Background:The cardiorenal effects of sodium-glucose cotransporter 2 inhibition (empagliflozin 25 mg QD) combined with angiotensin-converting enzyme inhibition (ramipril 10 mg QD) were assessed in this mechanistic study in patients with type 1 diabetes with potential renal hyperfiltration.Methods:Thirty patients (out of 31 randomized) completed this double-blind, placebo-controlled, crossover trial. Recruitment was stopped early because of an unexpectedly low proportion of patients with hyperfiltration. Measurements were obtained after each of the 6 treatment phases over 19 weeks: (1) baseline without treatment, (2) 4-week run-in with ramipril treatment alone, (3) 4-week combined empagliflozin-ramipril treatment, (4) a 4-week washout, (5) 4-week combined placebo-ramipril treatment, and (6) 1-week follow-up. The primary end point was glomerular filtration rate (GFR) after combination treatment with empagliflozin-ramipril compared with placebo-ramipril. GFR was corrected for ramipril treatment alone before randomization. At the end of study phase, the following outcomes were measured under clamped euglycemia (4 to 6 mmol/L): inulin (GFR) and para-aminohippurate (effective renal plasma flow) clearances, tubular sodium handling, ambulatory blood pressure, arterial stiffness, heart rate variability, noninvasive cardiac output monitoring, plasma and urine biochemistry, markers of the renin-angiotensin-aldosterone system, and oxidative stress.Results:Combination treatment with empagliflozin-ramipril resulted in an 8 mL/min/1.73 m² lower GFR compared with placebo-ramipril treatment (P=0.0061) without significant changes to effective renal plasma flow. GFR decrease was accompanied by a 21.3 mL/min lower absolute proximal fluid reabsorption rate (P=0.0092), a 3.1 mmol/min lower absolute proximal sodium reabsorption rate (P=0.0056), and a 194 ng/mmol creatinine lower urinary 8-isoprostane level (P=0.0084) relative to placebo-ramipril combination treatment. Sodium-glucose cotransporter 2 inhibitor/angiotensin-converting enzyme inhibitor combination treatment resulted in additive blood pressure–lowering effects (clinic systolic blood pressure lower by 4 mm Hg [P=0.0112]; diastolic blood pressure lower by 3 mm Hg [P=0.0032]) in conjunction with a 94.5 dynes × sex/cm⁵ lower total peripheral resistance (P=0.0368). There were no significant changes observed to ambulatory blood pressure, arterial stiffness, heart rate variability, or cardiac output with the addition of empagliflozin.Conclusions:Adding sodium-glucose cotransporter 2 inhibitor treatment to angiotensin-converting enzyme inhibitor resulted in an expected GFR dip, suppression of oxidative stress markers, additive declines in blood pressure and total peripheral resistance. These changes are consistent with a protective physiologic profile characterized by the lowering of intraglomerular pressure and related cardiorenal risk when adding a sodium-glucose cotransporter 2 inhibitor to conservative therapy.Registration:URL: https://www.clinicaltrials.gov; Unique identifier: NCT02632747.

中文翻译：

---

SGLT2 和血管紧张素转换酶联合抑制的肾脏和血管效应

背景：在这项机制研究中评估了钠-葡萄糖协同转运蛋白 2 抑制剂（恩格列净 25 mg QD）联合血管紧张素转换酶抑制剂（雷米普利 10 mg QD）对潜在肾高滤过的 1 型糖尿病患者的心肾效应。方法： 30 名患者（随机分配的 31 名患者）完成了这项双盲、安慰剂对照、交叉试验。由于超滤患者的比例出乎意料地低，因此提前停止了招募。在 19 周的 6 个治疗阶段中的每一个阶段后都获得了测量值：(1) 基线未治疗，(2) 雷米普利单独治疗 4 周磨合期，(3) 4 周依帕列净-雷米普利联合治疗，(4) 4 周清除，(5) 4 周安慰剂-雷米普利联合治疗，以及 (6) 1 周随访。主要终点是与安慰剂雷米普利相比，恩格列净-雷米普利联合治疗后的肾小球滤过率 (GFR)。GFR 在随机分组前针对单独的雷米普利治疗进行了校正。在研究阶段结束时，在钳制血糖正常（4 至 6 毫摩尔/升）的情况下测量了以下结果：菊糖 (GFR) 和对氨基马尿酸盐（有效肾血浆流量）清除率、肾小管钠处理、动态血压、动脉硬度、心率变异性、无创心输出量监测、血浆和尿液生化、肾素-血管紧张素-醛固酮系统标志物和氧化应激。结果：与依格列净-雷米普利联合治疗导致 8 mL/min/1.73 m GFR 在随机分组前针对单独的雷米普利治疗进行了校正。在研究阶段结束时，在钳制血糖正常（4 至 6 毫摩尔/升）的情况下测量了以下结果：菊糖 (GFR) 和对氨基马尿酸盐（有效肾血浆流量）清除率、肾小管钠处理、动态血压、动脉硬度、心率变异性、无创心输出量监测、血浆和尿液生化、肾素-血管紧张素-醛固酮系统标志物和氧化应激。结果：与依格列净-雷米普利联合治疗导致 8 mL/min/1.73 m GFR 在随机分组前针对单独的雷米普利治疗进行了校正。在研究阶段结束时，在钳制血糖正常（4 至 6 毫摩尔/升）的情况下测量了以下结果：菊糖 (GFR) 和对氨基马尿酸盐（有效肾血浆流量）清除率、肾小管钠处理、动态血压、动脉硬度、心率变异性、无创心输出量监测、血浆和尿液生化、肾素-血管紧张素-醛固酮系统标志物和氧化应激。结果：与依格列净-雷米普利联合治疗导致 8 mL/min/1.73 m²与安慰剂-雷米普利治疗相比，GFR 更低（P =0.0061），有效肾血浆流量没有显着变化。GFR 降低伴随着近端液体绝对重吸收率降低 21.3 mL/min（P = 0.0092）、近端钠重吸收率绝对值降低 3.1 mmol/min（P = 0.0056）和下尿 8-194 ng/mmol 肌酐异前列烷水平 ( P =0.0084) 相对于安慰剂-雷米普利联合治疗。钠-葡萄糖协同转运蛋白 2 抑制剂/血管紧张素转换酶抑制剂联合治疗可产生附加的降压效果（临床收缩压降低 4 mm Hg [ P = 0.0112]；舒张压降低 3 mm Hg [P =0.0032]) 结合 94.5 达因 × 性别/厘米⁵较低的总外周阻力 ( P=0.0368）。添加恩格列净后，动态血压、动脉僵硬度、心率变异性或心输出量没有观察到显着变化。结论：将钠-葡萄糖协同转运蛋白 2 抑制剂治疗添加到血管紧张素转换酶抑制剂导致预期的 GFR 下降，抑制氧化应激标记物，血压和总外周阻力的累加下降。这些变化与保护性生理特征一致，其特征是在保守治疗中加入钠-葡萄糖协同转运蛋白 2 抑制剂后，肾小球内压力和相关心肾风险降低。注册：URL：https://www.clinicaltrials.gov；唯一标识符：NCT02632747。