Cardiovascular Disease And Proteinuria

Urinary albumin excretion has been linked to all-cause and, especially, cardiovascular mortality in patients with diabetes and in the general population [56, 66, 110-119]. The Framingham Heart Study identified the direct correlation between diabetes and the morbidity and mortality associated with coronary heart disease. The total number of deaths from cardiac causes in diabetic patients is greater than that from the next five most common causes of death combined. The net effect of diabetes increases the risk of coronary death and coronary events approximately two fold, regardless of whether or not coronary disease is a pre-existing condition in these populations. Studies in diabetic patients with proteinuria at all levels have demonstrated an increased risk of cardiovascular events in these patients, and this risk increases with the severity of the underlying nephropathy. In fact, proteinuria might be considered to be a marker for generalized endothelial damage and atherosclerosis [100, 120-123]. Cardiovascular complications can occur with proteinuria even at levels that are currently considered to be low normal in the general population, in patients with diabetes, and in patients with diabetic or non-diabetic renal disease [119]. The presence of microalbuminuria in otherwise healthy individuals is probably associated with increased risk of cardiovascular disease but perhaps the association is stronger in the presence of other risk factors for cardiovascular disease [124].

The Heart Outcomes Prevention Evaluation (HOPE) trial demonstrated the benefit of angiotensin converting enzyme inhibition with ramipril when compared with the routine standard of care in reducing cardiac events in patients at increased risk of cardiovascular disease. The inclusion criteria for HOPE required either a history of vascular disease or diabetes, and the mean duration of follow-up was 4.5 years. The ramipril treatment group experienced a significant benefit in the reduction of cardiovascular events and mortality [125]. In the diabetic HOPE subgroup, the magnitude of benefits were more pronounced. The HOPE investigators also analyzed a sub-population of patients with pre-existing nephropathy, and found that the presence of nephropathy conferred an increased risk of cardiac events when compared to patients with normal renal function [126]. The HOPE study was designed as a cardiovascular outcome trial and did not demonstrate a benefit of therapy on renal outcome of end-stage renal disease.

The Losartan Intervention For Endpoint reduction in hypertension (LIFE) trial provided an opportunity to study the effects of treatment with the angiotensin II receptor antagonist losartan versus the beta-blocker atenolol in hypertensive patients with diabetes. This study investigated the effects of losartan- versus atenolol-based therapy in 9193 patients with hypertension and left ventricular hypertrophy followed for a mean of 4.8 years [127]. Lindholm et al analyzed the LIFE subgroup of 1195 patients with diabetes, hypertension, and left ventricular hypertrophy, and reported that in this subgroup of patients losartan reduced the risk of the primary composite endpoint of cardiovascular morbidity and mortality by 24%; P=0.031. The risk of cardiovascular mortality was 37% lower in the losartan group than in the atenolol group (P=0.028). Total mortality was 39% lower in the losartan group (P=0.002) [128].

The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study included three secondary cardiovascular endpoints: 1) the time to first event of cardiovascular morbidity and mortality (a composite of myocardial infarction, stroke, cardiovascular-related death, coronary or peripheral revascularization procedures, or first hospitalization for heart failure or unstable angina); 2) changes in the level of proteinuria; and 3) progression of renal disease. The RENAAL trial was not powered to detect differences in cardiovascular endpoints, and found no difference between treatment groups in cardiovascular events and mortality. There was, however, an observed trend towards a reduction in myocardial infarction (risk reduction 28%, P=0.08), and a statistically significant reduction in the time to first hospitalization for heart failure in the losartan group (risk reduction 32%, P=0.005) [89].

In IDNT, the secondary efficacy measure was the time to first event of the composite endpoint of death from cardiovascular causes, non-fatal myocardial infarction, hospitalization for heart failure, a permanent neurologic deficit caused by cerebrovascular event, or lower limb amputation above the ankle. There were no significant differences among the treatment groups in the secondary composite cardiovascular outcomes.

RENAAL and IDNT were designed as renal protective studies, not cardiovascular outcome trials. With regard to heart failure, the blockade of angiotensin II's effect on transforming growth factor-beta (TGF-beta-1) in the heart may retard the formation of fibrosis and the preservation of cardiac function [129, 130]. However, further studies are needed in this area.

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