AOls DRUG EVALUATION Drugs 1997 May: 53 (5): 828-847

OOI2 -6667/97/CXXl5-0828/ S20.OJ/O

© Ad is Int ernational Umited . All rights reserved .

Atorvastatin
A Review of its Pharmacology and Therapeutic Potential in
the Management of Hyperlipidaemias
Andrew P. Lea and Donna McTavish
Adis International Limited, Auckland, New Zealand

Various sections of the manuscript reviewed by:

J.D. Best, Department of Medicine, St Vincent's Hospital, Fitzroy, Victoria, Australia; A. Dart, Alfred and
Baker Medical Unit, The Alfred Hospital, Prahan, Victoria, Australia; P.D. Flynn, Department of Medi cine,
University of Cambridge, Addenbrooke's Hospital, Cambridge, England; WR Garnett, Department of
Pharmacy and Pharmaceutics, Medical College of Virginia, Virginia Commonwealth University, Richm ond,
Virginia, USA; RJ. Havel, Cardiova scular Research Institute, University of California, San Franci sco,
California, USA; D.R Illingworth, Department of Medicine, Oregon Health Service s University, Portl and,
Oregon, USA; A.D. Marais, Department of Internal Medi cine, Uni ver sity of Cape Town Medical School,
Cape Town, South Africa; R Naoumova, Clinical Sciences Centre, Royal Postgraduate Medic al School,
Hammersm ith Hospital, London, England; C.E. Rackley, Division of Cardiology, Georgetown University
Medic al Center, Washington, D.C., USA.

Contents
Summary . 828
1. Pharmac odynamic Properties . . . . 831
1.1 Effects on Cholesterol Synthesis . 831
1.2 Other Effects . 833
2. Pharmacokinetic Properties 833
2.1 Drug Interactions . . . . 835
3. Therapeutic Potential . .. . 835
3.1 Primary Hypercholesterolaemia 836
3.1 .1 Comparisons with Placebo 836
3.1 .2 Comparisons with Other HMG-CoA Reductase Inhibitors 837
3.1 .3 In Combination with Colest ipol . 838
3.1.4 Homozygous Familial Hypercholesterolaemia . . . . . . . 839
3.2 Hypertriglyceridaemia or Combined Hyperlipidaemia . . . . . 839
3.3 Hypercholesterolaemia or Combined Hyperlipidaemia Secondary to NIDDM . 840
4. Tolerability . 840
5. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . 841
6. Potential Place of Atorvastatin in the Management of Hyperlipidaemias 841

Summary
Synopsis Atorvastatin is a synthetic HMG-CoA reductase inhibitor which lowers plasma
cholesterol levels by inhibiting endoge nous cholesterol synthesis . It also reduces
triglycerid e levels through an as yet unproven mechani sm.
Dose-depend ent reduction s in total cholesterol, low density lipop rotein
(LDL)-cholesterol and triglyceride levels have been observed with atorvasta tin
 Atorvastatin: A Review 829

in patients with hypercholesterolaemia and in patients with hypertriglyceridae-

mia. In large trials involving patients with hypercholesterolaemia, atorvastatin
produced greater reductions in total cholesterol. LDL-cholesterol, apolipopro-
tein B and triglyceride levels than lovastatin, pravastatin and simvastatin . In
patients with primary hypercholesterolaemia, the combination of atorvastatin
and colestipol tended to produce larger reductions in LDL-cholesterollevels and
smaller reductions in triglyceride levels than atorvastatin monotherapy.
Although atorvastatin induced smaller reductions in triglyceride levels and
more modest increases in high density lipoprotein (HDL)-cholesterollevels than
eitherfenofibrate or nicotinic acid in patients with combined hyperlipidaemia, it
produced larger reductions in total cholesterol and LDL-cholesterol.
As with other HMG-CoA reductase inhibitors. the most frequently reported
adverse events associated with atorvastatin are gastrointestinal effects. In com-
parative trials. atorvastatin had a similar adverse event profile to that of other
HMG-CoA reductase inhibitors .
Clinical data with atorvastatin are limited at present. However, with its ability
to markedly reduce LDL-cholesterol levels, atorvastatin is likely to join other
members ofits class as afirst-line agentfor the treatment ofpatients with hyper-
cholesterolaemia. if changes in lipid levels with atorvastatin convert to reductions
in CHD mortality and morbidity. Atorvastatin may be particularly suitable for
patients with heterozygous or homozygous familial hypercholesterolaemia be-
cause of the marked reductions in LDL-cholesterol experienced with the drug.
Additionally. because of its triglyceride-lowering properties, atorvastatin ap-
pears to have the potential to become an appropriate treatment for patients with
combined hyperlipidaemia or hypertriglyceridaemia.
Pharmacodynamic Like other members of its class, atorvastatin inhibits HMG-CoA reductase and
Properties impedes the formation of mevalonic acid, which is a rate-limiting step in the
biosynthesis of cholesterol. The resulting effect is a reduction in intracellular
cholesterol leading to an increase in the number oflow density lipoprotein (LDL)-
receptors and increase in LDL-cholesterol clearance from plasma. HMG-CoA
reductase inhibitors may also lower plasma cholesterol levels by decreasing he-
patic production of very low density lipoprotein (VLDL)- and LDL-cholesterol.
Atorvastatin inhibited cholesterol synthesis by 50% in human liver-derived
cell line (Hep-G2) at a concentration of 73 nmoI/L. Atorvastatin 80 mg/day re-
duced fasting plasma mevalonic acid levels by 59% in patients with heterozygous
familial hypercholesterolaemia.
Patients with hypertriglyceridaemia receiving atorvastatin either 20 or 80
mg/day for 4 weeks experienced significant reductions in plasma levels of total
cholesterol, triglycerides and apolipoproteins B, C-II, C-III and E.
Two indirect mechanisms have been suggested to explain the reduction in
triglyceride levels with atorvastatin. Firstly, marked inhibition of cholesterol syn-
thesis would impair the assembly and secretion of VLDL particles. of which
cholesterol is an essential component, therefore causing reductions in triglyceride
levels . Secondly, reductions in hepatocyte cholesterol levels caused by substantial
inhibition of cholesterol synthesis would lead to increases in LDL-receptor ex-
pression and hence increased binding of VLDL particles and LDL , resulting in
the reduction of both cholesterol and triglyceride levels.
There is some evidence that atorvastatin, like other drugs of its class, may have
antiatherogenic effects. The drug inhibits smooth muscle cell proliferation and/or

