Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Department of Nephrology, Ziekenhuisgroep Twente, Almelo and Hengelo, the Netherlands.
Diabetes Obes Metab. 2017 Oct;19(10):1363-1370. doi: 10.1111/dom.12936. Epub 2017 Jun 8.
Albuminuria reduction is essential for renal and cardiovascular protection. We characterized the efficacy of dapagliflozin, a sodium-glucose co-transporter 2 inhibitor, on albuminuria. Secondly, we assessed whether the albuminuria-lowering effect varies among patients, and whether this variability in response is reproducible.
A double-blind, randomized, placebo controlled crossover trial was conducted. Patients with type 2 diabetes and albumin:creatinine ratio > 100 mg/g on a stable dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) were enrolled. Patients were assigned to 6-week treatment periods with dapagliflozin 10 mg/d or placebo in random order, separated by 6-weeks wash-out periods. After the 2 treatment periods, half of the patients were re-exposed for 6 weeks to dapagliflozin 10 mg/d. Primary outcome was change in 24-hour urinary albumin excretion rate (24 h UAE). To assess reproducibility in individual albuminuria response, responses from the first and second exposure to dapagliflozin were correlated.
A total of 33 patients (age, 61 years; female gender, 24.2%; median 24 h UAE, 470 mg/24 h) completed the study. Dapagliflozin, as compared to placebo, reduced 24 h UAE by 36.2% (95% CI, 22.9-47.2; P < .001). Systolic blood pressure fell by 5.2 mm Hg (95% CI, 0.5-10.0) and eGFR by 5.3 (95% CI, 2.7-8.0). All effects were reversible directly after treatment discontinuation. In a subgroup of 15 patients who were exposed twice to dapagliflozin, 24 h UAE responses showed a large variation among individuals: first exposure (range, -76% to +52%) and second exposure (-90% to +95%) and first and second individual response were significantly correlated (r = 0.69 [95% CI, 0.27-0.89]; P < .004).
Dapagliflozin significantly reduces albuminuria when given as adjunct to ACEi or ARB. The albuminuria response to dapagliflozin markedly varies among patients. This variation is not a random phenomenon, but is reproducible upon re-exposure. These data support personalized therapy approaches to optimize diabetic kidney disease.
白蛋白尿的减少对于肾脏和心血管保护至关重要。我们研究了钠-葡萄糖共转运蛋白 2 抑制剂达格列净对白蛋白尿的疗效。其次，我们评估了白蛋白尿降低的效果是否在患者之间存在差异，以及这种反应的变异性是否具有可重复性。
进行了一项双盲、随机、安慰剂对照交叉试验。纳入了正在服用血管紧张素转换酶抑制剂（ACEi）或血管紧张素受体阻滞剂（ARB）且稳定剂量下白蛋白与肌酐比值（albumin:creatinine ratio）>100mg/g 的 2 型糖尿病患者。患者随机分为达格列净 10mg/d 或安慰剂治疗 6 周，然后进行 6 周洗脱期。在 2 个治疗期之后，一半的患者再次暴露于达格列净 10mg/d 6 周。主要结局是 24 小时尿白蛋白排泄率（24 h UAE）的变化。为了评估个体白蛋白尿反应的可重复性，将第一次和第二次暴露于达格列净的反应进行了相关性分析。
共有 33 名患者（年龄 61 岁；女性 24.2%；中位数 24 h UAE 470mg/24 h）完成了研究。与安慰剂相比，达格列净降低了 24 h UAE 36.2%（95%置信区间，22.9-47.2；P < .001）。收缩压下降了 5.2mmHg（95%置信区间，0.5-10.0），eGFR 下降了 5.3（95%置信区间，2.7-8.0）。所有的效果在治疗停止后直接逆转。在 15 名再次暴露于达格列净的患者亚组中，个体间的 24 h UAE 反应差异很大：第一次暴露（范围，-76%至+52%）和第二次暴露（-90%至+95%），并且第一次和第二次个体反应显著相关（r=0.69 [95%置信区间，0.27-0.89]；P < .004）。
达格列净作为 ACEi 或 ARB 的辅助治疗，可显著降低白蛋白尿。达格列净对白蛋白尿的反应在患者之间差异很大。这种变异性不是随机现象，而是在再次暴露时可重现的。这些数据支持采用个性化治疗方法来优化糖尿病肾病的治疗。
