Drugs 50 (2): 334-363. 1995 0012-6667/95/0008-0334/$3000/0 DRUG EVALUATION © Adis International Limited. All rights reserved. Simvastatin A Reappraisal of its Pharmacology and Therapeutic Efficacy in Hypercholesterolaemia Greg L. Plosker and Donna McTavish Adis International Limited Various sections of the manuscript reviewed by: D.R. Abernethy, Division of Clinical Pharmacology, Departments of Pharmacology and Medicine, Georgetown University Medical Center, Washington, D.C., USA; C. Alessandri, Istituto di Terapia Medica Sistematica, University of Rome "La Sapienza", Rome, Italy; A. Corsini, Institute of Pharmacological Sciences, University of Milan, Milan, Italy; J. Frohlich, Atherosclerosis Specialty Laboratory, Lipid Clinic, St. Paul's Hospital, Vancouver, British Columbia, Canada; C.J. Lintott, Lipid, and Diabetes Research Group, Christchurch Hospital, Christchurch, New Zealand; T.R. Pedersen, Cardiology Section, Medical Department, Aker Hospital, Oslo, Norway; P.D. Roach, Division of Human Nutrition, CSIRO (Australia), Adelaide, South Australia, Australia; Y. Saito, Department of Laboratory Medicine, Yamagata University School of Medicine, Yamagata, Japan; CA. Seymour, Department of Clinical Biochemistry, St. George's Hospital Medical School, University of London, London, England; G.R. Thompson, Medical Research Council Lipoprotein Team, Hammersmith Hospital, London, England; R.A. Wright, Medical Unit, Western General Hospital, Edinburgh, Scotland. Contents Summary …...................................................................... ........ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . … . . 1. Overview of Pharmacodynamic Properties . ….. . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . 2. Overview of Pharmacokinetic Properties ...................................... ....................... ....................…... 3. Therapeutic Efficacy ….... ......................................................................... ......................….............. 3.1 Primary Hypercholesterolaemia .............................................................. ….......................... 3.1.1 Noncomparalive Studies .......................................................... ….................................... 3.1.2 Dose-Response Studies and Comparisons with Placebo........……...................................... 3.1.3 Comparisons with Other Antihyperlipidaemic Drugs……………………………………….. 3.1.4 Use in Combination with Other Antihyperlipidaemic Drugs ....................................... …. 3.2 Secondary Hypercholesterolaemia ………………………………………………………………….. 4. Pharmacoeconomic Considerations ................. ...........................................................................….. 5. Tolerability ....................................................................................... .......................... ...............….. 6. Dosage and Administration…......................................................................................................... … 7. Place of Simvastatin in Therapy.......................................................... …………… ........................… 334 339 341 343 343 343 344 347 350 352 353 354 356 356 Summary Synopsis Simvastatin is an HMG-CoA reductase inhibitor used in the treatment of patients with hvpercholesterolaemia. Since the time simvastatin was previously reviewed in Drugs, a number of large clinical trials have confirmed its clinical efficacy. Thus, reductions from baseline were approximately 20 to 40% for serum levels of total cholesterol, 35 to 45% for low density lipoprotein (LDL)-cholesterol and 10 to 20% for triglycerides in patients with primary hypercholesterolaemia Simvastatin: A Reappraisal 335 receiving simvastatin 10 to 40 mg/day. High density lipoprotein (HDL)-cholesterol levels were increased modestly by about 5 to 15%. Recent data from long term studies indicate that little or no attenuation of these changes in serum lipid and lipoprotein levels occurred with administration of simvastatin for 3 to 5.4 years. Comparative studies with other HMG-CoA reductase inhibitors (lovastatin, pravastatin and fluvastatin), which were lacking at the time of the previous review of simvastatin, demonstrated greater reductions in serum levels of total cholesterol and LDL-cholesterol with simvastatin than equal dosages of lova-statin or pravastatin. Reductions in serum levels of total cholesterol and LDL-cholesterol were similar between agents only when lovastatin or pravastatin were administered at a total daily dosage twice that of simvastatin and when fluvastatin was administered at a total daily dosage approximately 8 limes that of simvastatin. In general, simvastatin 10 to 40 mg/day was also more effective than standard dosages of bile acid sequestrants,fibrates or probucol in lowering serum levels of total cholesterol and LDL-cholesterol; however, fibrates usually produced greater reductions in serum triglycerides and greater elevations in HDL-cholesterol levels. The Scandinavian Simvastatin Survival Study (4S), a large secondary prevention study in patients with coronary heart disease and concomitant hyperchol-esterolaemia, demonstrated that simvastatin 20 to 40 mg/day for a median of 5.4 years significantly reduced overall mortality (the primary endpoint of the study) by 30% compared with placebo, which was attributed to a 42% relative reduction in coronary mortality. Coronary morbidity was also significantly reduced by simvastatin in the 4S trial. The tolerability profile of simvastatin appears to be comparable to that of other HMG-CoA reductase inhibitors. The most frequently reported adverse events are gastrointestinal disturbances, which are generally mild and tend to occur less frequently than with cholestyramine. In conclusion, simvastatin is among the most effective agents available for treating patients with hyperchalesterolaemia. The efficacy and tolerability profiles of simvastatin compare favourably with those for other HMG-CoA reductase inhibitors, fibrates and bile acid sequestrants and therapeutic efficacy has been shown to be maintained during long term administration of simvastatin for 5.4 years. Furthermore, results of the 4S trial with simvastatin have convincingly demonstrated, for the first time, a significant reduction in overall mortality with a lipid-lowering agent used as secondary prevention. This overall profile of findings has firmly established simvastatin as a first-line agent for cholesterol-lowering therapy. Pharmacodynamic Properties Adis International Limited. All rights reserved. Simvastatin is an inactive prodrug which is hydrolysed in the liver to its major active -hydroxyacid metabolite, a competitive and reversible inhibitor of HMDCoA reductase. HMG-CoA reductase is the enzyme responsible for conversion of HMG-CoA to mevalonic acid, a rate-limiting step in the early stages of the cholesterol biosynthetic pathway. Inhibition of hepatic cholesterol biosynthesis by HMG-CoA reductase inhibitors gives rise to increased expression of low den-sity lipoprotein (LDL) receptors in the liver which bind LDL particles and remove them from the circulation, thereby lowering serum total cholesterol levels. In vitro studies and in vivo data from animal models of atherosclerosis suggest that simva- statin may have antiatherogenic activity apart from the effects on serum, lipid and lipoprotein levels. Simvastatin markedly inhibited animal and human arterial Drugs 50 (2) 1995 336 Plosker & McTavish myocyte proliferation and reduced or reversed atherosclerotic lesions in coronary arteries and the aorta of cholesterol-fed rabbits. Simvastatin may also inhibit the uptake of LDL by macrophages into foam cells present in atherosclerotic lesions by reducing the susceptibility of LDL to oxidation, and experimental evidence indicates that cholesterol ester formation and accumulation in macrophages is reduced by simvastatin. In patients with hypercholesterolaemia, simvastatin reduced factor VIIc activity and inhibited platelet activation - effects which may also reduce the risk of vascular events. On the basis of pharmacodynamic studies and long term clinical use of the drug, simvastatin does not appear to have clinically significant potential to increase cataract formation or adverse effects on adrenocortical and sex hormone production or function. Pharmacokinetic Properties After oral administration, simvastatin is well absorbed ( 60 to 80%) but under-goes extensive first-pass hepatic metabolism. In the liver, simvastatin is rapidly hydrolysed from the inactive lactone form to the corresponding active hydroxyacid metabolite and other less important metabolites, some of which are active. After oral administration of a radiolabelled dose of simvastatin 100mg to healthy volunteers, active metabolites accounted for 14% of radioactivity using area under the plasma concentration-time curve (AUC) measurements. Simva-statin and its active metabolites are predominantly concentrated in the liver, which is the main target site of the drug. Circulating simvastatin and its active -hydroxyacid metabolite are about 95% bound to plasma proteins. The elimination half-life of the major active metabolite is 1.9 hours and total body clearance is 31.8 L/h. Approximately 60% of an administered dose is recovered in the faeces; this represents unabsorbed drug and simvastatin and its metabolites following biliary secretion. About 13% is recovered in the urine, almost entirely as inactive metabolites. The pharmacokinetic profile of simvastatin is not affected when the drug is administered immediately before a low-fat meal. Mean steady-state plasma concentrations of inhibitors were higher in elderly than in younger patients and among female than male patients, but the differences were not great enough to necessitate recommendations for dosage modifications in these patient groups. Therapeutic Efficacy At the time simvastatin was previously reviewed in Drugs, clinical trials had typically been conducted in small groups of patients with primary hypercholesterol-aemia who received the drug for relatively short periods. Over the past 5 years, results of larger noncomparative, dose-response and placebo-controlled studies, in which simvastatin 10 to 40 mg/day was administered for up to 5.4 years, have confirmed that simvastatin achieves statistically and clinically significant reductions from baseline in serum levels of total cholesterol (usually ranging from 20 to 40%) and LDL-cholesterol (usually ranging from 35 to 45%). In most studies serum triglyceride levels were also reduced by approximately 10 to 20% and high density lipoprotein (HDL)-cholesterol levels increased moderately by about 5 to 15%, although these changes did not always achieve statistical significance. In the Multicentre Anti-Atheroma Study (MAAS), simvastatin 20 mg/day achieved changes in serum lipid and lipoprotein levels similar to those outlined above, and these were sustained throughout the 4-year study period. Importantly, angio-graphic assessment demonstrated that simvastatin significantly slowed progression of coronary atherosclerosis compared with placebo. In the Scandinavian Simvasiatin Survival Study (4S), administration of simvastatin 20 to 40 mg/day for a median of 5.4 years to patients with coronary heart disease (CHD) and Adis International Limeted. All rights reserved. Drugs 50 (2) 1995 Simvastatin: A Reappraisal Pharmacoeconomic Considerations 337 concomitant hypercholesterolaemia achieved a highly significant 30% relative reduction in overall mortality, which was the primary end-point of the study. The reduction in overall mortality was attributed to a 42% relative reduction in coronary mortality. Nonfatal cardiovascular events were also markedly reduced by simvastatin compared with placebo, and modifications in scrum lipid and lipoprotein levels were similar to those achieved in the MAAS trial. The number of noncardiovascular deaths among simvastatin recipients was similar to that for placebo recipients. Therefore, the 4S trial is the first large placebo-controlled study to demonstrate that lowering serum cholesterol levels improves overall survival in patients with CHD. In general, simvastatin has compared favourably with other drugs used in the treatment of primary hypercholesterolaemia. In large comparative trials with other HMG-CoA reductasc inhibitors, simvastatin achieved significantly greater percentage reductions in serum total cholesterol and LDL-cholesterol levels than equal dosages of lovastatin or pravastatin; similar reductions were achieved be- tween agents when lovastatin or pravastatin were administered at a total daily dosage twice that of simvastatin