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.......................................................... …………… ........................…
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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
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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
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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%
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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-
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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]
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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
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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 p0.01.
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 hyperAdis 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. Simvastatin but not
pravastatin has a direct inhibitory effection and human
myocyle proliferation. Clin Biochem 1992; 25: 399-400
34. Corsini A, Mazzotti M, Raiteri M, et al. Relationship between
mevalonate pathway and arterial myocyic proliferation: in vitro
studies with inhibitors of HMG-CoA reductase. Atheroscle
rosis 1993; 101: 117-25
35. Fukuo Y, Nagashima M, Saitoh A, et al. Effects of simvastatin
on serum lipids and atherosclerosis in WHHL rabbits. Clin
Ther 1991; 13: 417-24
36. Kobayashi M, Ishida F, Takahashi T, et al Preventative effect
of MK-733 (simvastatin), an inhibitor of HMG-CoA reduc
tase, on hypercholesterolemia and atherosclerosis induced
by cholesterol feeding in rabbits. Jpn J Pharmacol 1989; 49:
125-33
37. Soma MR, Donetti E, Parolini C, et al. HMG CoA reductase
inhibitors. In vivo effects on carotid intimal thickening in normo
cholesterolemic rabbits. Arterioscler Thromb 1993; 13:571-8
38. Giroux LM, Davignon J, Naruszewicz M. Simvastalin inhibits
the oxidation of low-density lipoproteins by activated human
monocyte-derived macrophages. Biochim Biophys Acta 1993;
1165:335-8
39. Kleinveld HA, Demacker PNM, De Haan AFJ, et al. Decreased
in vitro oxidizability of low-density lipoprotein in hypercholesterolaemic patients treated with 3-hydroxy-3-methylglutarylCoA reductase inhibitors. Eur J Clin Invest 1993; 23: 289-95
40. Kempen HJM, Vermeer M, de Wit E, et al. Vastatins inhibit
cholesterol ester accumulation in human monocyte-derived
macrophages. Arterioscler Thromb 1991; I I : 146-53
41. Bernini F, Didoni G, Bonfadini G, et al. Requirement for mevalonate in acetylated LDL induction of cholesterol esterification in macrophages. Atherosclerosis 1993; 104: 19-26
42. MAAS Investigators. Effect of simvastatin on coronary atheroma: the multicentre anti-atheroma study (MAAS). Lancet
1994; 344: 633-8
43. Alessandri C, Basili S, Maurelli M, et al. Effects of hydroxymethylglutaryl-coenzyme A reductase inhibitors on some blood
coagulation parameters. Curr Ther Res 1993; 53: 188-95
44. Davi G, Averna MR, Catalano I, et al. Plasma fibrinogen levels
in hypercholesterolemia: effects of simvastatin therapy, Curr
Ther Res 1991; 50: 79-84
45. Schror K. Platelet reactivity and arachidonic acid metabolism
in type II hyperlipoproteinaemia and its modification by cholesterol-lowering agents. Eicosanoids 1990; 3: 67-73
46. Bo M, Poli L, Gottero M, et al. Modifications of The coagulative
and rheologic pattern in hygercholesterolemic patients trealed
with bezafibrate R or simvastatin. Archives Gerontol Geriatr
1991 Suppl. 2: 401-8
47. Branchi A, Rovellini A, Sommariva D. Effect of three fibrate
derivatives and of two HMG-CoA reductase inhibitors on plasma
fibrinogen level in patients with primary hypercholesterolemia. Thromb Haemost 1993; 70: 241-3
48. Coumar A, Gill JK, Barradas MA, et al. The effect of treatment
with simvastatin on platelet function indices in hypercholesterolaemia. J Drug Dev 1991 ;4:79-86
49. Henry SF, Bolli P, Katzman PL, et al. Platelet reactivity, effects
of simvastatin therapy [abstract]. Am J Hypertens 1993; 6
(Part 2): 101A
50. Notarbartolo A, Davi G, Averna M, et al. Inhibition of thromboxane biosynthesis and platelet function by simvastatin in
type IIa hypercholesterolemia. Arterioscler Thromb Vasc Biol
1995; 15:247-51
Drugs 50(2) 1995
Simvastatin: A Reappraisal
51. Jacobs H, Van-de-Werf F, Lesaffre E, et al. A randomized
placebo controlled trial on the effects of simvastatin, a HMGCoA rcductase inhibitor, on blood lipids and fibrinolytic parameters. Acta Clin Belg 1992; 47: 82-9.
52. Smals AGH, Weusten JJAM, Benraad TJ, et al. The HMG-CoA
reductase inhibitor simvastatin suppresses human testicular
testosterone synthesis in vitro by a selective inhibitory effect
on 17-ketosteroid-oxidoreductase enzyme activity. J Steroid
Biochem Mol Biol 1991; 38: 465-8
53. Azzarito C. Bolardi L. Zini M, et al. Long-term therapy with
high-dose simvastatin does not affect adrenocortical and gonadal hormones in hypercholesterolemic patients. Metabolism 1992:41: 148-53
54. Bernini GF, Argenio GF, Gasperi M, et al. Effects of long-term
simvastatin treatment on testicular and adrenal steroidogenesis in hypercholestcrolemic patients. J Endocrinol Invest
1994; 17:227-33
55. Candrina R, Balestrieri G, Salvi A, et al. Cortisol secretion in
patients on simvastatin. Lancet l990; 335: 53-4
56. Ide H. Fujiya S, Aanuma Y. et al. Effects of simvastatin, an
HMG-CoA reductase inhibitor, on plasma lipids and steroid
hormones. Clin Ther 1990: 12:410-20
57. Mol MJ, Stalenhoef AF. Adrenocortical function in patients on
simvastatin [letter: comment]. Lancet 1990; 335: 412-3
58. Prihoda JS, Pappu AS, Smith FE, et al. The influence of simvastatin on adrenal corticosteroid production and urinary mevalonate during adrenocorticotropin stimulation in patients
with heterozygous familial hypercholesterolemia. J Clin
Endocrinol Metab 1991; 72: 567-74
59. Rossato M, Guarneri G, Lavagnini T, et al. Simvastatin influences testicular steroidogenesis in human [letter]. Horm
Metab Res 1993; 25:503-5
60. Bargossi. AM, Battino M, Gaddi A, et al. Exogenous CoQ 10
preserves plasma ubiquinone levels in patients treated with 3hydroxy-3-methylgultaryl coenzyme A reductase inhibitors.
