Department of Medicine, Division of Nephrology (D.Z.I.C., M.M., V.L., A.L.) and the Department of Medicine, Division of Endocrinology (B.A.P.), Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada; Boehringer Ingelheim Canada Ltd./Ltée, Burlington, Ontario, Canada (N.S.); Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT (N.M.F., M.v.E.); and Boehringer Ingelheim Pharma GmbH & Co.KG, Ingelheim, Germany (H.J.W., O.E.J., U.C.B.).
Circulation. 2014 Feb 4;129(5):587-97. doi: 10.1161/CIRCULATIONAHA.113.005081. Epub 2013 Dec 13.
The primary objective of this mechanistic open-label, stratified clinical trial was to determine the effect of 8 weeks' sodium glucose cotransporter 2 inhibition with empagliflozin 25 mg QD on renal hyperfiltration in subjects with type 1 diabetes mellitus (T1D).
Inulin (glomerular filtration rate; GFR) and paraaminohippurate (effective renal plasma flow) clearances were measured in individuals stratified based on having hyperfiltration (T1D-H, GFR ≥ 135 mL/min/1.73m(2), n=27) or normal GFR (T1D-N, GFR 90-134 mL/min/1.73m(2), n=13) at baseline. Renal function and circulating levels of renin-angiotensin-aldosterone system mediators and NO were measured under clamped euglycemic (4-6 mmol/L) and hyperglycemic (9-11 mmol/L) conditions at baseline and end of treatment. During clamped euglycemia, hyperfiltration was attenuated by -33 mL/min/1.73m(2) with empagliflozin in T1D-H, (GFR 172±23-139±25 mL/min/1.73 m(2), P<0.01). This effect was accompanied by declines in plasma NO and effective renal plasma flow and an increase in renal vascular resistance (all P<0.01). Similar significant effects on GFR and renal function parameters were observed during clamped hyperglycemia. In T1D-N, GFR, other renal function parameters, and plasma NO were not altered by empagliflozin. Empagliflozin reduced hemoglobin A1c significantly in both groups, despite lower insulin doses in each group (P≤0.04).
In conclusion, short-term treatment with the sodium glucose cotransporter 2 inhibitor empagliflozin attenuated renal hyperfiltration in subjects with T1D, likely by affecting tubular-glomerular feedback mechanisms.
http://www.clinicaltrials.gov. Unique identifier: NCT01392560.
本机制开放性、分层临床试验的主要目的是确定 8 周依帕列净（钠-葡萄糖共转运蛋白 2 抑制剂）25mgQD 治疗对 1 型糖尿病（T1D）患者肾高滤过的影响。
根据基线时是否存在高滤过（T1D-H，GFR≥135ml/min/1.73m²，n=27）或正常 GFR（T1D-N，GFR 90-134ml/min/1.73m²，n=13）将个体分层，测量菊粉（肾小球滤过率；GFR）和对氨马尿酸（有效肾血浆流量）清除率。在基线和治疗结束时，在夹闭的正常血糖（4-6mmol/L）和高血糖（9-11mmol/L）条件下测量肾功能和循环肾素-血管紧张素-醛固酮系统介质和一氧化氮（NO）水平。在夹闭的正常血糖状态下，依帕列净使 T1D-H 的高滤过减少了-33ml/min/1.73m²（GFR 从 172±23ml/min/1.73m²降至 139±25ml/min/1.73m²，P<0.01）。这种作用伴随着血浆 NO 和有效肾血浆流量下降以及肾血管阻力增加（均 P<0.01）。在夹闭高血糖状态下，也观察到对 GFR 和肾功能参数的类似显著影响。在 T1D-N 中，依帕列净并未改变 GFR、其他肾功能参数和血浆 NO。两组的血红蛋白 A1c 均显著降低，尽管每组的胰岛素剂量均较低（P≤0.04）。
总之，短期应用钠-葡萄糖共转运蛋白 2 抑制剂依帕列净可减轻 T1D 患者的肾高滤过，可能是通过影响肾小管-肾小球反馈机制。
