Prediction of the effect of atrasentan on renal and heart failure outcomes based on short-term changes in multiple risk markers.

BACKGROUND: A recent phase II clinical trial (Reducing Residual Albuminuria in Subjects with Diabetes and Nephropathy with AtRasentan trial and an identical trial in Japan (RADAR/JAPAN)) showed that the endothelin A receptor antagonist atrasentan lowers albuminuria, blood pressure, cholesterol, hemoglobin, and increases body weight in patients with type 2 diabetes and nephropathy. We previously developed an algorithm, the Parameter Response Efficacy (PRE) score, which translates short-term drug effects into predictions of long-term effects on clinical outcomes. DESIGN: We used the PRE score on data from the RADAR/JAPAN study to predict the effect of atrasentan on renal and heart failure outcomes. METHODS: We performed a post-hoc analysis of the RADAR/JAPAN randomized clinical trials in which 211 patients with type-2 diabetes and nephropathy were randomly assigned to atrasentan 0.75 mg/day, 1.25 mg/day, or placebo. A PRE score was developed in a background set of completed clinical trials using multivariate Cox models. The score was applied to baseline and week-12 risk marker levels of RADAR/JAPAN participants, to predict atrasentan effects on clinical outcomes. Outcomes were defined as doubling serum creatinine or end-stage renal disease and hospitalization for heart failure. RESULTS: The PRE score predicted renal risk changes of -23% and -30% for atrasentan 0.75 and 1.25 mg/day, respectively. PRE scores also predicted a small non-significant increase in heart failure risk for atrasentan 0.75 and 1.25 mg/day (+2% vs. +7%). Selecting patients with >30% albuminuria reduction from baseline (responders) improved renal outcome to almost 50% risk reduction, whereas non-responders showed no renal benefit. CONCLUSIONS: Based on the RADAR/JAPAN study, with short-term changes in risk markers, atrasentan is expected to decrease renal risk without increased risk of heart failure. Within this population albuminuria responders appear to contribute to the predicted improvements, whereas non-responders showed no benefit. The ongoing hard outcome trial (SONAR) in type 2 diabetic patients with >30% albuminuria reduction to atrasentan will allow us to assess the validity of these predictions.

Albuminuria, estimated GFR, traditional risk factors, and incident cardiovascular disease: the PREVEND (Prevention of Renal and Vascular Endstage Disease) study.

BACKGROUND: Abnormal levels of both albuminuria and estimated glomerular filtration rate (eGFR) have been reported separately to be associated with cardiovascular risk. This study assessed the contribution of each separately in correctly identifying individuals at cardiovascular risk in the general population beyond traditional risk markers. STUDY DESIGN: Prospective community-based cohort study. SETTING & PARTICIPANTS: 8,507 individuals from the city of Groningen in the Netherlands followed up for 10.5 years for cardiovascular morbidity and mortality. PREDICTOR OR FACTOR: The contribution of albuminuria and eGFR separately on top of the traditional Framingham risk factors was assessed. OUTCOMES: The composite of first occurrence of myocardial infarction, stroke, ischemic heart disease, revascularization procedure, and all-cause mortality. MEASUREMENTS: At the baseline visit, albuminuria was measured in 2 consecutive 24-hour urine samples. eGFR was calculated using the serum creatinine-based CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation. RESULTS: In multivariable Cox regression models, albuminuria, but not eGFR, was associated independently with the primary study outcome (HR, 1.08 [95% CI, 1.04-1.12] per doubling of albuminuria). When added to the risk model consisting of Framingham risk factors, albuminuria significantly contributed to better risk stratification, shown by an increase in net reclassification index of 7.2% (95% CI, 3.3%-11.0%; P<0.001) and increase in relative incremental discrimination improvement of 3.0% (95% CI, 0.9%-5.1%; P=0.006). LIMITATIONS: The cohort includes mainly individuals of European ancestry. Therefore, results should not be extrapolated to other ethnicities. CONCLUSION: In a general population cohort, albuminuria, but not eGFR, significantly adds to traditional cardiovascular risk factors in identifying individuals at risk of cardiovascular morbidity and all-cause mortality.

