Fluvastatin

Publisher Website
Google Scholar
Abstract
Fluvastatin is an HMG-CoA reductase inhibitor used to treat patients with hypercholesterolaemia. Since fluvastatin was last reviewed in Drugs, trials have shown its efficacy in the secondary prevention of coronary heart disease (CHD) events and death and have expanded knowledge of its effects in primary CHD prevention and its mechanisms of activity. In addition to reducing total (TC) and low density lipoprotein (LDL-C) cholesterol, fluvastatin has antiatherogenic, antithrombotic and antioxidant effects, can improve vascular function, and may have immunomodulatory effects. Although fluvastatin interacts with bile acid séquestrants (requiring separation of doses), its pharmacokinetics permit oral administration to most patient groups. Fluvastatin is well tolerated, with adverse effects usually mild and transient. Use of fluvastatin to reduce lipids in patients with primary hypercholesterolaemia is well established. Its effects are similar in most patient groups, with 20 to 80 mg/day reducing LDL-C by 22 to 36%, triglycérides (TG) by 12 to 18% and apolipoprotein B by 19 to 28% and increasing high density lipoprotein cholesterol by 3.3 to 5.6%. Attempts to find fluvastatin dosages with efficacy equivalent to that of other HMG-CoA reductase inhibitors produce variable results, but larger per-milligram fluvastatin dosages are needed when patients switch from other HMG-CoA reductase inhibitors. Combinations of fluvastatin with fibric acid derivatives and bile acid séquestrants produce additive effects. Small non-comparative studies suggest fluvastatin reduces LDL-C in patients with hyper-cholesterolaemia secondary to kidney disorders by ≤40.5% and with type 2 diabetes mellitus by ⪯32%. Three large randomised, double-blind trials show fluvastatin can help prevent CHD events or death and slow disease progression in patients with CHD with or without hypercholesterolaemia. In the Fluvastatin Angiographic Restenosis trial in patients undergoing balloon angioplasty, fluvastatin 80 mg/day for 40 weeks reduced the postangioplasty rate of deaths plus myocardial infarctions (1.5% vs 4% with placebo, p < 0.025) without altering vessel luminal diameters. In the Lipoprotein and Coronary Atherosclerosis Study in patients with coronary artery stenosis, luminal diameter reduced to a significantly lesser extent after fluvastatin 20mg twice daily than placebo after 2.5 years (−0.028 vs −0.01mm, p < 0.005). The Lescol in Symptomatic Angina study found reductions in all cardiac events or cardiac death in patients after 1 year of fluvastatin 40 mg/day (1.6% vs 5.6% for placebo, p < 0.05). Conclusions: An evolving pattern of data suggests that, in addition to its well established efficacy and cost effectiveness in reducing hypercholesterolaemia, fluvastatin may now also be considered for use in the secondary prevention of CHD. Fluvastatin is a structurally distinct synthetic inhibitor of HMG-CoA reductase in the liver that reduces cholesterol biosynthesis, thus lowering serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C). The drug also promotes concentration-dependent induction of LDL-C receptor activity, increasing catabolism of LDL-C and further reducing serum LDL-C levels. Fluvastatin can also inhibit cholesterol synthesis in peripheral tissues, although high first-pass metabolism prevents this by reducing unbound circulating drug. Further, it reduces serum apolipoprotein B levels in parallel with LDL-C levels and increases apolipoprotein A-I levels in parallel with high density lipoprotein cholesterol (HDL-C) levels. Antiatherogenic effects of fluvastatin include reduction of collagen fibre and smooth muscle cell content of atherosclerotic plaques, inhibition of cholesterol esterification and potential plaque stabilising effects. The drug also can affect coagulation factors and fibrinolysis by reducing platelet aggregation, factor VII, von Willebrand factor antigen, tissue plasminogen activator and tissue factor. Antioxidant effects of fluvastatin appear to occur when it binds to LDL-C surface phospholipids, reducing the oxidation of LDL-C without affecting concentrations of antioxidants such as tocopherol and retinol. Fluvastatin has direct vascular effects, such as increasing aortic compliance and myocardial perfusion, improving artery structural wall properties and endothelial function, and reducing blood pressure. The drug also has potential immunological effects. Oral fluvastatin is 98% absorbed; first-pass hepatic metabolism results in absolute bioavailability of 20 to 30%. Food reduces bioavailability and delays the peak plasma concentration, but does not alter clinical effects of fluvastatin. Plasma protein binding of fluvastatin was ≥99%. Most of the drug is taken up by the liver, where it is extensively metabolised to inactive metabolites by cytochrome P450 enzymes CYP2C9, CYP3A4 and CYP2D6, and eliminated mostly via the bile and faeces. The half-life of fluvastatin is 1.2 hours and clearance is 0.97 L/h/kg. Age and gender do not affect fluvastatin pharmacokinetics, but kinetics of the drug are affected by hepatic insufficiency. Clinically significant interactions reducing the effectiveness of fluvastatin include those with bile acid sequestrants and rifampicin (rifampin). In vitro data suggest a potential for interaction between fluvastatin and substrates of cytochrome P450 isozymes, but in vivo this is not clinically significant, and appears to be less common than with other HMG-CoA reductase inhibitors. Data from 12 placebo-controlled 6-month studies in 1621 fluvastatin recipients with type IIa/IIb hyperlipidaemia showed LDL-C reduced by 22, 25 and 36%, HDL-C increased by 3.3, 4.4 and 5.6%, triglycerides (TG) reduced by 12, 13.5 and 18% and apolipoprotein B reduced by 19, 18 and 28% after 20, 40 and 80 mg/day, respectively. Greater LDL-C reductions occurred in women than...

This publication has 64 references indexed in Scilit: