In the review by Hoogwerf that appeared in the January supplement to The American Journal of Cardiology , the author very well explained all the most relevant trials supporting the clinical utility of blocking the renin-angiotensin system in diabetic nephropathy. Nevertheless, we believe that this issue is not complete without citing some other important trials that have been published concerning this subject, particularly the analysis of the Diabetic Retinopathy Candesartan Trials (DIRECT) by Bilous et al, which studied 3,326 and 1,905 mainly normotensive patients with type 1 and type 2 diabetes, respectively. In these randomized trials, patients were given either candesartan 16 mg/day, increasing to 32 mg/day, or placebo. After a mean follow-up period of 4.7 years, candesartan showed little effect in preventing microalbuminuria.

Even more important is the Renin-Angiotensin System Study (RASS) trial by Mauer et al, evaluating renal outcomes from early blockade of the renin-angiotensin system in patients with type 1 diabetes who were given enalapril, losartan, or placebo. After 5 years of follow-up, there was no statistical difference for diabetic nephropathy progression. In fact, biopsy-proved mesangial fractional volume per glomerulus and glomerular filtration rate were not affected by treatment after 5 years. Mesangial fractional volume, the primary prespecified renal end point in the trial, is the variable most closely correlated with reduction of glomerular filtration rate in diabetic nephropathy. Furthermore, microalbuminuria was significantly worse in patients who received losartan compared to placebo (but not in those receiving enalapril). Microalbuminuria developed in 6% of patients receiving placebo but in 17% of those receiving losartan (p = 0.01).

The results of these studies raise doubts about the possibility that early blockade of the renin-angiotensin system could provide an effective primary prevention of renal disease in normotensive patients with diabetes without evidence of nephropathy. This population would in fact be the real target for an effective prevention, because many patients with type 2 diabetes already have hypertension and evidence of nephropathy when first diagnosed. Moreover, these patients will probably receive these therapies for very long periods.

Furthermore, the data in the study by Mauer et al on the increased risk for progression to microalbuminuria in patients receiving losartan, although they need confirmation from other studies, indicate at least that caution is warranted in using angiotensin receptor blockers in normotensive patients with type 1 diabetes and that their microalbuminuria should be monitored frequently. In fact, a new model is probably emerging for early nephropathy in patients with type 1 diabetes, and these advances may inspire novel and more effective therapeutic approaches for prevention in these patients.