Int J clin Lab Res 1994: 24: 171-6
61. Elmberger PG. Kalen A. Lunk E. et al. Effects of pravastatin
and cholestyramine on products of the mevalonate pathway
in familial hypercholesterolemia. J Lipid Res 1 99 1 : 32:
935-40
62. Ghirlanda G, Oradei A. Manto A. et al. Evidence of plasma
CoQ 10-lowering effect by HMG-CoA rcductase inhibitors: a
double-blind, placebo-controlled study. J Clin Pharmacol
1993: 33: 226-9
63. Laaksonen R, Ojala J-P, Tikkanen MJ, et al. Serum ubiquinone
concentrations after short- and long-term treatment with
HMG-CoA reductase inhibitors. Eur J Clin Pharmacol 1994:
46(4):313-7
64. Watts GF, Castelluccio C, Rice-Evans C. et al. Plasma coenzyme
Q (ubiquinone) concentrations in patients treated with simvastatin. J Clin Pathol 1993:46: 1055-7
65. Duane WC. Hunninghake DB. Freeman ML. et al. Simvastatin.
a competitive inhibitor of HMG-CoA reductase. lowers
cholesterol saturation index of gallbladder bile. Hepatology
1988-.8: 1147-50
66. Mazzella G. Parini P. Festi D, et al. Effect of simvastatin. ursodeoxycholic acid and simvastatin plus ursodeoxycholic acid
on biliary lipid secretion and cholic acid kinetics in nonfamilial hypercholesterolemia. Hepatology 1992; 15: 1072-8
67. Mauro VF. Clinical pharmacokinetics and practical applications of simvastatin. Clin Pharmacokinet 1993; 24: 195-202
68. Cheng H. Schwartz MS, Vickers S. et al. Metabolic disposition
of simvastatin in patients with T-tube drainage. Drug Metab
Dispos 1994; 22: 139-42
 Adis International Limited. All rights reserved.
359
69. Pentikainen PJ, Saraheimo M,. Schwartz Jl, et al. Comparative
pharmacokinetics of lovastatin, simvastatin and pravastatin
in humans. J Clin Pharmacol 1992: 32: 136-40
70. Cheng H, Rogers JD, Sweany AE, el al. Influence of age and
gender on the plasma profiles of 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase inhibitory activity following multiple doses of lovastatin and simvastatin. Pharm
Res 1992:9: 1629-33
71. Vickers S, Duncan CA, Chen I-W. et al. Metabolic disposition
studies on simvastatin, a cholesterol-lowering prodrug. Drug
Metab Dispos 1990; 18: 138-45
72. Merck & Co. Inc. Simvastatin prescribing information. US, 1994,
73. Blum CB. Comparison of properties of four inhibitors of 3hydroxy-3-methylglutaryl-coenzyme A reductase. Am J Cardiol 1994; 73:3D-l1D
74. Levy RI, Troendle AJ, Fattu JM. A quarter centruy of drug
treatment of dyslipoproteinemia with a focus on the new
HMG-CoA reductase inhibitor fluvastatin. Circulation 1993;
87 Suppl. 3: .15-53
75. Vyas KP, Kari PH, Pitzenberger SM. Regioselectivity and stereoselectivity in the metabolism of HMG-CoA reductase inhibitors. Biochem Biophys Res Commun 1990; 166. 1155-62
76. Vickers S. Duncan CA, Vyas KP, et al. ln vitro and in vivo
biotransformation of simvastatin, an inhibitor of HMG CoA
reductase. Drug Metab Dispos 1990; 18: 476-83
77. Betteridge DJ, Dodson PM, Durrington PN. et al. Management
of hyperlipidaemia: guidelines of the British hyperlipidaemia
association. Postgrad Med J 1993; 69: 359-69
78. Frick MH, Elo O. Haapa K, et al. Helsinki heart study: primaryprevention trial with gemfibrozil in middle-aged men with
dyslipidemia. N Engl J Med 1987: 317 (20): 1237-45
79. Multiple Risk Factor Intervention Trial Research Group.
Multiple risk factor intervention trial. JAMA 1982; 248 (12):
1465-77
80. Anonymous. The lipid research clinics coronary primary prevention trial results. I. Reduction in incidence of coronary
heart disease. JAMA 1984: 2 51 : 351-64
81. Anonymous. the li p i d research clinics coronary primary prevention t ri al results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA
1984:251: 365-74
82. Schucker B. Wittes JT. Santanello NC, et al. Change in cholesterol awareness and action: results from national physician
and public surveys. Arch Intern Med 1991; 151: 666-73
83. Thelle DS. Epidemiology of hypercholesterolemia and European management guidelines. Cardiology 1990; 77 Suppl. 4:
2-7
84. Clifton PM, Noakes M, Nestel PJ. Gender and diet interactions
with simvastatin treatment. Atherosclerosis 1994; 110: 25-33
85. Alessandri C. Peverini F, Basili S. et al. Effect of simvastatin
treatment on high-density lipoprotein cholesterol. Curr Ther
Res 1992: 52: 98-105
86. DeKnijff P, Stalenhoef AFH. Mol MJ, et al. Influence of apo E
polymorphism on the response to simvastatin treatment in
patients with heterozygous familial hypercholesterolemia.
