Effects of blood pressure on renal and cardiovascular outcomes in Asian patients with type 2 diabetes and overt nephropathy: a post hoc analysis (ORIENT-blood pressure).

BACKGROUND: Blood pressure (BP) control may have different effects on cardiovascular (CV) and renal outcomes in diabetes. We examined the impact of systolic BP (SBP) on renal and CV outcomes in a post hoc analysis in the Olmesartan Reducing Incidence of Endstage Renal Disease in Diabetic Nephropathy Trial. METHODS: We stratified mean follow-up SBP into three categories (≤130, 131-140 and >140 mmHg) and used a Cox regression model to estimate the hazard ratio (HR, 95% confidence interval) for the outcomes. The composite renal outcome was doubling of serum creatinine, end-stage renal disease and all-cause death. The composite CV outcome included CV death, nonfatal stroke, nonfatal myocardial infarction, hospitalization for unstable angina or heart failure, revascularization and lower extremity amputation. We also compared the slope of estimated glomerular filtration rate (eGFR) in all three groups. RESULTS: After a mean follow-up period of 3.2 years, the follow-up SBP was linearly associated with risk of renal outcomes in all 566 patients. In patients with heavy proteinuria (≥1 g/gCr), a follow-up SBP > 130 mmHg was associated with an HR of 2.33 (1.62-3.36) for renal outcomes with referent to SBP ≤ 130 mmHg. In patients without history of CV disease, a follow-up SBP > 140 mmHg was associated with an HR of 2.04 (1.23-3.40) for CV outcomes with referent to SBP < 140 mmHg. The median (interquartile range) slopes of eGFR were -3.27 (-6.90, -1.63), -4.53 (-8.08, -2.29) and -7.13 (-10.90, -3.99) dL/mg/year in patients with SBP ≤ 130, 131-140 and > 140 mmHg, respectively (P = 0.008 between ≤130 and 131-140, P < 0.001 between ≤ 130 and > 140 mmHg). CONCLUSION: In Asian type 2 diabetic patients with chronic kidney disease and heavy proteinuria, reduction of SBP ≤ 130 mmHg was associated with greater renoprotection than cardioprotection. However, our results emphasize the need to individualize BP targets in type 2 diabetes.

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).

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.

Reduction and residual proteinuria are therapeutic targets in type 2 diabetes with overt nephropathy: a post hoc analysis (ORIENT-proteinuria).

BACKGROUND: Proteinuria is a major predictor for progression of renal disease, including diabetic nephropathy. In a post hoc analysis of the ORIENT, a double-blinded randomized trial of 566 type 2 diabetic patients with nephropathy, we examined the risk association of composite renal outcome [end-stage renal disease, ESRD, doubling of serum creatinine (SCr) and death] with baseline, change and residual urinary protein/creatinine ratio (UPCR). METHODS: We estimated the hazard ratios (HRs) with 95% confidence interval (CI) of composite renal outcome with baseline UPCR (low <1.0 g/gCr; moderate ≥ 1.0 g/gCr, <3.0 g/gCr and high ≥ 3.0 g/gCr) as well as percentage reduction of UPCR (Δ) (worsening: <0%; moderate: ≥ 0%, <30% and high ≥ 30%) and residual UPCR at 24 weeks (remission <1.0 g/gCr; moderate ≥ 1.0 g/gCr, <3.0 g/gCr and heavy ≥ 3.0 g/gCr). RESULTS: Compared with the low group with baseline UPCR < 1.0 g/gCr, the respective HRs with 95% CI in the moderate and high UPCR groups were 3.02 (1.76-5.19) and 9.24 (5.43-15.73). Compared with patients with a worsening UPCR (<0%) at 24 weeks, the HR was 0.54 (0.39-0.74) in those with ≥ 0%, <30% ΔUPCR and 0.43 (0.31-0.61) in those with ≥ 30% ΔUPCR. Compared with the remission at 24 weeks, the HR was 2.12 (1.28-3.49) in moderate residual proteinuria and 4.59 (2.74-7.69) in heavy residual proteinuria. Compared with patients with residual UPCR ≥ 1.0 g/gCr and ΔUPCR <30%, the HR in those with ΔUPCR ≥ 30% and residual UPCR<1.0 g/gCr was 0.38 (0.22-0.64). CONCLUSIONS: In patients with type 2 diabetes and overt nephropathy, over 30% reduction of UPCR compared with baseline and/or residual UPCR<1.0 g/gCr at 24 weeks predicted renoprotection. These values may be used as targets to guide anti-proteinuric and renoprotective therapy in diabetic nephropathy. TRIAL REGISTRATION: ClinicalTrials.gov NCT00141453.