© Adis lnternotionol Limited . All rights reserved. Drugs 1997 May ; 53 (5)
 830 Lea & McTavish

migration. Compared wit h untreated controls, atorvastatin 2.5 mg/kg signifi-

cant ly reduced rabbit atherosclerotic lesion size by 67 %. Furthermore, in patients
with hyperlipidaemia, atorvastatin 80 mg/d ay reduced plasma visco sity by 10%,
factor VII activity by 8%, red blood cell sedimentation rate by 33% and arachi-
donic acid-induced whole blood aggregation by 11 %.
Pharmacokinetic Multiple daily dose s of atorvastatin 2.5 to 80mg produced steady-state maximum
Properties pla sma concentration s (Cmax) of 1.95 to 252 ug/L within 2 to 4 hours after ad-
mini stration and area under the pla sma concentration-time curve (AUq value s
of 25 .2 to 1293 ug/L >h. The drug has an ab solute bioavailability of 12%.
Atorvastatin is ~98 % protein-bound in pla sma and has a mean elimination half-
life of about 14 hours , but as a result of active metabolites the half- life of HMG-
CoA reductase inhibition is 20 to 30 hours. Less than 2% of the parent drug and
metabolites are excreted renally.
Atorvastatin Cmaxand AUC values may be prolonged in patients with hepatic
impairment. Renal impairment had no effect on atorvastatin pharmacokinetic
parameters. Although some accumulation was evident in the elderly, this did not
produce clinically significant changes in lipid reduction .
Therapeu tic Efficacy Currently, results of studies investigating the potential benefits of ator vastatin on
mortality and morbidity in patients with or without coronary heart disease are not
available. Therefore, clinical evaluation of atorvastatin at thi s time is based on
lipid-lowerin g effects, a surrogate marker of clinical efficacy.
In placebo-controlled dose-response studies in patients with primary hyper-
cholesterolaemia, atorvastatin 10 to 80 mg/day produced 35 to 61 % reduction s
in LDL- cholesterol level s. 90 % of the max imum observed reduction in LDL-
cholesterol level s wa s attained after 2 week s of treatment. In patients with
hypertriglyceridaemia, atorvastatin 5, 20 or 80 mg/d ay reduced trigly ceride levels
by 26 to 46 %, LDL-cholesterol level s by 17 to 41 % and total cholesterol levels
by 20 to 43 %.
In large double-blind trial s of I year's duration involving patients with hyper-
cholesterolaemia, reductions in total cholesterol, LDL -cholesterol , apolipopro-
tein B and triglyceride levels were significantly greater with atorvastatin 10 to
20 mg/day than with lovastatin 20 to 40 mg/day , pravastatin 20 to 40 mg/day or
simvastatin 10 to 20 mg/day. Atorvastatin, lova statin , pravastatin and simvas tatin
all raised HDL -cholesterol levels by 7 to 10%. A greater number of patients tended
to reach US National Cholesterol Education Program (NCEP) LDL -cholesterol
goals with atorvastatin than with lovastatin, pravastatin or simvastatin. As a result,
fewer patients receiving atorvastatin than these other agents tended to require
upward dosage titration after 16 weeks of treatment.
In one study, the combination of atorvastatin 10 mg/day and cole stip ol 20
g/day tended to produce larger reductions in LDL-cholesterol level s and sma ller
reductions in triglyceride level s than atorvastatin 10 mg/day monotherapy, in
patients with primary hypercholesterolaemia.
In patients with co mbined hyperlipidaemia (elevated LDL -cholesterol and
triglyceride level s), ator vastatin 10 mg/da y produced larger reductions in total
cholesterol and LDL-cholesterol than fenofibrate 100mg 3 time s daily or nico-
tini c acid (niacin) 100 to 1000mg 3 time s dail y. Howe ver, smaller redu ction s in
trigly ceride level s and more mode st incre ases in high den sity lipoprotein (HDL)-
cholesterol level s were achieved with atorvas tatin than with both fenofibr ate and
nicotinic acid .

