Losartan and end-organ protection-lessons from the renaal study

Abstract

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 ≤ 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.

A Nonpeptide, Piperidine Renin Inhibitor Provides Renal and Cardiac Protection in Double-Transgenic Mice Expressing Human Renin and Angiotensinogen Genes

“…tion Evaluation (HOPE) [6][7][8], Losartan Intervention For Endpoint reduction in hypertension (LIFE) [9,10], Reduction of Events with Angiotensin Converting Enzyme Inhibition (RENAAL) [11,12] and Irbesartan Diabetic Nephropathy Trial (IDNT) [13]. The ability of RAS inhibitors to mitigate cardiovascular risk is thought to be mediated, not only by their ability to lower blood pressure, but also by their inhibitory effects on atherosclerosis, left ventricular hypertrophy and renal damage in diabetic patients.…”

Role of Asymmetric Dimethylarginine in Inflammatory Reactions by Angiotensin II

“…It has been demonstrated that Ang II induces monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) release via activation of the nuclear factor (NF)-ĸB pathway [1]. A large scale of clinical studies have demonstrated that blockade of Ang II by angiotensin-converting enzyme inhibitor (ACEI) or AT 1 receptor antagonist reduces the incidence of cardiovascular events in patients with hypertension, atherosclerosis (AS) and after myocardial infarction [2,3,4]. …”

Significant association between glycemic status and increased estimated postglomerular resistance in nondiabetic subjects - study of inulin and para-aminohippuric acid clearance in humans

“…; Viberti and Wheeldon ; Kowey et al. ). These studies also support the activated state of intrarenal RAS in the early stage of diabetic nephropathy.…”