Our analysis elucidated various risk profiles across the GLP-1 RA spectrum. The patient data included equal numbers in the treatment and control groups for each medication: oral semaglutide (35,744 patients in each group), injectable semaglutide (173,437 patients in each group),(Table 1,2) liraglutide (130,637 patients in each group), dulaglutide (297,047 patients in each group), exenatide (36,019 patients in each group), and lixisenatide (9,360 patients in each group).Oral semaglutide exhibited a non-significant difference in cholecystitis (HR: 0.846, P=0.070) and gastroparesis risks compared to control group (HR: 0.840, P=0.056). Injectable semaglutide was linked with increased gastroparesis (HR: 1.203, P<0.001) and pancreatitis risks (HR: 1.129, P<0.001). Liraglutide injections showed increased occurrences of cholangitis (HR: 1.218, P=0.004), pancreatitis (HR: 1.312, P<0.001), and gastroparesis (HR: 1.433, P<0.001). Dulaglutide was associated with higher pancreatitis risk (HR: 1.097, P<0.001). Exenatide increased risks of gastroparesis (HR: 1.394, P<0.001), cholangitis (HR: 1.421, P=0.003), and pancreatitis (HR: 1.250, P<0.001). Lixisenatide presented an elevated gastroparesis risk (HR: 1.437, P=0.004). Notably, no GLP-1 RA formulation was found to significantly increase the risk of biliary or pancreatic cancers.

Conclusion: This large retrospective study provides valuable insights into the safety profile of GLP-1 RAs, particularly concerning gastrointestinal and hepatobiliary side effects. Our findings indicate that GLP-1 RAs do not show an increase in GI cancer risk which is a significant clinical takeaway. However, caution and vigilance remain key, especially considering that each GLP-1 RA formulation carries its own spectrum of gastrointestinal and hepatobiliary side effects.