Atherosclerosis 1990; 83: 89-97
87. Eckardt H, Bocker K. Dreyer M. et al. Simvastatin in the treatment of primary bypercholesterolemia. Interim results of the
German Multicenter Simvastatin Study [in German]. Munch
Med Wochenschr 1992; 134: 39-45
88. Ghizzoni G, Rusconi C. Faggiano P, et al. Effectiveness and
tolerability of simvastatin in patients with moderate or severe
hypercholeslerolemia. Results after 12 months of treatment
[ i n It ali an ]. Minerva Cardioangiol 1993; 41: 105-9
Drugs 50 (2) 1995
360
89. Goto Y, Nakaya N, Goto Y, et al. Clinical effect of MK-733
(simvastatin) on hyperlipidemia - results of multiclinical open
study. Rinsho Iyaku 1989; 5 (S): 119-52
90. Hersch AD, UK and Eire Simvastatin Study Group. A one-year
multicentre study of simvastatin in the treatment of hypercholesterolaemia. Br J Clin Pract 1994; 48 (5): 231-5
91. Simons LA. Simvastatin in severe primary hypercholeslerclemia: efficacy, safety, and tolerability in 595 patients over 18
weeks. Clin Cardiol 1993; 16: 317-22
92. Sirtori CR, Area M, Barone A, el al. Clinical evaluation of simvastatin in patients with severe hypercholesterolemia. An Italian open study. Curr Ther Res 1989; 46: 230-9
93. Steyn K, Weich HFH, Vermaak WJH. et al. A 6-month trial of
simvastatin (HMG-CoA reductase inhibitor) in the treatment
of hypercholesterolaemia. S Afr Med J 1991; 79: 639-45
94. Vermaak WJH, Ubbink JB. Ungerer JPJ. et al. Using changes
in attributable risk to predict long-term efficacy of simvastatin
treatment. Clin Chem 1992; 38: 2033-7
95. Stalenhexi AFH. Correspondence. Lancet 1494; 344: I7oo-7
96. Frohlich J. Brun LD, Blank D, et al. Comparison of the short
term elficacy and tolerability of lovastatin and simvastatin in
the management of primary hypercholesterolemia. Can J Cardiol 1993; 9: 405-12
97. Giannini SD, de-Goes JM, Dereviaek BE. et al. Simvastatin
(MK-733). a new HMG-CoA reductase inhibitor, in the treatment of hypercholesterolemia in elderly patients with atherosclerosis [in Portaguese]. Arq Bras Cardiol 1990; 54: 407-14
98. Tamburrini LR. Simvastatin in the treatment of hypercholesterolemia in geriatrics. An epidemiological and clinical study (in
Italian). Minerva Med 1992; 83: 347-53
99. Barlow CW, Friedman BM, Myburgh DP, et al. Effects of
therapy with diet and Simvastatin on atherosclerosis in hypercholesterolemic patients. Cardiovasc Drugs Ther 1990; 4:
1389-94
100. Salvetti A, Argenio GF, Bernini GP, et al. A multicenter
Italian study on the efficacy and tolerability of simvastatin in
male patients with essential hypertension and primary hypercholesterolemia [abstract]. J Hypertens 1993 Dec; 11 Suppl.
5: S477-8
101. YoshimotoT. Naruse K, Naruse M. et al. Effects of simvastatin
or the escape phenomenon followin g pravastatin therapy in
patients with hypercholesterolemia [abstract]. Am J Hypertens
1994; 7 (Part 2): 57A
102. Stuyt P, Demacker P, Mol M. et al. Effect of simvastatin on
serum lipids and lipoproteins in familial dysbetalipoproteinemia Abstract. Presented at the Sth International Symposium
on Atherosclerosis. Rome, 9-13 October, 1988.
103. Stuyt PMJ.Mol MJTM. Stalenhoef AFH. Long-term effects of
simvastatin in familial dysbetalipoproteinaemia. J Intern Med
1991; 230: 151-5
104. Ducobu J. Brasseur D, Chaudron J-M, et al. Simvastatin use in
children [letter]. Lancet 1992; 339: 1488
105. Bakker HD, Bruin T, Schaap MC, et al. The prediction of t h e
therapeutic response to cholesterol lowering drugs in an 11year-old boy with homozygous familial hypercholesterolaemia. J Inherit Metab Dis 1991; 14: 389-92
l06. Aranda P, Aranda F, Frutos M, et al. Conventional vs low doses
simvastatin for treating hypercholesterolemic essential bypertensives [abstract]. Am J Hypertens 1994; 7 (Part 2): 57A
107. Keech A, Collins R, MacMahon S, et al. Three-year follow-up
of the Oxford Cholesterol Study: assessment of the efficacy
and safety of simvastatin in preparation for a large mortality
study. Eur Heart J 1994; 15: 255-69
108. Marshall S, Meredith PA, Elliott HL. Correspondence. Lancet
1994:344: 684
© Adis International Limited. All rights reserved.
Plosker & McTavish
109. Tuomilehto J, Guimaraes AC, Kettner H, et al. Dose-response
of simvastatin in primary hypercholesterolemia. J Cardiovasc
Pharmacol 1994; 24: 941-9
110. Walker JF, Pingeon RA, Shapiro DA. Efficacy and tolerability
of simvastatin (epistatin) in the elderly. Drug Invest 1990; 2
Suppl. 2: 53-6
111. Walker JF, Tobert JA. The clinical efficacy and safety of lovastatin and MK-733-an overview, Eur Heart J 1988; 8 (Suppl. E):
93-6
112. Saito Y, Yoshida S, Nakaya N.et al. Comparison between morning and evening doses of simvastatin in hyperlipidemic subjects.
