Effects of ACE inhibition on cardiovascular risk factors, insulin resistance, and microalbuminuria

Hypertension is one of the three major risk factors for cardiovascular disease, but levels of blood pressure are by themselves poor predictors of cardiovascular risk. Among subjects with hypertension, a number of phenotypic characteristics are capable of predicting cardiovascular events, but in turn these variables are only weakly related to levels of blood pressure, and may indeed be found in the normotensive as well as the hypertensive population. Among the most powerful predictors of cardiovascular risk are left ventricular hypertrophy (LVH) and microalbuminuria, which may in part represent end-organ damage from elevated blood pressure, but which may also result from the consequence of a common antecedent to that of hypertension. Another common finding in hypertensive subjects is that of insulin resistance, where euglycemia is maintained only at the expense of elevated concentrations of insulin. Several studies, both in diabetic and in nondiabetic subjects, have shown an association between insulin resistance and cardiovascular risk, although it is as yet unclear whether this is independent of the obesity and dyslipidemia associated with insulin resistance. The renin-angiotensin system has been implicated in the etiology of both microalbuminuria and LVH. In insulin-dependent diabetic subjects with microalbuminuria, angiotensin-converting enzyme (ACE) inhibitors have been shown to retard progression to proteinuria and to lower albumin excretion to a greater degree than can be explained by the reduction of blood pressure alone; the same is true in studies of left ventricular mass regression in hypertensive subjects. The relationship between the renin-angiotensin system and insulin resistance is less clear, but ACE inhibitors appear to produce a reduction in insulin resistance, particularly in the non-fasting state. ACE inhibitors may achieve these effects via restoration of endothelial function. The ultimate test of the benefit of any antihypertensive agent is the demonstration of reductions in stroke and in cardiovascular events in large randomized, controlled studies. In the absence of such studies, the potential advantages of newer agents must be set against the proven efficacy of thiazides and beta blockers in providing around 50% reversibility of coronary heart disease risk and virtually 100% reversibility in stroke risk. To attempt to predict the likely efficacy of new agents, the effects of these drugs on a series of surrogate end points must be used. The observations of benefit from ACE inhibitors in terms of left ventricular mass regression and reductions in insulin resistance and in microalbuminuria might predict benefit in reducing major end points. It must be remembered, however, that risk markers such as microalbuminuria and insulin resistance may not represent mechanisms of damage, and thus reversibility of these variables may not necessarily produce better outcomes than can be achieved with older drugs. It is only with end point studies that such questions can be answered.