and when fluvastatin was administered at a total daily dosage approximately 8 times that of simvastatin. It is noteworthy that indirect clinical comparisons suggest that simvastatin is 4 times as potent as fluvastatin on a milligram per milligram basis. Therefore, the maximum recommended fluvastatin dosage of 40 mg/day would not be expected to achieve re-ductions as great as those obtained with simvastatin 20 to 40 mg/day, which were associated with marked mortality reductions in the 4S trial. In comparative trials with standard dosages of bile acid sequestrants (cholestyramine or colestipol), fibrates (gemfibrozil, bezafibrate, ciprofibrate or fenofibrate) or probucol, simva-statin 10 to 40 mg/day usually achieved greater reductions in serum levels of total and LDL-cholesterol, although fibrates typically achieved more marked increases in serum HDLcholesterol levels (10 to 25% with librates vs 5 to 10% with simvastatin) and greater reductions in serum triglycerides (25 to 40% vs 10 to 20%). Combined treatment with simvastatin plus either cholestyramine or colestipo, usually in patients with severe hypercholesterolaemia, achieved reductions in serum cholesterol and LDL-cholestcrol levels approximately 10 to 15% greater than those achieved with simvastatin monotherapy. Although combined treatment with simvastatin plus either a fibrate or nicotinic acid has been used in small clinical trials, such combinations increase the risk of myopathy and should generally be avoided unless potential benefits outweigh potential risks. Simvastatin has also been evaluated in a number of small placebo-controlled and noncomparative studies in patients with hypercholesterolaemia secondary to other causes, such as diabetes mellitus, nephrotic syndrome and renal disorders. Changes in serum lipid and lipoprotein levels induced by simvastatin 10 to 40 mg/day were similar among dyslipidaemic patients with or without non-insulindependent diabetes (NIDDM), and glycaemic control and insulin resistance were not significantly affected in patients with NIDDM. Marked reductions of 30 to 50% in serum levels of total and LDL-cholesterol were achieved among small groups of patients with nephrotic syndrome receiving simvastatin 10 to 40 mg/day. Pharmacoeconomic analyses have consistently demonstrated that simvastatin is more cost effective than bile acid sequestrants in terms of cost per life-year saved when used in primary prevention of CHD. Less detailed analyses have shown that the cost per 1 % reduction in serum cholesterol levels was approxi mately 20% Adis International Limited. All rights reserved. Drugs 50 (2) 1995 338 Plosker & McTavish lower with simvastatin than pravastatin, but, in terms of cost per 1 mmol/L reduction in serum LPL-cholesterol levels, simvastatin was about 20% more ex~ pensive than gemfibrozil. However, these less comprehensive analyses did not take into consideration clinical end-points such as reductions in overall mortality and cardiovascular morbidity and mortality, as demonstrated with simvastatin in the 4S secondary prevention trial. A pharmacoeconomic analysis of the 4S trial, which is currently under way, may overcome some of the weaknesses and assumptions made in other studies. Tolerability In general, adverse events associated with simvastatin are mild and transient and most frequently include gastrointestinal problems (constipation, diarrhoea, dyspepsia, flatulence and nausea). In a large cohort of more than 2400 patients with hypercholesterolaemia who participated in controlled trials and their open extensions, simvastatin was considered to be associated with constipation in 2.5%, abdominal pain in 2.5%, flatulence in 2.0%, nausea in 1.2% and dyspepsia in 0.7% of patients. Other adverse events, which occur in approximately 1 to 3% of patients, include headache, sleep disturbances and asthenia. The rate of discontinuation of treatment because of adverse events appears to be similar between simvastatin and placebo. Mild transient elevations in serum transaminases occur in approximately 3,5% of patients and sustained elevations (>3 times normal) occur in about 1% of patients: clinically symptomatic hepatitis or hepatic impairment is rare. Modest elevations of creatine kinase levels of 3 times the upper limit of normal occur in about 5% of patients, but this is often transient and not usually of clinical significance. Some patients receiving HMG-CoA reductase inhibitors experience myositis, with or without creatine kinase elevations, but this is usually selflimiting. Myopathy, characterised by muscle pain/weakness and marked elevation of creatine kinase levels (10 times the upper limit of normal), is a rare but important adverse event associated with simvastatin and other HMG-CoA reduc-tase inhibitors, which may lead to rhabdomyolysis and subsequent renal failure. The frequency of myopathy with HMG-CoA reductase inhibitors is 0.2% and the risk is increased when these drugs are used concurrently with gemfibrozil (and probably other fibrates), nicotinic acid, cyclosporin or erythromycin ( i n seriously i l l patients such as those receiving the antibiotic intravenously). Therefore, combined therapy with simvastatin plus either a fibrate or nicotinic acid is generally not recommended unless potential benefits outweigh the potential risks, and for patients requiring concomitant simvastatin plus cyclosporin, simvastatin dosage adjustments are required. Data from comparative studies indicate that the tolerability profile of simvastatin is similar to that of other HMG-CoA reductase inhibitors and similar or, in some cases, tended to be better than that of other agents such as bile acid sequestrants or fibrates. In particular, adverse gastrointestinal effects tend to occur much less frequently with simvasiaiin than with cholestyramine. Extensive use in clinical practice and evaluation in clinical trials have not demonstrated any potential of simvastatin to increase cataract formation. Dosage and Administration Simvastatin is administered orally as a single dose in the evening. The recommended starting dosage is 5 to 10 mg/day which is then titrated according to individual response at intervals of at least 4 weeks to a maximum dosage of 40_ mg/day. Dosage adjustments are not necessary in patients with mild to moderate renal failure. For patients with severe renal insufficiency or those receiving con- Adis International Limited. All rights reserved. Drugs 50 (2) 1995 Simvastatin: A Reappraisal 339 comitant cyclosporin the recommended starting dosage is 5 mg/day and patients should be monitored closely. The recommended maximum simvastatin dosage for patients receiving concomitant cyclosporin is 10 mg/day. Dosages of 20 to 40 mg/day may be necessary in patients with CHD to achieve cardiovascular risk reduction comparable to that observed in the 4S trial. At the time simvastatin was previously reviewed in Drugs[1] most clinical trials involved short to medium term administration of the drug to small numbers of patients with hypercholesterolaemia. Comparisons with other HMG-CoA reductase inhibitors and long term tolerability data were lacking. Over the past 5 years, a number of large controlled clinical trials have confirmed the beneficial effects of simvastatin on the serum lipid profile of patients with hypercholesterolaemia. Comparative studies nave focused on other HMG-CoA reductase inhibitors or fibrates and long term tolerability data are now available. Furthermore, a recently published large secondary prevention trial has demonstrated significant benefits, including a reduction in overall mortality, with simvastatin in patients with coronary heart disease (CHD) and concomitant hypercholesterolaemia. 1. Overview of Pharmacodynamic Properties The pharmacodynamic properties of simvastatin have been reviewed in detail by Todd and Goa in a previous issue of Drugs.[1] This section provides a brief overview of these data with an emphasis on more recently published pharmacodynamic studies. Simvastatin is an orally administered prodrug. Following absorption simvastatin is hydrolysed in the liver from the inactive lactone form to the corresponding -hydroxyacid, the major active metabolite, which is a competitive and reversible inhib-itor of the enzyme HMG-CoA reductase. This enzyme is responsible for the conversion of HMGCoA to mevalonic acid, an early and rate-limiting step in the biosynthesis of cholesterol. In vitro data and those from in vivo studies in animal models and in humans have shown that simvastatin is a potent inhibitor of cholesterol biosynthesis.[1-7] Adis International Limited. All rights reserved. As outlined in section 3, administration of simvastatin to patients with hypercholeslerolaemia achieved marked reductions in serum levels of total cholesterol and low density lipoprotein (LDL)-cholesterol, which were usually accompanied by modest reductions in serum triglycerides and increases in high density lipoprotein (HDL)-cholesterol. The mechanism by which HMG-CoA reductase inhibitors increase serum levels of HDL-cholesterol is poorly understood. In several studies, simvastatin markedly reduced serum apolipoprotein B levels in parallel with LDL-cholesterol, while apolipoprotein A-l and HDL-cholesterol were modestly increased to a similar degree.[8-16] However, the clinical significance of changes in serum levels of these apolipoprotcins has not yet been determined,[17] Simvastatin does not appear to have a significant effect on serum levels of lipoprotein (a) in most patients with hypercholesterolaemia.[10,18,19] Inhibition of hepatic cholesterol biosynthesis by HMG-CoA reductase inhibitors gives rise to increased expression of LDL receptors on the cell surface. These receptors hind LDL particles and remove them from the circulation in animals and humans, thereby lowering serum total cholesterol levels.[20] LDL receptors are located in the liver as well as other tissues, but the liver is the predominant site of LDL catabolism.[21] Administration of simva-statin to cholesterol-fed rabbits produced a dose-dependent increase in LDL-receptor activity (specific binding and/or number of hepatic LDL receptors), which had been markedly reduced by dietary cholesterol intake.[22,23] After intravenous administration of radiolabelled human LDL in a guinca-pig model, receptormediated metabolism of LDL was significantly increased in animals receiving simvastatin 10 mg/kg/day for 2 weeks compared with those not receiving simvastatin, while the fractional catDrugs 50(20) 1995 340 abolic rate of the LDL receptor-independent pathway was not significantly affected by simvastatin.[24] On the basis of studies in the rabbit, changes in LDLreceptor activity of circulating mononuclear cells appear to reflect changes in LDL-receptor activity in the liver,[23] Thus, because simvastatin l0 to 40 mg/day in patients with hypercholesterol-aemia caused a 70% increase in LDL-receptor activity of mononuclear cells, upregulation of the hepatic LDL receptor may also have been involved in the observed 26% reduction in serum total cho-, lesterol levels.[25] While the main actions by which simvastatin lowers serum cholesterol levels appear to be inhibition of cholesterol biosynthesis leading to enhanced receptor-mediated LDL catabolism in the liver, other possible mechanisms for beneficial effects on the serum lipid profile have been suggested. Indeed, the lipid-lowering effect of simvastatin in a patient with LDL receptor-negative homozygous familial hypercholesterolaemia supports the view that mechanisms other than increased LDL-receptor expression are involved.[ 2 6 ] Studies in cholesterol-fed rabbits showed that multiple doses of simvastatin inhibited cholesterol absorption from the gastrointestinal tract, as demonstrated by increased faecal concentrations of neutral sterols;[27,28] however, this has not been clearly demonstrated in humans. [4] In vivo data from patients with hypercholesterolaemia showed that simvastatin 20 mg/day for 10 weeks enhanced the clearance of very low density lipoprotein (VLDL) [subfraction (S f) 20 to 60] and its remnants (intermediate density lipoprotein; IDL) from the circulation before conversion to LDL. [14] These data suggest that increased LDL-receptor ac-tivity may have preferentially increased the clearance of VLDL and IDL from the circulation in these patients, thereby reducing the pool of these lipoproteins available for conversion to LDL. However, the recent observation that VLDL from patients treated with simvastatin was catabolised faster by cultured skin fibroblasts when obtained during treatment than before treatment[29] suggests that upregulation of the LDL receptor may not be necessary for decreased LDL production. Simvastatin Adis International Limited. All rights reserved Plosker & McTavish seemed to increase VLDL catabolism before conversion to LDL by stimulating VLDL-cellular interactions and catabolism, possibly reflecting alterations of the physico-chemical properties of the particles. In vitro studies of rat hepatocytcs. in primary culture suggest that simvastatin may affect apolipoprotein B synthesis by a direct action on hepatocytes.