A double-blind comparative study. Arterioscler Thromb 1991;
11: 816-26
113. Capurso A, Resta F, Bertolini S, et al. Lipid control with
low-dosage simvastatin in patients with moderate hypercholesterolaemia. An Italian multicentre double-blind placebocontrolled study. Eur Heart J 1992 Jul; 13 Suppl. B: 11-6
114. Farish E, MacDonald N-J, Barnes JF, et al. A double-blind
twelve-week placebo-controlled study to assess the efficacy of
simvastatin in the treatment of hypercholesterolaemia in
hypertensive patients. J Drug Dev 1990 Aug; 3 Suppl. 1: 259-63
115. McDowell IF, Smye M, Trinick T, et al. Simvastatin in severe
hypercholesterolaemia: a placebo controlled trial. Br J Clin
Pharmacol 1991; 31: 340-3
116. Pedersen TR, Scandinavian Simvastalin Survival Study Group.
Randomised trial of cholesterol lowering in 4444 patients with
coronary heart disease: the Scandinavian simvastatin survival
study (4S). Lancet 1994; 344: 1383-9
117. Bach LA, Cooper ME, O'Brien RC, et al. The use of simvastatin, an HMG CoAreductase inhibitor, in older patients with
hypercholeslerolemia and atherosclerosis. J Am Geriatr Soc1990; 38: 10-4
118. Ose L, Scott R, Simvastatin-fluvastatin Study Group. Doubleblind comparison of the efficacy and tolerability of simvastatin
and fluvaslalin in patients with primary hypercholesterolemia.
Clinical Drug Investigation. In press
119. Farmer JA, Washington LC, Jones PH, et al. Comparative effects of simvastatin and lovastatin in patients with hypercholesterolemia. Clin Ther 1992; 14: 708-17
120. Douste-Blazy P, Ribeiro VG, Seed M, et al. Comparative study
of the efficacy and tolerability of simvastalin and pravastatin
in patiems with primary hypercholesterolaemia. Drug Invest
1993; 6: 353-61
121. Lambrecht LJ, Mulini PL, European SG. Efficacy and tolerability of simvastatin 20 mg vs pravastatin 20 mg in patients
with primary hypercholesterolemia. Acta Cardiol 1993; 48
(6): 541-54
122. Lefebvre P, Scheen A, Materne P. Efficacy and tolerability of
simvastatin and pravastatin in patients with primary hypercholesterolemia. (Multicountry comparative study). Am J
Cardiol 1992; 70: 1281-6
123. Simvastatin Pravastatin Study Group. Comparison of the efficacy, safety and tolerability of simvastatin and pravastatin for
hypercholesterolemia. Am J Cardiol 1993; 71; 1408-14
124. Steinhagen-Thiessen E. Comparative efficacy and tolerability
of 5 and 10 mg simvastatin and 10mg pravastatin in moderate
primary hypercholesterolemia. Cardiology 1994; 85: 244-54
125. Illingworth DR, Bacon S, Pappu AS, et al. Comparative hypolipidemic effects of lovaslatin and simvaslatin in patients with
heterozygous familial hypercholesterolemia. Atherosclerosis
1992; 96; 53-64
126. Lintott CJ,Scott RS.Sutherland WHF,et al.Trealing hypercholesterolaemia with HMG CoA reductase inhibitors: a direct
Drugs 50 (2) 1995
Simvastatin: A Reappraisal
comparison of simvastatin and pravastatin. Aust N Z J Med
1993:23:38l-6
127. Stalenhoef AFH, Lansberg PJ. Kroon AA, et al Treatment of
primary hypercholesterolaemia. Short-term efficacy and safety
of increasing doses of simvastatin and pravastatin: a doubleblind comparative study. J Intern Med 1993; 234: 77-82
128. Volpe R, Arca M, Ginnetti MG, et al. The efficacy and safety
of pravastatin and simvastatin in patients with primary hype cholesterolemia. Curr Ther Res 1992; 51: 422-30
129. Ditschuneit HH, Kuhn K, Ditschuneit H. Comparison of different HMG-CoA reductase inhibitors. Eur J Clin Pharmacol
1991 Feb;40Suppl. 1:27-32
130. di Veroli C, Pastorelli R. Effectiveness and tolerability of simvastatin versus pravastatin. Curr Ther Res 1992; 52 (1): 1-6
131. Muggeo M. Travia D, Querena M, et al. Long term treatment
with pravastatin, simvastatin and gemfibrozil in patients with
primary hypercholesterolaemia: a controlled study. Drug Invest 1992; 4(5): 376-85
132. O'Connor P, Cooke T, Feely J. Effects of HMG Co-A reductase
inhibitors on lipids and lipoprotein (a) in hypercholesterolaermia. Drug Invest 1992; 4(3): 227-31
133. Illingworth DR, Erkelens DW, Keller U, et al. Defined daily
doses in relation to hypolipidaemic efficacy of lovastatin
pravastatin and simvastatin. Lancet 1994; 343: 1554-5
134. IlIingworth DR.Tobert JA. A review of clinical trials comparing
HMG-CoA reductase inhibitors. Clin Ther 1994; 16 (3):
366-85
135. Tikkanen MJ, Bocanegra TS, Walker JF, et al. Comparison of
low-dose simvastatin and gemfibrozil in the treatment of elevated plasma cholesterol. Am J Med 1989; 87 Suppl. 4A:
47-53
136. Forti N. Reductions in lipid fraction plasma levels induced by
simvastatin and bezafibrate. Brazilian multicenter study [ i n
Portuguese]. Arq Bras Cardiol 1993; 60: 437-44
137. Farnier M. Truong-Tan N, Regy C. Comparative multicentre
trial of the efficacy and tolerability of ciprofibrate and simvastatin in the treatment of mixed type IIB hyperlipoproteinaemias. J Drug Dev 1992; 5: 13-21
138 Farnier M. French SG. Comparison of simvastalin and ciprofibrate in the treatment of primary hypercholesterolaemia - a
French multicentre study Atherosclerosis 1992 Dec;97 Suppl.;
S59-66
139. Bard J-M. Parra H-J. Camare R, et al. A multicenter comparison
of the effects of simvastatin and fenofibrate therapy in severe
primary hypercholesterolemia with particular emphasis on
lipoproteins defined by their apolipoprotein composition.