© Ad is lnte rno nono l Umited . All rig hts reserved. Drugs 1997 Ma y; 53 (5)
Atorvastatin: A Review 831

Atorvastatin 10 to 20 mg/day caused a greater reduction in triglyceride levels

than simvastatin 10 to 20 mg/day in patients with raised cholesterol and tri-
glyceride levels secondary to non-insulin-dependent diabetes mellitus (NIDDM).
Tolerability Atorvastatin has been generally well tolerated in clinical studies of up to 52
weeks' duration . Like other HMG-CoA reductase inhibitors, gastrointestinal ef-
fects (including flatulence, dyspepsia, constipation and abdominal pain) are the
most frequently reported adverse events associated with atorvastatin. In total,
<2% of 2502 patients withdrew from treatment with atorvastatin in clinical trials
because of adverse events . In comparative trials, atorvastatin had a similar ad-
verse event profile to that of lovastatin, pravastatin and simvastatin .
Hepatic dysfunction (raised serum aspartate or alanine aminotransferase lev-
els) and myopathy (myalgia and abnormal creatine phosphokinase levels >10
times the normal limit) are the most serious tolerability concerns associated with
HMG-CoA reductase inhibitors . To date, myopathy has not yet been reported with
atorvastatin, although the drug has not been used as extensively as other HMG-
CoA reductase inhibitors . 3% of the atorvastatin group (n = 132) in one study
reported myalgia, but no patients had persistent increases in creatine phosphoki -
nase levels> I0 times the normal limit.
Elevated serum transaminase levels were reported in 0.2, 0.6, 0.6 and 2.3% of
patients receiving atorvastatin 10,20,40 and 80 rug/day, respectively . In patients
receiving atorvastatin in clinical trials, the total incidence of persistent elevations
in serum transaminases was 0.7%. After 52 weeks of treatment in a large study,
the incidence of abnormal transaminase levels was similar with atorvastatin and
lovastatin. Pancreatitis was reported in I of 1135 patients receiving atorvastatin
in 3 trials.
Dosage and Atorvastatin 10 to 80 mg/day may be used to reduce the raised lipid levels in
Administration patients with primary hypercholesterolaemia (heterozygous familial , homozyg-
ous familial or nonfamilial) or combined dyslipidaemia
The dosage of atorvastatin should be adjusted according to respon se.
Atorvastatin may be taken at any time of day with or without food. In patients
with hepatic insufficiency dosage reductions may be required . The drug is con-
traindicated in patients with active hepatic disease or unexplained persistent el-
evations in serum transaminases.
Concomitant use of atorvastatin with cyclosporin, nicotinic acid, fibric acid
derivatives, erythromycin or azole antifungals is likely to increase the risk of
adverse events (e.g. myopathy or rhabdomyolysis), and these combinations
should be avoided where possible .

1. Pharmacodynamic Properties formation by HMG-CoA reductase inhibitors re-

1,1 Effects on Cholesterol Synthesis
Atorvastatin is a synthetic reversible competi-
tive inhibitor of 3-hydroxy-3-methylglutaryl-co-
enzyme-A (HMG-CoA) reductase (fig . 1). The
conversion of HMG-CoA to mevalonic acid is an
early and rate-limiting step in the formation of en-
dogenous cholesterol. The inhibition of cholesterol
duces intracellular stores of cholesterol. This re-
sults in upregulation of the number of low density
lipoprotein (LDL) receptors, which increases the
clearance ofLDL-cholesterol from plasma, thus re-
storing intracellular cholesterol homeostasis.' 1.2J
Plasma cholesterol levels may also be lowered
by HMG-CoA reductase inhibitor inhibition of
hepatic synthesis of very low density lipopro-
tein (VLDL)-cholesterol, a precursor of LDL-

