Importance of baseline distribution of proteinuria in renal outcomes trials: lessons from the reduction of endpoints in NIDDM with the angiotensin II antagonist losartan (RENAAL) study.

A key issue in the analysis of outcome trials is the adjustment for baseline covariates that influence the primary outcome. Imbalance of an important covariate between treatment groups at baseline is of considerable concern if one treatment group is favored over another with respect to the hypothesis testing outcome. With the use of the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study database as an example, the influence of baseline proteinuria on the primary composite endpoint, ESRD, and ESRD or death after adjusting for baseline proteinuria as a continuous covariate was examined. Increasing baseline proteinuria was associated with increased risk for renal events, confirming that proteinuria is an important covariate for renal outcomes. When the randomization was stratified according proteinuria <2000 mg/g or >/=2000 mg/g, within the higher proteinuria stratum (>/=2000 mg/g), patients in the losartan group had a higher baseline mean proteinuria value. When the imbalance was adjusted, an increase in the magnitude and the significance of the risk reduction with losartan for each outcome was observed. No apparent interaction between treatment effect and baseline proteinuria was found, and there was no heterogeneity in the treatment response in patients with different baseline proteinuria levels. After proteinuria was adjusted as a continuous variable, greater treatment effects were observed in the RENAAL study. This effect was due solely to the imbalance in baseline proteinuria. Considering the importance of proteinuria as a risk factor, adjustment for baseline proteinuria as a continuous covariate should be prespecified in the design and analysis of clinical trials involving renal outcomes, even when patients are stratified on the basis of level of proteinuria.

Losartan and end-organ protection--lessons from the RENAAL study.

BACKGROUND: The Reduction in ENdpoints with the Angiotensin Antagonist Losartan (RENAAL) study reported that losartan delayed the progression of renal disease in patients with type 2 diabetes and nephropathy. Diabetic or renally impaired patients are at high cardiovascular risk, a risk potentially increased in patients with both conditions. HYPOTHESIS: This post hoc analysis examined whether baseline proteinuria was predictive of cardiovascular outcomes, and whether losartan modifies the risk of cardiovascular outcomes in these patients given its renal-protective effects. METHODS: The RENAAL study compared losartan with placebo (in addition to conventional antihypertensive medications) in type 2 diabetic patients with proteinuria. Morbidity and mortality due to cardiovascular causes were ascertained, and the relationship between baseline proteinuria and cardiovascular outcome was determined. The effect of treatment with losartan was examined using three time-to-event analyses of composite cardiorenal outcomes as described below. RESULTS: Increasing baseline proteinuria was associated with significantly increased risk of myocardial infarction (MI) and all-cause or cardiovascular death, but not stroke. Losartan significantly reduced the risk for the combined endpoint of end-stage renal disease (ESRD), MI, stroke, or death by 21% (p < or = 0.005), irrespective of whether all-cause or cardiovascular death was included in the analysis. In addition, losartan reduced the risk for the composite of ESRD or cardiovascular death by 19.2% (p < 0.05). CONCLUSION: In patients with type 2 diabetes and nephropathy, there is an increased risk of MI and cardiovascular or all-cause mortality. Treatment with losartan is associated with a reduction in proteinuria, a delay in the onset of ESRD, and no increased risk of cardiovascular events in this pre-ESRD population.

Detecting and managing patients with type 2 diabetic kidney disease: proteinuria and cardiovascular disease.

BACKGROUND: The increasing prevalence of type 2 diabetes (T2DM) places more patients at risk for developing chronic kidney disease (CKD) or cardiovascular (CV) events. Effective therapy for CKD or CV disease (CVD) requires a method of identifying affected patients and monitoring the effectiveness of therapy. METHODS: We tested the predictive value of proteinuria for identifying patients at risk for progressive CDK and CVD, and monitoring treatment was determined using RENAAL study results. RESULTS: Baseline proteinuria identified patients at risk for progressive CKD and CVD. Suppression of proteinuria was associated with decreased likelihood of CKD or CVD. CONCLUSION: Proteinuria identifies the risk of CKD and CVD, and can be used to monitor the effectiveness of therapy.

Renin angiotensin aldosterone system blockade and renal disease in patients with type 2 diabetes. An Asian perspective from the RENAAL Study.

OBJECTIVE: Asia is predicted to have the largest population of patients with diabetes who are at high risk for renal disease. In the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study, approximately 17% of patients were Asians. In this subgroup analysis, we examined the characteristics, response, and adherence to treatment of the Asian population, as well as their baseline predictors of risk of renal end points. RESEARCH DESIGN AND METHODS: A total of 252 Asian patients were enrolled in the RENAAL study, which compared losartan (50 mg titrated to 100 mg) to placebo in addition to conventional antihypertensive medications in type 2 diabetic patients with nephropathy. Mean follow-up was 3.2 years. The effect of losartan therapy on renal and cardiovascular outcomes was examined, and baseline predictors of risk were determined using a Cox proportional hazards model with prespecified baseline covariates. RESULTS: Losartan reduced the risk of the primary composite end point composed of a doubling of serum creatinine, end-stage renal disease, or all-cause mortality in Asian patients by 35% (P = 0.02). No difference between losartan and placebo was observed for the cardiovascular composite outcomes. Losartan reduced the level of proteinuria by 47% (P < 0.001) and rate of decrease in renal function by 31% (0.0074). Discontinuations were lower in the losartan-treated patients. The strongest baseline predictors of risk of renal end points were proteinuria (hazard ratio 1.42, P < 0.0001) and low Hb (0.81, P < 0.0001). CONCLUSIONS: In this subgroup analysis of the RENAAL study, losartan conferred significant renal benefits and was well tolerated in Asian patients with type 2 diabetes and clinical nephropathy. Baseline proteinuria and low Hb were strong predictors of risk of renal outcomes.