Metabolism 1992: 41: 498-503
140. Frieker J. Douste-Blazy P. Drouin P. et al. Effectiveness and
tolerability of simvastatin and fenofibrate in primary hypercholesterolemia [in French]. Presse Med 1990; 19: 1927-30
141. Abate G, Bertolini S. Capurso F. et al. Genifibrozil versus simvastatin in primary moderate hypercholesterolemia with low
high-density lipoprotein cholesterol: a multicenter comparison. Nutr Metabol Cardiovasc Dis 1994; 4: 148-54
142. Berioli S. Bentivoglio M, Conti R. et al. Simvastatin versus
gemfibrozil in the treatment of primary hypercholesterolemia
in hypertensive patients treated with hydrochlorothiazide [in
Italian]. Cardiologia 1990: 35: 335-40
143. Bredie SJH. deBruinTWA. Demacker PNM. et al. Comparison
of gemfibrozil versus simvastatin in familial combined hyperlipidemia and effects on apolipoprotein-B-containing lipoproteins, low-density lipoprotein subfraction profile, and
low-density lipoprotein oxidizability. Am J Cardiol 1995; 75:
348-53
 Adis International Limited. All rights reserved.
361
144. Bruckert E, Truffert J. DeGennes JL. Comparison about the
efficacy and tolerability between simvastatin and
bezafibrate in the treatment of hypercholesterolemia. [in
French]. Ann Med Interne Paris 1991; 142: 505-10
145. Farnier M, Bonnefous F. Debbas N. et al. Comparative efficacy
and safety of micronized fenofibrate and simvastatin in patients with primary type IIa or IIb hyperlipidemia. Arch Intern
Med 1994; 154:441-9
146. Lecerf JM, Boyer J. Jacquet P. et al. Comparison of the efficacy
and value of bezafibrate and simvastatin in mixed hyperlipidemia [in French]. Sem Hop 1994; 70: 656-63
147. Lim MCL, Foo WM. Efficacy and cost-effectiveness of simvastatin and gemfibrozil in the treatment of hyperlipidaemia.
Ann Acad Med Singapore 1992; 21: 34-7
148. Nakandakare E. Garcia RC, Rocha JC, et al Effects of simvastatin, bezafibrate and gemfibrozil on the quantity and
composition of plasma lipoproteins. Atherosclerosis 1990;
85:211-7
149. Smith DHG, Neutel JM, Jankelow D. et al. Bezafibrate and
simvastatin (MK-733) in the treatment of primary hypercholesterolaemia. S Afr Med J 1990; 77: 500-3
150. Muls E, Hofmans E, Droussin AM, et al. Sequential management of hypercholesterolaemia with a fibrate and simvastatin.
The Belgian general practitioners' trial. Clinical Drug Investigation l995; 9 (2): 116-26
151. Gould AL, Rossouw JE, Santanello NC. et al. Cholesterol reduction yields clinical benefit: a new look at old data. Circu
lation 1995; 91 (8): 2274-82
152. Da Col PG. Fonda M. Fisicare M. et al. Tolerability and efficacy
of combination therapy with simvastatin plus gemfibrozil in
type IIb refractory familial combined hyperlipidemia. Curr
Ther Res 1993: 53 (5): 473-83
153. Deslypere JP. Addition of fibrates to simvastatin therapy in
hyperlipidaemic patients. Atherosclerosis 1992 Dec; 97
Suppl.: S67-71
154. Feussner G. Eichinger M. Ziegler R. The influence of simvastatin alone or in combination with gemfibrozil on plasma
lipids and lipoproteins in patients with type III hyperlipoproteinemia.Clin Investig 1992:70: 1027-35
155. Hutchesson ACJ. Moran A. Jones A F. Dual bezafibratesimvastatin Therapy for combined hyperlipidaemia. J Clin
Ph arm Ther l991; 19; 387-9
156. Brocard jl. Keller U. Oberhansli A. et al. Effects and side effects of one-year treatment of hypercholesterolemia with
simvastatin [ i n German]. Schweiz Med Wochenschr 1991;
121: 977-83
157. Illingworth DR. Clinical implications of new drugs for lowering
plasma cholesterol concentrations. Drugs 1991;41: 151-60
158. Da Col PG. Cattin L. Valenti M. et al. Efficacy of simvastatin
plus cholestyramine in the two-year treatment of heterozygous hypercholesterolemia. Curr Ther Res 1990: 48 (5):
798-808
159. Desager JP. Horsmans Y, Harvengt C. Lecithin: cholesterol acyltransferase activity in familial hypercholesterolemia treated
with simvastatin and simvastatin plus low-dose colestipol. J
Clin Pharmacol 1991; 31: 537-42
160. Geisel J, Oette K. Burrichter H. HMG-CoA reductase inhibitors
in familial hypercholesterolemia. Therapy with simvastatin
alone and in combination with cholestyramine in low dosage:
a report of 2 years experiences [in German). Fortschr Med
1990; 108: 71-2,75-6
161. Geisel J, Schleifenbaum T, Octte K. Pharmacological Therapy
for hypercholesterolaemia in patients with familial defec
tive apolipoprotein B 100 [i n German]. Med Welt 1992:43:
9 4 6 -5 0
Drugs 50 (2) 1995
362
162. Pernigotti L, Bo M, Poli L, et al. Treatment of hypercholesterolemic patients of different age with simvastatin: 1-year
