Renal and Retinal Effects of Enalapril and Losartan in Type 1 Diabetes

Abstract

Background Nephropathy and retinopathy remain important complications of type 1 diabetes. It is unclear whether early administration of drugs that block the renin-angiotensin system slows their progression. Methods The Renin Angiotensin System Study [RASS] was a multicenter controlled trial in 285 normoalbuminuric, normotensive type 1 diabetic patients who were randomized to losartan (100mg daily), enalapril (20mg daily) or placebo and followed for 5 years. The primary endpoint was change in glomerular mesangial fractional volume in kidney biopsies. The retinopathy endpoint was a 2-step or greater progression in retinopathy severity scale. Intention-to-treat data analyses used linear and logistic regression models. Results Ninety and 82% of patients had complete renal biopsy and retinopathy data, respectively. Change in mesangial fractional volume per glomerulus over 5 years in placebo (0.016 units) was not significantly different from enalapril (p=0.38) or losartan (p=0.26), nor were there significant changes in other biopsy assessed renal structural variables. Five-year cumulative microalbuminuria incidence was higher for losartan than placebo (14% vs. 4%; logrank p=0.015) but not for enalapril (6% vs. 4%; logrank p=0.96). Two-step or more retinopathy progression incidence was reduced by 65% in the enalapril (O.R. 0.35; 95% C.I., 0.14–0.85) and 70% in the losartan group (O.R. 0.30; 95% C.I., 0.12–0.73) independent of changes in blood pressure. There were three biopsy-related serious adverse events that completely resolved. Chronic cough occurred in 12 enalapril, 6 losartan and 4 placebo patients. Conclusions Early renin-angiotensin system blockade did not modify nephropathy progression in type 1 diabetic patients, but had important effects in slowing retinopathy.

Aliskiren reduces vascular pathology in diabetic retinopathy and oxygen-induced retinopathy in the transgenic (mRen-2)27 rat

“…These findings have, to some extent, been translated into clinical trials such as the DIabetic REtinopathy Candesartan Trial (DIRECT), which reported that ARB reduced the incidence of retinopathy in type 1 diabetic patients and increased regression of retinopathy in type 2 diabetic patients [12,13]. ACE inhibition and ARB have also been reported to reduce the progression of diabetic retinopathy in normoalbuminuric and normotensive patients [14]. On the other hand, other randomised controlled clinical trials have reported ACE inhibition to be either equally effective as other blood-pressure-lowering strategies [15,16], or to have no benefit [17].…”

The clinical significance of hyperfiltration in diabetes

“…Initiation of antihypertensive therapy has also been shown to result in reversible decreases in GFR of around 10% [66], an effect not limited to RAS inhibitors. In normoalbuminuric, normotensive patients with type 1 diabetes, RAS inhibition has not been shown to prevent progression from normo-to microalbuminuria [67]. By contrast, in hypertensive patients with type 2 diabetes, progression from normoto microalbuminuria has been prevented by RAS inhibition using trandolapril, but not by similar blood pressure reduction with verapamil [68].…”

The contribution of hypertension to diabetic nephropathy and retinopathy: the role of inflammation and oxidative stress

“…103 However, a more recent trial has shown that use of ACE inhibitors was unable to prevent the development of microalbuminuria in normoalbuminuric type 1 diabetic patients. 104 Two large placebocontrolled studies, DR Candersartan Trial (DIRECT)-Prevent 1 and DIRECT-Protect 1, failed to detect any protective effect against the development of microalbuminuria over a median of 4.7 years of treatment with the ARB candesartan in 3326 patients with type 1 diabetes. 105 In type 2 diabetic patients, the use of an ACE inhibitor was associated with a reduction in the incidence of macroalbuminuria 106 and the development of microalbuminuria in hypertensive normoalbuminuric patients.…”

“…The odds of progression of DR by two or more steps was reduced by 65% with enalarpil (odds ratio 0.35, confidence interval 0.14-0.85) and 70% with losartan (odds ratio 0.30, confidence interval 0.12-0.73), independent of changes in blood pressure or glycemic control. 104 The DIRECT enrolled 1905 individuals with type 2 DM and 3326 individuals with type 1 DM and followed them over a median of approximately 5 years. 105,111 Three outcomes were evaluated in this trial: the development of DR in type 1 DM (DIRECT-Prevent 1), the progression of DR in type 1 (DIRECTProtect 1) and the progression of DR in type 2 DM (DIRECT-Protect 2).…”