[7] In healthy volunteers,simvastatin reduced esterified cholesterol transfer from HDL to VLDL and LDL.[30] Data from in vitro studies using rat and human arterial myocytes and animal models of atherosclerosis or intimal hyperplasia suggest that simvastatin and other HMG-CoA reductase inhibitors may affect the regulation of aortic smooth muscle cell growth and division, possibly by reducing mevalonate production.[31-37] In cholesterol-fee rabbits, simvastatin 10 mg/kg/day for 12 to 24 weeks reduced or completely reversed atherosclerotic lesions in coronary arteries and the aorta.[35,36] In many of these studies, other HMG-CoAreductase inhibitors were also evaluated[31-34,37] and, interestingly, not all agents achieved potential antiatherogenic effects despite similar effects on plasma lipid and lipoprotein levels. Simvastatin and other HMG-CoA reductase inhibitors also reduced the in vitro susceptibility of LDL to oxidation.[38,39] This suggests a possible additional mechanism for preventing pro gression of atherosclerosis, since LDL must undergo oxidation before it can be taken up by macrophagederived foam cells present in atherosclerotic lesions.[39] Simvastatin and other HMG-CoA reduc tase inhibitors have been shown to interfere with cholesterol ester formation and accumulation in human monocyte-derived[40] and mouse peritoneal macrophages,[41] and this action may also contrib ute to an antiatherosclerotic effect. As outlined in section 3.1.2, angiographic assessment of patients with both coronary heart disease (CHD) and hypercholesterolaemia demonstrated that long term sim vastatin administration significantly slowed pro gression of coronary atherosclerosis compared with placebo. [42] Elevated plasma levels of some coagulative factors, including fibrinogen and factor VIIc activity, Drugs 50 (2) 1995 Simvastatin: A Reappraisal are considered to be independent risk factors for atherosclerosis and have been associated with hyper-cholesterolaemia[43,44] Platelet hyperreactivity, which occurs frequently among patients with hyperchol-esterolaemia, may also increase the risk of vascular events.[45] In studies evaluating the effects of sim-vastatin on coagulation parameters in patients with hypercholesterolaemia, only a modest reduction[44] or no change was observed for plasma fibrinogen levels,[46-48] but factor VIIc activity was decreased in some studies.[43,46] Inhibition of platelet activation, as evidenced by decreased platelet aggregation ,[48] intracellular calcium concentration[49] and thromboxane A2 production or release,[48,50] has been reported in hypercholesterolaemic patients treated with simvastatin. However, simvastatin did not affect blood Fibrinolytic activity[51] and the clinical significance of these effects is unknown. Theoretically, on the basis of the pharmacodynamic actions and preclinical studies of simvastatin and other HMG-CoA reductase inhibitors, these drugs could potentially have adverse effects on adrenocortical function, promote cataract development and cause problems associated with decreased serum ubidecarenone (ubiquinone; CoQ) levels; however, available data indicate otherwise. In vitro simvastatin inhibited the synthesis of sex hormones by human testicular homogenates, but only at concentrations above those expected to be achieved in vivo.[52] Furthermore, patients with hypercholesterolaemia receiving simvastatin 10 to 40 mg/day for up to 1 year did not have significant changes in adrenocortical and sex hormone production or function,[53-58] other than modest elevations in plasma androstenedione and luteinising hormone levels in a small study of 10 patients treated for 1 year.[59] As reported by Todd and Goa,[1] a low incidence of cataracts has been reported in dogs receiving very high dosages of simvastatin corresponding to serum levels more than 60-fold higher than those in humans receiving maximal therapeutic dosages. Data from large numbers of patients who received simvastatin in clinical trials, including some who received the drug on a long term basis, have not demonstrated any potential of simva Adis International Limited. All rights reserved. 341 statin to increase cataract formation (see section 5). In patients with hypercholesterolaemia, simvastatin and other HMG-CoA reductase inhibitors decreased plasma levels of ubidecarenone, which has an important role in mitochondrial electron transport and antioxidant activities; however, it is unclear whether changes in serum ubidecarenone are associated with changes in tissue levels of ubidecarenone, and the clinical significance of reduced serum levels of ubidecarenone is not known.[60-64] Simvastatin reduced the biliary cholesterol saturation index in patients with hypercholesterolaemia, indicating no increased (and possibly a decreased) propensity for development of gallstones.[23,65,66] 2. Overview of Pharmacokinetic Properties The pharmacokinetic properties of simvastatin have been previously reviewed in Drugs[1] and more recently by Mauro.[67] This section provides a brief overview of these data supplemented with information from recently published pharmacokinetic studies of simvastatin. Simvastatin is an inactive prodrug which is well absorbed (60 to 80% in animal and human studies) but undergoes extensive first-pass hepatic metabolism following oral administration.[1,67,68] Simvastatin is rapidly hydrolysed in the liver from the inactive lactone form to the corresponding active -hydroxyacid metabolite and to several less important active and inactive metabolites. Following oral administration of simvastatin in healthy volunteers, bioavailability of the major -hydroxyacid metabelite was less than 5% relative to that after intravenous administration of the active metabolite.[1,67] Several studies in healthy volunteers[1,67,69] and patients with hypercholesterolaemia[70] indicate that peak plasma concentrations of active metabolites occur between 1.1 and 3 hours after administration of simvastatin. However, in a small study of 4 patients with hypercholesterolaemia receiving radiolabelled simvastatin l00mg. peak plasma radioactivity and peak enzyme inhibition both occurred 4 hours after oral administration.[71] Simvastatin absorption was not affected Drugs 50 (2) 1995 342 when the drug was administered immediately before u low-fat meal.[72] In some studies, simvastatin and its active metabolites were measured on the basis of HMG-CoA reductase inhibitory activity. Active inhibitors represented active metabolites, While total inhibitors included active plus latent (after base hydrolysis) inhibitors. Area under the plasma concentrationtime curve (AUC) measurements after oral administration of a radiolabelled dose of simvastatin l00mg to healthy volunteers demonstrated that active inhibitors of HMG-CoA reduetase activity accounted for 14 % of radioactivity compared with 28% for total inhibitors. These data indicate that most of the chemical species present were inactive or only weak inhibitors of HMG-CoA reductase. In general, AUC of active inhibitors increased linearly with increasing oral simvastatin doses over the range of 5 to 120 mg in healthy volunteers.[1,67] On the basis of enzyme inhibition activity and radiolabelled drug studies in animals, simvastatin and its active metabolites concentrate in the liver (the primary site of HMG-CoA reductase inhibition), with only a small portion of metabolites distributing to other nontarget tissue sites. [1, 67] These data are supported by results of a 3-way crossover study investigating pharmacokinetic profiles after administration of single oral 40mg doses of simvastatin, lovastatin and pravastatin in 12 healthy volunteers.[69] Maximum plasma concentration for inhibitory activity was approximately 5-fold higher and AUC for inhibitory activity 2- to 3-fold greater with pravastatin than simvastatin or lovastatin, suggesting potentially less distribution to peripheral tissues with simvastatin or lovastatin. Both simvastatin and its corresponding -hydroxyacid metabolite are approximately 95% bound to, human plasma proteins.[1,67] Simvastatin and lovastatin are more hydrophobic than pravastatin or fluvastatin; however, adverse events such as insomnia have.not been shown to occur more frequently with the hydrophobic than the hydrophilic HMG-CoA reductase inhibitors.[73,74] The metabolic fate of simvastatin in humans is not fully known, although it appears to be exten Adis International Limited. All rights reserved. Plosker & Mc Tavish sively metabolised by the cytochrome P450 sys tem.[75] In vitro animal liver microsomal studies have identified at least 5 metabolites including hydroxyacid simvastatin.[76] The major active me tabolites found in human plasma are -hydroxyacid simvastatin and its 6'-hydroxy, 6'-hydroxymethyl and 6'-exomethylene derivatives.[72] Several other metabolites, as well as most of the metabolites resulting from microsomal production, have been identified in the bile in both lactone and acid forms in animal studies.[76] The elimination half-life of the major active hydroxyacid metabolite is 1.9 hours and total body clearance is 31.8 L/h.[67] After administration of l00mg of radiolabelled simvastatin in healthy volunteers, 13% of the radioactivity was recovered in urine with only a small proportion (<0.5%) of the dose detected in the urine as active metabolites (measured as active HMG-CoA reductase inhibitors). Approximately 60% of the radioactivity was recovered in faeces, which represented unabsorbed drug and biliary excretion of simvastatin and its metabolites.[1,67] In a small study of 4 cholecystectomised patients with T-tube drainage, approximately 35% of a radiolabelled dose of simvastatin l00mg was eliminated in the urine (only 2% of the dose as total inhibitors of HMG-CoA reductase), 25% in the bile and 20% in the faeces.[68] The influence of age and gender on the pharmacokinetic profile was determined after administration of simvastatin 40 mg/day for several days in 16 elderly (aged 70 to 78 years) and 18 younger (aged 19 to 30 years) patients with hypercholeaterolacmia.[70] Time to achieve peak plasma concentrations of active and total HMG-CoA reductase inhibitors was not significantly affected by age or gender; however, mean steady-state plasma concentrations of active and total HMG-CoA reductase inhibitors were 40 to 60% higher in elderly than younger patients and 20 to 50% higher among female than male patients. The authors of the study concluded that the effects of age and gender on the pharmacokinetic profile are not great enough to necessitate simvastatin dosage modifications, since the drug has a broad therapeutic window. Drugs 50 (2) 1995 Simvastatin: A Reappraisal 3. Therapeutic Efficacy The main goal of therapy in patients with hypercholesterolaemia is to reduce the risk of developing premature CHD (primary prevention) or, in those with existing CHD, recurrence of vascular events (secondary prevention).[77] Results of large epidemiological and intervention trials, such as the Helsinki Heart Study, the Multiple Risk Factor Intervention Trial and the Lipid Research Clinics Coronary Primary Prevention Trial, indicate that lowering serum cholesterol levels in patients with hypercholesterolaemia markedly reduces both coronary mortality and morbidity.[78-81] Epideiniologieal data from the US and Europe indicate that approximately 15% of adults have hypercholesterolaemia. and the proportion of middle-aged men and women with this condition is even higher.[82,83] According to recently published guidelines from the US National Cholesterol Education Program (NCEP), for patients without CHD, a high serum cholesterol level is defined as 240 mg/dl (6.2 mmol/L) and a highrisk scrum LDL-cholesterol level is defined as >160 mg/dl (4.1 mmol/L).[17] For patients requiring therapy for hypercholesterolaemia. the recommended target serum LDL-cholesterol level is l60 mg/dl for those with fewer than 2 other CHD) risk factors, <130 mg/dl (3.4 mmol/L) for those with 2 or more other CHD risk factors and 100 mg/dl (2.6 mmol/L) for patients with existing CHD or other clinical atherosclerotic disease.