© Adl s Internati onal Limited. All right s reserved. Drugs 1997 May; 53 (5)
 832
Fig. 1. Structural formula of atorvastatin.
cholesterol, causing reduced production of LDL-
chole sterol .U'f Apolipoprotein B secretion was re-
duced by 76% in guinea-pigs receiving atorvastatin
20 mg/kg/day, indicating reduced produ ction of he-
patic VLDL particles.P-"
In a similar manner to fluvastatin and prava-
statin, atorvastatin is administered in the active
hydroxy-acid form, wherea s lovastatin and simva-
statin are administered as prodrugs and require in
vivo conversion to their active form sJI .s.9)
Inhibition of HMG-CoA reductase by atorv a-
statin has been demon strated in several in vitro
studies and in vivo animal modelsJ IO-17l In a human
hepatoblastom a cell line (Hep-G2), atorvastatin ,
fluvastatin, lova statin and pravastatin inhibited
chole sterol synthesis by 50% (lC so) at respective
concentration s of 73 , 43.3 , 42 .7 and 2650
nmol/LJ J21
Plasma mevalonic acid level s give a good indi-
cation of the in vivo rate of cholesterol biosyn-
thesi s.U'" Atorvastatin 80 mg/day, pravastatin 40
mg/day and simvastatin 40 mg/day reduced fasting
plasma mevalonic acid level s by 59, 32 and 49%,
respect ively, in 3 separate studies of 6 weeks' dura-
tion involving patient s with heterozygous familial
hyperchole sterolaemia.U 'f Furthermore, a single
dose of atorvastatin suppressed plasma mevaloni c
acid level s for a longer period than the equi valent
dose of simvastatin in patients with homoz ygous
familial hypercholesterolaemia.[20]
Atorvastatin 40 mg/day for 15 days, taken in the
evening by 16 normolipidaemic volunteers, re-
© Ad is Inte ma lio nal Umlted , All rig hts rese rved,
Lea & McTavish
@
Ca
duced total chole sterol by 34%, LDL-ch olesterol
by 48 %, VLDL-cholesterol by 37%, trigly cerides
by 25%, apolipoprotein A-I by 6% and apolipo-
protein B by 34%. High density lipoprotein (HDL)-
cholesterol levels were increa sed by only 2%)211
In 27 patients with hypertriglycerid aemia re-
cei ving atorva statin either 20 or 80 mg/da y for 4
week s, significant reduction s in plasma levels of
total chole sterol (32 and 39%), triglycerides (27
and 37%), apolipoproteins B (31 and 38%), C-II
(28 and 38%), C-III (16 and 23%) and E (38 and
41 %) were observed.F"
It is generally accepted that HMG-C oA reduc-
tase does not playa direct role in the regulation of
triglyceride level s. However, atorvastatin produces
marked reductions in trigl yceride levels and two
indirect mechani sms have been sugges ted to ex-
plain this effect,123] Cholesterol is requir ed in the
normal production of VLDL particles; thus sub-
stantial inhibition of chole sterol synthesis may im-
pair VLDL particle assembly and secretion , result-
ing in lower triglyceride levels, as VLDL transports
triglycerides around the body.[23-311 A second hy-
pothe sis suggests that atorvastatin-induced marked
reductions in hepatocyte chole sterol levels lead to
increased LDL-receptor expression (B, E recep-
tors),[6] which in turn cau ses redu ctions in tri-
glyceride levels through increased bind ing of
VLDL particle s and LDL. Furth ermore, LDL re-
ceptors recognise apolipoproteins B and E, and as
various VLDL particle s contain both of these
Drug s 1997 May: 53 (5)
 Atorvastatin: A Review 833

apolipoproteins.Uf VLDL remnants may have
greater affinity than LDL for these receptors.l23,33J
Although it has been suggested that atorvastatin
reduces triglyceride levels because of its more pro-
nounced inhibitory effect on cholesterol synthesis
compared with other HMG-CoA reductase inhibi-
tors,l23l ator vastatin is probably not unique in its
abilit y to lower triglyceride levels as other HMG-
CoA reductase inhibitors also lower triglyceride
levels, if given at sufficiently high doses.l S,8.34- 361
1.2 Other Effects
Apart from their effects on cholesterol synthe-
sis, there is evidence that HMG-CoA reductase in-
hibitors have additional mechanisms of action
which may contribute to their anti atherogenic ef-
fects.[37]
Previou sly, inhibition of vascular smooth mus-
cle cell s (VSMCs) was con sidered to be a desirable
effe ct , as it was thought that proliferation of
VSMC s led to atherosclerosis.Pt - ?' However, it
has recently been propo sed that proliferation of in-
timal VSMCs may be beneficial and could be a part
of important proces ses which stabilise and repair
athero sclerotic plaque s.P'" Atorvastatin has been
reported to inhibit the in vitro proliferation and/or
migration of VSMC s.l40-42] The effect of HMG -
CoA redu ctase inhibitors on induced athero scle-
rotic lesion size has been assessed in rabbit s. Com-
pared with that in untreated controls, lesion size in
animal s that recei ved atorvastatin 2.5 mg/kg was
reduced by 67% (p <0.05), whereas lovastatin 2.5
mg/kg , pravastatin 2.5 mg/kg and simvastatin 2.5
mg/kg did not reduce lesion size.l ISl
Haemorrheological effects have been reported
in 22 pat ients with hyperlipidaemia who were
treated with ator vastatin 80 mg/day. Apart from ef-
fectively lowering lipids, atorvastatin reduced
plasma viscosity by 10% (p < 0.00 I), factor VII
activity by 8%, red blood cell sedimentation by
33 % and arachidonic acid-induced whole blood
aggregation by II %.[43l
Platelet depo sition rate was reduced by 20% (p
< 0.0 I) in atherosclerotic rabbits given atorvastatin
compared with untreated controls.P'!
In rats and rabbit s, atorvastatin was not terato-
genic,14S.46] nor was the drug mutagenic in bacte rial
or ham ster lung cell preparations.F'l Doses of
atorvastatin >80 mg/kg were associated with his-
topathologicallesions in dog s.l48l
2. Pharmacokinetic Properties
The pharmacokinetic properties of atorvastatin
have been investigated in healthy volunteers and
in patients with hypercholesterolaemia (table I).
Oral ator vastatin 2.5 to 80mg was used in single or

