Abstract-Statins (HMG-CoA reductase inhibitors) are used widely for the treatment of hypercholesterolemia. They inhibit HMG-CoA reductase competitively, reduce LDL levels more than other cholesterol-lowering drugs, and lower triglyceride levels in hypertriglyceridemic patients. Statins are well tolerated and have an excellent safety record. Clinical trials in patients with and without coronary heart disease and with and without high cholesterol have demonstrated consistently that statins reduce the relative risk of major coronary events by Ϸ30% and produce a greater absolute benefit in patients with higher baseline risk. Proposed mechanisms include favorable effects on plasma lipoproteins, endothelial function, plaque architecture and stability, thrombosis, and inflammation. Mechanisms independent of LDL lowering may play an important role in the clinical benefits conferred by these drugs and may ultimately broaden their indication from lipid-lowering to antiatherogenic agents.
Mechanism of ActionStatins competitively inhibit HMG-CoA reductase, the enzyme that catalyzes the rate-limiting step in cholesterol biosynthesis. 1 The resultant reduction in hepatocyte cholesterol concentration triggers increased expression of hepatic LDL receptors, which clear LDL and LDL precursors from the circulation. 2 Statins may inhibit hepatic synthesis of apolipoprotein B-100 and decrease the synthesis and secretion of triglyceride-rich lipoproteins. 3,4 Although the primary mechanism of action for LDL lowering is enhanced clearance of LDL via LDL receptors, reduced hepatic production and secretion of lipoproteins may explain the observation that atorvastatin and simvastatin are capable of lowering LDL in patients with homozygous familial hypercholesterolemia who have no functional LDL receptors. 5,6 Pharmacology Lovastatin, pravastatin, and simvastatin are derived from fungal fermentation. Fluvastatin, atorvastatin, and cerivastatin are entirely synthetic. Lovastatin, simvastatin, atorvastatin, and cerivastatin utilize the cytochrome P 450 (CYP) 3A4 pathway for metabolism or biotransformation. 7 Fluvastatin metabolism occurs via CYP2C9, and pravastatin does not use the CYP pathway significantly. 8
Effects on Plasma Lipids and LipoproteinsStatins are highly effective in reducing LDL and modestly effective in raising HDL. Triglyceride lowering is directly proportional to the baseline triglyceride level and to the LDL-lowering potency of the drug. 9,10 Table 1 shows the comparative efficacy and potency of statins on lipids and lipoproteins in patients without hypertriglyceridemia. In general, LDL is reduced an additional 7% with each doubling of the dose. 11 Statins do not lower lipoprotein(a) [Lp(a)] concentration. 16 Statins are also ineffective in modifying the size and density of LDL. 17
Adverse EffectsAs a class, statins are well tolerated, and there are no known differences in safety. The most important adverse effects are liver and muscle toxicity. The incidence of transaminase increases greater than 3-fold is Ϸ1% for all...