[17] In some studies of simvastatin, patients were categorised as having either heterozygous familial hypercholesterolaemia, a genetic disorder in which patients have about half the normal number of functional LDL receptors and therefore have decreased catabolism of plasma LDL-cholesterol in the liver, or nonfamilial (polygenic) hypercholesterolaemia, derived from multiple genetic and environmental factors. However, not all studies of primary hypercholesterolaemia distinguished these patients and, since the percentage change in serum lipid and lipoprotein levels achieved with simvastatin was similar in patients with familial or nonfamilial hypercholesterolaemia, results in these patient groups are described together. Some studies evaluated simva Adis International Limited. All rights reserved. 343 statin in patients with hypercholesterolaemia secondary 10 diabetes mellitus, nephrotic syndrome, chronic renal failure or other clinical conditions, and these are described in section 3.2. Typically, changes in serum lip id and lipoprotein levels reported in clinical trials were measured from basel i n e values established after at least 4 weeks of dietary control, with or without placebo administration. Dietary modifications were usually continued throughout the treatment protocol. This is important because not only should every effort be made to lower serum cholesterol levels by dietary means prior to drug therapy, but also because lower serum levels of total cholesterol and LDL-cholesterol can be achieved with simvastatin in patients on a low-fat and low-cholesterol diet than in those on a high-fat and high-cholesterol diet.[84] 3.1 Primary Hypercholesterolaemia 3.1.1 Noncomparative Studies In general, results of noncomparative studies, in which at least 30 patients with hypercholeslerolaemia received simvastatin 10 to 40 mg/day for 3 to 24 months, demonstrated statistically significant reductions of 20 to 40% in mean serum total cholesterol levels and 35 to 45% in LDL-cholesterol levels.[8,11,85-94] Serum triglyceride levels were reduced by approximately 10 to 20% from baseline values and HDL-cholesterol levels increased by about 5 to 15%; these latter changes did not always reach statistical significance. The ratio of LDLcholesterol/HDL-cholesterol (an index of atherogenic potential) was markedly and favourably reduced by approximately 20 to 40%. In most noncomparative studies, the dosage of simvastatin was gradually increased at 4- to 6-week intervals if target serum cholesterol levels were not achieved. The proportion of patients requiring dosage titration to 40 mg/day varied widely between studies and appeared to be related to the severity of hypercholesterolaemia at baseline. For example, only 25% of 188 patients required simvaslatin 40 mg/day in a study in which the mean serum total cholesterol level at baseline was 308 mg/dl (8.0 Drugs 50 (2) 1995 344 mmol/L)[87] compared with approximately 70 to 85% of patients in studies in which mean baseline levels were at least 360 mg/dl (9.3 mmol/L).[90,91,93,94] Once an adequate response was achieved, usually 4 to 12 weeks after initiating therapy, the efficacy of simvastatin was maintained with continued treatment for up to 2 years.[11,85,87,88,90,93,94] In a brief report of 17 patients with heterozygous familial hypercholesterolaemia receiving simvastatin 40 mg/day, the effects on serum l ip id and lipoprotein levels were maintained for 6.5 years with continued treatment.[95] In general, the percentage change in serum lipid and lipoprotein levels with simvastatin does not appear to be dependent on the severity of hypercholesterolaemia.[1,96] Other findings from noncomparative studies indicate that elderly patients respond to simvastatin equally as well as younger patients.[9,91,97,98] Patients with CHD or those at high risk of CHD.[12,88,90,99] and patients with concomitant hypertension[100] did not have diminished responses to simvastatin therapy. Changes in serum lipid and lipoprotein levels were independent of gender, age or lipid phenotype (IIa or IIb) in a large multicentre study of 595 patients receiving simvastatin 10 to 40 mg/day for 18 weeks. [ 9 1 ] However, in a small crossover study of 12 men and 13 women with hypercholesterolaemia, women were more sensitive to the effects of simvastatin on reducing serum LDL-cholesterol levels than men when consuming a high-fat diet, and men had greater increases in HDL-cholesterol than women while receiving high- or low-fat diets.[84] Preliminary results of a Japanese study of 23 patients with escape phenomenon' (return towards baseline serum lipid and lipoprotein levels) after 24 weeks of therapy with pravastatin showed adequate response with simvastatin 5 mg/day, although a trend of increasing cholesterol levels towards baseline was noted after 40 weeks.[101] Simvastatin 40 mg/day for up to 66 weeks has also demonstrated efficacy in small groups of patients with familial dysbetalipoproteinaemia (Fredrickson type III hyperlipidaemia), with reductions in serum levels of total cholesterol, LDL-cholesterol, triglycerides and VLDL-cholesterol ranging from Adis International Limited. All rights reserved. Plosker & McTavish approximately 35 to 50%.[102,103] Simvastatin 10 to 40 mg/day has also been used successfully in a small group of 16 children (<17 years of age) with hypercholesterolaemia, achieving statistically and clinically significant improvements in serum lipid profiles.[104] A reduction in serum LDL-cholesterol levels from approximately 773 mg/dl (20 mmol/L) to 387 mg/dl (10 mmol/L) was also demonstrated with simvastatin 40 mg/day in an 11-year-old patient with homozygous familial hypercholesterolaemia but with 30% residual LDL-receptor function.[105] 3.1.2 Dose-Response Studies and Comparisons with Placebo Preliminary dose-response studies with short term administration of simvastatin 2.5 to 80 mg/day generally demonstrated a log-linear relationship between dosages up to 40 mg/day and percentage change in scrum lip id and lipoprotein levels; increasing the daily dosage above 40mg provided minimal further benefit.[1] However, results of more recent and larger studies with simvastatin 2.5 to 40 mg/day indicate that the dose-response gradient may be less steep above 10 nig/day (table I). In the largest of these studies, patients continued simvastatin therapy for a mean duration of 3.4 years with minimal attenuation of efficacy.[107] Compared with placebo, serum total cholesterol levels were reduced by 29% after 8 weeks and by 26% after 3 years of simvastatin 40 mg/day, and reductions of 27% after 8 weeks and 22% after 3 years were achieved with simvastatin 20 mg/day. In studies in which apolipo-proteins were measured, changes in serum levels of apolipoproteins B and A-I were analogous to those for LDL-cholesterol and HDL-cholesterol, respectively. [ 1 0 6 , 1 0 7 ] In most clinical trials simvastatin has been administered as a single daily dose,although some studies used twice daily regimens. A review of efficacy and tolerability data found no clinically significant differences between once daily and twice daily regimens of the same total daily dosage. [111] A double-blind study of 172 patients with hypercholesterolaemia evaluated the efficacy of once daily regimens of simvastatin 2.5 and 5 mg/day, administered as a morning or an evening dose. Results of Drugs 50 (2) 1995 Simvastatin: A Reappraisal 345 Table I. Summary of recent randomised dose-response studies with simvastatln in patients with primary hypercholesterolaemia Reference No. of patients (mg/day) Dosage regimen Atanda et al[106] 38 37 207 208 206 41 41 41 41 28 28 28 27 26 29 31 10x6mo 20 x 6mo Placebo 20x8wk a 40 x 8wka Placebo 10 x12wk 20 x 12wk 40 x 12wk Placebo 2.5 x 8wk 5 x 8wk 1 0 x 8wk 20 x 8wk 40 x 8wk Placebo 32 32 32 32 2.5x4wk 5x4 wk 10x4 wk 20x4 wk Keech et al.[107] Marshall et al.[108] Tuomilehto et al. [109]c Walker et al.[110] a Mean percentage change in serum lipid and lipoprotein levels versus baseline total-C -15 -19 LDL-C -23 -28 HDL-C +8 +10 TG -7 -9 -27b -29b -38b -41b +5b +6b -17 b -19 b -3 -16 -20 -22 -25 -30 -3 -29 b -36b -41 b -5 -21 -25 -28 -33 -41 -3 -17 -19 -23 -28 -23 -27 -31 -37 +11 +7 -15 -20 Results after 8 weeks, although patients were ultimately treated for mean duration of 3.4 years and effects were largely sustained. b Versus placebo. c Percentage reductions represent mean values of reported ranges. Acbreviations: C = cholesterol; HDL = high density lipoprotein; LDL = low density lipoprotein; mo = months; TG = triglyceride; wk = weeks. this trial found modest but statistically significant greater reductions in total serum cholesterol with the evening dosage regimens.[112] Simvastatin is normally administered once daily in the evening. Placebo-controlled trials have produced similar results 10 noncomparative and dose-response studies in terms of percentage change in serum lipid and lipoprotein levels.[42,113,115] Indeed, some doseresponse studies also included a placebo control group (see table I).[107-110] Thus, administration of simvastatin 10 to 40 mg/day for 8 weeks to patients with hypercholesterolaemia achieved reductions generally within previously described ranges (section 3.1.1) for serum levels of total cholesterol (20 to 40% reduction vs baseline or placebo). LDLcholesterol (35 to 45%), triglycerides (10 to 20%) and LDL/HDL ratio (20 to 40%). In virtually all comparisons between simvastatin and placebo, these reductions were statistically significant. While percentage increases in serum levels of HDL-cholesterol were usually within the range of 5 to 15% Adis International Limited. All rights reserved. with simvastatin, a statistically significant difference between treatment groups was not always noted. In some studies, serum levels of apolipoprotein B were also measured and these were markedly reduced by approximately 30% in parallel with reductions in LDL-cholesterol levels.[42,114,115] The beneficial effects of simvastatin on serum lipid and lipoprotein levels did not appear to be diminished in patients with CHD,[42,116] in those receiving concomitant therapy for hypertension[114] or in elderly patients with atheromatous disease.[117] Anti-Atheroma Study In the Multicentre Anti-Atheroma Study (MAAS) 381 eligible patients were randomised to receive double-blind treatment with either simvastatin 20 mg/day (n = 193) or placebo (n =188) for 4 years, and quantitative coronary angiography was performed at baseline and after 2 and 4 years to assess the rale of change in coronary atherosclerosis over time.[42] Statistically significant effects of simvaDrugs 50 (2) 1995 346 Plosker & McTavish Table II. Main angiographic findings of the Multicentre Anti-Atheroma Study (MAAS) after 4 years of treatment with simvastatin 20 mg/day or placebo-[42] Angiographic parameter (per patient) [mean change from baseline] Angiographic classification (per patient) [no. (%) of patients] simvastatin simvastatin placebo Mean lumen diameter (mm) -0.02 -0.08* - Minimum lumen diameter (mm) -0.04 0.13** Diameter stenosis (%) 1.0 3.6** Progressor placebo 41 (23.0) 54(32.3)*a 33(18.6) a Statistically significant difference between treatment groups only for combined treatment effect. Statistically significant difference between treatment groups: * p < 0.05; ** p < 0.01. 20(12.0)*a Regressor statin on serum lipid and lipoprotein levels are depicted in figure 1. Importantly, simvastatin-induced changes in lipid levels were generally consistent throughout the 4-year period and angiographic assessment of 345 patients demonstrated that simvastatin significantly slowed progression of coronary atherosclerosis. In addition, significantly more simvastatin than placebo recipients were classified as showing angiographic regression. The main quantitative angiographic findings of the MAAS trial are summarised in table II. While simvastatin had no statistically significant effect on clinical endpoints, such as the number of patients who died or had myocardial infarction, the study population was not large enough and the trial was not specifically designed to detect such differences between treatment groups. significantly reduced by 42% with simvastatin compared with placebo (5.0 vs 8.5%), which accounted for the improvement in overall survival. No statistically significant difference was demonstrated between treatment groups for noncardiovascular mortality. Nonfatal cardiovascular events were also markedly decreased by simvastatin, including relative risk reductions of 37% for nonfatal (hospitalverified definite or probable) acute myocardial, infarction and 37% in the need for coronary artery bypass grafting or percutaneous transluminal coronary angioplasty (p = 0.00001) [fig. 3]. A post-hoc analysis showed a statistically significant difference between treatment groups favouring simva- Secondary Prevention Trial The 4S trial is the first large placebo-controlled trial to show that reducing serum cholesterol levels in patients with CHD significantly reduces overall mortality - the primary end-point of the study.