He Long, Li Jinwei, Cheng Xiong, Luo Li, Huang Yilan
Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
School of Pharmacy, Southwest Medical University, Luzhou, China.
Front Pharmacol. 2025 Feb 17;16:1509561. doi: 10.3389/fphar.2025.1509561. eCollection 2025.
Incretin-based therapies, including glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, are essential treatments in diabetes management due to their efficacy in glycemic control and the additional benefits of GLP-1 RAs, which include cardiovascular and renal protection. However, concerns about potential associations with biliary disorders necessitate ongoing pharmacovigilance. This study analyzes the link between these drugs and biliary adverse events (AEs) using the FDA Adverse Event Reporting System (FAERS) to enhance clinical safety.
We extracted AE data for GLP-1 RAs and DPP-4 inhibitors from FAERS between Q1 2013 and Q1 2024 using OpenVigil 2.1. Analytical methods such as the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM) were employed to assess AE risk.
A search of biliary disorders by standard MedDRA analytical queries (SMQs) identified 2,215 reports of biliary AEs, with 1,709 related to GLP-1 RAs and 506 to DPP-4 inhibitors. DPP-4 inhibitors showed a significant association with biliary disorders (ROR, 3.09; 95% CI, 2.83-3.37), particularly sitagliptin (ROR, 3.46; 95% CI, 3.13-3.83). Although the overall association for GLP-1 RAs (ROR, 1.60; 95% CI, 1.52-1.68) was not significant, semaglutide (ROR, 4.06; 95% CI, 3.76-4.39) and liraglutide (ROR, 3.88; 95% CI, 3.50-4.29) indicated a notable risk. The SMQ subgroup analyses of sitagliptin, semaglutide, and liraglutide with the SMQ subgroup categories of "biliary tract disorders," "gallbladder related disorders," "gallstone related disorders," and "infectious biliary disorders' demonstrated a statistically significant correlation. Notably, liraglutide, alogliptin, sitagliptin, and linagliptin were linked to "biliary malignant tumors" with statistical significance. The proportion of serious outcomes was higher for DPP-4 inhibitors (n = 389, 76.88%) compared to GLP-1 RAs (n = 881, 51.55%).
DPP-4 inhibitors are potentially linked to biliary disorders, warranting vigilance. While the overall association for GLP-1 RAs was not significant, specific drugs like semaglutide, liraglutide, and sitagliptin showed concerning signals, suggesting a need for heightened awareness among clinicians regarding the risk of biliary AEs.
基于肠促胰岛素的疗法，包括胰高血糖素样肽1受体激动剂（GLP-1 RAs）和二肽基肽酶-4（DPP-4）抑制剂，因其在血糖控制方面的疗效以及GLP-1 RAs的额外益处（包括心血管和肾脏保护作用），在糖尿病管理中是重要的治疗方法。然而，对与胆道疾病潜在关联的担忧使得持续的药物警戒成为必要。本研究使用美国食品药品监督管理局不良事件报告系统（FAERS）分析这些药物与胆道不良事件（AEs）之间的联系，以提高临床安全性。
我们使用OpenVigil 2.1从2013年第一季度至2024年第一季度的FAERS中提取了GLP-1 RAs和DPP-4抑制剂的不良事件数据。采用报告比值比（ROR）、比例报告比值比（PRR）、贝叶斯置信传播神经网络（BCPNN）和经验贝叶斯几何均值（EBGM）等分析方法来评估不良事件风险。
通过标准医学词典分析查询（SMQs）对胆道疾病进行检索，共识别出2215例胆道不良事件报告，其中1709例与GLP-1 RAs相关，506例与DPP-4抑制剂相关。DPP-4抑制剂与胆道疾病显示出显著关联（ROR，3.09；95%置信区间，2.83 - 3.37），特别是西他列汀（ROR，3.46；95%置信区间，3.13 - 3.83）。虽然GLP-1 RAs的总体关联（ROR，1.60；95%置信区间，1.52 - 1.68）不显著，但司美格鲁肽（ROR，4.06；95%置信区间，3.76 - 4.39）和利拉鲁肽（ROR，3.88；95%置信区间，3.50 - 4.29）显示出明显风险。西他列汀、司美格鲁肽和利拉鲁肽与“胆道疾病”、“胆囊相关疾病”、“胆结石相关疾病”和“感染性胆道疾病”的SMQ亚组分析显示出统计学上的显著相关性。值得注意的是，利拉鲁肽、阿格列汀、西他列汀和利奈格列汀与“胆道恶性肿瘤”存在统计学显著关联。与GLP-1 RAs（n = 881，51.55%）相比，DPP-4抑制剂的严重后果比例更高（n = 389，76.88%）。
DPP-4抑制剂可能与胆道疾病有关，需要警惕。虽然GLP-1 RAs的总体关联不显著，但司美格鲁肽、利拉鲁肽和西他列汀等特定药物显示出令人担忧的信号，这表明临床医生需要提高对胆道不良事件风险的认识。
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