Are There Effects of Renin–Angiotensin System Antagonists Beyond Blood Pressure Control?

Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are recognized to reduce cardiovascular and renal morbidity and mortality, which is primarily attributed to their antihypertensive effects. Activation of the renin–angiotensin system (RAS) may also play an important role in the pathogenesis of cardiovascular and renal disease through blood pressure–independent mechanisms mediated by angiotensin II. Thus, inhibiting the RAS with either an ARB or an ACE inhibitor may confer additional benefit in people with advanced nephropathy that cannot be explained totally by reductions in blood pressure. Preclinical evidence suggests that blood pressure lowering is not solely responsible for the organ and tissue protective effects of ACE inhibitors or ARBs. Furthermore, clinical studies evaluating effects on end organs and surrogate markers have shown that these agents have blood pressure–independent effects. There is also intriguing evidence that agents in the same class may differ in their effects on renal function despite similar blood pressure control. Support for blood pressure–independent effects comes from outcome studies. Agents evaluated in such studies and that appear to have effects independent of blood pressure lowering include irbesartan, losartan, ramipril, and telmisartan. Taken together, this body of evidence indicates that the clinical benefits of ARBs and ACE inhibitors in patients with advanced nephropathy extend beyond blood pressure reduction. Therefore, although antihypertensive efficacy is of primary importance in choosing a treatment to provide cardiovascular and renal protection, consideration should be given to the effects of an agent that extend beyond blood pressure.