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| 蛋白尿是糖尿病肾病治疗最好用的代表参数。蛋白尿的程度与肾脏和心血管事件相关(1)。蛋白尿减少与肾功能降低
减慢相关(2)。阻滞肾素-血管紧张素-醛固酮系统（RAAS）是早期和症状明显的糖尿病肾病治疗的基础，
2型糖尿病和微蛋白尿（IRMA）患者依贝沙坦2研究(3)和依贝沙坦糖尿病肾病试验（IDNT）(1)认为，血管紧张素II受体阻滞剂（ARBs）如依
贝沙坦是2型糖尿病的标准治疗。 阿利吉仑代表一种阻滞RAAS的新原理，直接抑制肾素并作用于限速阶段。该药被批准用于治疗高血压，但也显示出在2型糖尿病和蛋白尿患者可能的肾脏保护作用(4,5)。 ARB和直接肾素抑制剂的联合应用可提高作用于受体水平和级联第一步的RAAS阻滞作用。我们比较了最大推荐剂量的阿利吉仑、依贝沙坦及两者联合应用在2 型糖尿病和蛋白尿患者的抗蛋白尿作用。我们同时评估了治疗对RAAS组成部分和炎症生物标记物、内皮功能障碍和心血管风险的影响。 目的 我们研究直接肾素抑制剂阿利吉仑的抗蛋白尿作用是否与依贝沙坦相当及两者联合的效果。 研 究设计与方法 本研究为一项双盲、随机、交叉试验。1个月的清除期后， 26名患有2型糖尿病、高血压和蛋白尿的患者（>100 mg/天）随机被分为为期2个月的 4个治疗组，随机接受安慰剂、300 mg阿利吉仑一天一次、300 mg依贝沙坦一天一次或联合应用相同剂量的药物。本研究期间患者接受固定剂量的呋塞米。主要终点为蛋白尿改变。次要结果包括24小时血压和肾小球滤过率 （GFR）的改变。 结果 安慰剂蛋白尿几何平均值为258 mg/天（范围84-2,361），24小时血压平均值±SD为140/73±15/8 mmHg，GFR为每1.73平方米89±27 ml/min。与安慰剂相比，阿利吉仑治疗使蛋白尿减少48%（95% CI 27-62）（P<0.001），与依贝沙坦治疗[与安慰剂相比减少58%（42-79），P<0.001]相比无显著差异。联合治疗使蛋白 尿减少71%（59-79），效果好于任何一种药物单独治疗（P<0.001和P=0.028）。白蛋白清除率分数显著减少（与安慰剂相比减少 46%、56%和67%）。阿利吉仑使24小时血压降低3/4 mmHg（NS/P=0.009），依贝沙坦降低12/5 mmHg（P<0.001/P=0.002），联合治疗降低10/6 mmHg（P=0.001/P<0.001）。阿利吉仑使GFR显著降低每1.73平方米4.6（95% CI 0.3-8.8）ml/min，依贝沙坦降低每1.73平方米 8.0（3.6-12.3）ml/min，联合治疗降低每1.73平方米11.7（7.4-15.9）ml/min。 结论 阿利吉仑与依贝沙坦联合应用在有蛋白尿的2型糖尿病患者的抗蛋白尿效果优于任何一种药物的单独治疗。 医学岛推荐原文： Albuminuria is the best available surrogate parameter in the treatment of diabetic nephropathy. Degree of proteinuria is associated with risk of renal and cardiovascular events (1). Proteinuria reduction is associated with a slowing of the decline in renal function (2). Blockade of the renin-angiotensin-aldosterone system (RAAS) is the cornerstone treatment of incipient and overt diabetic nephropathy, and in type 2 diabetes angiotensin II receptor blockers (ARBs) such as irbesartan are considered standard treatment after the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA) 2 Study (3) and Irbesartan Diabetic Nephropathy Trial (IDNT) (1). Aliskiren represents a new principle of blocking the RAAS, inhibiting renin directly and acting at the rate-limiting step. The drug is approved for treatment of hypertension but has also shown renoprotective potential in patients with type 2 diabetes and albuminuria (4,5). Combining an ARB and a direct renin inhibitor could offer improved RAAS blockade by acting both at the receptor level and at the first step of the cascade. We compared the antiproteinuric effect of maximal recommended doses of aliskiren, irbesartan, and the combination in patients with type 2 diabetes and albuminuria. We also assessed the impact of the treatments on RAAS components and biomarkers of inflammation, endothelial dysfunction, and cardiovascular risk. OBJECTIVE We investigated whether the antiproteinuric effect of the direct renin inhibitor aliskiren is comparable to that of irbesartan and the effect of the combination. RESEARCH DESIGN AND METHODS This was a double-blind, randomized, crossover trial. After a 1-month washout period, 26 patients with type 2 diabetes, hypertension, and albuminuria (>100 mg/day) were randomly assigned to four 2-month treatment periods in random order with placebo, 300 mg aliskiren once daily, 300 mg irbesartan once daily, or the combination using identical doses. Patients received furosemide in a stable dose throughout the study. The primary end point was a change in albuminuria. Secondary measures included change in 24-h blood pressure and glomerular filtration rate (GFR). RESULTS Placebo geometric mean albuminuria was 258 mg/day (range 84–2,361), mean ± SD 24-h blood pressure was 140/73 ± 15/8 mmHg, and GFR was 89 ± 27 ml/min per 1.73 m2. Aliskiren treatment reduced albuminuria by 48% (95% CI 27–62) compared with placebo (P < 0.001), not significantly different from the 58% (42–79) reduction with irbesartan treatment (P < 0.001 vs. placebo). Combination treatment reduced albuminuria by 71% (59–79), more than either monotherapy (P < 0.001 and P = 0.028). Fractional clearances of albumin were significantly reduced (46, 56, and 67% reduction vs. placebo). Twenty-four-hour blood pressure was reduced 3/4 mmHg by aliskiren (NS/P = 0.009), 12/5 mmHg by irbesartan (P < 0.001/P = 0.002), and 10/6 mmHg by the combination (P = 0.001/P < 0.001). GFR was significantly reduced 4.6 (95% CI 0.3–8.8) ml/min per 1.73 m2 by aliskiren, 8.0 (3.6–12.3) ml/min per 1.73 m2 by irbesartan, and 11.7 (7.4–15.9) ml/min per 1.73 m2 by the combination. |
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