study [ i n Italian]. Recenti.Prog Med 1991; 82: 155-62
163. Simons LA, Simons J. Partitt A. Successful management of
primary hypercholeslerolaemia with simvastatin and low-dose
colestipol. Med J Aust 1992; 157: 455-9
164. Barbir M, Hunt BJ, Galloway D, et al. A randomized pilot trial
of low-dose combination lipid-lowering therapy following
coronary artery bypass grafting. Clin Cardiol 1994; 17:59-64
165. Farrer M, Winocour PH, Evans K, et al. Simvastatin in noninsulin-dependent diabetes mellitus: effect on serum lipids,
lipoproteins and haemostatic measures. Diabetes Res Clin
Pract 1994; 23: 111-9
166. Nielsen S, Schmitz O, Moller N, et al. Renal function and insuli n sensitivity during simvastatin treatment in type 2 (noninsulin-dependent) diabetic patients with microalbuminuria,
Diabetologia 1993;36: 1079-86
167. Paolisso G, Sgambato S, De Riu S, et al. Simvastatin reduces
plasma lipid levels and improves insulin action in elderly, noninsulin dependent diabetics, Eu r J Clin Pharmacol 1991; 40: 2731
168. Kalen J, Sartoi G, Katzman P, et al Si m v a s t a t i n treatment of
hypercholesterolemia in patients wi t h i n s u l i n dependent diabetes mellilus [abstract]. Eur J Endocrinol 1994 Apr; 130 Suppl.
1:26
169. Kjaer K, Hangaard J, Petersen NE, et al. Effect of simvastatin
in patients with type I (insulin-depandent) diabetes mellitus
and hypercholesterolemia. Acta Endocrinol 1992; 126: 229-32
170. Sartor G, Katzman P, Eizyk E, et al. Simvastatin treatment of
hypercholesterolemia in patients with insulin dependent diabetes mellitus. International Journal of Clinical Pharmacology and Therapeutics 1995; 33:3-6
l7l. Camarda G. Use and effect of simvastatin in type II diabetics [in
Italian]. Clin Ter 1993: 143: 105-7
172. Daubresse JC, Machowski R, Pulinx E. Efficacy of simvastatin
for lowering cholesterol in non-insulin dependent diabetic putients with hypercholeslerolemia. Acta Clin Belg 1994; 49: 6875
171. Pipicelli G, Pentimone E, Frustaci G, et al. Diabetes mellilus,
hypercholesterolemia and therapeutic possibilities with simvastatin. General appraisal and personal experience [in Italian]. Minerva Med 1992; 83: 819-25
174. Steyn K, Weich HFH, Bonnici F, et al. Simvastatin in non-insulindependent diabetic patients with hypercholesterolaemia. S Afr
Med J 1982; 82: 402-6
175. Takahashi K, Inoue I, Harada Y, et al. Effect of simvastatin on
serum lipids, lipoproteins, apolipoproteins and pot-heparin
plasma lipoprotein lipase activity in patients with non-insulindependent diabetes mellitus. Rinsho Iyaku 1994 (10); 2359-66
176. Torri A, Sommariva D, Maraffi F, et al. Long-term effects of
low-dose simvaslatin in hypercholesterolemic type 2 diabetic
patients. Curr Ther Res 1992; 51: 28-36
177. Zambon S, Lapolla A, Sartore G, et al. Long-term treatment with
simvastatin in hypercholeslerolemic non-insnlin-dopendent diabetic patients. Curr Ther Res 1992;52;221- 9
178. Cassander M, Rula G, Gambino R, et al. Hypercholesteroleromia
in non-insulin-dependent diabetes mellilus: different effect of
simvastatin on VLDL and LDLcholesterol levels. Atherosclerosis 1993; 99: 47-53
179. Martini S, Gabelli C, Pagano GF, et al. Efficacy and safety of
simvastatin for the treatment of hypercholeslerolemia in pa:
tients with and without type II diabetes. Curr Ther Res 1992;
52:281-90
180. Miccoli R, Berlolotto A, Giovannilli MG, et al. Simvastatin for
lowering cholesterol levels in non-insulin-dependent diabetes
 Adis International Limited. All rights reserved.
Plosker & McTavish
mellitus and in primary hypercholesterolemia. Curr Ther Res
1992; 51; 66-74
181. van-Deursen RT, Nleuwenhuljzen-Kruseman AC, Degenaar CP,
et al. The effects of the cholesterol synthesis inhibitor simvastatin in patients with hypercholeslerolemia with and with
out diabetes mellitus [in Dutch]. Ned Tijdschr Genceskd 1990;
134:2142-6
182. Lintott CJ, Scott RS, Sutherland WHF, et al. Comparison of
simvastatin vs gemfibrozil therapy on lipid, glycaemic and
haemorheological parameters in Type-II diabetes-mellitus,
Diabetes Nutr Metab 1992; 5: 183-9
183. Bazzato G, Landini S, Fracasso A,et al.Treatment of nephrotic
syndrome hyperlipidemia with simvastatin. Curr Ther Res 1991;
50:744-52
184. Rabelink.AJ, Hene RJ, Erkelens DW, et al. Effects of simvastatin and cholestyramine on lipoprotein profile in hyperlipidaemia of nephrotic syndrome. Lancet 1988; 2: 13.15-8
185. Rabelink AJ, Hene RJ, Erkelens DW, et al. Partial remission of
nephrotic syndrome in patient on long term simvastatin [let ter].