Table I. Pharmacok inetic parameters of HMG-CoA reductase inhibitors IS,7,8,34,50-53)

Parameter Atorvastatin Fluvastatin Lovastatin Simvastatin Pravastatin
Absorption (%) ? 98 30 60-85 35
Effect of food on bioavailability L13 ! 15-25 i50 !30
(% change in AUC)
Plasma protein binding (%) ~98 ~99 ~95" 95-98" 45
Hepatic extract ion ? ~70 ~70 ~80 45
(% of absorbed dose)
Crosses blood -brain barrier ? No Yes Yes No
Elimination half-life (h) 14b 1.2 3 1.9c 3
Renal excretion (% )d <2 6 30 13 60
a For both parent drug and correspond ing ~-hydroxyacid metabo lite.
b For unmetabolised atorvastatin only, The half-life of HMG-CoA reductase inhibition is 20 to 30h as a result of active metabol ites,!7,47)
c For main active metabolite .IS2)
d Renal excretion of radiolabelled parent drug plus metabolites is given as a percentage of an intravenous dose .
Abbreviation and symbols : AUC = area under the plasma concentration-time curve ; L indicates decreased by; T indicates increased by;
H indicates no change ; ? data not available.

© Ad is Internati ona l Umited. All rig hts reserved . Drugs 1997 Ma y; 53 (5)
 834
multiple doses. Atorvastatin plasma concentrations
were analysed by an HMG-CoA reductase inhibi-
tion assay for atorvastatin or its equivalents (active
metabolites of atorvastatin), or by a ga s chromatog-
raph y/mass spectrometry assay for unmetaboli sed
atorvastatin .l''?'
Multiple daily dosages of atorvastatin 2.5 to
80mg capsules produced maximum steady-state
pla sma concentrations (C max) of 1.95 to 252 Ilg/L,
time to C max (tmax) of 2 to 4 hours and area under
the plasma concentration-time curve (AUC) of
25.2 to 1293 ug/L • h.lsS] AUC increased in propor-
tion to dose of atorvastatin, atorvastatin equiva-
lents and active metabolites, but increases in C max
were greater than proportional to dose.l 49]The drug
has an absolute bioavailability of 12% and is ~98 %
protein-bound in pla sma. F' Multiple-dose pharma-
cokinetic parameters of atorvastatin are predictable
from single-dose paramerers.P f
Metabolism of atorvastatin, at lea st in part by
cytochrome P450 3A4,f7.57] produces ortho- and
para-hydrox ylated derivati ve s and various p-
oxidation products.F' Two hydroxylated deri va-
tives of atorvastatin, PD 152873 and PD 142542,
have been identified as acti ve metabolites in in
vitro human liver microsomes, but their activity
ha s not been described in detaiJ.ls71ln vitro inhibi-
tion of HMG-CoA reductase by ortho- and para-
hydroxylated metabolites is equivalent to that pro-
duced by arorvastatin.Fl 70 % of the HMG-CoA
reductase inhibition associated with atorvastatin
ha s been attributed to its active metabolites.!"l
The me an terminal elimination half-life (t Y2~) of
atorvastatin is about 14 hours, but the half-life of
HMG-CoA reductase inhibition is 20 to 30 hours
as a result of long-lasting active metabolites. Pv'Pl
Food significantly decreased the rate and extent
of absorption of atorvastatin; C max and AUC de-
creased by 48 and 13% (both p < 0.05), respec-
tivel y, when the drug was taken after food .ISO]Time
to C max and t 1/2~ were not significa ntly altered by
food intake.lsO] Thus, because the efficacy of
HMG-CoA redu ctase inhibitors is rel ated more to
do se than plasma concentration,ISS.S8] whether or
© Adi s Inte rnational Umited . All righ ts reserved.
Lea & McTavish
not atorvastatin is taken with food is expected to
have little effect on the clinical efficacy of the dru g.
Elderly recipients of atorvastatin 20mg (mea n
age 75 years) had a 43 % higher Cmax. 27 % greater
AUC and 36 % longer t Y2~ than younger recipi ent s
(mean age 28 years). Additionally, in women C max
tended to be 18% higher, AUC 11% lower and t1/2 ~
20% shorter than in men. However, LDL-cholesterol
reductions ob served in elderly patients and fem ale
patients were not significantly different from tho se
seen in young patients at similar do sages (section
5) .l7,S9,60]
The effects of hepatic and renal impairment
on atorvastatin 10mg pharmacokinetic parameters
were studied.ls!' In comparison with tho se in
healthy ind ividuals, atorvastatin C max and AUC
values were 5-fold greater in patients with Childs
Pugh Cla ss A hepatic impairment, and 16- and 11-
fold gre ater, respecti vel y, in patients with Childs
Pugh Cla ss 8 impairment (section 5). Ren al im-
pairment had no effect on atorvastatin pharm aco-
kinetic parameter s (section 5).
Since the major site of endogenous choles tero l
sy nthes is is the liver, it ha s been sugges ted that
inhibition of HMG-CoA exclu sivel y within the
liver may be reg arded as the goal of HMG-CoA
reductase therapy. Al so, inhibition of chol esterol
synthesis outside the liver by HMG-CoA redu ctase
inhibitors may be the cause of some adverse events
associated with the se agents.l 14,62] However, the se
