Early Blockade of RAS DOES NOT Delay Diabetic Nephropathy in Type I DM

Nephrologists have had a love affair with ACE inhibitors and Angiotensin receptor blockers since some great early data starting in the 1980s.

Data has not been strong on the use of ACEi or ARBs very early on in diabetics without hypertension. Nevertheless, many Nephrologists (including myself) have given low doses of ACEi or ARBs in order to achieve renoprotection and delay (or avoid) any progression towards diabetic nephropathy.

A study which appears this week in the New England Journal of Medicine took a closer look at this issue. Does blockade of the RAS at a very early stage delaythe progression of two important complications of Type 1 DM; diabetic nephropathy and retinopathy?

A multicenter controlled trial incorporating 285 normotensive and normoalbumuric patients with type 1 DM. They were randomly assigned to receive losartan (Cozaar) 100 mg daily, enalapril (Vasotec) 20 mg daily or placebo and were followed for 5 years.

The three study groups had similar glycated hemoglobin levels (P=0.54) and insulin doses (P=0.29) during the 5-year period. The clinic-obtained systolic and diastolic blood pressures (mean ±SD) during the study were lower in the enalapril group (113±9/66±6 mm Hg) and the losartan group (115±8/66±6 mm Hg) than in the placebo group (117±8/68±5 mm Hg) (P<0.001 for the two systolic and P0.02 for the two diastolic comparisons, respectively). Hypertension developed in nine patients in the placebo group, three in the enalapril group, and four in the losartan group (P=0.04).

The albumin excretion rate increased significantly from baseline only in the losartan group (P=0.04). As compared with placebo, the 5-year average rate was higher by 4.0 µg per minute with losartan (P=0.03) but was not significantly higher with enalapril (P=0.47). The albumin excretion rate at 5 years was higher with losartan than with placebo, by 8.0 µg per minute (P=0.007), but not with enalapril (P=0.74). The microalbuminuria 5-year cumulative incidence was higher with losartan than with placebo (17% vs. 6%, P=0.01 by the log-rank test) but was not significantly higher with enalapril (4% vs. 6%, P=0.96 by the log-rank test). The GFR decreased similarly in all three groups over the 5 years: by 6.6 to 8.9 ml per minute (P<0.002 for all three)

A progression in diabetic retinopathy of two steps or more occurred in 38% of patients receiving placebo but only 25% of those receiving enalapril (P=0.02) and 21% of those receiving losartan (P=0.008).

CONCLUSION: The study did not detect structural or functional benefits on nephropathy from the blockade of the renin–angiotensin system with an ACE inhibitor or an ARB in normotensive patients with type 1 diabetes and normoalbuminuria. Given the current status of our ability to predict the risk of nephropathy, blockade of the renin–angiotensin system for the primary prevention of diabetic nephropathy in patients with type 1 diabetes is not supported by the present evidence. In contrast, we found beneficial effects of the ACE inhibitor enalapril and the ARB losartan in reducing the risk of progression of diabetic retinopathy.

The days of giving a low dose ACEi or ARB for the normotensive, normoalbuminuric patient to prevent or delay the onset of diabetic nephropathy may be over....