Pharmacokinetics, safety, and antihypertensive efficacy of losartan in combination with hydrochlorothiazide in hypertensive patients with renal impairment.

The pharmacokinetics and pharmacodynamics of 7 days of treatment with losartan 50 mg/hydrochlorothiazide 12.5 mg were evaluated in 14 patients with normal renal function and in 12 patients with mild to moderate renal impairment. The efficacy of losartan 50 mg/hydrochlorothiazide 12.5 mg titrated to losartan 100 mg/hydrochlorothiazide 25 mg was examined in 32 hypertensive patients with mild to moderate renal impairment who were treated for 12 weeks. Safety was assessed in both studies by the incidence of adverse experiences. After 7 days of treatment, the AUC for losartan, E-3174, and hydrochlorothiazide was slightly higher in patients with mild to moderate renal impairment, but the reduction in blood pressure (BP) after 7 days was not different between the two groups. The final (week 12) mean reductions in trough sitting diastolic and systolic BP were 15.0 +/- 7.1 mmHg (p < 0.01) and 20.8 +/- 16.7 mmHg (p < 0.01), respectively. There were no observed increases in drug-related adverse experiences in either study. Overall, the combination of losartan/hydrochlorothiazide was effective in lowering blood pressure and was well tolerated in patients with mild to moderate renal impairment.

Analysis of metabolic parameters as predictors of risk in the RENAAL study.

OBJECTIVE: Metabolic factors such as glycemic control, hyperlipidemia, and hyperkalemia are important considerations in the treatment of patients with type 2 diabetes and nephropathy. In the RENAAL (Reduction of End Points in Type 2 Diabetes With the Angiotensin II Antagonist Losartan) study, losartan reduced renal outcomes in the patient population. This post hoc analysis of the RENAAL study reports the effects of losartan on selected metabolic parameters and assesses the relationship between baseline values of metabolic parameters and the primary composite end point or end-stage renal disease (ESRD). RESEARCH DESIGN AND METHODS: Glycemic control (HbA(1c)) and serum lipid, uric acid, and potassium levels were compared between the losartan and placebo groups over time, and baseline levels were correlated with the risk of reaching the primary composite end point (doubling of serum creatinine, ESRD, or death) or ESRD alone. RESULTS: Losartan did not adversely affect glycemic control or serum lipid levels. Losartan-treated patients had lower total (227.4 vs. 195.4 mg/dl) and LDL (142.2 vs. 111.7 mg/dl) cholesterol. Losartan was associated with a mean increase of up to 0.3 mEq/l in serum potassium levels; however, the rate of hyperkalemia-related discontinuation was similar between the placebo and losartan groups. Univariate analysis revealed that baseline total and LDL cholesterol and triglyceride levels were associated with increased risk of developing the primary composite end point. Similarly, total and LDL cholesterol were also associated with increased risk of developing ESRD. CONCLUSIONS: Overall, losartan was well tolerated by patients with type 2 diabetes and nephropathy and was associated with a favorable effect on the metabolic profile of this population.

Losartan in patients with type 2 diabetes and proteinuria: observations from the RENAAL Study.

BACKGROUND: Recently, the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) Study demonstrated the benefit of losartan in reducing renal outcomes in patients with type 2 diabetes and proteinuria. Additional questions concerning the reduction of proteinuria and its relationship to end-stage renal disease (ESRD) as well as cardio-renal outcomes and the safety and tolerability of losartan remain to be addressed. METHODS: Three analyses were performed: (a) the impact of losartan on the relationship between the reduction of proteinuria and ESRD; (b) a time-to-event analysis of the cardio-renal composite endpoint of ESRD, myocardial infarction, stroke or all-cause death; and (c) additional analyses of adverse events, particularly in patients with serum creatinine >or=2.0 mg/dL. RESULTS: After adjusting the values for proteinuria over the entire study, the reduction of proteinuria accounted for approximately half of the treatment effect of losartan on the risk reduction for ESRD. In addition, losartan was associated with a 21% risk reduction for the composite cardio-renal outcome (P=0.003). The addition of losartan to a conventional antihypertensive regimen did not increase the overall incidence of adverse events, regardless of severity of renal impairment. CONCLUSIONS: Losartan significantly reduced the risk of cardiorenal outcomes and was well tolerated by patients, including those with serum creatinine levels >or=2.0 g/dL. In addition, although this study shows that the reduction of proteinuria does not completely explain the impact of intervention on outcomes such as ESRD, reduction of proteinuria must remain an important consideration when treating patients with type 2 diabetes and nephropathy. However, the reduction of outcomes such as ESRD should remain the goal of therapy when evaluating renal protection in this patient population.