, Volume 57, Issue 4, pp 583–606


A Review of its Use in Lipid Disorders


    • Adis International Limited
  • Anthony Markham
    • Adis International Limited
Adis Drug Evaluation

DOI: 10.2165/00003495-199957040-00009

Cite this article as:
Langtry, H.D. & Markham, A. Drugs (1999) 57: 583. doi:10.2165/00003495-199957040-00009



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.

Clinical Efficacy

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 men, but fluvastatin induced similar LDL-C reductions in elderly and younger patients, in patients with initially high or low LDL-C levels, and in patients with secondary or primary hypercholesterolaemia. Noncomparative studies also showed fluvastatin to be effective in decreasing LDL-C in patients with hypercholesterolaemia secondary to type 2 diabetes mellitus (by ≤32%) or nephrotic syndrome and in kidney transplant recipients and patients undergoing peritoneal dialysis (by ≤40.5%). Comparative trials found fluvastatin 20 mg/day was similar in efficacy to gemfibrozil 1200 mg/day, and fluvastatin 40 mg/day was superior to bezafibrate 400 mg/day in reducing TC and LDL-C levels, but that fibric acid derivatives were superior to fluvastatin in reducing TG and increasing HDL-C at these fluvastatin dosages. Cholestyramine 16 g/day produced slightly greater reductions in TC and LDL-C than fluvastatin 40 mg/day. When other lipid-lowering agents are added to fluvastatin, the resultant effects on TC, LDL-C, TG and HDL-C levels appear to be additive. Fluvastatin has been effectively combined with cholestyramine, nicotinic acid, bezafibrate, probucol, gemfibrozil and fenofibrate.

Comparative studies in patients with hyperlipidaemia generally suggest that a higher milligram dosage of fluvastatin is required than for other HMG-CoA reductase inhibitors, but many did not test the full fluvastatin dosage range (20 to 80 mg/day) and thus produced variable dosage equivalence results. On LDL-C levels, fluvastatin 40 to 80 mg/day was similar in efficacy to pravastatin 20 or 40 mg/day. Variable dosage ratios were seen between fluvastatin and simvastatin in trials involving reformulation of fluvastatin (≤40 mg/day). A recent well controlled trial using marketed formulations determined a 2: 1 dosage ratio for fluvastatin (40 and 80 mg/day): simvastatin (20 and 40 mg/day). A4: 1 dosage ratio was found for fluvastatin: lovastatin in trials using a maximum of fluvastatin 40 mg/day. Early fluvastatin versus atorvastatin trials failed to find equivalent dosages but did not test fluvastatin 80 mg/day. A recent trial found fluvastatin 80 mg/day and atorvastatin 40 mg/day had similar effects on LDL-C and TC, although atorvastatin 10 mg/day was superior to fluvastatin 20 mg/day in these effects, indicating that fluvastatin has a steeper dose-response effect on LDL-C than atorvastatin. Results of studies examining the ability of HMG-CoA reductase inhibitors to achieve National Cholesterol Education Program (NCEP)-recommended LDL-C targets are inconclusive, because fluvastatin dosage ranges did not reflect dosage equivalence with other agents.

Three randomised, double-blind, parallel-group, multicentre studies enrolling large numbers of patients with CHD have found that, in addition to having favourable effects on plasma lipids, fluvastatin may reduce the incidence of clinical events and slow the progression of atherosclerotic plaques. In FLARE (Fluvastatin Angiographic Restenosis trial), fluvastatin 80 mg/day was administered for 2 to 4 weeks before and 40 weeks after percutaneous transluminal coronary angioplasty (PTCA) in patients with ≥1 stenotic lesion amenable to that procedure and LDL-C levels <6 mmol/L. In LCAS (the Lipoprotein and Coronary Atherosclerosis Study), CHD patients with mild to moderate hyperlipidaemia (LDL-C 3.0 to 4.9 mmol/L) and stenosis of ≥1 coronary vessel received fluvastatin 20mg twice daily for 2.5 years. In LISA (the Lescol in Symptomatic Angina study), patients with symptomatic CHD and at least moderately elevated lipid levels (TC 6.5 mmol/L, LDL-C >4.1 mmol/L) received fluvastatin 40 or 80 mg/day for 1 year.

