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.

Although the study by Mauer et al. raises doubts about the benefits of therapy used to inhibit the renin–angiotensin system, it also challenges the existing concept concerning the natural history of early diabetic nephropathy.

Change in the degree of microalbuminuria is inconsistently associated with decline in renal function or progression of morphologic lesions.

This "uncoupling" of microalbuminuria and renal function, seen in other studies,^4,12 raises major concern over the exclusive use of urinary albumin excretion as a clinical trial end point for early diabetic nephropathy instead of also evaluating decline in renal function.

Among the subjects with normoalbuminuria who received placebo in the present study, one quarter lost approximately 2.5 to 8 ml per minute per 1.73 m² of body-surface area in glomerular filtration rate per year — equivalent to an ominous loss of approximately 12.5 to 40 ml per minute during the 5-year study period (Fig. 2 in the Supplementary Appendix of the article by Mauer et al., available with the full text of that article at NEJM.org).

A similar proportion was observed in all three study groups.

Clearly, clinical trials would be stronger if they focused on early decline in renal function rather than microalbuminuria alone.

Ultimately, prevention of the events initiating the process of early decline in renal function will be the most clinically meaningful management tactic for preventing or ameliorating nephropathy.¹³

The pathologic mechanisms of early complications of diabetes are heterogeneous. Inhibition of the renin–angiotensin system can prevent early retinopathy, but not early nephropathy.

This set of observations is in sharp contrast to the situation in more advanced stages of diabetic complications, in which inhibition of the renin–angiotensin system mitigates the loss of renal function without apparent influence on retinopathy progression.

Regarding the prevention of nephropathy, the results of Mauer et al. 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.⁴

For retinopathy, the evidence does not show a beneficial role of inhibition of the renin–angiotensin system in patients with type 1 diabetes who have established retinopathy, nor in those with type 2 diabetes regardless of retinopathy status.

However, the normotensive patient with type 1 diabetes and normoalbuminuria in whom retinopathy is minimal or absent stands to benefit from reduction in the advancement of retinal change through inhibition of the renin–angiotensin system.

Definitive determination of the benefit of angiotensin-converting–enzyme therapy will require a confirmatory study like the one for angiotensin-receptor blockade.

Although inhibition of the renin–angiotensin system is clearly effective in the study by Mauer et al., further work is required before the strategy is used for retinopathy prevention in clinical practice.

The duration of therapy remains to be determined.

From a risk–benefit perspective, the subgroup of patients less likely to benefit from inhibition of the renin–angiotensin system must be identified, including, for example, those with the best glycemic control or those with more advanced stages of retinopathy.

Determining these thresholds and the logistical framework for standardized, accurate, and timely reporting of retinal findings between eye specialists and diabetes care providers requires active research — these are not trivial tasks.

Dr. Aiello reports receiving consulting fees from Merck and Novartis. No other potential conflict of interest relevant to this article was reported.

SEE FULLTEXT

NEJM Volume 361:83-85 July 2, 2009 Number 1

Bruce A. Perkins, M.D., M.P.H., Lloyd Paul Aiello, M.D., Ph.D., and Andrzej S. Krolewski, M.D., Ph.D.

http://content.nejm.org/cgi/content/full/361/1/83

http://www.e-medicum.com/noticiasDelDia/verNoticia.php?noticia=82887