DataSheet1_Analysis of acute pancreatitis associated with SGLT-2 inhibitors and predictive factors of the death risk: Based on food and drug administration adverse event report system database.ZIP

Background and objectives: The US FDA and Health Canada have successively published potential red flags for acute pancreatitis caused by sodium-dependent glucose transporter 2 inhibitors (SGLT-2i). However, existing studies have focused on case reports. We aimed to assess the possible association of SGLT-2i with acute pancreatitis by analyzing postmarketing adverse events reported in the FDA adverse event reporting system (FAERS), to explore risk factors for SGLT-2i-related acute pancreatitis death, and to build a nomogram.
Methods and Results: We used a disproportionality analysis of suspected acute pancreatitis-related reports in the FAERS database of patients from the use of SGLT-2i from the first quarter of 2013 to the fourth quarter of 2021. Single-factor and multi-factor logistic regression analyses were performed using the relevant clinical information of patients, and risk factors were combined with the age of patients to construct a SGLT-2i risk prediction model for acute pancreatitis-related death. A total of 757 reports were retrieved. The largest number of acute pancreatitis-related cases were caused by canagliflozin (317 reports), which was also the strongest agent associated with acute pancreatitis, with the information component (IC 2.41, lower 95% one-sided confidence interval 2.16), the reporting odds ratio (ROR 5.37, 95% two-sided confidence interval 4.8–5.99), and the empirical Bayesian geometric mean (EBGM 5.32, lower 90% one-sided confidence interval 4.85). The median time to acute pancreatitis was 54 (interquartile range [IQR] 14–131) days, and approximately 83% of adverse events occurred within 6 months. Odds ratio(OR) adjusted by acute pancreatitis and the coadministration of SGLT-2i with dipeptidyl peptidase 4 inhibitor (DPP-4i), glucagon-like peptide 1 analog (GLP-1RA), and angiotensin converting enzyme inhibitor (ACEIs) was 1.39, 1.97, and 1.34, respectively, all of which were statistically significant. Logistic regression analysis showed that different SGLT-2i type and their combinations with statins were independent risk factors for acute pancreatitis mortality in the patients (p < 0.05). The mortality risk prediction model showed good discrimination and clinical applicability in both the training set (AUC 0.708) and the validation set (AUC 0.732).
Conclusion: SGLT-2i may increase the risk of acute pancreatitis especially within the first 6 months of drug administration. Combination with DPP-4i, GLP-1RA or ACEIs significantly increases the risk of acute pancreatitis. In addition, different SGLT-2i type and their combination with statins are risk factors that can predict the risk of death following acute pancreatitis.

背景与目的：美国食品药品监督管理局（US FDA）与加拿大卫生部先后发布了钠-葡萄糖协同转运蛋白2抑制剂（sodium-dependent glucose transporter 2 inhibitors, SGLT-2i）引发急性胰腺炎的潜在风险信号，但现有研究多聚焦于个案报告。本研究旨在通过分析2013年第一季度至2021年第四季度美国FDA不良事件报告系统（FDA Adverse Event Reporting System, FAERS）中的上市后不良事件报告，评估SGLT-2i与急性胰腺炎的潜在关联，探索SGLT-2i相关急性胰腺炎死亡的危险因素，并构建列线图（nomogram）。
方法与结果：本研究对2013年第一季度至2021年第四季度FAERS数据库中使用SGLT-2i患者的疑似急性胰腺炎相关报告开展不成比例分析。利用患者的相关临床信息进行单因素及多因素logistic回归分析，并结合患者年龄构建SGLT-2i相关急性胰腺炎死亡风险预测模型。本研究共检索到757份报告，其中坎格列净（canagliflozin）引发的急性胰腺炎相关病例数最多（317份），同时也是与急性胰腺炎关联最强的药物，其信息分量（information component, IC）为2.41（单侧95%置信下限2.16）、报告比值比（reporting odds ratio, ROR）为5.37（95%双侧置信区间4.8~5.99）、经验贝叶斯几何均值（empirical Bayesian geometric mean, EBGM）为5.32（单侧90%置信下限4.85）。急性胰腺炎的中位发病时间为54天（四分位间距[IQR] 14~131天），约83%的不良事件发生在用药后6个月内。校正后的比值比（odds ratio, OR）显示，SGLT-2i与二肽基肽酶4抑制剂（dipeptidyl peptidase 4 inhibitor, DPP-4i）、胰高糖素样肽-1类似物（glucagon-like peptide 1 analog, GLP-1RA）及血管紧张素转换酶抑制剂（angiotensin converting enzyme inhibitor, ACEIs）联用时的OR值分别为1.39、1.97和1.34，均具有统计学显著性。Logistic回归分析显示，不同类型SGLT-2i及其与他汀类药物联用是患者急性胰腺炎死亡的独立危险因素（p < 0.05）。该死亡风险预测模型在训练集（AUC 0.708）与验证集（AUC 0.732）中均表现出良好的区分度与临床适用性。
结论：SGLT-2i可能增加急性胰腺炎的发病风险，尤其在用药初始6个月内。与DPP-4i、GLP-1RA或ACEIs联用可显著升高急性胰腺炎的发病风险。此外，不同类型的SGLT-2i及其与他汀类药物联用，是预测急性胰腺炎患者死亡风险的独立危险因素。