Fluvastatin therapy was associated with clear reductions in the occurrence of death and myocardial infarction (1.5 vs 4% with placebo, p < 0.025) in FLARE and of all cardiac events in LISA (3 of 214 patients vs 10 in 215 placebo recipients, p < 0.035). LCAS was not designed to detect differences in clinical events between groups, but a trend towards reduced events with fluvastatin emerged early in the trial. In LISA, cardiac events or cardiac death occurred in 1.6% of fluvastatin versus 5.6% of placebo recipients (p < 0.05). In LCAS, fluvastatin significantly slowed progression of CHD in patients with mildly-to-moderately elevated LDL-C levels; women and patients with higher HDL-C levels were the least likely to show progression of lesions. Also in LCAS, a smaller reduction occurred in minimal luminal diameter (MLD) after fluvastatin than placebo (−0.028mm vs −0. lmm, p < 0.005), and this was associated with fewer fluvastatin than placebo patients requiring revascularisation. However, in FLARE, the drug had no effect on restenosis or MLD (−0.23mm in both groups).


Adverse events associated with fluvastatin are generally mild and transient. Headache, dyspepsia, diarrhoea, abdominal pain, nausea and insomnia occurred more frequently with fluvastatin than placebo. Elevated transaminase levels have been reported during prolonged treatment, but resolved when fluvastatin was halted. In clinical trials, fluvastatin was as well tolerated as gemfibrozil, bezafibrate, cholestyramine, pravastatin, simvastatin and atorvastatin. Although rare with fluvastatin and unreported in fluvastatin clinical trials, myopathy (including myositis and rhabdomyolysis) has been reported as a class effect of HMG-CoA reductase inhibitors associated with hypothyroidism or concomitant use of fibric acid derivatives, nicotinic acid or cyclosporin. Asymptomatic elevations of creatine phosphokinase have occurred during fluvastatin therapy (0.3% of patients).

Pharmacoeconomic Considerations

Comparisons of drug acquisition costs versus expected reductions in LDL-C suggest that fluvastatin may be more cost effective than simvastatin, pravastatin and lovastatin. Cost-effectiveness studies also have found that in the treatment of hypercholesterolaemia, depending on the country and study perspective, fluvastatin costs were 13 to 57% less than those of simvastatin, 26 to 60% less than lovastatin and 60 to 64% less than pravastatin per percentage reduction in LDL-C. Another trial found 44 to 53% lower costs associated with reaching an LDL-C target of 4.5 mmol/L using fluvastatin than lovastatin. Trials comparing fluvastatin with atorvastatin failed to examine all fluvastatin dosages and found dosages of 40 mg/day to be less effective than maximum dosages of atorvastatin, simvastatin or lovastatin, or found fluvastatin (≤40 mg/day only) and simvastatin next most cost effective to atorvastatin when compared with pravastatin and lovastatin.

When patients were switched to fluvastatin from simvastatin, lovastatin or gemfibrozil, no significant change in resource utilisation, LDL-C levels or achievement of NCEP targets occurred in one managed-care organisation. Programmes to assist a switch to fluvastatin are documented in the literature and appear to be capable of reducing formulary costs. However, when patients are switched from other HMG-CoA reductase inhibitors to fluvastatin, lipid monitoring is required and fluvastatin dosage adjustments may be needed.

Dosage and Administration

Before and during fluvastatin treatment, patients should undertake dietary changes to reduce cholesterol levels. Fluvastatin is administered orally without regard to meals in dosages from 20 to 80 mg/day. Monthly monitoring should take place and dosages should be individualised to patients’ serum TC and LDL-C concentrations. Most patients require long term therapy, during which serum lipoprotein concentrations should be monitored periodically. Fluvastatin is contraindicated in patients with unexplained persistent elevated serum transaminase levels, pregnant or lactating women and patients <18 years of age. The drug should be used with caution in patients with severe renal impairment or liver disease or during heavy alcohol ingestion. Fluvastatin may be combined with cholestyramine or other bile acid séquestrants if doses are separated by >5 hours.

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© Adis International Limited 1999