Effects of dual blockade of the renin–angiotensin system on renal and cardiovascular outcomes in type 2 diabetes with overt nephropathy and hypertension in the ORIENT: a post-hoc analysis (ORIENT–Hypertension)

Abstract

Combination therapy with angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors (ACEIs) requires further evaluation in patients with diabetic nephropathy and hypertension. In a post hoc analysis of the Olmesartan Reducing Incidence of Endstage renal disease in diabetic Nephropathy Trial with hypertension, we examined the effects of olmesartan on renal and cardiovascular outcomes in the presence or absence of an ACEI. Among 563 patients randomized to receive either olmesartan (n=280) or placebo (n=283), 73.5% (n=414) received a concomitant ACEI. Compared with placebo, olmesartan significantly reduced proteinuria in both the ACEI-treated and non-ACEI-treated groups. The respective changes in the urinary protein creatinine ratio in the olmesartan-treated and placebo-treated groups were −32.6% and +21.1% without an ACEI (P=0.001) and −17.0% and +2.2% with an ACEI (P=0.028). In the olmesartan group, 115 patients developed primary renal outcomes (41.1%) compared with 129 (45.6%) in the placebo group (hazard ratio (HR): 0.97, P=0.787). The respective HRs in the ACEI-treated and non-ACEI-treated groups were 1.02 (P=0.891) and 0.84 (P=0.450). 40 olmesartan-treated patients (14.3%) and 53 placebo-treated patients (18.7%) developed secondary cardiovascular outcomes (HR: 0.65, P=0.042). The respective HRs in the ACEI-treated and non-ACEI-treated groups were 0.69 (P=0.129) and 0.51 (P=0.129). Olmesartan was well tolerated. Dual blockade treatment caused more hyperkalemia than monotherapy. In patients with diabetic nephropathy and hypertension, olmesartan significantly reduced proteinuria, independent of ACEI treatment and cardiovascular outcome but failed to show additional renal benefit compared with ACEI treatment alone. The cardiovascular benefit of dual treatment requires further evaluation.

The Prevalence and Management of Diabetic Nephropathy in Asia

“…Hyperkalemia was more frequent in the olmesartan group than in the placebo group. It is concluded that olmesartan was well tolerated but did not improve the outcome on top of the ACE inhibitor [37]. In patients with DN, combination therapy with an ACE inhibitor (lisinopril) and an ARB (losartan) decreases proteinuria but its safety profile and effects on the progression of kidney disease are still uncertain [38].…”

“…In 2011, Imai and Chan and colleagues [37] examined the effects of olmesartan, an ARB, on the primary outcome of doubling of serum creatinine, ESKD and death in type 2 diabetic patients with overt nephropathy from Japan and China. A total of 577 patients (377 Japanese, 200 Chinese) treated with antihypertensive therapy and who received concomitant ACE inhibitors (n = 424, 73.5%) were given either olmesartan once daily (n = 288) or a placebo (n = 289) over 3.2 ± 0.6 years (mean ± 1 SD).…”

Dual Renin-Angiotensin-Aldosterone Blockade: Promises and Pitfalls

“…The study by Imai et al [50] was a post hoc analysis of the ORIENT-Hypertension study. This was a randomized, double-blind study of 563 patients with type 2 diabetes and hypertension.…”

“…Several clinical trials have shown that dual RAAS blockade is superior to single RAAS blockade in improving protein excretion and preventing the progression of CKD to end-stage renal disease (ESRD) [44][45][46], whereas others have shown mixed results with respect to the difference in protein excretion or improvement in renal function between the dual and single RAAS blockade [47][48][49][50][51][52][53][54][55][56]. The beneficial effects of RAAS blockers have been attributed to the lowering of intraglomerular pressure through their preferential action on the efferent glomerular arteriole and the prevention of renal fibrosis and scarring through their blocking effect on mediators of inflammation and oxidative stress [55][56][57].…”

Problems in Pharmacotherapy of Resistant Arterial Hypertension

“…Показано, что двой-ная блокада РААС чаще приводила к гиперкалие-мии. Независимо от наличия или отсутствия инги-битора АПФ, олмесартан существенно снижал выра-женность протеинурии при диабетической и гипертонической нефропатии, а также общую частоту сердечно-сосудистых исходов [16].…”