Diabetes, Endocrinology, and Obesity Branch, NIDDK, Bethesda, MD, USA.
Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
Diabetes Metab Res Rev. 2017 Nov;33(8). doi: 10.1002/dmrr.2924. Epub 2017 Sep 29.
Regulatory agencies have concluded that sodium glucose cotransporter 2 (SGLT2) inhibitors lead to ketoacidosis, but published literature on this point remains controversial.
We searched the FDA Adverse Event Reporting System (FAERS) for reports of acidosis in patients treated with canagliflozin, dapagliflozin, or empagliflozin (from the date of each drug's FDA approval until May 15, 2015). We compared the number of SGLT2 inhibitor-related reports to reports of acidosis in patients treated with the 2 most commonly used DPP4 inhibitors: sitagliptin and saxagliptin. We estimated relative risks of acidosis by relating the number of reports to cumulative drug sales (a surrogate for patient exposure).
FAERS contained 259 reports of acidosis (including 192 reports of ketoacidosis) for SGLT2 inhibitors compared with 477 reports of acidosis for DPP4 inhibitors (including 71 reports of ketoacidosis). Based on estimated patient exposure, the overall risk of developing acidosis was ~14-fold higher for SGLT2 inhibitors. Among 51 SGLT2 inhibitor-related reports with quantifiable metabolic information, 20 cases occurred in patients with type 1 diabetes (T1D), 25 in type 2 diabetes (T2D), and 6 in patients with unspecified type of diabetes. After excluding patients with T1D and focusing on patients identified as having T2D, we estimate that SGLT2 inhibitors were associated with ~7-fold increase in developing acidosis. Seventy-one percent had euglycemic ketoacidosis.
Our results support the FDA's warning that SGLT2 inhibitors lead to ketoacidosis, as evidenced by an increased reporting rate for acidosis above that in a comparator population treated with DPP4 inhibitors.
监管机构得出结论，钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂会导致酸中毒，但关于这一点的已发表文献仍存在争议。
我们在 FDA 不良事件报告系统（FAERS）中搜索了接受卡格列净、达格列净或恩格列净治疗的患者酸中毒报告（从每种药物获得 FDA 批准之日起至 2015 年 5 月 15 日）。我们将 SGLT2 抑制剂相关报告的数量与接受最常用的 2 种 DPP4 抑制剂（西格列汀和沙格列汀）治疗的患者酸中毒报告的数量进行了比较。我们通过将报告数量与累计药物销售额（患者暴露的替代指标）相关联，估计酸中毒的相对风险。
FAERS 包含 259 例 SGLT2 抑制剂相关酸中毒报告（包括 192 例酮症酸中毒报告），而 DPP4 抑制剂相关酸中毒报告为 477 例（包括 71 例酮症酸中毒报告）。基于估计的患者暴露量，SGLT2 抑制剂发生酸中毒的总体风险约高 14 倍。在 51 例具有可量化代谢信息的 SGLT2 抑制剂相关报告中，20 例发生在 1 型糖尿病（T1D）患者中，25 例发生在 2 型糖尿病（T2D）患者中，6 例发生在未明确类型糖尿病患者中。排除 T1D 患者并关注被确定为 T2D 的患者后，我们估计 SGLT2 抑制剂与酸中毒的发生风险增加约 7 倍。71%的患者为血糖正常性酮症酸中毒。
我们的结果支持 FDA 的警告，即 SGLT2 抑制剂会导致酮症酸中毒，这一点可通过酸中毒报告率的增加得到证明，该报告率高于接受 DPP4 抑制剂治疗的对照组人群。