Lancet 1990; 335:1045-6
186. Rayner BL, Byrne M, van Zyl-Smit R. et al. A clinical trial
comparing the treatment of hypercholesterolemia wi t h sim vastatin
and diet versus diet alone in patients with idiopathic
membranous nephropathy. A preliminary report [abstract].
Kidney Int 1993; 43: 1183
187. Rayner BL, Byrne M, van Zyl-Smit R. Treatment of hyperlipidaemia with simvastatin (SV) and diet, vs diet alone in
idiopathic membranous nephropathy (IMN). Nephrol Dial
Transplant 1994; 9 (7); 963
188. Thomas ME, Harris KPG, Ramaswamy C, et al. Simvastatin
therapy for hypercholesterolemic patients wilh nephrotic syndrome or significant proteinuria. Kidney Int 1993; 44: 1124-9
189. Wanner C, Bohler J, Eckardt HG. Effects of simvastatin on
lipoprolein (a) and lipoprotein composition in patients with
nephrotic syndrome. Clin Nephrol 1994; 41; 138-43
190. Warwick GL, Packard CJ, Murray L, et al. Effect of simvastatin
on plasma lipid and lipoprotein concentrations and low-density
lipoprotein metabolism in the nephrotic syndrome. C l i n Sci
1992:82:701-8
191. Harris DC, Simons LA, Mitchell P, et al. Management of nonnephrotic hyperlipidaemia of chronic renal failure wilh simvastatin [letter], Med J Aust 1991; 155: 573
192. Hommel E, Andersen P, Gall MA, et al. Plasma lipoproteins and
renal function during simvastatin treatment in diabetic nephropathy. Diabetologia 1992; 35: 447-51
193. De-Vecchi A, Scalamogna A, Paparella M, et al. Effect of simvastatin in CAPD patients with hypercholesterolemia. Adv
Perit Dial 1992;8;33l-3
194. DiPaolo B,DelRosso G,Catucci G, et al. Therapeutic effects of
simvastatin on hyperlipidemia in CAPD patients. ASA1O
Trans 1990; 36: M578-80
195. Marangoni R, Civardi F, Masi F, et al. Dislipemia in patients
undergoing conlinuous ambulatory peritoneal dialysis: pharmacological therapy (simvastatin) versus hemodialysis, Perit
Dial Int 1993; 13 Suppl 2: S431-3
I96. Matthys E, Schurgers M, Lamberigts G, et al. Effect of simva-statin
treatment on the dyslipoproteinemia in CAPD patients.
Atherosclerosis 1991;86:183-92
197. Wanner C, Lubrich-Birkner I, Summ 0, et al. Effect of simvastatin on qualitative:and quantitative changes of lipoprotein
metabolism in CAPD patients. Nephron 1992; 62: 40-6
198. Fiorini F, Patrone E, Ardu F, et al. Efficacy and safety of simvastatin in the treatment of hyperlipidemia in uremic patients
undergoing hemodialsis treatment [in Italian). Minerva Urol
Nefrol 1992;44; 165-8.
Drugs 50 (2) 1995
Simvastatin: A Reappraisal
199. Wanner C, Horl WH, Luley CH. et al. Effects of HMG-CoA
reductase inhibitors in hypercholesterolemic patients on
hemodialysis. Kidney Int 1991; 39: 754-60
200. Arnadottir M, Eriksson L-0, Germershausen JI.et al. Low-dose
simvastatin is a well-tolerated and efficacious cholesterollowering agent in ciclosporin-treated kidney transplant recipients: double-blind, randomized, placebo-controlled study in
40 patients. Nephron 1994; 68: 57-62
201. Castelao AM, Grino JM, Andres E, et al. HMG CoA reductase
inhibitors lovastatin and simvastatin in the treatment of hypercholesterolemia after renal transplantation. Transplant Proc
l993; 25 ( 1 ) : 1013-6
202. Devuyst O, Goffin E, Pirson Y. Hypercholesterolemia treatment
in a renal transplant patient [letter]. Clin Nephrol 1994; 41: 319
203. Martinez-Hernandez BE, Persaud IW, Varghese Z. et al Low-dose
simvastatin is safe in hyperlipidaemic renal transplant
patients. Nephrol Dial Transplant 1993; 8: 637-41
204. Munoz MA, Morales JM, Andres A, et al. Simvastatin therapy of
hypercholesterolemia associated with chronic rejection after
renal transplantation. A prospective study [abstract]. Kid-ney
Int 1993:44; 1497
205. Carisp P, Lewis NJW, Milne BJ. Simvastatin. A pharmacocconomic evaluntion of its cost-effectiveness in hypercholesterolaemia and prevention of coronary heart disease
PharmacoEconomics 1992; 1: 124-45
206. Thompson D, Oster G. Cost-effectiveness of drug therapy for
hypercholesterolaemia. A review of the literature. PharmacoEconomics 1992: 2; 34-42
207. Hj a lt e K. Lindgren B, Persson U. Cost-effectiveness of simvastatin versus cholestyramine. Results for Sweden. PharmacoEconomics 1992; l:213-6
208. Smart AJ, Walters L. Pharmaco-economic assessment of the
HMG-CoA reductase inhibitors. S Afr Med J 1994; 84 (12):
834-7
209. Martens LL. Effect of biological and analytical variation in
cholesterol measurement on the cost-effectiveness of cholesterol-lowering therapy, PharmacoEconomics 1992; 2:414-21
210. Plasker GL, Wagstaff AJ. Fluvastatin, A review of i t s pharmacology and therapeutic efficacy in hypercholesterolaemia.
