Cherney David, Lund Søren S, Perkins Bruce A, Groop Per-Henrik, Cooper Mark E, Kaspers Stefan, Pfarr Egon, Woerle Hans J, von Eynatten Maximilian
Toronto General Hospital, 585 University Ave, 8N-845, Toronto, ON, Canada, M5G 2N2.
Department of Medicine, Division of Nephrology, and Department of Physiology, University of Toronto, Toronto, ON, Canada.
Diabetologia. 2016 Sep;59(9):1860-70. doi: 10.1007/s00125-016-4008-2. Epub 2016 Jun 17.
AIMS/HYPOTHESIS: Sodium glucose cotransporter 2 (SGLT2) inhibition lowers HbA1c, systolic BP (SBP) and weight in patients with type 2 diabetes and reduces renal hyperfiltration associated with type 1 diabetes, suggesting decreased intraglomerular hypertension. As lowering HbA1c, SBP, weight and intraglomerular pressure is associated with anti-albuminuric effects in diabetes, we hypothesised that SGLT2 inhibition would reduce the urine albumin-to-creatinine ratio (UACR) to a clinically meaningful extent.
We examined the effect of the SGLT2 inhibitor empagliflozin on UACR by pooling data from patients with type 2 diabetes and prevalent microalbuminuria (UACR = 30-300 mg/g; n = 636) or macroalbuminuria (UACR > 300 mg/g; n = 215) who participated in one of five phase III randomised clinical trials. Primary assessment was defined as percentage change in geometric mean UACR from baseline to week 24.
After controlling for clinical confounders including baseline log-transformed UACR, HbA1c, SBP and estimated GFR (according to the Modification of Diet in Renal Disease [MDRD] formula), treatment with empagliflozin significantly reduced UACR in patients with microalbuminuria (-32% vs placebo; p < 0.001) or macroalbuminuria (-41% vs placebo; p < 0.001). Intriguingly, in regression models, most of the UACR-lowering effect with empagliflozin was not explained by SGLT2 inhibition-related improvements in HbA1c, SBP or weight.
CONCLUSIONS/INTERPRETATION: In patients with type 2 diabetes and either micro- or macroalbuminuria, empagliflozin reduced UACR by a clinically meaningful amount. This effect was largely independent of the known metabolic or systemic haemodynamic effects of this drug class. Our results further support a direct renal effect of SGLT2 inhibitors. Prospective studies are needed to explore the potential of this intervention to alter the course of kidney disease in high-risk patients with diabetes.
Clinicaltrials.gov NCT01177813 (study 1); NCT01159600 (study 2); NCT01159600 (study 3); NCT01210001 (study 4); and NCT01164501 (study 5).
目的/假设：钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂可降低2型糖尿病患者的糖化血红蛋白（HbA1c）、收缩压（SBP）和体重，并减少与1型糖尿病相关的肾高滤过，提示肾小球内高血压降低。由于降低HbA1c、SBP、体重和肾小球内压力与糖尿病患者的抗蛋白尿作用相关，我们推测SGLT2抑制可将尿白蛋白与肌酐比值（UACR）降低至具有临床意义的程度。
我们通过汇总参与五项III期随机临床试验之一的2型糖尿病合并微量白蛋白尿（UACR = 30 - 300 mg/g；n = 636）或大量白蛋白尿（UACR > 300 mg/g；n = 215）患者的数据，研究SGLT2抑制剂恩格列净对UACR的影响。主要评估定义为从基线到第24周几何平均UACR的百分比变化。
在控制包括基线对数转换后的UACR、HbA1c、SBP和估计肾小球滤过率（根据肾脏病饮食改良[MDRD]公式）等临床混杂因素后，恩格列净治疗显著降低了微量白蛋白尿患者（-32% vs 安慰剂；p < 0.001）或大量白蛋白尿患者（-41% vs 安慰剂；p < 0.001）的UACR。有趣的是，在回归模型中，恩格列净降低UACR的大部分作用并非由SGLT2抑制相关的HbA1c、SBP或体重改善所解释。
结论/解读：在2型糖尿病合并微量或大量白蛋白尿的患者中，恩格列净将UACR降低至具有临床意义的程度。这种作用在很大程度上独立于该类药物已知的代谢或全身血流动力学效应。我们的结果进一步支持SGLT2抑制剂对肾脏的直接作用。需要进行前瞻性研究以探索这种干预措施改变糖尿病高危患者肾脏疾病进程的潜力。
Clinicaltrials.gov NCT01177813（研究1）；NCT01159600（研究2）；NCT01159600（研究3）；NCT01210001（研究4）；以及NCT01164501（研究5）。
