Lovastatin

Abstract

Lovastatin is the first of a new class of cholesterol lowering drugs that competitively inhibit HMG-CoA reductase. This new drug decreases cholesterol synthesis and apolipoprotein B concentrations, and increases LDL receptor activity without adverse effects on other products in the cholesterol pathway. In patients with heterozygous familial or polygenic (non-familial) hypercholesterolaemia, oral lovastatin 20 to 40mg twice daily reduces plasma total cholesterol and LDL-cholesterol concentrations by 25 to 40% over a period of several weeks. Lovastatin also produces decreases in plasma triglyceride and VLDL-cholesterol concentrations, although to a lesser extent. In addition, small though significant increases in HDL-cholesterol concentrations have been observed. Combined administration of lovastatin with other lipid-lowering drugs results in further reductions in plasma total and LDL-cholesterol concentrations beyond those seen with either drug alone. From findings in short term studies, lovastatin appears to be well tolerated with a low incidence of side effects. However, liver function tests and eye examinations for possible lens opacities are advised, and further long term studies in larger groups of patients are necessary before the side effect profile of lovastatin will be clearly established. As would be expected at this relatively early stage of its clinical ‘life’, lovastatin has not yet been studied in a manner that would determine its effect on cardiovascular mortality during long term administration. Nevertheless, if the substantial improvements to patients’ lipid and lipoprotein profiles observed in short term studies are maintained during long term administration, then lovastatin will have an important role in the pharmacological management of hyperlipidaemia. Lovastatin is a reversible competitive inhibitor of HMG-CoA reductase in hepatocytes, an early and rate-limiting enzyme in the biosynthesis of cholesterol. Lovastatin effectively reduces cholesterol synthesis in vivo and in vitro, without depleting vital stores of cholesterol in vivo. It markedly lowers plasma cholesterol and LDL-cholesterol in animals, other than rodents, which are normolipidaemic or hypercholesterolaemic. In rodents, lovastatin is ineffective in reducing plasma cholesterol; in this model the inhibition of HMG-CoA reductase is accompanied by an increase in its synthesis and a decrease in its degradation. Double-blind studies with placebo in healthy volunteers have shown lovastatin in doses from 12.5 to 100mg daily to significantly lower serum total cholesterol concentrations without significant alteration to HDL-cholesterol, VLDL-cholesterol and serum triglyceride concentrations. Administration of lovastatin decreases apolipoprotein B concentrations by 25 to 34% in healthy volunteers receiving 6.25 to 50mg twice daily, and by 23 to 33% in hyperlipidaemic patients receiving 20 to 40mg twice daily. Small elevations of approximately 10% were also observed for apolipoprotein A I and A II concentrations following similar doses of lovastatin in patients with heterozygous familial or non-familial (polygenic) hypercholesterolaemia. Lovastatin increases the number of hepatic LDL receptors and increases the fractional catabolic rate of LDL. The reduction in apolipoprotein B concentrations appears to be a result of an increase in LDL degradation, and thus the plasma cholesterol concentration is lowered. Adrenocortical function, as assessed by response to ACTH, is not impaired to any significant degree following short term administration of lovastatin to healthy volunteers and hypercholesterolaemic patients. Lovastatin is converted to a number of active metabolites, with peak plasma concentrations occurring within 2 to 4 hours following oral administration, and steady-state concentrations are achieved within 2 to 3 days. Lovastatin undergoes extensive first-pass hepatic extraction with less than 5% of an oral dose reaching the general circulation as active HMG-CoA reductase inhibitors. Major metabolites are the β-hydroxyacid of lovastatin, its 6′-hydroxyderivative and two other unidentified metabolites. Parent drug and the metabolites are predominantly excreted in bile. The majority of clinical studies have been conducted in patients with heterozygous familial hypercholesterolaemia or other less well defined causes of primary hypercholesterolaemia (non-familial), and have been mainly short term (1 to 2 months). Administration of lovastatin 20 to 40mg twice daily decreases plasma total cholesterol by 23 to 40% and LDL-cholesterol concentrations by 24 to 39% in patients heterozygous for familial hypercholesterolaemia, with similar reductions in patients