Target-organ protection in hypertension and diabetes: The promise of combination therapy

An increase in arterial pressure is a potent risk factor for cardiovascular morbidity and mortality. Since the pioneering observations of Freis, we know that antihypertensive therapy diminishes this risk. However, although blood pressure can be reduced to normal levels, there is an excessive risk for cardiovascular morbidity and mortality in treated patients, despite normal blood pressure levels. This risk may be, at least to some extent, related to the inherent risks and toxicity associated with antihypertensive therapy. Clearly, therefore, the more specific the blood pressure reduction, the greater the potential risk/benefit ratio. These considerations become even more important in diabetic hypertensive patients. Combination therapy may provide a multifactorial risk reduction, and therefore may provide specific organ-protective effects that exceed those achieved by reduction in blood pressure alone. Specifically, a calcium antagonist and an angiotensin-converting enzyme (ACE) inhibitor might mutually improve endothelial function, the calcium antagonist by blunting endothelial constriction and the ACE inhibitor by enhancing nitric oxide release by inhibition of angiotensin II formation. Calcium antagonists bind calcium and may inhibit artherogenesis, and ACE inhibitors have been shown to prevent collagen synthesis induced by angiotenxin II. Both drug classes reduce left ventricular mass and thereby decrease another powerful risk factor for cardiovascular disease. ACE inhibitors predominantly improve systolic function, whereas calcium antagonists predominantly improve left ventricular filling. By different mechanisms, each of the two drug classes reduces proteinuria and appears to improve or conserve renal function, particularly in diabetic hypertensive patients. Heart rate-limiting calcium antagonists appear to have an advantage over the dihydropyridine calcium antagonists with regard to microproteinuria and in the post-MI patient. The combination of a calcium antagonist with an ACE inhibitor has the potential to offer multifactorial protection of the vascular tree and target organs that may be independent of antihypertensive efficacy.