Renoprotective Effects of Adding Angiotensin II Receptor Blocker to Maximal Recommended Doses of ACE Inhibitor in Diabetic Nephropathy

Kasper Rossing, MD, Peter Jacobsen, MD, Lotte Pietraszek, Hans-Henrik Parving, PROF, DMSC, MD

Disclosures

Diabetes Care. 2003;26(8) 

In This Article

Abstract and Introduction

Objective: We evaluated the renoprotective effects as reflected by short-term changes in albuminuria of dual blockade of the renin-angiotensin system (RAS) by adding an angiotensin II receptor blocker (ARB) to treatment with maximal recommended doses of an ACE inhibitor (ACEI) in patients with type 2 diabetes and nephropathy.
Research Design and Methods: A total of 20 patients (17 men and 3 women) with type 2 diabetes along with hypertension and nephropathy were enrolled in this double-blind, randomized, two-period, crossover trial of 8 weeks of treatment with the ARB candesartan 16 mg daily and placebo added in random order to existing treatment with lisinopril/enalapril 40 mg daily or captopril 150 mg daily. At the end of each treatment period, we evaluated albuminuria in three 24-h urinary collections by turbidimetry, 24-h ambulatory blood pressure (ABP) using the Takeda-TM2420, and glomerular filtration rate (GFR) by the 51Cr-EDTA plasma-clearance technique.
Results: During monoblockade of the RAS by ACEI treatment, albuminuria was 706 (349-1,219) mg/24 h [geometric mean (IQR)]; 24-h ABP was 138 ± 3/72 ± 2 mmHg (mean ± SE); and GFR was 77 ± 6 ml · min-1 · 1.73 m-2 (mean ± SE). During dual blockade of the RAS by addition of candesartan 16 mg daily, there was a mean (95% CI) reduction in albuminuria of 28 (17-38) compared with ACEI alone (P < 0.001). There was a modest reduction in systolic/diastolic 24-h ABP of 3/2 mmHg (-2 to 8 systolic, -2 to 5 diastolic; NS). Changes in albuminuria did not correlate to changes in ABP. Addition of candesartan 16 mg daily induced a small, insignificant decrease in GFR of 4 (-1 to 9) ml · min-1 · 1.73 m-2.
Conclusions: Dual blockade of the RAS provides superior short-term renoprotection independent of systemic blood pressure changes in comparison with maximally recommended doses of ACEI in patients with type 2 diabetes as well as nephropathy.

Diabetic nephropathy occurs in 30-40% of all diabetic patients and has become the leading cause of end-stage renal disease in the western world.[1] In diabetic patients, albuminuria independently predicts poor renal and cardiovascular outcome.[1] Several clinical studies have clearly demonstrated that blockade of the renin-angiotensin system (RAS), either by an ACE inhibitor (ACEI) or an angiotensin II receptor blocker (ARB), reduces albuminuria, retards the progressive loss in renal function, and improves survival.[2,3,4,5,6,7] The antiproteinuric response upon blockade of the RAS has been demonstrated to predict the subsequent long-term rate of decrease in glomerular filtration rate (GFR), i.e., the greater the initial decrease in albuminuria, the less the long-term decrease in kidney function.[8,9] Consequently, the short-term reduction in albuminuria may serve to monitor treatment efficacy and long-term prognosis in diabetic nephropathy, and it has previously been advocated that albuminuria should be reduced as far as possible to obtain maximal renoprotective effects.[10]

Despite the proven benefit of RAS blockade by either ACEIs or ARBs, clinical studies to date have found that such treatment slows but does not completely arrest the progression of renal disease toward end-stage renal disease. Because ACEIs and ARBs antagonize the RAS at different sites, these agents may have additive effects that result in even greater renoprotection when used in combination. Such beneficial additive effects have previously been reported in diabetic patients with microalbuminuria[11] and macroalbuminuria.[12,13] However, in these studies, the full renoprotective potential of the RAS blocking agents may not have been reached because either the ACEI or the ARB was not given in maximal recommended doses and the beneficial effects of dual RAS blockade may have been overestimated. When combining two drugs working on the same hormone system, an additive effect specific for the combination can only be demonstrated when compared with monotherapy at the top of the dose response. Therefore, it remains unknown whether similar beneficial renoprotective effects can be obtained when adding an ARB to maximally recommended doses of an ACEI.

The objective of the present study was to evaluate the renoprotective effects, as reflected by short-term changes in albuminuria, of dual blockade of the RAS by adding an ARB at a maximally effective dose[14] to treatment with maximally recommended doses of an ACEI in patients with type 2 diabetes and nephropathy.

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