HMG CoA-reductase inhibitors
HMG CoA-re·duc·tase in·hib·i·tors
The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, generically called statins, lower total cholesterol and LDL cholesterol in people with hyperlipidemia, delay progression of atherosclerosis, and decrease the risk of cardiovascular morbidity and mortality. In the synthesis of cholesterol in the liver, HMG CoA is converted to mevalonic acid by the enzyme HMG CoA reductase. Normally this enzyme is inhibited by a high dietary intake of cholesterol, and conversely a reduction of dietary cholesterol may increase HMG CoA reductase activity. Drugs that block the action of HMG CoA-reductase are structural analogues of HMG CoA and competitively inhibit the enzyme, preventing cholesterol synthesis. A decline in intracellular cholesterol levels promotes increased expression of cell surface LDL receptors and uptake of circulating LDL. HMG-CoA inhibitors such as atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin reduce plasma concentrations of LDL cholesterol by 20-60%, increase HDL cholesterol by 5-15%, and reduce triglyceride by 10-45%. Reduction of LDL cholesterol is the chief mechanism whereby these agents oppose atherogenesis. Controlled studies have shown that in people with a history of angina pectoris or heart attack, statins substantially reduce cardiovascular mortality, conferring protection against unstable angina and lowering the risk of fatal and nonfatal myocardial infarction, the number and duration of hospitalizations, the need for revascularization procedures, and the incidence of transient ischemic attacks and strokes. Prospective studies on the use of these agents by people with normal cholesterol levels have shown substantial reduction in the risk of a major coronary event in people with Type 2 diabetes mellitus (DM), postmenopausal women, people of both sexes over 65, and those who have undergone percutaneous transluminal coronary angioplasty (PTCA) with or without stent placement. In contrast, studies in which cholesterol was lowered by diet alone or by other drugs (for example, cholestyramine, gemfibrozil) have shown no consistent effect on the rate of either heart attacks or strokes. The beneficial effects of cholesterol lowering with statins are independent of concomitant medicines such as aspirin, beta-blockers, and calcium-channel blockers. Hence reduction in the progression of atheroma formation (which has been demonstrated by intravascular ultrasound) may not be the principal mechanism by which cholesterol reduction alters cardiac risk. Statins lower blood pressure slightly, perhaps by increasing expression of endothelial nitric oxide synthase in arterial walls. Pravastatin has also been shown to reduce C-reactive protein, an independent marker of cardiovascular disease risk. There is experimental evidence that statins affect immune function and the proliferation and metabolism of macrophages and endothelial cells independently of changes in plasma LDL concentrations. Animal studies suggest that statins may reduce the risk of thrombosis after plaque disruption by inhibiting platelet aggregation and maintaining a favorable balance between prothrombotic and fibrinolytic mechanisms. The statins are generally well tolerated but occasionally cause rhabdomyolysis, which in rare instances has been fatal.