INTRODUCTION: Incretin-based therapies, including glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 inhibitors (DPP-4Is), are widely used in the management of type 2 diabetes mellitus (T2DM). However, concerns have emerged regarding their potential association with an increased risk of cholangiocarcinoma (CCA), and current evidence remains inconclusive. This review aims to evaluate and clarify the association between incretin-based therapies and the risk of CCA in patients with T2DM.
METHODS: This review followed PRISMA 2020 guidelines and was registered in PROSPERO (CRD42025641616). A comprehensive search was performed across PubMed, ProQuest, EBSCOhost, Wiley, and SAGE databases. Eligible observational studies reporting the association between incretin-based therapies and CCA were included. Study quality was assessed using the Newcastle-Ottawa Scale (NOS). Pooled hazard ratios (HRs) and risk ratios (RRs) with 95% confidence intervals (CIs) were calculated using RevMan with a random-effects model.
RESULT: Four studies (three cohort and one case-control) were included. The pooled HRs showed no significant association between incretin-based therapies and CCA risk, with estimates of 1.07 (95% CI: 0.70-1.63) for GLP-1RAs and 1.05 (95% CI: 0.83-1.34) for DPP-4Is. Pooled RR analyses yielded similarly non-significant results. All included studies were assessed as having a low risk of bias according to the NOS.
CONCLUSION: Incretin-based therapies do not significantly increase the risk of CCA in T2DM patients. Within the limitations of the available observational evidence, these findings provide reassurance regarding their safety profile, while highlighting the need for ongoing pharmacovigilance and further large-scale studies to confirm these results.
