Dual Blockade of the Renin-Angiotensin System in Diabetic Nephropathy

The accelerated progression of atherosclerosis in diabetes is most probably the end result of the cumulative impact of the major risk factors that are more prevalent in diabetic subjects, namely obesity and dyslipidemia, the derangement in carbohydrate metabolism (hyperglycemic environment, hyperinsulinism, and insulin resistance), a prothrombotic tendency, and, perhaps most important, microalbuminuria and hypertension (1–5). At least two additional cardiovascular risk factors are probably more pronounced in diabetes; they are endothelial dysfunction (6) and an inflammatory reaction in the affected blood vessels mediated by the proinflammatory interleukins and expressed by elevated levels of C-reactive protein (7). Microalbuminuria is often the first clinical manifestation of early microvascular derangement. In type 2 diabetes, it is the hallmark of subsequent diabetic nephropathy and a surrogate marker of cardiovascular disease and increased cardiovascular mortality (8). Furthermore, the presence of microalbuminuria predicts a worse outcome after percutaneous coronary intervention. The 2-year mortality after percutaneous coronary intervention in diabetic patients with microalbuminuria was increased by 85% compared with individuals with normal urinary albumin excretion (9). Microalbuminuria is associated with echocardiographic evidence of left ventricular hypertrophy and identifies overall cardiovascular risk also in hypertensive nondiabetic patients (10,11). It is therefore mandatory to screen all diabetic as well as nondiabetic hypertensive patients for the presence of microalbuminuria. Indeed, all the relevant professional associations have included annual screening for microalbuminuria in their recommendations (12,13). Treatment strategies aimed at reducing urinary albumin excretion were found to be effective in retarding the progression of renal disease, as manifested by prolongation of the time to doubling of serum creatinine and postponement of end-stage renal disease and the need to renal replacement therapy (14–17). Furthermore, the magnitude of early decline in albuminuria in response to a given therapeutic intervention is a reliable predictor …