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【NEJM】糖尿病并发症与RAS系统 两篇
The hypothesis that inhibition of the renin–angiotensin system may be effective in preventing diabetic nephropathy was based on a large body of evidence.1 Positive findings from studies in animal models and subsequent clinical trials fostered enthusiastic hope that systematic use of agents blocking the renin–angiotensin system in the management of diabetic nephropathy would reduce the risk of end-stage renal disease.2,3,4 Out of such studies was born a concept that gained wide acceptance: inhibition of the renin–angiotensin system in patients with diabetes is beneficial with regard to both early and advanced stages of nephropathy. As an extension, studies were initiated to investigate the mechanism and role of inhibition of the renin–angiotensin system in other complications of diabetes, such as retinopathy and neuropathy.5,6
The study by Mauer et al.7 in this issue of the Journal (ClinicalTrials.gov number, NCT00143949 [ClinicalTrials.gov] ) changes the accepted concept. Although numerous, the majority of studies of inhibition of the renin–angiotensin system in patients with early nephropathy were of short duration and focused primarily on one surrogate manifestation of nephropathy: urinary albumin excretion (microalbuminuria). In this context, the present study is extraordinary. Not only does it compare two strategies for inhibition of 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 — as well as the progression of retinopathy. Notwithstanding, the findings are surprising. Inhibition of the renin–angiotensin system did not reduce the incidence of microalbuminuria and mitigated neither the decline of renal function nor the development of morphologic lesions. In contrast to its failure to prevent development of early nephropathy, however, inhibition of the renin–angiotensin system reduced the advancement of retinal changes by 60 to 70% as compared with placebo, most likely independently of blood-pressure reduction.
The reduction in the risk of retinopathy observed in this study parallels that from intensive insulin therapy.8 However, the much larger Diabetic Retinopathy Candesartan Trials (DIRECT)–Prevent 1 trial of a different type of renin–angiotensin system inhibitor, the angiotensin-receptor blocker candesartan, reported a modest relative risk reduction for the advancement of retinal change (18%, vs. placebo; P=0.051). In corresponding studies of candesartan therapy in subjects with both type 1 and type 2 diabetes who had retinopathy at baseline, the drug failed to mitigate retinopathy progression.5,9 Differences in sample size and the drugs and doses administered might explain the inconsistencies among the study by Mauer et al. and the two DIRECT trials.
Although the results of the present trial with regard to retinopathy results are very encouraging, additional questions remain. The vast majority of subjects had no, minimal, or early nonproliferative diabetic retinopathy, casting doubt on the benefits of such therapy in patients with more advanced stages. The duration of the protective effect is unknown beyond 5 years, as is whether the benefit may endure in the absence of inhibition of the renin–angiotensin system. Finally, although preclinical studies suggest that inhibition of the renin–angiotensin system may ameliorate diabetic macular edema, a major cause of visual loss, this outcome was not addressed.10 The findings with regard to early nephropathy are disappointing but not completely unexpected. The most influential trial in support of the dominant concept that inhibition of the renin–angiotensin system is effective for nephropathy — the Collaborative Study Group's captopril trial3 — pointed to the same possibility. Although that trial showed, with captopril as compared with placebo, a relative risk reduction for doubling of the creatinine level in patients with advanced nephropathy characterized by proteinuria, such a benefit was not conferred in those with creatinine levels of less than 1.5 mg per deciliter (133 µmol per liter). This lack of benefit has been commonly overlooked in the interpretation of the captopril trial results. In addition, subsequent trials highlighted that the degree of microalbuminuria was suppressed by this therapy without affecting the course of renal-function decline.4 The fact that the present study shows a paradoxical increase in the risk of microalbuminuria with longer-term angiotensin-receptor blockade is a major setback for the dominant concept that inhibition of the renin–angiotensin system is salutary. To "rescue" this concept, one might propose the use of megadose inhibition, various combinations of drugs, or various therapeutic targets. While questioning the safety and efficacy of some approaches,11 we emphasize the need for research into new therapeutic protocols and agents for treating early diabetic nephropathy.
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作者:admin@医学,生命科学 2010-09-27 12:36
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