with non-familial hypercholesterolaemia. Maximal hypocholesterolaemic effects are usually evident within 4 to 6 weeks. In 2 double-blind placebo-controlled multicentre trials, lovastatin decreased total triglyceride concentrations by 14 to 16% and by 23 to 27% in patients with familial or non-familial hypercholesterolaemia, respectively, following administration of 20 to 40mg twice daily for 6 weeks. Significant elevations in HDL-cholesterol concentrations of approximately 10% have frequently been observed in patients with primary hypercholesterolaemia during short term administration of lovastatin 20 to 40mg twice daily. At this dosage, ‘target’ therapeutic objectives of lowering concentrations of plasma total and LDL-cholesterol to 2.4 and 1.6 g/L or below, respectively, and lowering the LDL-C: HDL-C ratio to 3 or less, have been achieved in patients with non-familial hypercholesterolaemia, but not in patients heterozygous for familial hypercholesterolaemia. Lovastatin had minimal effect in reducing plasma cholesterol concentrations in the few homozygous patients studied. Combined administration of lovastatin and other lipid-lowering drugs, such as the bile acid resins, has proved more effective than monotherapy in reducing elevated plasma cholesterol concentrations in patients with primary hypercholesterolaemia. Further reductions of 31 and 35% in the plasma total cholesterol concentration, and of approximately 50% in the LDL-C: HDL-C ratio, have been observed following addition of lovastatin 20mg 2 or 3 times daily for over 6 and 12 months, respectively, to the treatment of heterozygous patients maintained on cholestyramine or colestipol and nicotinic acid (niacin). In 2 large comparative studies, lovastatin 40mg twice daily for 12 to 14 weeks reduced LDL-cholesterol concentrations to a significantly greater extent than cholestyramine 4 to 12g twice daily or probucol lg daily in patients with familial or non-familial hypercholesterolaemia. Although in the few patients followed for long periods of continued treatment (up to 4 years) lovastatin maintained its hypocholesterolaemic effect, further long term studies in larger groups of patients are needed to confirm the continued effectiveness of this drug during treatment periods of several years, and to establish the effect of such treatment on cardiovascular morbidity and mortality. Gastrointestinal disturbances, such as flatulence, irregular bowel movements and nausea, account for the majority of clinical symptoms reported during lovastatin therapy. Headaches, rashes, insomnia and myalgia occur in a small proportion of patients. Although lovastatin is generally well tolerated, the intensity and duration of unwanted events have been severe enough to warrant discontinuation of treatment in approximately 2% of patients. Increases in lens opacities have been observed after short term treatment with lovastatin, although the overall prevalence did not increase. However, further studies are required to clarify the clinical significance (if any) of this finding. Myopathy, associated with increases in creatine phosphokinase and often characterised by myalgia or muscle weakness, has occurred in 0.5% of patients receiving lovastatin; this condition has also been noted in patients receiving concurrent cyclosporin, gemfibrozil, nicotinic acid or combinations of these drugs. Elevations in serum transaminases have occurred in 5% of patients, resulting in occasional withdrawal from lovastatin treatment. Enzyme elevations evident during lovastatin treatment are usually mild and transient, and dosage reductions or withdrawal of therapy have resulted in a return of these increases to within normal limits. Since most studies reported to date have been relatively short term, and since lovastatin will be administered continuously over long periods in clinical practice, further long term studies are needed to confirm its side effect profile. Lovastatin is indicated as adjunct therapy in patients with elevated plasma cholesterol concentrations secondary to elevations of LDL-cholesterol when dietary measures alone, including weight reduction and limitation of alcohol intake, do not achieve adequate results. The standard starting dose is 20mg once daily with the evening meal for less severe forms of hypercholesterolaemia. These starting doses may be increased to a maximum of 80mg in single or divided doses, depending on the patient’s response. Dosage adjustments should be undertaken at intervals of 4 weeks or more. Dietary measures should be continued during lovastatin therapy. Eye examinations using a slit lamp, and laboratory measures of liver function, should be regularly undertaken during lovastatin administration.