钠-葡萄糖共转运蛋白2抑制剂致急性肾损伤风险:基于美国FDA不良事件报告系统相关数据的研究

Risks of acute kidney injury due to sodium glucose co-transporter 2 inhibitors: a study based on the related data in the US Food and Drug Administration Adverse Event Reporting System

目的评价钠-葡萄糖共转运蛋白2(SGLT2)抑制剂(卡格列净、达格列净、恩格列净和埃格列净)致急性肾损伤(AKI)的风险。方法检索美国FDA不良事件报告系统(FAERS)2013年1月1日至2018年9月30日收到的SGLT2抑制剂与非SGLT2抑制剂致AKI事件的报告,采用报告比值比(ROR)法,分析上述药物与所有患者和糖尿病患者发生AKI的关系。结果共检索到SGLT2抑制剂致AKI事件报告2949份(占数据库检索时限内收到的117843份AKI事件报告的2.50%),非SGLT2抑制剂致AKI事件报告114894份。整体SGLT2抑制剂、卡格列净、达格列净、恩格列净致所有患者AKI事件的ROR分别为4.14(95%CI:3.98~4.30)、5.58(95%CI:5.35~5.83)、2.62(95%CI:2.35~2.92)和1.96(95%CI:1.76~2.19),致糖尿病患者AKI事件的ROR分别为2.84(95%CI:2.71~2.98)、3.90(95%CI:3.69~4.12)、1.70(95%CI:1.48~1.94)和1.30(95%CI:1.15~1.48),因埃格列净上市较晚,致AKI事件报告少于3份,故未进行相关统计。联合用药分析显示,SGLT2抑制剂与利尿剂联用致所有患者AKI事件的ROR为8.05(95%CI:7.10~9.13),较单用SGLT2抑制剂致所有患者AKI事件的ROR增加80.90%,致糖尿病患者AKI事件的ROR为6.07(95%CI:5.27~7.00),较单用SGLT2抑制剂致糖尿病患者AKI事件的ROR增加了92.09%;SGLT2抑制剂与非甾体类抗炎药联用致所有患者AKI事件的ROR为5.87(95%CI:4.89~7.04),较单用SGLT2抑制剂致所有患者AKI事件的ROR增加了39.43%,致糖尿病患者AKI事件的ROR为4.66(95%CI:3.79~5.74),较单用SGLT2抑制剂致糖尿病患者AKI事件的ROR增加了61.25%;SGLT2抑制剂与血管紧张素转换酶抑制剂/血管紧张素受体拮抗剂联用致所有患者AKI事件的ROR为5.60(95%CI:5.12~6.14),较单用SGLT2抑制剂致所有患者AKI事件的ROR增加25.56%,致糖尿病患者AKI事件的ROR为4.05(95%CI:3.66~4.48),较单用SGLT2抑制剂致糖尿病患者AKI事件的ROR增加了27.36%。结论SGLT2抑制剂可能增加致AKI的风险,该风险主要来自卡格列净,提示使用达格列净和恩格列净相对比较安全。联合应用SGLT2抑制剂与利尿剂或非甾体类抗炎药可能增加发生AKI的风险。

Objective To evaluate the risk of acute kidney injury (AKI) induced by sodium glucose co-transporter 2 (SGLT2) inhibitors (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin).MethodsReports of AKI events induced by SGLT2 inhibitors and non-SGLT2 inhibitors received from January 1, 2013 to September 30, 2018 in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database were collected. The relationship between the drugs mentioned above and the AKI events in all patients and especially in patients with diabetes mellitus, respectively, were analyzed by the method of reporting odds ratio (ROR).ResultsA total of 2 949 reports of SGLT2 inhibitors-induced AKI (2.50% of 117 843 AKI event reports in the database during the study period), and 114 894 reports of non-SGLT2 inhibitors-induced AKI were retrieved from the database. The ROR values of AKI events induced by overall SGLT2 inhibitors, canagliflozin, dapagliflozin, and empagliflozin in all patients were 4.14 (95%CI: 3.98-4.30), 5.58 (95%CI: 5.35-5.83), 2.62 (95%CI: 2.35-2.92), and 1.96 (95%CI: 1.76-2.19), respectively, and in patients with diabetes mellitus were 2.84 (95%CI: 2.71-2.98), 3.90 (95%CI: 3.69-4.12), 1.70 (95%CI: 1.48-1.94), and 1.30 (95%CI: 1.15-1.48), respectively. Due to the short time to market, less than 3 reports of AKI events induced by ertugliflozin were reported, thus ROR analysis was not conducted for ertugliflozin. The analyses of combined medication showed that in all patients, the ROR value of AKI events induced by SGLT2 inhibitors was 8.05 (95%CI: 7.10-9.13) when SGLT2 inhibitors were combined with diuretics, which increased by 80.90% compared with that when SGLT2 inhibitors were given alone and in patients with diabetes mellitus, it was 6.07 (95%CI: 5.27-7.00), which increased by 92.09%;in all patients, the ROR value of AKI events induced by SGLT2 inhibitors was 5.87 (95%CI: 4.89-7.04) when SGLT2 inhibitors were combined with non-steroidal anti-inflammatory drugs (NSAID), which increased by 39.43% compared with that when SGLT2 inhibitors were given alone and in patients with diabetes mellitus, it was 4.66 (95%CI: 3.79-5.74), which increased by 61.25%;in all patients, the ROR value of AKI events induced by SGLT2 inhibitors was 5.60 (95%CI: 5.12-6.14) when SGLT2 inhibitors were combined with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, which increased by 25.56% compared with that when SGLT2 inhibitors were given alone and in patients with diabetes mellitus, it was 4.05 (95%CI: 3.66-4.48), which increased by 27.36%.ConclusionsSGLT2 inhibitors might increase the risk of AKI and this risk was mainly from canagliflozin, suggesting that dapagliflozin and empagliflozin were relatively safe to patients. The risk of AKI might increase when SGLT2 inhibitors were combined with diuretics or NSAID.