An initial reduction in serum uric acid during angiotensin receptor blocker treatment is associated with cardiovascular protection: a post-hoc analysis of the RENAAL and IDNT trials.

OBJECTIVE: Increased levels of serum uric acid (SUA) are thought to be an independent risk marker for cardiovascular complications. Treatment with the angiotensin receptor blocker (ARB) losartan lowers SUA in contrast to other ARBs. Whether reductions in SUA during ARB therapy are associated with cardiovascular protection is unclear. We aimed to investigate this. METHOD: In a post-hoc analysis of the Reduction of Endpoints in Non insulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan (RENAAL) and Irbesartan Diabetic Nephropathy (IDNT) trials we determined whether the short-term effect of losartan and of irbesartan on SUA is related with long-term cardiovascular outcome by means of Cox regression. RESULTS: Compared to placebo, losartan significantly changed SUA [-0.16  mg/dl; 95% confidence interval (CI) -0.01 to -0.30; P = 0.031], whereas irbesartan did not (-0.09  mg/dl; (95% CI 0.09 to -0.28; P = 0.30). Each 0.5  mg/dl decrement in SUA during losartan treatment in the first 6 months resulted in a reduction in the risk of cardiovascular outcomes by 5.3% (95% CI 0.9 to 9.9; P = 0.017). Losartan reduced the risk of cardiovascular outcomes by 9.2% (95% CI -7.9 to 23.6). Adjustment for the 6-month change in SUA attenuated the treatment effect to 4.6% (95% CI -16.2 to 22.0), suggesting that part of the cardiovascular protective effect of losartan is attributable to its short-term effect on SUA. CONCLUSION: Losartan but not irbesartan significantly lowers SUA compared to placebo in patients with type 2 diabetes and nephropathy. The degree of reduction in SUA explains part of the cardiovascular effect of losartan. This supports the hypothesis that SUA is a modifiable risk factor for cardiovascular disease, at least in type 2 diabetics with nephropathy.

Drug-induced changes in risk/biomarkers and their relationship with renal and cardiovascular long-term outcome in patients with diabetes.

BACKGROUND: Optimal renal and cardiovascular risk management in diabetic patients includes optimal maintenance of blood pressure and control of glucose and lipids. Although the optimal control of these risk factors or "risk/biomarkers" has proven to be effective, it often is difficult to achieve. Consequently, the risk for renal and cardiovascular complications remains devastatingly high. Many risk/biomarkers have been discovered that accurately predict long-term renal and cardiovascular outcome. However, the aim of measuring risk/biomarkers may not be only to determine an individual's risk, but also to use the risk/biomarker level to guide therapy and thereby improve long-term clinical outcome. CONTENT: This review describes the effects of various drugs on novel risk/biomarkers and the relationship between (drug induced) short-term changes in risk/biomarkers and long-term renal and cardiovascular outcome in patients with diabetes. SUMMARY: In post hoc analyses of large trials, the short-term reductions in albuminuria, transforming growth factor-ß, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) induced by inhibitors of the renin-angiotensin-aldosterone system were associated with a decreased likelihood of long-term adverse renal and cardiovascular outcomes. However, the few studies that systematically investigated the utility of prospectively targeting novel risk/biomarkers such as hemoglobin or NT-proBNP failed to demonstrate long-term cardiovascular protection. The latter examples suggest that although a risk/biomarker may have superior prognostic ability, therapeutically changing such a risk/biomarker does not necessarily improve long-term outcome. Thus, to establish the clinical utility of other novel risk/biomarkers, clinical trials must be performed to prospectively examine the effects of therapeutically-induced changes in single or multiple risk/biomarkers on long-term risk management of patients with diabetes.