Effects of Dapagliflozin on Volume Status When Added to Renin-Angiotensin System Inhibitors
Effects of Dapagliflozin on Volume Status When Added to Renin-Angiotensin System Inhibitors
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DOI：
10.3390/jcm8060779
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发表时间：
2019-06-01
影响因子：
3.9
通讯作者：
Heerspink, Hiddo J. L.
中科院分区：
文献类型：
--
作者：
Eickhoff, Mie K.;Dekkers, Claire C. J.;Heerspink, Hiddo J. L.
钠葡萄糖协同转运蛋白2（SGLT 2）抑制剂可降低2型糖尿病患者的心脏和肾脏衰竭风险，可能是由于利尿作用。之前使用SGLT 2抑制剂进行的非安慰剂对照研究观察到健康个体和肾功能保留的2型糖尿病患者的体积标志物变化。目前还不清楚2型糖尿病患者和肾脏损害的迹象是否显示出类似的变化。因此，对两项随机对照试验（n = 69）进行了事后分析，评估了达格列净10 mg/天在2型糖尿病和尿白蛋白/肌酐比值>= 30 mg/g的患者中加入肾素-血管紧张素系统抑制剂时的作用。在持续6周和12周的治疗期开始和结束时收集血液和24小时尿液。确定了与安慰剂相比，达格列净对容量状态的各种标志物的影响。在33例患者中评估了近端肾小管钠重吸收的标志物--锂排泄分数。与安慰剂相比，达格列净使尿糖排泄增加217.2 mmol/24 h（95%置信区间（CI）：从155.7至278.7，p < 0.01），尿渗透压增加60.4 mOsmol/kg（从30.0至90.9，p < 0.01）。部分锂排泄增加了19.6%（从6.7到34.2; p < 0.01），表明近端小管中钠重吸收的抑制。肾素和和肽素分别增加了46.9%（从21.6增加到77.4，p < 0.01）和33.0%（从23.9增加到42.7，p < 0.01）。游离水清除率（FWC）降低了-885.3 mL/24 h（从-1156.2降至-614.3，p < 0.01）。这些容量状态标志物的变化表明，达格列净在2型糖尿病和肾损害患者中发挥渗透和利钠利尿作用，如尿渗透压和锂排泄分数增加所反映。因此，补偿机制被激活以保留钠和水。
Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of heart and kidney failure in patients with type 2 diabetes, possibly due to diuretic effects. Previous non-placebo-controlled studies with SGLT2 inhibitors observed changes in volume markers in healthy individuals and in patients with type 2 diabetes with preserved kidney function. It is unclear whether patients with type 2 diabetes and signs of kidney damage show similar changes. Therefore, a post hoc analysis was performed on two randomized controlled trials (n = 69), assessing effects of dapagliflozin 10 mg/day when added to renin-angiotensin system inhibition in patients with type 2 diabetes and urinary albumin-to-creatinine ratio >= 30 mg/g. Blood and 24-h urine was collected at the start and the end of treatment periods lasting six and 12 weeks. Effects of dapagliflozin compared to placebo on various markers of volume status were determined. Fractional lithium excretion, a marker of proximal tubular sodium reabsorption, was assessed in 33 patients. Dapagliflozin increased urinary glucose excretion by 217.2 mmol/24 h (95% confidence interval (CI): from 155.7 to 278.7, p < 0.01) and urinary osmolality by 60.4 mOsmol/kg (from 30.0 to 90.9, p < 0.01), compared to placebo. Fractional lithium excretion increased by 19.6% (from 6.7 to 34.2; p < 0.01), suggesting inhibition of sodium reabsorption in the proximal tubule. Renin and copeptin increased by 46.9% (from 21.6 to 77.4, p < 0.01) and 33.0% (from 23.9 to 42.7, p < 0.01), respectively. Free water clearance (FWC) decreased by -885.3 mL/24 h (from -1156.2 to -614.3, p < 0.01). These changes in markers of volume status suggest that dapagliflozin exerts both osmotic and natriuretic diuretic effects in patients with type 2 diabetes and kidney damage, as reflected by increased urinary osmolality and fractional lithium excretion. As a result, compensating mechanisms are activated to retain sodium and water.