are controversial issues, as the relevance of liver
selectivity to clinical efficacy or tolerability has yet
to be established.
Tissue disposition studies of atorvastatin hav e
been conducted in a number of in vitro, ex vivo and
in vivo animal models. Although HMG-CoA redu c-
tase inhibitors have differing tissue selec tivities,
results vary according to the models and meth od s
used. 114,62,63] Nevertheless, HMG-CoA redu ctase
inhibitors with low calculated lipophilicity « 1.0)
tended to ha ve high hepatic selec tiv ity.I'<' Al -
though atorvastatin has a high calculated lip ophil-
icity (4. 06) in comparison with pra vastatin (0.57)
and lovastatin (3. 11), it has high hepatic selectiv ity,
Drugs 1997 Ma y: 53 (5)
 Atorvastatin: A Review
as it is extensively metabolised by the liver through
a first-pass mechanism.Uf
2.1 Drug Interactions
Atorvastatin, ethinyl estradiol and erythromy-
cin are all cytochrome P450 3A4 substrates and
therefore may be expected to interact. Coad-
ministration of atorvastatin 40 mg/day with a con-
traceptive pill containing ethinyl estradiol 35
ug/day and norethisterone (norethindrone) I
mg/day in 16 healthy women resulted in 30 and
19% increases in ethinyl estradiol C max and AVC,
respectively, compared with ethinyl estradiol
alone. The t~·W of ethinyl estradiol was unchanged,
but the C max and AUC of norethisterone were in-
creased by 24 and 28%)64]
In the presence of erythromycin 500mg 4 times
daily, the C max and AUC of atorvastatin or equiva-
lents were, respectively, 38 and 33% greater (sec-
tion 5»)64]
Coadministration of atorvastatin lOmg and a
commonly available nonprescription antacid
(Maalox TC®) resulted in the t max of atorvastatin
or equivalents increasing from 2.9 to 5.7 hours and
reductions in C max and AUC by 34% each . This
decreased rate and extent of atorvastatin absorp-
tion was not reported to have affected LDL-
cholesterol reductions in this study (no further in-
formation provided»)65]
The plasma concentration of atorvastatin is de-
creased by 25% during coadministration with col-
estipol .F'
3. Therapeutic Potential
Elevated plasma levels of lipoproteins, rich in
cholesterol or triglycerides, can be caused by pri-
mary dietary and/or genetic factors , but can also be
secondary to diseases such as diabetes [both insu-
lin-dependent diabetes mellitus (IDDM) and non-
IDDM (NIDDM)],[66J hypothyroidism, nephrotic
syndrome or other renal disorders)67.68] Patients
with dyslipidaemias (elevated non-HDL-cholesterol
levels or low HDL-cholesterollevels) are at an in-
creased risk of developing atherosclerosis and sub-
sequent coronary heart disease (CHD). Elevated
© Ad is International Limited. All righ ts reserved.
835
LDL-cholesterollevels are considered to be a pri-
mary risk factor for CHD, but more recently low
HDL-cholesterol and elevated triglyceride levels
have been identified as important risk factors)69 ,70]
Other risk factors include patient age, male sex,
cigarette smoking, diabetes mellitus, severe obe-
sity, lack of physical exercise, hypertension and a
family history of hyperlipidaemia or coronary ar-
tery disease.[67]
The goal of therapy in patients with dyslipid-
aemias is to normalise lipoprotein levels. In the
first instance, nonpharmacological interventions
(diet/weight control, exercise and other lifestyle
modifications) should be initiated. Pharmacologi-
cal intervention should be considered only if pa-
tients fail to respond to these primary measures.
The US National Cholesterol Education Program
(NCEP), for example, has published comprehen-
sive guidelines for the diagnosis and treatment of
dyslipidaemia in patients with or without CHD (ta-
ble II»)67] Similar guidelines are also available in
other countries.[71 .72]
Evidence from several studies using lipid-low-
ering drugs , including HMG-CoA reductase inhib-
itors, has shown that lowering LDL-cholesterol
levels significantly reduces the risk of CHD mor-
tality and morbidity[73-77] and even total mortal-
ityP3,78] In the absence of such data, the clinical
evaluation of newer antihyperlipidaemic agents
such as atorvastatin is based on lipid-lowering ef-
fects, an important surrogate marker of clinical ef-
ficacy .
Atorvastatin has been evaluated mainly in pa-
tients with primary hypercholesterolaemia, but
some data are available from patients with hyper-
triglyceridaemia and combined hyperlipidaemia
(elevated cholesterol and triglyceride levels).
Results of studies involving patients with hetero-
zygous familial hypercholesterolaemia will be de-
scribed with those concerning nonfamilial (poly-
genic) hypercholesterolaernia, as many studies did
not distinguish between these patient type s. How -
ever, patients with homozygous hypercholesterol-
aemia are described separately.
Drugs 1997 May: 53 (5)
836 Lea & McTavish