Drugs. In press
211. Boccuzzi SJ. Keegan ME. Hirsch LJ. et al. 1 mg term experience
w i t h simvastatin. Drug Invest 1993: 5(2): 135-40
2 12. Mantell G. Extended worldwide experience HMG-CoA reductase inhibilors lovaslalin and simvastalin [i n French]. Therapic
1992; 47: 161-4
213. Thompson GR. Adverse reactions profile: 10. Simvastatin and
pravastatin. Preser J 1993; 33 (5): 217-20
214. Feldmann R, Mainetti C, Saurat J-H. Skin lesions due In treatment with simvastatin (Zocor ). Dermatology 1993; 186 (4):
272
215. Krasovec M, Elsner P, Burg G. Generalized cezematous skin
rash possibly due to HMG-CoA rcductase inhibitors. Dermatology 1993; 186 (4): 248-52
216. Bradford RH. Shear CL, Chremos AN, et al. Expanded clinical
evaluation of lovastatin (EXCEL) study results. I. Efficacy in
modifying plasma lipoproteins and adverse event profile in
8245 patients with moderate hypercholesterolaemia. Arch
Intern Med 1991; 151: 43-9
217. McGovern ME. Mellies MJ. Long-term experience with pravastatin in clinical research trials. Clin Ther 1993; 1 5 (1 ) : 57-64
2 18. Mitchel YB. The long-term tolerability profile of lovaslatin and
simvastatin. Atherosclerosis 1992 Dec: 97 Suppl.: S33-9
219. Feher MD. Foxton J, Banks D. Long-term safety of fibratestatin combination therapy in the treatment of hypercholesterolaemia [abstract]. Br J Clin Pharmacol 1994. 37: 511P
 Adis Internationol Limited. All rights reserved.
220 Berland Y, Coponat HV, Durand C, el al. Rhabdomyolysis v
simvastatin use. Nephron 19 91 ;5 7 : 365-6
221. Bertrand F, Fournier JP. Martinez P. et al. Rhabdomyolysis v
simvastatin: report of a case [i n French ]. Therapic 1992;47:
222. Bizzaro N, Bagolin E. Milani L. Massive rhabdomyolysis v
simvastatin [letter]. Clin Chem l992; 38: 1504
223. Chariot P, Abadia R. Agnus D. et al. Simvastatin-induced rhab
myolysis followed by a MELAS syndrome. Am J Med 19 94;
109-10
224. Deslypere JP, Vermculen A. Rhabdomyolysis and simvastat
Ann Intern Med 1991; 114: 342
225. Dromer C, Vedrenne C, Billey T. et al, Simvastatin-induc
rhabdomyolysis. Report of a case with a review of the lite ture
[i n French]. Rev Rhum Mal Osteoartic 1992; 59: 281
226. Blaison G, Weber JC. Sachs D, et al. Simvastatin-induced rhabdo
myolysis in a beat transplant recipient receiving cyclospot [in
French]. Rev Med Interne 1992: 13: 61-3
227. Corpier CL, Jones PH, Suki WN, et a l. Rhahdomyolysis at
renal injury with lovastatin use. JAMA 1988; 260 (2): 239
228. Glueck CJ.Oakes N.Speirs J.et al.Gemfibrozil-lovastatin the
apy for primary hyperlipoproteinemias. Am J Cardiol 1991
70: 1-9
229. Tobert JA. Efficacy and long term adverse effect p a t i e n t
lovastatin. Am J Cardiol 1988; 62 (II): 28J-34J
230. Arnadottir M, Eriksson L-0. Thysell H, et al. Plasma concer
tration profiles of simvastatin 3-hydroxy-3-methyl-glutary
coenzyme A reductase inhibitory activi ty in kidney transplat
recipients with and without ciclosporin. Nephron 1993: 65 4103
231. Walker JF. Worldwide experience with simvustatin/lovastatin
Eur Heart J 1992 Jul; 13 Suppl. B: 21-2
232. Bilheimer DW. Long-term clinical tolerance of lovastatin and
simvastatin. Cardiology 1990; 77 Suppl. 4: 58-65
233. Boccuzzi SJ. Bocanegra TS, Walker JE. Long-term safety and
efficacy profile of simvastatin. Am J Cardiol 1991; 68: 1127-31
234. Behrens-Baumann W. Thiery J, Wieland E, et a l . 3-Hydroxy-3methylglutaryl coenzyme A reductase inhibitor simvastatin
and the human lens. Clinical results of a 3-year follow up
Arzneimittel Forschung 1992; 42: 1023-4
235. Leino M, Rouhiainen P. Tuovinen E. et al . Lens opacity: five
year follow-up of patients with hypercholesterolemia receiv-ing
simvastatin treatment. J Toxicol Cutaneous Ocul Toxicol 1993;
12(4): 285-92
236. Lundh BL, Nilsson SEG. Lens changes in matched normals and
hyperlipidemic patients treated w i t h simvastatin for 2 year,
Acta Ophthalmol 1990; 68: 658-60
237. Molgaard J, Lundh BL, von Schenck H, et al. Long-term efficacy and safety of simvastatin alone and in combination therapy in treatment of hypercholesterolaemia. Atherosclerosis
1991 Dec; 91 Suppl.: 21-8
238. Schmidt J, Schmitt C, Hockwin O. The HMG-CoA reductase
inhibitors, simvastatin and pravastatin. No evidence of side
effects in eyes in use in humans [ in German ]. Fort Ophthalmol
1991:88:843-5
239. 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
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Drugs 50 (2) 1995