The coronary artery disease paradox: the role of hyperinsulinemia and insulin resistance and implications for therapy.

Hypertension is one of the primary risk factors for cardiovascular disease, especially coronary artery disease (CAD), cerebrovascular disease, and congestive heart failure. Recent analysis of the numerous prospective clinical trials of the efficacy of antihypertensive therapy performed during the past quarter century has shown that active treatment reduces mortality and cerebrovascular disease but has not prevented CAD. The reason for this paradox--that lowering blood pressure does not reduce CAD mortality or morbidity--is uncertain. During the past several years, it has become clear that hyperinsulinemia and peripheral insulin resistance constitute the link between hypertension, obesity, and non-insulin-dependent diabetes mellitus, three conditions in which the rate of CAD is very high. Other studies have shown that hyperinsulinemia is a potent cardiovascular risk factor. Epidemiologic surveys and retrospective reviews of clinical experience have pointed out the surprising fact that when hypertension and non-insulin-dependent diabetes mellitus occur in the same patient, hypertension is likely to be diagnosed first and the risk of developing diabetes is much higher if antihypertensive drugs (thiazide diuretics or beta-adrenoreceptor blockers) were given. Recently, careful studies have shown that both thiazide diuretic and beta-adrenoreceptor blockers worsen insulin sensitivity, whereas angiotensin converting enzyme inhibitors (captopril) and peripheral alpha 1-blockers (prazosin) improve it and also favorably affect the levels of other atherogenic risk factors. Although it is too early to be certain, this information suggests that, pending the results of long-term clinical trials that measure clinical events, treatment of hypertension might be better able to reduce CAD if it were directed at improving insulin sensitivity. Nonpharmacologic measures that reduce hyperinsulinemia, weight loss, and exercise should be vigorously recommended, and pharmacologic therapy should be aimed at avoiding drugs that worsen insulin sensitivity, as long as blood pressure is successfully reduced.