Table II. Classification of treatment objectives by plasma cholesterol levels " in adults with and without coronary heart disease (CHD)167] as
proposed by the US National Cholesterol Education Program
Category ...,N.:..:o.:..:n,..:fa'7's.:..:tin;'-'g'-,l.:..:ev.:..:e':'-I----;-:=-;-----;--;--;-----;----;--;:- _ Fasting LDL-cholesterolb
total cholesterol HDL-cholesterol plasma level follow-up treatment
plasma level plasma level (mmol/l.)? goal
(rnrnol/l.]? (mrnol/l.)? (mrnol/l.) "

Pati ents without CHD

Desirable <5 .2 ~.9 Repeat within 5y
<5.2 <0 .9 Do LDL-cholesterol <3.4 None
analys is
Borderline-high 5.2-6.2 ~.9 and <2 Dietary/lifestyl e advice; 3.4-4 .1 and <2 Dietary/lifestyle adv ice; <3.4
risk factors" repeat withi n 1-2y risk tactors" repeat ann ually
5.2-6.2 <0.90r~ Do LDL-cholesterol 3.4-4 .1 and ~ Dietary/lifestyle adv ice; <3.4
risk factors " analysis risk tactors'' repeat within 1-8wk
High ~6. 2 Do LDL-cholesterol ~4. 1 and <2 Dietary/l ifestyle advice <4.1
analysis risk tactors''
~4. 1 and ~2 Dietary/lifestyle advice; <3.4
risk factors" drug therapy
~4 . 9 Dietary/l ifestyle advice; <4.1
drug therapy"

Pat ient s with CHD

$2.6 Dietary/lifestyle advice;
repeat annually
2.6-3.3 Dietary/l ifestyle advice ' $2.6
~3. 4 Dietary/lifestyle advice ; $2.6
drug therapy
a Primary classification in adults without evidence of CHD is based on total cholesterol and HDL-cholesterol, whereas in adults with
evidence of CHD , it is based on LDL-cholesterol.
b Measured after 9 to 12h of fas ting .
c To convert from mmo VL to mgl dl multiply by 38.7.
d Positive risk factors for CH D are age (man ~45y, woman ~55y) , family history of premature CHD, current cigarette smoking,
hypertension, low HDL-cholesterol «0.9 mmoVL), severe obesity, lack of physical exercise and diabetes mellitus. HDL -cholesterol
level ~ 1 . 6 mmoVL is considered a negative risk factor for CHD and for these patients 1 risk factor should be sUbtracted.'64J
e In men <35y of age and premenopausal women with LDL-cholesterollevels ranging from 4.9 to 5.7 mrnol/t , drug therapy should be
delayed except in high risk patients (e.g. with diabetes mellitus).
f Drug therapy may be requ ired even after appropriate dietary measures have been implemented; this should be decided by the physic ian.
Abbreviations : HDL =high dens ity lipoprotein; LDL =low dens ity lipoprotein.