[116] The double-blind trial randomised 4444 patients with CHD and concomitant mild to moderate hypercholesterolaemia (serum total cholesterol levels 5.5 to 8,0 mmol/L; 213 to 309 mg/dl) to receive simvastatin 20 to 40 mg/day or placebo for a median of 5.4 years. Compared with placebo, simvastatin achieved a 30% reduction in overall mortality (11.5 vs 8.2%; p = 0.0003). Thus, 3 to 4 lives were saved per 100 patients treated with simvastatin over this period. Overall mortality of patients over time is depicted in figure 2. Cardiovascular mortality was Adis International Limited. All rights reserved Fig. 1. Statistically significant (p < 0.001) effects of simvastatin 20 mg/day on serum lipid and lipoprotein levels in the Multicentre Anti-Atheroma Study (MAAS).Treatment effects represent the difference between simvastatin and placebo groups for mean within-patient lipid changes from baseline over 4 years.[42] Drugs 50 (2) 1995 Simvastatin: A Reappraisal 347 sion or violence between simvastatin and placebo recipients. 3.1.3 Comparisons with Other Antihyperlipidaemic Drugs Fig. 2. Proportion of patients who died versus time since randomisation to receive simvastatin (20 or 40 mg/day) or placebo in the Scandinavian Simvastatin Survival Study (4S).[116] statin for the number of fatal plus nonfatal cerebrovascular events (70 vs 98 patients with such events; p = 0.024). The effects of simvastatin on serum lipid and lipoprotein levels were similar to those reported in the MAAS trial, with reductions over 5.4 years in total and LDL-cholesterol of 25 and 35%, respectively, and a modest increase in HDL-cholesterol of 8%. After 1 year, 72% of simvastatin recipients had achieved the pre-defined target serum total cholesterol level of <5.2 mmol/L (201 mg/dl), although in subsequent years there was a small increase in mean serum levels of total cholesterol and LDL-cholesterol. Subgroup analysis of the 4S trial demonstrated that treatment effects of simvastatin remained statistically significant whether patients were aged <60) years or 60 years.[116] Major cardiac events were significantly reduced by simvastatin in both men and women, although risk reduction for overall mortality did not reach statistical significance in women because of the relatively low number of deaths in this patient population. The relative risk of a major coronary event among women receiving simvastatin versus those receiving placebo was 0.65 (14.5 vs 21.7%), which was similar to the relative risk of 9.66 (20.5 vs 29.4%) for men. Analysis of noncardiovascular mortality showed a similar low incidence of death associated with suicide, depres Adis International Limited. All rights reserved. At the time simvastatin was first reviewed in Drugs, comparative clinical trials had shown that simvastatin generally achieved greater reductions in serum total cholesterol and LDL-cholesterol levels than various comparator agents, including cholestyramine, colestipol, probucol and fibrates (bezafibrate, fenofibrate and gemfibrozil), although simvastatin produced less marked reductions in serum levels of triglycerides and smaller increases in serum HDL-cholesterol levels than fibrates.[1] Many of these earlier comparative trials included small numbers of patients and lacked study details or statistical analysis, and there was a lack of comparisons with other HMG-CoA reductase inhibitors. Over the past 5 years comparative trials with simvastatin, including some relatively large trials, have focused on comparisons with other HMG-CoA reductase inhibitors and fibrates. These more recent and larger studies are highlighted in this section In general, the beneficial effects of simvastatin on serum lipid and lipoprotein levels in comparative Fig. 3. Effects of simvastalin (n = 2221) versus placebo (n = 2223) on mortality and nonfatal cardiovascular events in the Scandinavian Simvastatin Survival Study (4S).[116] Relative risk reduction with simvastatin was highly significant (p 0.0003) for all events shown. Abbreviations: CABG = coronary artery bypass grafting; Ml = myocardial infarction; PTCA= percutaneous transluminal coronary angioplasty. Drugs 50 (2) 1995 348 studies were of similar magnitude to those observed in noncomparative, dose-response and placebocontrolled studies (sections 3.1.1 and 3.1.2). In virtually all studies, simvastatin-induced reductions in serum levels of total and LDL-cholesterol were statistically significant compared with baseline levels, and in most larger trials changes in serum, triglyceride, HDL-cholesterol and apolipoprotein B levels and LDL/HDL ratio were also statistically significant. HMG-CoA Reductase Inhibitors Results of larger (>100 patients) randomised studies comparing simvastatin with lovastatin, prava-statin or fluvastatin for up to 24 weeks in patients with primary hypercholesterolaemia are summarised in table III. In these trials[118-124,239] and in several smaller studies, [125-128] simvastatin achieved significantly greater percentage reductions in serum levels o f total and LDL-cholesterol from baseline than other HMG-CoA reductase inhibitors administered at the same daily dosages, and reductions were similar between agents when lovastatin or pravastatin were administered at a total daily dosage twice that of simvastatin or when fluvastatin was administered at a total daily dosage approximately 8 times that of simvastatin. In addition, a number of smaller studies showed trends toward greater reductions with simvastatin than comparator agents.[129-132] Since it is now established that simvastatin achieves similar effects on the serum lipid profile to those attained with twice the daily dosage of lovastatin or pravastatin,[133,134] it is apparent that some of the studies outlined in table III did not compare equivalent dosages of HMG-CoA reductase inhibitors, It is also noteworthy that, while results of two recent large multicentre comparative trials demonstrated a potency ratio between simvastatin and fluvastatin of approximately 8 to l,[118,.239] indirect clinical comparisons suggested similar cholesterol-lowering effects when fluvastatin was administered at a total daily dosage approximately 4 times that of simvastatin.[134] A greater percentage of patients receiving simvastatin 10 to 40 mg/day for 18 weeks achieved target serum LDL-cholesterol levels of < 130 mg/dl Adis International Limited. All rights reserved. Plosker & McTavish (3.36 mmol/L) than those receiving pravastatin 10 to 40 mg/day (65 vs 39%; p < 0.001) in a large comparative study of 550 patients.[123] These results occurred despite fewer patients in the simvastatin group receiving dosages titrated to the max-imum level of 40 mg/day (48 vs 66%). Results of a smaller study comparing the same regimens in 47 patients with hypercholesterolaemia demonstrated statistically significant reductions in serum total and LDL-cholesterol levels among those patients who were switched to simvastatin after an inadequate response to pravastatin. [126] Other Lipid-Lowering Agents Earlier comparisons between simvastatin and cholestyramine, colestipol, probucol and filtrates in patients with primary hypercholesterolaemia have been previously reviewed in Drugs by Todd and Goa.[1] In general, these studies demonstrated significantly greater reductions in serum levels of total and LDL-cholesterol with simvastatin 10 to 40 mg/day than with standard dosages of comparator agents when administered for up to 12 weeks. Simvastatin reduced serum levels of total cholesterol by approximately 20 to 40% and LDL-cholesterol by 35 to 45% from baseline values. These results compared favourably with corresponding reductions of approximately 15 to 25% and 25 to 35% with cholestyramine or colestipol, and reductions for both total- and LDL-cholesterol of 10 to 20% with probucol and 15 to 25% with fibrates. Furthermore, cholestyramine was associated with no change or, in some cases, a marked increase in serum triglyceride levels compared with a modest reduction with simvastatin, and probucol produced significant reductions in HDL-cholesterol compared with a moderate increase with simvastatin.[1] Thus,probucol in particular can increase as well as reduce established risk factors for CHD.[17] As indicated previously, earlier comparisons with fibrates generally showed greater increases in serum levels of HDL-cholestcrol and more marked reductions in triglycerides with fibrates than simvastatin.[1] Most of these studies included small numbers of patients, with the notable exception of a randomised double-blind study which compared Drugs 50 (2) 1996 349 Simvastatin: A Reappraisal Table lII. Summary of large, double-blind, randomised, paratiel-group, comparative studies between simvastatin (S) and other HMG-CoA recuctase inhibitors in patients with primary hypercholesterolaemia Reference No. of evaluable patients Comparisons with fluvastatin (F liingworth 94 et al.[239] 91 89 89 91 Ose 01 aU"s> 109 Dosage regimen (mg/day) Mean percentage change in serum iipid/lipoprotein levels versus baseline a total-C LDL-C HDL-C TG LDL-C/ HDL-C ) S 5x 5wk S10x5wk S 20 x 5wk F 20 x 5wk F 40 x 5wk S 5 x 6wk -15.5 -19.4 -23.5 -11.6 -16.9 -19** b S 10x6wk F 20 x 6wk F 40 x 6wk -23** c -16 -19 Comparisons with lovastatin (L) 'Farmer etal.[118] 134 135 137 134 Frohlich et al. [96]c 149 149 S 1 0 x 24wk S 20 x 24wk L 20 x 24wk L 40 x 24wk S 10-40x 18wk L20-80x18wk Comparisons with pravastatin (P) Douste-Blazy 135 [119] et al. 133 Larnbrecht 97 et al.[120] 103 Lefebvre 142 et al.[122] 141 Sirr.va statin 275 +7.8 +8.0 +8.9 +5.3 +7.0 + 10 -7.9 -4.6 -12.9 -2.6 -8.8 -12 -26.1 -32.1 -37.5 -20.0 -27.1 - 30* *b -30** c -22 -26 +12*d +6 +13 -15* d -10 -13 -35 -24 -33 -19.6 -25.4** b -18.6 - 22.6 -26 to -30 -26 to-31 -27.5 -34.7** b -25.4 -3 1 .2 -34 to -37 -33 to -38 +4.6 +4.6 +4.2 +7.4 +8 +4 to 10 -3.9 -10.3 -10.5 -10.3 -1 6 t o - 1 7 -11 to-22 -20.5 -37. 1**b -27.4 -34.9 S 10x6wk P 20 x 6wk S 20 x 4wk P 20 x 4wk S 1 0 x 6wk P 1 0 x 6wk S 10-40x18wk -21.2** -18.4 -27.7** -21.0 -23** -16 -27** -28.3** -25.0 -37.5** -28.5 -32** -22 -38** +6.3 +6.1 +6.7 +7.3 +7 +5 +15* -13.8 -12.9 -14.3 -10.9 -13* -6 -1 8* -30.2* -27.7 -40.5** -30.8 -35** -24 -44** 275 P 10-40x18wk -19 -26 +12 -14 -32 139 S 5 x 6wk then S 10 x 6wk P 1 0 x 12wk -18.6** -26.8** +8.1 -9.5 -26.3" -1 0. 8 -16.5 +8.3 -4.2 -17.3 110 105 108 Fravastatin Study Group[122] SteinhagenThiessen et al.[123] -21.4**b -27.4**c -3 2. 3 -16.0 -22.8 -26* b 135 a All changes in total-C and LDL-C were statistically significant compared with baseline. b Statistically significant difference between treatment groups refers to S 5 versus F 20. c Statistically significant difference between treatment groups: S 10 versus F 20**; S 10 versus F 40* (Ose et al.); S 10 versus F 20 and F 40** (Illingworth et al.). d Statistically significant difference between treatment groups refers to S 10 versus F 20. e Statistically significant difference between treatment groups refers to S 20 versus L 20.% f Results presented as ranges due to stratification by severity of hypercholesterolaernia. g Nonblind study. Abbreviations and symbols: C = cholesterol; HDL= high density lipoprotein; HMG-CoA= 3-hydroxy-3-methylglutaryl coenzyme A; LDL=low density lipoprotein; TG = triglycaride; wk = weeks; statistically significant differences between treatment groups: * indicates p 0.05; ** indicates p0.01. simvastatin 5 or 10 mg/day with gemfibrozil 1200 mg/day in 137 patients with moderate hypercholesterolaemia [serum LDL-cholesterol levels between 4.3 and 5 mmol/L(166 to 193 mg/dl)] and simvastatin 10 or 20 mg/day with gemfibrozil 1200mg/day in another 153 patients with more severe hyperAdis International Limited. All rights reserved. cholesterolaemia [serum LDL-cholesterol levels 5 mmol/L(193 mg/dl)].[135] Results of this trial, which used relatively low dosages of simvastatin, showed trends towards greater reductions in total and LDL-cholesterol levels and smaller increases in HDL-cholesterol levels with simvastatin than Drugs 50(2)1995 350 Plosker & McTavish Table IV. Summary of large, double-blind, randomised, parallel-group, comparative studies between simvastatin (S) and fibrates in patients with primary hypercholesterolaemia Reference evaluable patients No. of Dosage regimen (mg/day) Mean percentage change in serum lipid/lipoprotein levels versus baseline total-C LDL-C HDL-C TG S 10-40 x12wk B 600x12wk -30.3** -18.8 -40.9** -24.8 +7.7 +25.9** -16.3 -33.7** S 10-20x16wk Cl 100-200 x 16wk S 10-40x 18wk Cl 100x 18wk -30 -28 -29.5** -15.5 -43* -38 -40.7** -19.8 +3 +15* +8.2 +9.7 -22 -4 2* * -11.4 -33. 