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Avosentan for overt diabetic nephropathy

热2 qxm123 添加于 2010-5-9 15:06 | 1773 次阅读 | 0 个评论

作者
Mann JFE, Green D, Jamerson K, Ruilope LM, Kuranoff SJ, Littke T, Viberti G
摘要
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.
详细资料
- 关键词: Aged; Blood Pressure/drug effects; Body Weight/drug effects; Diabetic Nephropathies/*drug therapy/mortality; Disease Progression; Endothelins/antagonists & inhibitors; Female; Glomerular Filtration Rate/drug effects; Heart Failure/chemically induced/mortality; Humans; Kaplan-Meiers Estimate; Kidney Failure, Chronic/*drug therapy; Male; Middle Aged; Proteinuria/*drug therapy/mortality; Pyridines/*administration & dosage/*adverse effects; Pyrimidines/*administration & dosage/*adverse e
- 文献种类:期刊
- 期刊名称: Journal of the American Society of Nephrology : JASN
- 期刊缩写: J Am Soc Nephrol
- 期卷页: 2010年第21卷第3期 527-535页
- 地址: Schwabing General Hospital, and Department of Medicine IV, University of Erlangen and KfH Kidney Centre, Munich, Germany
- ISBN: 1046-6673
- 备注:PMID:20167702
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qxm123 的文献笔记订阅

一项研究表明， 2型糖尿病患者的标准治疗中加入Avosentan可减少患者蛋白尿和显性肾病，但会导致显著的液体潴留和充血性心力衰竭。

　　从短期作用来看内皮素拮抗剂avosentan可减少蛋白尿，但尚不明确这种作用是否可防止肾功能的进行性减退。为探讨avosentan对于显性糖尿病肾病进展的作用，德国慕尼黑Schwabing总医院Johannes F.E. Mann等人进行了这项多国、多中心、双盲、安慰剂对照临床研究。

　　研究入选1392例2型糖尿病患者，随机给予患者口服avosentan（25或50mg）或安慰剂，同时继续服用血管紧张素转换酶抑制剂和/或血管紧张素受体阻滞剂。主要复合终点为血清肌酐加倍的时间、终末期肾病（ESRD）或死亡。次要终点包括蛋白/肌酐比（ACR）和心血管结局。

　　由于avosentan组的额外心血管事件，研究者在平均随访4个月（最长16个月）后提前终止了试验。两组之间主要终点发生的频率未见差异。Avosentan显著降低了ACR：服用Avosentan25 mg/日、50 mg/日和安慰剂治疗的患者中，ACR中位降低分别为44.3、49.3和 9.7%。Avosentan组由于不良事件导致的试验药物停用显著多于安慰剂组（19.6％和18.2％对安慰剂组的11.5％），主要不良事件为体液负荷超载和充血性心力衰竭；三组中死亡例数分别为21例（4.6%; P = 0.225）、17例（3.6%; P = 0.194和12例（2.6%）。

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