肾素-血管紧张素系统阻滞不能减缓糖尿病肾病，但能减缓视网膜病变

Neither angiotensin-converting enzyme inhibitors nor angiotensin-receptor blockers slow nephropathy progression in type 1 diabetes, according to a report in the July 2 issue of the New England Journal of Medicine.

Both agents for blocking the renin-angiotensin system failed to reduce the rate of microalbuminuria or to mitigate the decline of renal function and the development of morphologic lesions. This surprising finding challenges the widely accepted view that inhibiting the renin-angiotensin system benefits patients with both early and advanced stages of nephropathy in diabetes, said Dr. Michael Maurer of the University of Minnesota, Minneapolis, and his associates (N. Engl. J. Med. 2009;361:40-51).

However, both agents slowed the progression of diabetic retinopathy by 65%-70%, compared with placebo. This benefit might represent direct effects on the eye because it occurred independently of the drugs’ effects on systemic blood pressure, Dr. Maurer and his associates reported.

In an editorial comment accompanying this report, Dr. Bruce A. Perkins of the University of Toronto and his colleagues at the Joslin Diabetes Center and Harvard Medical School, Boston, termed this study “extraordinary,” in comparison with previous studies that were of shorter duration and focused on only one surrogate measure of nephropathy.

Dr. Maurer’s study not only compared two different strategies for inhibiting the renin-angiotensin system, “it is the longest study in this field of investigation and it evaluated all three common measures of the renal phenotype–the presence or absence of microalbuminuria, the glomerular filtration rate, and the presence or absence of renal morphologic features,” the editorialists noted.

The findings “should eliminate consideration of inhibition of the renin-angiotensin system in normotensive patients with type 1 diabetes and normoalbuminuria, and should further question current management protocols for microalbuminuria in patients with type 1 or type 2 diabetes, since evidence of prevention of early decline in renal function is limited,” Dr. Perkins and colleagues said (N. Engl. J. Med. 2009;361:83-85).

In their 5-year multicenter study, which was sponsored in part by Merck (U.S.A.) and Merck Frosst (Canada), Dr. Maurer and his associates followed 285 normotensive adult and adolescent patients who had type 1 diabetes but no clinically detectable renal disease. These subjects were randomly assigned to take the ACE inhibitor enalapril (20 mg daily), the angiotensin-receptor blocker losartan (100 mg daily), or placebo daily.

During 5 years of follow-up, the mesangial fractional volume–the prespecified renal endpoint and the variable most closely correlated with reduced glomerular filtration rate (GFR) in diabetic nephropathy–increased, as did all glomerular structural features of diabetic nephropathy, in all three groups. Neither enalapril nor losartan significantly reduced rates of nephropathy progression, compared with placebo.

Similarly, neither drug improved albuminuria or GFR.

Dr. Maurer reported receiving consulting and lecture fees from Genzyme and research grants from Merck and Genzyme. One of the editorialists, Dr. Lloyd Paul Aiello, reported receiving consulting fees from Merck and Novartis; no other potential conflict of interest was reported.

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

根据7月2日发表在《新英格兰医学杂志》(New England Journal of Medicine)上的研究结果，血管紧张素转换酶抑制剂(ACE-I)和血管紧张素受体阻滞剂均不能减缓1型糖尿病肾病的进展。

两种肾素-血管紧张素系统阻滞药物均未减少微量白蛋白尿发生率或缓解肾功能的衰退以及形态学病变的进展。来自明尼阿波利斯市明尼苏达大学的Michael Maure医生和其同事指出，学界曾广泛认为阻滞肾素-血管紧张素系统对早期和进展期糖尿病肾病患者均有益处，然而现在这一令人惊讶的发现对上述观点提出了挑战(参见N. Engl. J. Med. 2009;361:40-51)。

然而与安慰剂组比较，两种药物均能减缓65%~70%糖尿病视网膜病变的进展。Maure医生和其同事认为，药物可能直接作用在眼部，该作用独立于其对收缩压的影响。

多伦多大学Bruce A. Perkins医生和他Joslin糖尿病中心及波士顿的哈佛医学院的同事针对该研究撰写了述评。他们认为，以前的研究要么持续时间较短，要么仅关注肾病单一的替代指标，与这些研究相比，该研究可称为取得“非凡的”成果。

述评作者指出，Maurer医生的研究不仅比较了阻滞肾素-血管紧张素系统的2种治疗方案，“而且是本领域持续时间最长的研究，并且评估了全部3个最常用的有关肾脏表型的指标，它们包括是否存在微量白蛋白尿、肾小球滤过率以及是否存在肾脏病理形态特征。”

Perkins医生及其同事认为，“该研究发现提供了可信的证据，说明阻滞肾素-血管紧张素系统对预防肾功能早期衰退作用有限。因此我们在治疗血压正常的1型糖尿病患者时，不应再考虑应用此项治疗方案，同时也应对伴有1型或2型糖尿病的微量白蛋白尿患者现有的处置规范进行深入探讨。”(参见N. Engl. J. Med. 2009;361:83-85)

这项持续5年的多中心研究由美国默克公司和加拿大默克福罗斯特公司提供资金资助。Maurer医生及其同事将285名血压正常的成年人和青少年患者作为研究对象，他们都患有1型糖尿病，但没有临床上可检出的肾脏疾病。研究者将这些参试者随机分为3组，ACE-I组患者每日应用依那普利20 mg，血管紧张素受体阻滞剂组患者每日应用氯沙坦100 mg，安慰剂组患者则每日应用安慰剂。

在5年随访期中，3组患者的系膜占肾小球面积比均增加，该指标是预先确定的肾脏研究终点，其变化与糖尿病肾病造成的肾小球滤过率(GFR)降低关系最为密切。其他糖尿病肾病的肾小球结构特征也有相似的表现。与安慰剂相比，无论是依那普利还是氯沙坦均没有显著降低肾病进展率。

同样，两种药物均未改善白蛋白尿状况或GFR。

Maurer医生声明接受了健赞公司提供的咨询费及演讲费，也接受默克公司和健赞公司的研究资助。述评作者之一，Lloyd Paul Aiello医生声明接受了默克公司和诺华公司的咨询费。没有其他潜在利益冲突需要声明。

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