9" -42.3** -25.0 S 20 x 6wk F 600 x 6wk S 20-40 x 10wk F 400-800 x 1 0wk -24.7* * -18.7 -29.9** -19.2 -27.4** -19.5 -35.4** -22.3 +6.9 +0.3 +7.2 +10.9 -21.2 -25.1 -16.7 -28.9** -38.2** -24.7 S 10 x 12wk G 1200x 12wk S5-10x12wk a G 1200 x 12wk a S 10-20x12wkb G1200x12wk b -24,0** -16.2 -21 -15 -27 -15 -32.9** -19.2 -26 -18 -34 -17 +13.0 +24.6** +7 +17 +9 +16 -9.7 -33.6** LDL-C/ HDL-C Comparison with bezafibrate (B) Forti[135] 60 66 Comparisons with ciprofibrate (Cl) Famier et al.[136] Famier et al.[137] 82 84 82 82 Comparisons with fenofibrate (F) Sard et al.[133] 88 88 Frickeretal.[139] 32 92 Comparisons with gemfibrozil (G) Abate et al.[140] Tikkanen et al.[134] 104 107 68 69 78 75 -39.2** -32.1 -28 -25 -37 -22 a Patients with moderate hypercholesterolaemia [LDL-C between 4.3 and 5 mmol/L (166 and 193 mg/dl) at baseline]. b Patients with more severe hypercholesterolaemia (LDL-C > 5 mmol/L) at baseline. Abbreviations and symbols: C = cholesterol; HDL = high-density lipoprotein; LDL = low-density lipoprotein; TG = triglyceride; wk = weeks; statistically significant differences between treatment groups; * indicates p 0.05; ** indicates p 0.01. gemfibrozil, both in moderate and severe hypercholesterolaemia (table IV). These findings have been confirmed in more recent comparisons between simvastatin and fibrates including bezafibrate, ciprofibrate, fenofibrate and gemfibrozil. Several studies included relatively large numbers of patients (>100) in randomised doubleblind protocols for up to 24 weeks, and results of these trials are summarised in table IV. Statistically significant differences were frequently noted between treatment groups, which typically favoured simvastatin for changes in total and LDL-cholesterol (similar to those indicated above) and fibrates for changes in HDL-cholesterol (+5 to+10% with simvastatin vs +10 to +25% with fibrates) and triglycerides (-10 to -20% vs -25 to-40%) [table IV]. Similar trends, which achieved statistical significance in some instances, were also noted in several smaller and nonblind studies.[142-149] In one of Adis International Limited. All rights reserved. the larger trials, a 12-week comparison of simvastatin 10 to 40 mg/day and bezafibrate 200mg 3 times daily in 126 patients, a significantly higher proportion of simvastatin than bezafibrate recipients achieved NCEP target cholesterol levels (see introduction to section 3) by the end of the trial (75 vs 47%; p = 0.001).[136] A large nonblind study evaluated the efficacy of sequential fibrate (bezafibrate, ciprofibrate, fenofibrate or gemfibrozil) and simvastatin in patients with severe hypercholesterolaemia.[150] Results showed that pre-defined serum total cholesterol target levels were achieved in 45% of 6422 patients treated with a fibrate for 12 weeks and in 84% of 3311 patients who received simvastatin 10 or 20 mg/day for 12 weeks after failing to achieve target goals with fibrate therapy. NCEP target goals for serum LDL-cholesterol levels were achieved by 13 and 34% of patients, respectively. Drugs 50 (2) 1995 3.1.4 Use in Combination with Other Antihyperlipidaemlc Drugs Simvastatin has been used in combination with other cholesterol-lowering agents, usually a bile acid sequestrant, in some clinical trials. Results of a recent and novel meta-analysis of cholesterol-lowering studies showed that the magnitude of benefit, both in terms of CHD mortality and total mortality, was related to the degree of reduction achieved in serum cholesterol levels,[151] While the analysis demonstrated adverse effects of certain agents (i.e. fibrates and hormones) on mortality, these specific effects were independent of reductions in serum cholesterol levels. Thus, results of this meta-analysis suggest the importance of aggressive lowering of serum cholesterol levels. Combined treatment is generally reserved for patients who do not respond adequately to monotherapy, particularly those with severe hyperlipidaemia, or to reduce the risk of adverse effects by using lower dosages of 2 agents instead of maximal dosages of a single drug.[17] A limited number of reports have evaluated simvastatin in combination with fibrates[152-155] or nicotinic acid,[26,156] although such regimens are generally not recommended unless potential benefits clearly outweigh increased risk of potentially serious adverse effects (see section 5).[72,157] Several small earlier clinical studies, predominantly in patients with severe hypercholesterolaemia, demonstrated that the combination of simvastatin plus either cholestyramine or colestipol generally achieved 10 to 15% greater reductions in serum levels of total and LDL-cholesterol than simvastatin monotherapy.[1] Elevations of serum HDLcholesterol levels were also somewhat higher with combined regimens, but reductions in serum triglycerides with simvastatin monotherapy tended to be partially offset when combined with a bile acid sequestrant. These results have been confirmed in more recent studies comparing the efficacy of simvastatin when used either as monotherapy or in combination with cholestyramine or colestipol.[158-163] Results were typified by those of a double-blind trial of 61 patients with severe hypercholesterolaemia © Adis International Limited. All rights reserved. Fig. 4. Effects of simvastatin titrated to 40 mg/day over 18 weeks, with or without concomitant colestipol (5 or 10g/day) and serum lipid and lipoprotein levels in 61 patients with severe hypercholesterolaemia.[162] The effect of combined therapy was statistically significant for changes in total cholesterol (p < 0.01) and LDLcholestsrol (p < 0.001). Abbreviations: HDL = high density lipoprotein; LDL= low density lipoprotein. who were randomised to receive simvastatin titrated to 40 mg/day with either placebo, colestipol 5 g/day or colestipol 10 g/day over 18 weeks (fig. 4).[163] The effect of combining simvastatin and cofestipol was statistically significant for changes in serum total cholesterol (p < 0.01) and LDL-cholesterol (p < 0.001) levels. Another randomised double-blind study of 33 patients who had undergone coronary artery bypass grafting showed a trend towards greater reductions in serum total cholesterol (-29 vs-17%) and LDL-cholesterol (-42 vs - 23%) after 2 months of treatment with simvastatin 10 mg/day plus colestipol 10 g/day compared with bezafibrate 400 mg/day plus colestipol 10 g/day, although changes in HDL-cholesterol and triglyceride levels were more favourable with the latter combination.[164] In a small study of 14 patients with heterozygous familial hypercholesterolaemia, a clear doseresponse relationship was demonstrated for reductions in serum levels of total and LDL-cholesterol as simvastatin was titrated from 10 mg/day to 40 mg/day over 4 months (r = 0.68; p <0.001). [158] Drugs 50 (2) 1995 352 Mean reductions from baseline of 31% for total cholesterol and 37% for LDL-cholesterol levels with simvastatin 40 mg/day were minimally affected by increasing the dosage to 80 mg/day, whereas addition of cholestyramine 12 g/day to simvastatin 40 mg/day achieved reductions of 43 and 53%, respectively, from baseline. Addition of bezafibrate 400 mg/day to simvastatin 40 mg/day achieved statistically and clinically significant reductions in serum lipid and lipoprotein levels compared with simvastatin monotherapy in a group of 40 patients with severe hypercholesterolaemia.[153] After 1 year of simvastatin monother-apy significant (p < 0.001) changes from baseline serum levels were demonstrated for total cholesterol (-22%), LDL-cholesterol (-25%), HDL-cholesterol (+19%) and triglycerides (-20%). In 18 patients who continued simvastatin monotherapy for an additional 1.5 years, percentage changes in serum lipid and lipoprotein levels from those at 1 year were minimal (-1, -5, +1.7, +2%, respectively, vs values at 1 year). In contrast, 22 patients who went on to receive 1.5 years of treatment with concomitant simvastatin and bezafibrate had further significant reductions in serum levels of total cholesterol (-239% vs values at 1 year; p <0.01), LDL-cholesterol (-26%; p < 0.001) and triglycerides (-24%; p <0.05). Results of a similar trial of 19 patients with type III hyperlipidaemia showed that addition of gemfibrozil 450 mg/day to simvastatin 40 mg/day for 8 weeks achieved further reductions in serum cholesterol and triglyceride levels of approximately 15% relative to those achieved with previous simvastatin monotherapy.[154] Unexpectedly, combined treatment also increased serum levels of LDL-cholesterol by 19% compared with simvastatin monotherapy. Very limited data are available on patients receiving concomitant simvastatin and nicotinic acid (or derivatives). One patient with homozygous familial hypercholesterolaemia had a marked reduction in serum cholesterol levels with combined treatment consisting of simvastatin 40 mg/day, nicotinic acid 300mg 3 times daily and probucol 500mg twice daily,[26] In another report of 10 patients receiving simvastatin plus either a nicotinic acid derivative Adis International Limited. All rights reserved. Plosker & Mc Tavish or bile acid sequestrant, mean reductions of 38% and 48% were achieved for total cholesterol and LDL-cholesterol levels, respectively.[156] 3.2 Secondary Hypercholesterolaemia At the time of the previous review in Drugs, limited data were available on the use of simvastatin in patients with secondary hypercholesterolaemia.[1] Over the past 5 years, simvastatin has been evaluated in a number of studies of patients with dyslipidaemias secondary to other causes such as diabetes mellitus, nephrotic syndrome and other renal disorders, although most of these trials included only 20 to 50 patients. Dyslipidaemia associated with controlled non-insulin-dependent diabetes mellitus (NIDDM) appears to be a contributing factor for CHD and is characterised by elevated serum triglyceride levels, low HDLcholesterol and mildly elevated LDL-cholesterol levels. Severely elevated serum LDL-cholesterol is a common feature among patients with nephrotic syndrome and some may develop hypertriglyceridaemia. For patients with chronic renal failure and those receiving dialysis, elevated triglycerides and low HDL-cholesterol levels are the most frequent lipid abnormalities, whereas patients undergoing renal transplantation may develop hypercholesterolaemia and/or hypertriglyceridaemia.[17] Small placebo-controlled studies have demonstrated statistically significant reductions in serum total cholesterol and LDL-cholesterol levels of approximately 20 to 35% and 25 to 40%, respectively, in patients with dyslipidaemias associated with NIDDM[165-167] or insulin-dependent diabetes mellitus[168-170] receiving simvastatin 10 to 40 mg/day for up to 36 weeks. Modest reductions in serum triglyceride levels and increases in HDL-cholesterol of approximately 10 to 25% were achieved with simvastatin and reached statistical significance in some of these trials. Similar modifications in serum lipid and lipoprotein levels were also noted with simvastatin in several small noncomparative studies in patients with dyslipidaemias secondary to NIDDM.[171-177] In general, placebo-controlled and noncomparative trials in patients with NIDDM did Drugs 60 (2) 1995 Simvastatin: A Reappraisal not demonstrate significant changes in glycaemic control (i.e. mean fasting and/or postprandial plasma glucose levels: HbAlc levels) or insulin resistance during simvastatin treatment. Equivalent modifications of serum lipid and lipoprotein levels were noted among dyslipidaemic patients with or without NIDDM in small comparative studies evaluating simvastatin 10 to 40 mg/day for up to 6 months.[178-181] In the largest of these trials, in which 40 patients with and 48 without NIDDM received simvastatin 10 to 40 mg/day for 6 months, total cholesterol levels were reduced by 30% and LDL-cholesterol levels by approximately 40% from baseline in both groups.[179] Modest, but statistically significant, changes from baseline levels were also noted for triglycerides (-14 vs-15%) and HDL-cholesterol (+11 vs +9%) in both groups. Glycaemic control was not altered among patients with NIDDM during simvastatin treatment. Similarly, glycaemic control was not affected by simvastatin 10 to 40 mg/day or gemfibrozil 1200 mg/day for 18 weeks in a randomised double-blind study of 18 patients with NIDDM.