Disproportionality analysis of semaglutide-associated bile-duct cancer: A vigibase study

Incretin-based therapies are essential in diabetes management, with semaglutide receiving attention due to its oral formulation and benefits in cardiovascular health, renal function and weight loss. However, rodent studies have shown that long-term Glucagon-like Peptide-1 Receptor Agonists (GLP-1RAs) exposure can induce proliferative changes, including thyroid C-cell tumors and epithelial cell hyperplasia, through GLP-1R-mediated pathways, raising concerns about potential mitogenic effects in other tissues. This study evaluates the association between semaglutide and bile duct cancer using pharmacovigilance data.

A disproportionality analysis was conducted using VigiBase, the WHO's global safety database. Individual Case Safety Reports from January 1, 2009, to July 31, 2023, were analyzed, focusing on neoplasms classified under System Organ Classes. Signal detection was assessed using the lower 95% credibility interval limit for the Information Component (IC025), Proportional Reporting Ratio (PRR025) and Reporting Odds Ratio (ROR025). Patient demographics, drug dosage, treatment duration and severity of reported cases were reviewed qualitatively.

Among 75,497 adverse events from 28,403 patients, 442 (0.58%) were linked to benign and malignant neoplasms. Pancreatic cancer (70 cases) was the most frequent, followed by breast (28 cases), thyroid (14 cases) and medullary thyroid cancer (15 cases). Six cases were identified in VigiBase-four as 'bile duct cancer' and two as 'cholangiocarcinoma'-potentially indicating overlapping diagnoses. Disproportionality analysis for bile duct cancer (n = 4) showed an OR₀₂₅ of 2.30, IC₀₂₅ of 0.23, and PRR₀₂₅ of 2.30, exceeding thresholds for signal detection.

While this study identifies a potential safety signal between semaglutide use and bile duct cancer, causality cannot be established. These findings underscore the importance of ongoing pharmacovigilance and the need for long-term observational studies and randomized controlled trials.