Department of Nephrology, Charité - Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany; Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Germany; The First Clinical Medical College of Jinan University, The First Affiliated Hospital of Jinan University, Guangzhou, China.
Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Germany; Translational Medicine & Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstr. 65, 88397 Biberach, Germany.
Biomed Pharmacother. 2022 Sep;153:113357. doi: 10.1016/j.biopha.2022.113357. Epub 2022 Jul 2.
The CREDENCE trial testing canagliflozin and the EMPA-REG OUTCOME trial testing empagliflozin suggest different effects on acute kidney injury (AKI). AKI diagnosis was mainly made based on changes of serum creatinine (sCr) although this also reflect mode of action of SGLT-2 inhibitors. We analyzed both compounds in a rat AKI model. The renal ischemia-reperfusion injury (I/R) model was used. Four groups were analyzed: sham, I/R+placebo, I/R+canagliflozin (30 mg/kg/day), I/R+ empagliflozin (10 mg/kg/day). Glucose excretion was comparable in both treatment groups indicating comparable SGLT-2 inhibition. Comparing GFR surrogate markers after I/R (sCr and blood urea nitrogen (BUN)), sCr peaked 24 h after I/R, BUN after 48 h, respectively, in the placebo treated I/R group. At all investigated time points after I/R sCr and BUN was higher in the I/R + canagliflozin group as compared to placebo treated rats, whereas the empagliflozin group did not differ from the placebo group. I/R led to tubular dilatation and necrosis. Empagliflozin was able to reduce that finding whereas canagliflozin had no effect. Treatment with empagliflozin also resulted in a significant reduction in an improved inflammatory score (p = 0.006). Renal expression of kidney injury molecule-1 (KIM-1) increased after I/R and empagliflozin but not canagliflozin significantly alleviated KIM-1 expression. I/R reduced urinary miR-26a excretion. Empagliflozin but not canagliflozin was able to restore normal levels of urinary miR-26a. This study in an AKI model confirmed safety data in the EMPA-REG OUTCOME trial suggesting that empagliflozin might reduce AKI risk. The empagliflozin effects on KIM-1 and miR-26a might indicate beneficial regulation of inflammation. These data should stimulate clinical studies with AKI risk as primary endpoint.
CREDENCE 试验测试卡格列净和 EMPA-REG OUTCOME 试验测试恩格列净表明对急性肾损伤 (AKI) 的影响不同。AKI 的诊断主要基于血清肌酐 (sCr) 的变化，尽管这也反映了 SGLT-2 抑制剂的作用模式。我们在大鼠 AKI 模型中分析了这两种化合物。使用肾缺血再灌注损伤 (I/R) 模型。分析了四组：假手术组、I/R+安慰剂组、I/R+卡格列净 (30mg/kg/天) 组、I/R+恩格列净 (10mg/kg/天) 组。两组治疗的葡萄糖排泄量相当，表明 SGLT-2 抑制作用相当。比较 I/R 后肾小球滤过率 (GFR) 替代标志物 (sCr 和血尿素氮 (BUN))，I/R 后 24 小时 sCr 峰值，I/R 后 48 小时 BUN 峰值，在安慰剂处理的 I/R 组中。与安慰剂治疗的大鼠相比，I/R+卡格列净组在所有研究时间点的 sCr 和 BUN 均升高，而恩格列净组与安慰剂组无差异。I/R 导致肾小管扩张和坏死。恩格列净能够减少这种发现，而卡格列净没有影响。恩格列净治疗还导致炎症评分显著降低 (p=0.006)。I/R 后肾损伤分子-1 (KIM-1) 的表达增加，恩格列净增加，而卡格列净则没有。I/R 减少了尿 miR-26a 的排泄。恩格列净但不是卡格列净能够恢复正常水平的尿 miR-26a。这项 AKI 模型研究证实了 EMPA-REG OUTCOME 试验的安全性数据，表明恩格列净可能降低 AKI 风险。恩格列净对 KIM-1 和 miR-26a 的作用可能表明对炎症的有益调节。这些数据应刺激以 AKI 风险为主要终点的临床研究。