[182] However, simvastatin achieved significantly greater reductions than gemfibrozil in serum levels of total cholesterol (31 vs 10%;p 0.001) and LDL-cholesterol (39 vs 7%; p 0.001), but less marked reductions in serum triglyceride levels (17 vs 45%; p 0.01). Simvastatin 10 to 40 mg/day for up to 15 months has also shown favourable effects on the lipid profiles of patients with nephrotic syndrome in small studies of fewer than 25 patients.[183-190] In particular, marked reductions of approximately 30 to 50% were noted for serum levels of both total cholesterol and LDL-cholesterol. In a recent preliminary report of 19 patients with nephrotic syndrome receiving dietary management with or without simvastatin 10 to 40 mg/day for 15 months, a trend was demonstrated among simvastatin recipients for reduced proteinuria and improved plasma albumin levels.[187] Partial remission of nephrotic syndrome, as evidenced by reductions in urinary albumin excretion, also occurred in 6 of 7 patients receiving simvastatin 40 mg/day for 48 weeks. [185] While spontaneous remission is unlikely to have occurred in © Adis International Limited. All rights reserved. 353 all of these patients, other investigators have demonstrated no significant effects on renal function in patients with nephrotic syndrome receiving simvastatin.[188] A number of small trials have shown that simvastatin favourably modifies serum lipid and lipoprotein levels in patients with dyslipidaemias associated with other renal disorders, including patients with chronic renal failure of various aetiologies[191] or diabetic nephropathy[192] and those undergoing continuous ambulatory peritoneal dialysis;[193-197] haemodialysis[198,199] or renal transplantation.[200-204] 4. Pharmacoeconomic Considerations A detailed pharmacoeconomic evaluation of the cost effectiveness of simvastatin in patients with hypercholesterolaemia is beyond the scope of this article. Studies of the cost effectiveness of simvastatin and a variety of lipid-lowering agents have been previously reviewed elsewhere;[205,206] therefore, this section provides only a brief overview of pharmacoeconomic data on simvastatin Most comparative cost-effectiveness studies of simvastatin have involved cholestyramine, and pharmacoeconomic evaluations have consistently shown that simvastatin is more cost effective than bile acid sequestrants.[205-207] Indeed, in primary prevention the cost per life-year saved determined for bile acid sequestrants in various pharmacoeconomic analyses ranged from approximately $100 000 to $200000 (1991 $US) compared with $45 000 to $65 000 for simvastatin.[206] In a recent analysis the cost per 1% reduction in serum cholesterol levels was approximately 20% lower with simvastatin than pravastatin, despite higher acquisition costs for simvastatin.[208] Furthermore, the cost per successfully treated patient (achieving a therapeutic goal of serum LDL-cholesterol 4.14 mmol/L) was about 28% lower with simvastatin than pravastatin, and these results appeared to be related to the greater potency of simvastatin on a milligram per milligram basis. A comparison of gemfibrozil 300 or 600mg twice daily and simvastatin 10 mg/day in 75 patients with hypercholesterolaemia showed that simvastatin achieved greater Drugs 50 (2) 1995 354 reductions in serum levels of LDL-cholesterol, but, in terms of cost per 1 mmol/L reduction, appeared to be about 20% more expensive than either regimen of gemfibrozil.[147] It is noteworthy that these analyses did not take into consideration clinical endpoints such as reductions in overall mortality and cardiovascular morbidity and mortality, as demonstrated with simvastatin in the 4S secondary prevention trial. The 4S trial showed, for the first time, a significant reduction in overall mortality in patients with concomitant hypercholesterolaemia and CHD treated with a lipid-lowering agent. In most cost-effectiveness analyses, data from the Framingham Study were used to model the effect of reducing serum cholesterol levels on CHD risk. However, Martens[209] recently showed that cost-effectiveness studies using these CHD risk estimates are likely to overestimate the cost per lifeyear saved by about 25%. Therefore, the cost of simvastatin per life-year saved may be lower than SUS45 000 to 65 000 (l991 $US), although the cost per life-year saved would be reduced for other agents as well. A pharmacoeconomic analysis of the 4S trial is currently under way, and may overcome some of the weaknesses and assumptions made in other studies. Importantly, the cost effectiveness of lipid-lowering agents, including simvastatin, is highly sensitive to variations in drug acquisition costs.[205, 206] Fluvastatin has a lower acquisition cost than comparable dosages of other HMG-CoA reductase inhibitors, and well-designed comprehensive pharmacoeconomic comparisons between fluvastatin and other HMG-CoA reductase inhibitors are awaited with interest.[210] In addition, lipid-lowering intervention, regardless of the agent used, is more cost effective in males than females, in younger than older patients, in those with high versus moderate cholesterol elevation, among those with other CHD risk factors versus those with none, and in patients with pre-existing CHD versus those withuot. [205,206] 5. Tolerability In general, simvastatin has been well tolerated in controlled clinical trials. Adverse events associ Adis International Limited. All rights reserved. Plosker & McTavish ated with simvastatin have usually been mild and_ transient. In carlier studies, 2% of patients receiving simvastatin discontinued treatment because of adverse events, although most of these trials were of short duration and included relatively small numbers of patients.[1] In the 4S trial, a placebocontrolled study of 4444 patients with a median follow-up of 5.4 years, the rate of discontinuation because of adverse events was the same (6%) for both simvastatin and placebo treatment groups.[116] Gastrointestinal problems, such as constipation, diarrhoea, dyspepsia, flatulence and nausea, are the most frequent adverse events.[211-213] In a large co-hort of more than 2400 patients with hypercholesterolaemia who participated in controlled trials and their open extensions, the frequency of adverse gastrointestinal events considered to be associated with simvastatin (for a mean treatment duration of 18 months) were: constipation 2.5% of patients, abdominal pain 2.5%, flatulence 2.0%, nausea 1.2% and dyspepsia 0.7%.[211] In general, these adverse gastrointestinal events were mild in nature and led to discontinuation of therapy in only 0.4% of patients. Other adverse events reported in 1to 3% of patients receiving simvastatin include headache, asthenia and sleep disturbances.[72,212,213] However, in a comparative trial in which 550 patients with hypercholeslerolaemia were randomised to receive simvastatin or pravastatin up to 40mg once daily in the evening for 18 weeks, results of a stand-ard sleep questionnaire given at baseline and at 6-week intervals indicated no impairment of sleep with either drug. [123] Less frequently reported adverse events include dizziness, fatigue and skin rash .[1,7 3 , 1 2 1 , 123,211,213-215] In a large cohort of 2423 patients receiving simvastatin for a mean duration of 18 months, approximately 3.5% of patients developed mild transient elevations in serum transaminases; persistent elevations greater than 3 times the upper limit of the normal range occurred in about 1% of patients.[211] Fewer than 1% of patients discontinued simvastatin therapy because of elevated serum transaminase levels and no patient had clinical evidence of hepatotoxicity or other hepatic impairment. Drugs 50 (2) 1995 Simvastatin: A Reappraisal Approximately 5% of simvastatin recipients have modest transient elevations of creatine kinase (from skeletal muscle) levels of 3 times the upper limit of normal, which are not usually of clinical significance. [72] Some patients receiving HMG-CoA reductase inhibitors experience myositis, with or without creatine kinase elevations, but this is usually self-limiting.[74] Myopathy is an uncommon but important adverse event associated with HMGCoA reductase inhibitor therapy in 0.2% of patients.[73,216,217] In nonblind studies of simvastatin involving more than 18 500 patients, the incidence of myopathy was similar to that for hepatitis at less than 0.02%.[218] A recent preliminary report of 103 patients receiving long term combined therapy with HMG-CoA reductase inhibitors and fibrates for up to 3 years demonstrated no myalgic symptoms or serious disturbances in biochemical markers of liver or muscle function[219] Myopathy is characterised by muscle pain and/or muscle weakness with concomitant elevatjon of creatine kinase levels greater than 10 times the upper limit of normal range, and in severe cases may lead to rhabdomyolysis and subseguent renal failure. Rhabdomyolysis has occurred only rarely with simvastatin;[211,220-225] however, the risk of myopathy and rhabdomyolysis is increased when HMG-CoA reductase inhibitors are administered concomitantly with gemfibrozil (and probably other fibrates), nicotinic acid, cyclosporin or erythromycin ( i n seriously i l l parents such as those receiving the antibiotic intravenously).[72,218,226-229) In general, concomitant administration of simvastatin and fibrates or nicotinic acid should be avoided unless potential benefits outweigh potential risks.[72] The dosage of simvastatin should be reduced when it is used concurrently with cyclosporin, such as in patients who have undergone renal or cardiac transplantation (see section 6).[230] The tolerability of simvastatin appears to be similar to that of other HMG-CoA reductase inhibitors: in larger comparative trials (section 3.1.3), no clinically and statistically significant differences were noted between simvastatin and other HMG-CoA reductase inhibitors, with the exception of fewer gastrointestinal complaints with simvastatin 5 or Adis International Limited. All rights reserved. 355 10 mg/day than fluvastatin 20 or 40 mg/day in one trial.[118] In general, the tolerability profile of simvastatin was similar to or, in some cases, tended to be better than that of other lipid-lowering agents such as cholestyramine, colestipol or fibrates in clinical trials. In particular, adverse gastrointestinal effects tended to occur much less frequently with simvastatin than with cholestyramine.[72] At the lime of the previous review in Drugs, tolerabilily data were limited to those derived from short to medium term studies will, simvastatin, often including relatively small numbers of patients. Simvastalin has now been studied in thousands of patients and has been prescribed for approximately 3 million patients worldwide (data on fil e Merck & Co. Inc.).1[211,211,231] Indeed, more than 2000 patients received simvastatin 20 to 40 mg/day for a median duration of 5.4 years in the 4S study; only 1 patient developed rhabdomyolysis and, as previously indicated, 6% of patients in both active and placebo treatment groups discontinued therapy because of adverse events.[116] Importantly, long term administration of simvastatin in the 4S trial was not associated with any unanticipated adverse events. Manufacturer's postmarketing surveillance data after 900 000 prescriptions for simvastatin indicate only 8 reports of clinically symptomatic hepatitis, with 1 report of hepatic failure, and 5 patents with rhabdomyolysis (4 of these patients had experienced simi l a r muscle problems when previously receiving fibrates).[211] On the basis of preclinical trials in which dogs receiving large doses of HMG-CoA reductase inhibitors developed lens opacities (see section 1) and the occurrence of lens opacities with triparanol, a drug that inhibits cholesterol biosynthesis through a different site of action in the cholesterol-biosynthetic pathway,[232] concern has been expressed about the potential of simvastatin to increase cataract formation. Administration of simvastatin to a total of 2700 patients in short term studies produced only small nonsignificant increases in lens opacity which were thought to be related to the normal aging process.[1]Long term studies, in which relatively small numbers of patients receiving simvastatin for 1 to Drugs 50 (2) 1995 356 5 years were evaluated for development of cataracts and other ocular effects, also demonstrated only age-related changes in lens opacity or other ocular parameters.[233-238] Thus, extensive clinical use and evaluation of simvastatin, including in larger long term trials, have confirmed that the overall incidence of adverse events with simvastatin is low, with most adverse events being mild and transient. 