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.

Figure 1

Change in blood pressure in type 2 diabetic patients with overt nephropathy and hypertension during treatment with olmesartan or placebo (a) all patients; (b) patients not treated with an ACEI and (c) patients treated with an ACEI). ACEI, angiotensin-converting enzyme inhibitor; DBP, diastolic blood pressure; SBP, systolic blood pressure.

Figure 2

Changes in proteinuria expressed as percentage change in the urinary protein to creatinine ratio from baseline during treatment with olmesartan or placebo in type 2 diabetic patients with overt nephropathy and hypertension ((a) all patients; (b) patients not treated with an angiotensin-converting enzyme inhibitor (ACEI) and (c) patients treated with an ACEI).

Figure 3

Distribution of changes in the estimated glomerular filtration rate (eGFR) decline according to 2 ml min^–1 per 1.73 m² per year intervals in type 2 diabetic patients with overt nephropathy and hypertension ((a) all patients; (b) patients not treated with an angiotensin-converting enzyme inhibitor (ACEI) and (c) patients treated with an ACEI).

Figure 4

Kaplan–Meier analysis of the time to the primary composite renal end point in type 2 diabetic patients with overt nephropathy and hypertension ((a) all patients; (b) patients not treated with an angiotensin-converting enzyme inhibitor (ACEI) and (c) patients treated with an ACEI). HR, hazard ratio.

Figure 5

Kaplan–Meier analysis of the time to the secondary composite cardiovascular end point in type 2 diabetic patients with overt nephropathy and hypertension ((a) all patients; (b) patients not treated with an angiotensin-converting enzyme inhibitor (ACEI) and (c) patients treated with an ACEI). HR, hazard ratio.