Schwabing General Hospital, and Department of Medicine IV, University of Erlangen and KfH Kidney Centre, Munich, Germany.
J Am Soc Nephrol. 2010 Mar;21(3):527-35. doi: 10.1681/ASN.2009060593. Epub 2010 Feb 18.
In the short term, the endothelin antagonist avosentan reduces proteinuria, but whether this translates to protection from progressive loss of renal function is unknown. We examined the effects of avosentan on progression of overt diabetic nephropathy in a multicenter, multinational, double-blind, placebo-controlled trial. We randomly assigned 1392 participants with type 2 diabetes to oral avosentan (25 or 50 mg) or placebo in addition to continued angiotensin-converting enzyme inhibition and/or angiotensin receptor blockade. The composite primary outcome was the time to doubling of serum creatinine, ESRD, or death. Secondary outcomes included changes in albumin-to-creatinine ratio (ACR) and cardiovascular outcomes. We terminated the trial prematurely after a median follow-up of 4 months (maximum 16 months) because of an excess of cardiovascular events with avosentan. We did not detect a difference in the frequency of the primary outcome between groups. Avosentan significantly reduced ACR: In patients who were treated with avosentan 25 mg/d, 50 mg/d, and placebo, the median reduction in ACR was 44.3, 49.3, and 9.7%, respectively. Adverse events led to discontinuation of trial medication significantly more often for avosentan than for placebo (19.6 and 18.2 versus 11.5% for placebo), dominated by fluid overload and congestive heart failure; death occurred in 21 (4.6%; P = 0.225), 17 (3.6%; P = 0.194), and 12 (2.6%), respectively. In conclusion, avosentan reduces albuminuria when added to standard treatment in people with type 2 diabetes and overt nephropathy but induces significant fluid overload and congestive heart failure.
短期内，内皮素拮抗剂阿伏生坦可减少蛋白尿，但这是否能防止肾功能进行性丧失尚不清楚。我们在一项多中心、多国、双盲、安慰剂对照试验中研究了阿伏生坦对显性糖尿病肾病进展的影响。我们将 1392 名 2 型糖尿病患者随机分为口服阿伏生坦（25 或 50mg）或安慰剂组，两组均继续接受血管紧张素转换酶抑制和/或血管紧张素受体阻断治疗。复合主要终点为血清肌酐倍增、终末期肾病或死亡的时间。次要终点包括白蛋白/肌酐比值（ACR）和心血管结局的变化。由于阿伏生坦组心血管事件过多，我们在中位随访 4 个月（最长 16 个月）后提前终止了试验。我们未发现两组主要结局的发生率存在差异。阿伏生坦显著降低 ACR：接受阿伏生坦 25mg/d、50mg/d 和安慰剂治疗的患者，ACR 的中位数降低分别为 44.3%、49.3%和 9.7%。不良事件导致试验药物停药的发生率阿伏生坦显著高于安慰剂（19.6%和 18.2%比 11.5%），主要原因是液体超负荷和充血性心力衰竭；死亡分别发生在 21 例（4.6%；P=0.225）、17 例（3.6%；P=0.194）和 12 例（2.6%）。总之，阿伏生坦在 2 型糖尿病和显性肾病患者的标准治疗基础上加用可减少白蛋白尿，但会引起明显的液体超负荷和充血性心力衰竭。