6. Dosage and Administration Before simvastatin therapy is initiated, nonpharmacological therapy should be undertaken with a standard cholesterol-lowering diet, and dietary management should continue throughout treatment with simvastatin. The recommended starting dosage is 5 to l0mg administered as a single dose in the evening, and dosage should be individualised according to response at intervals of 4 weeks or more. The maximum recommended dosage is 40 mg/day administered as a single dose in the evening. Evening administration of a single daily dose is preferred since cholesterol biosynthesis is greatest during the night and in the early morning hours. Dosage of 20 to 40 mg/day may be necessary in patients with CHD to achiave cardiovascular risk reduction comparable to that observed in the 4S trial. In general, efficacy and tolerability of simvasstatin in elderly patients are similar to those in the population as a whole, although maximum reductions in serum levels of LDL-cholesterol may be achieved with dosage of 20 mg/day. Dosage modifications should not be necessary in patients with mild to moderate renal dysfunction, since simvastatin does not undergo significant renal execretion. In patients with severe renal insufficiency, the recommended starting dosage is 5 mg/day and patients should be monitored closely. Concomitant administration of simvastatin with nicotinic acid or fibrates (e.g. gemfibrazil) should generally be avoided because of increased risk of myopathy and rhabdomyolysis. The recommended starting dosage of simvastatin is 5 mg/day for patients receiving concomitant immunosuppressive the Adis International Limited. All rights reserved Plosker & McTavish apy with cyclosporin and the maximum simvastatin dosage should not exceed 10 mg/day. 7. Place of Simvastatin in Therapy As a member of the HMG-CoA reductase inhibitor class of drugs, simvastatin is clearly an effective agent for lowering serum cholesterol and LDL-cholesterol levels in patients with hypercholesterolacmia. At the time simvastatin was previously reviewed in Drugs[1] there were few data on the long term use of the drug and no studies comparing simvastatin and other HMG-CoA reductase inhibitors. Since then, large clinical studies have demonstrated little or no attenuation of the lipid-lowering effect of simvastatin when it is taken for 3 to 5.4 years. Extensive clinical use and evaluation in controlled studies in patients with primary hypercholesterolaemia, including long term trials, have confirmed that simvastatin is generally well tolerated, does not increase cataract formation and that hepatitis and rhabdomyolysis are very rate adverse events. Comparative studies with other HMG-CoA reductase inhibitors (lovastatin, pravastatin and fluvastatin) indicate similar tolerability profiles among these agents, but reductions in serum cholesterol and LDL-cholesterol levels were similar between agents only when lovastatin or pravastatin were administered at total daily dosages twice that of simvastatin and when fluvastatin was administered at a total daily dosage approximately 8 times that of simvastatin. As a group, the HMG-CoA reductase inhibitors are generally more potent lipid-lowering drugs than fibrates, bile acid sequestrants or other agents in clinical use. In addition, 2 recently published large clinical trials with simvastatin have provided interesting and important results. While the MAAS trial showed that simvastatin 20 mg/day slowed the progression of coronary atherosclerosis,[42] the 43 trial demonstrated a marked reduction in overall mortality (as a result of reduced coronary mortality) and coronary morbidity in patients with concomitant hypercholesterolaemia and CHD receiving simvastatin 20 to 40 mg/day on a long term basis.[116] The 4S trial was the first large controlled study to demonDrugs 50 (2) 1995 Simvastatin: A Reappraisal strate that reducing cholesterol in such patients improved overall survival. In fact, it was the first unifactorial trial with any agent used to treat hypercholesterolaemia that showed a reduction in total mortality or even coronary mortality during the planned follow-up period. Another large randomised trial is in progress (the Heart Protection Study; HPS) which will evaluate the effects of simvastatin on overall and cause-specific mortality in patients with hypercholesterolaemia who are at high risk of CHD.[107] While data are still limited on the use of simvastatin in patients with hypercholesterolaemia secondary to other causes, such as diabetes mellitus or nephrotic syndrome, a number of small studies have confirmed its effectiveness in reducing serum total and LDL-cholesterol levels in these patients. Recent studies have also confirmed earlier reports that combined therapy with simvastatin plus a bile acid sequestrant usually in patients with severe hypercholesterolaemia. achieves a greater reduction in serum total cholesterol and LDL-cholesterol levels than monotherapy. In pharmacoeconomic evaluations, simvastatin has generally compared favourably with other lipidlowering agents, particularly bile acid sequestrants. in primary prevention of patients with hypercholesterolaemia. These analyses did not take into consideration the beneficial effects on overall and coronary mortality and coronary morbidity, as demonstrated with simvastatin in the 4S secondary prevention trial. Thus, simvastatin has demonstrated good efficacy and tolerability in patients with hypercholesterolaemia, including those receiving long term administration for several years. Comparative data indicate that simvastatin is more effective than fibrates or bile acid sequestrants at lowering serum levels of total cholesterol and LDL-cholesterol, and the tolerability of simvastatin is similar to or, in some cases, tends to be better than that of these agents. Efficacy of lovastatin and pravastatin is similar to that of simvastatin only when these drugs are administered at twice the total daily dosage of simvastatin and, on the basis of the potency ratio be Adis International Limited. All rights reserved. 357 tween fluvastatin and simvastatin, the maximum recommended fluvastatin dosage of 40 mg/day would not be expected to achieve serum cholesterol and LDL-cholesterol reductions as great as those obtained with simvastatin 20 to 40 mg/day, which were associated with marked mortality reductions in the 4S trial. In conclusion, with its long term efficacy and tolerability now confirmed, a favourable clinical activity profile compared with related compounds, and, importantly, a convincingly demonstrated beneficial effect on morbidity and mortality in secondary prevention, simvastalin is now solidly established as a first-line agent when cholesterollowering pharmacotherapy is indicated. References 1. Todd PA, Goa KL. Simvastatin: a review of its pharmacological properties and therapeutic potential in hyperchlosterolaemia. Drugs 1990:40:583-607 2. Alberts AW. Effects of HMG CoA reductase inhibitors on cholesterol synthesis. Drug Invest 1990: 2 Suppl. 2: 9-17 3. Chao Y. Chen JS, Hunt VM, el al. Lowering of plasma cholesterol levels in animals by lovastatin and simvastatin. Eur J Clin Pharmacol 1991 Feb; 40 Suppl. l : S l l - 4 4. Miettinen TA, Vanhanen H, Ojala J-P, ct al Non-cholesterol sterols and faecal elimination of cholesterol during statin and fibrate treatment. Atherosclerosis 1992 Dec: 97 Suppl.: S73-80 5. Nagata Y. Hidaka Y. Ishida F. et al. Effect of simvasiatin (MK733) on the regulation of cholesterol synthesis in Hep G2 cells. Biochem Pharmacol 1990:40: 843-50 6. Nagata Y. Hidaka Y. Ishida F. el al. Effects of simvastatin (MK733) on branched pathway of mevalonate. Jpn J Pharmacol 1990:54:315-24 7. Riheiro A. Mangency M. Lorielte C. ct al. Effect of simvastatin on Ihe synthesis and secretion of lipoproteins in relation to the metabolism of cholesterol in cultured hepatocytes. Biochim BiophysActa 1991: 1086: 279-86 8. Alessandri C. Basi li S. Manrelli M, et al. Effecti d e l la simvastatina sulle lipoproteine plasmatiche. Clin Ter 1994; 144: 3-9 9. Antonicelli R. Onorato G. Pagelli P. et al. Simvastatin in the treatment of hypercholesterolemia in elderly patients. Clin Ther 1990: 12:165-71 10. Crook D. Bruce: R. Worthington M. et al. Effect of simvastatin on high density lipoprotein subfractions and apolipoproteins in type IIa hypercholesterolemia. Cardiovase Drugs Ther 1992; 6: 633-9 11. Finardi G, Perani G, Tramarin R, et al. Effectiveness and tolerabilily of simvastatin in subjects with primary hypercholesterolemia. Multicenter study [in Italian]. Clin Ter 1993: 142:225-33 12. French JK, White HD. Greaves SC. Simvastatin therapy for hypercholeslerolaemia in patients with coronary heart dis ease. N Z Med J 1990; 103: 41-3 13. Fruchart JC, Bard JM, Parra HJ. Comparative effects of pravastatin, simvastatin, fenofibrate and cholestyramine on plasma Drugs 50 (2) 1995 358 apolipoprotein Al containing plasma lipoprotein particles. J Drug Dev 1990 Aug; 3 Suppl. 1: 103-6 14. Gaw A, Packard CJ. Murray EF, et al. Effects of simvastatin on ApoB metabolism and LDL subfraction distribution. Arterioseler Thromb 1993; 13: 170-89 15. Mol MJ. Stuyt PM, Demacker PN, et al. The effects of simvastatin on serum lipoproteins in severe hypereholesterolaemia. NethJ Med 1990; 36: 182-90 16. Riesen WF, Keller U. Stohler R. et al. Effect of simvastatin therapy on apolipoproteins. Drug Invest 1990; 2 Suppl. 2: 48-52 17. Anonymous. National cholesterol education program: second report of the expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel 11). Circulation 1994; 89; 1333-445 18. Crook D, Sidhu M, Bruce R. Simvstatin and lipoprotein(a). Lancet 1992: 339: 313-4 19. Slunga L. Johnson O. Dahlen GH. Changes in Lp(a) lipoprotein levels during the treatment of hypercholesterolaemia with simvastatin. Eur J Clin Pharmacol 1992: 43: 369-73 20. Slater EE. MacDonald JS. Mechanism of action and biological profile of HMG CoA reductase inhibitors: a new therapeutic approach. Drugs 1988; 36 Suppl. 3: 72-82 21. Brown MS. Goldstein JL. Lipoprotein receptors in the liver control signals for plasma cholesterol traffic. J Clin Invest 1983:72:743-9 22. Ishida F, Walanabe K, Sato A. et al. Comparative effects of simvastatin (MK-733) and pravastatin (CS-514) on hypercholesterolemia induced by cholesterol feeding in rabbits. Biochim Biophys Acta 1990; 1042: 365,73 23. Roach PD, Kerry NL, Whiting MJ, et al. Coordinate changes in the low density lipoprotein receptor activity of liver and mononuclear cells in the rabbit. Atherosclerosis 1993; 101: 157-64 24. Matsunaga A, Sasaki J, Takada Y, et al. Effect of simvastatin on receptor mediated metabolism of low density lipoprotein in guinea pigs. Atherosclerosis 1991 ; 90: 31-7 25. Roach PD, Hosking J, Clition PM, et al. The effects of hypercholesterolaemia, simvastatin and dietary fat on the low density lipoprotein receptor of unstimulated mononuclear cells. Atherosclerosis 1993; 103: 245-54 2o. Feher MD. Webb JC. Patel DD, et al. Cholesterol-lowering drug therapy in a patient with receptor-negative homozygous familial hypercholesterolaemia. Atherosclerosis 1993; 103: 171-80 27. Ishida F, Sato A, Gizuka Y. et al. Effects of MK-733, an inhibiotr of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, on absorption and excretion of 3H chosterol in rabbits. Biochim Biophys Acta 1988; 963: 35-41 28. Ishida F, lizuka Y. Kakubari K.et al. Effect of simvastatin (MK733) on sterol and bile acid excretion in rabbits. Jpn J Pharmacol 1990; 53: 35-45 29. Sehayek E, Butbul E, Avner R, et al. Enhanced cellular metabolism of very low density lipoprotein by simvastatin. A novel mechanism of action of HMG-CoA reductase inhibitors. Eur J Clin Invest 1994; 24: 173-8 30. Ahnadi C-E, Berthezene F, Ponsin G. Simvastatin-induced decrease in the transfer of cholesterol esters from high density lipoproteins to very low and low density lipoproteins in normolipidemic subjects. Atherosclerosis 1993; 99:.219-28 31. Bocan TMA, Mazur MJ. Mueller SB, et al. Antiatherosclerotic activity of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase in chosterol-fed rabbits: a biochemical and morphological evaluation. Atherosclerosis 1994;111; 127-42 Adis International Limited. All rights reserved. Plosker & McTavish 32. Corsini A, Raiteri M, Soma M, et al. Simvastatin but not pravastatin inhibits the proliferation of rat aorta myocytes. Pharmacol Res 1991; 23: 173-80 33. Corsini A, Raiteri M, Soma MR, et al. 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Illingworth DR. Stein EA, Knopp RH. et a l . A randomised multicenter trial comparing the efficacy of simvastatin and f luvastatin. J Cardiovasc Pharmacol Ther. In press Correspondence: Donna McTavish, Adis lnternational Limited. 41 Centorian Drive, Private Bag 65901, Mairangi Bay. Auckland 10, New Zealand. Drugs 50 (2) 1995