The objective of treating patients with hypertension is not simply to reduce blood pressure but rather to prevent the associated morbidity and mortality. Recent assessments of clinical trials have shown that while the risk of stroke is consistently lower with antihypertensive therapy, the same degree of success has not been demonstrated for coronary artery disease (CAD). Although there are many explanations of why we have not done as well in preventing CAD, one possibility is that the therapy used in clinical trials, primarily thiazide diuretics and beta-adrenoreceptor blockers, has increased the patient's risk of developing coronary atherosclerosis or lethal arrhythmias. Four classes of antihypertensive agents are recommended for initial therapy-thiazide diuretics, beta-adrenoreceptor blockers, angiotensin-converting enzyme (ACE) inhibitors, and calcium entry blockers. The metabolic effects of thiazide diuretics include electrolyte disturbances (hypokalemia, hypomagnesemia, and hyponatremia), dyslipidemia (increased triglycerides), abnormalities of glucose metabolism (hyperglycemia, hyperinsulinemia, and peripheral insulin resistance), and hyperuricemia. beta-Adrenoreceptor blockers have many of the same metabolic adverse reactions. beta-Adrenoreceptor blockers without intrinsic sympathomimetic activity (ISA) also cause dyslipidemias (lowered high-density lipoprotein cholesterol and increased triglycerides) and abnormalities of glucose metabolism (hyperglycemia, hyperinsulinemia, and peripheral insulin resistance). beta-Adrenoreceptor blockers with ISA and third-generation beta-blockers with selective partial agonist activity (celiprolol and dilevalol) do not cause dyslipidemia and to date do not appear to induce abnormalities in glucose metabolism. ACE inhibitors may decrease triglycerides and increase high-density lipoprotein cholesterol, and captopril may improve insulin sensitivity. Calcium entry blockers are metabolically neutral. Of the drugs used primarily as second or third agents, alpha-adrenoreceptor blockers have the same beneficial effects on lipids and glucose as ACE inhibitors. Sympatholytics and vasodilators are metabolically neutral. Since many patients require combined therapy with two or three agents, the metabolic effects of combination treatment cannot be ignored. Thiazide diuretics and beta-adrenoreceptor blockers without ISA cause the same if not more significant dyslipidemias and glucose/insulin abnormalities as either drug alone. When thiazide diuretics and ACE inhibitors are used together, the dyslipidemia seen with thiazides does not occur and the decrease in serum potassium and the increase in serum glucose are partially ameliorated. The combination of thiazide diuretics and alpha-adrenoreceptor blockers appears also to be free of significant metabolic abnormalities. Little is known about other combinations or about combination therapy that includes beta-adrenoreceptor blockers with ISA or partial agonist activity. The clinical significance of the metabolic abnormalities resulting from antihypertensive therapy is uncertain. Until proper clinical trials are done, it is not appropriate to ignore these changes but rather to adjust therapy, especially in patients who already have dyslipidemias or glucose intolerance, or in those who would be at significant risk from even minor hypokalemia.