In most trials, patients followed the NCEP Step I
diet for several weeks before initiation of drug treat-
ment and were encouraged to maintain this diet
throughout the study.[79] Atorvastatin was adminis-
tered once daily in the evening with or without food
and trials included men and women who met entry
criteria. As with other HMG-CoA reductase inhibi-
tors, therapeutic response to atorvastatin correlates
better with dose than with blood concentration s.[55,58]
3.1 Primary Hypercholesterolaemia
3. 1. 1 Comparisons with Placebo
In dose-response studies, atorvastatin signifi-
cantly reduced total chole sterol, LDL-cholesterol
and triglyceride levels compared with placebo (ta-
ble III).f8o-82 ] As with other HMG-CoA reductase in-
hibitors, LDL-cholesterol levels were reduced in a
nonlinear dose-dependent manner, with atorvastatin
2.5mg causing a 25% reduction, 5mg a 29% reduc-
tion, IOmgreductions of 35 to 42%, 20mg reductions
of 42 and 44%, 40mg reductions of 50 and 50% and
80mg reductions of 59 and 61%.[80-82] Atorvastatin
2.5 to 80 mg/day reduced apolipoprotein B levels by
17 to 50% compared with placebo.f8o ,8 1]
Triglyceride levels were decreased by 10 to
45 % after daily atorvastatin dosages of 2.5 to
80mg.f 80 ,8 1] The effect of atorvastatin on HDL-
cholesterol levels was variable (table III) .I80 ,8 1]

© Adis Inte rnationa l Umite d . All rights reserved . Drug s 1997 May: 53 (5)
Atorvastatin: A Review 837

In one trial it was estimated that 90% of the
maximum observed reduction in LDL-choIesterol
levels wit h atorvastatin 2.5 to 80 mg/day was at-
tained after 2 weeks of treatment.I'i' J
In postmenopausal women , atorvastatin 10 mg/
day (n = 20) reduced total chole sterol, LDL-choles-
terol and triglyceride levels by 3 1, 43, and 7%, re-
spectively, whereas placebo had little effect on these
parameters in a study of 12 weeks' duration ,!88]
3.1.2 Comparisons with Other HMG-CoA
·Reduc tase Inhibitors
Atorvastatin 10 to 20 mg/day has been com-
pared with lovastatin 20 to 40 mg/day, pravastatin
20 to 40 mg/day and simvastatin 10 to 20 mg/day
in large double-blind trials of 1 year 's duration (ta-
ble III). Patients initially received the lower dose
of each drug, which was titrated to the higher dose
if LDL-cholesterol le vels did not reach NCEP
goal s (table II) after 16 weeks,! 59.83.84]
After 52 week s of treatment, reductions in LDL-
chol esterol levels were significa ntly greater with
atorvastatin than lovastatin (37 vs 29 %), prava-
statin (35 vs 23%) or simvastatin (38 vs 33%) [table
III]. Total cholesterol and trigl yceride levels were
al so reduced more in atorvastatin groups than
lovastatin, pravastatin and simvastatin gro ups (all

Table III. Summary of clinical trials comparing the efficacy of atorvastatin (ATO), placebo (PLA) and other lipid-lowering agents in patients
with hypercholesterolaemia. Study drugs were generally taken once daily in the evening
Reference Study design Lipid level No. of Drug and dosage Percentage change in lipid levels from
and duration inclusion criteria evaluated (mg/day) baseline to treatment end-point
(wk) (mmoVLa) patients total C LDL-C HDL-C TG
Comp arisons wit h placebo
Heinonen et al.[821 mc,db,r,26 LDL-C ~4. 1 ; 18 AT010 ! 26' ! 35' !1 ! 21'
TG 91.5 17 PLA i1 i2 rs i 14
Gmerek et al.[80]b nb,r,6 LDL-C ~4 . 1 65c ATO 10-80 !29-45t ! 37-59t NR !27-45t
PLA NR H NR i26
Nawrocki et al.[811 mc,db,r,6 LDL-C ~4 . 1; 67 ATO 2.5-80 ! 17-46t !25-61t i5-!3 ! 10-27t
TG $;3 .4 12 PLA i5 ta !2 !1

Compa risons with othe r HMG-CoA reductase inhibit or s

Davidson et aL[591d . mc,db,r,52 LDL-C ~4 .1 ; 789 ATO 10-20 ! 27' ! 37' i7 ! 16'
TG 91.5 260 LOV 20-40 ! 21 ! 29 i7 !8
Bertolini et al.[83 ] mc,db,r,52 LDL-C ~4 . 1 -$;6. 4 ; 214 ATO 10-20 ! 25' ! 35' i7 ! 14'
TG 91.5 '74 PRA 20-40 ! 16 ! 23 i 10 !3
Dart et aLI841 mc,db,r,52 LDL-C ~4. 1 -g. 8 ; 132 ATO 10-20 ! 30' ! 38' i7 ! 21'
TG $;4.5 45 SIM 10-20 !25 ! 33 i7 ! 12

Compa risons with colesti pol (COL)

Heinonen et aL185.861be mc,NR,52 Severe hyper- ATO 80
189 ! 43* ! 52* i7
cholesterolaemia ATO 40 + COL 20g'
124 !42 !53 i9
SIM 40 + COL 20g'
124 ! 36 !46 i10
Heinonen et al.[8l lb NR,r,12 LDL-C >4.1; 106c
ATO 10 NR ! 36 i 12
TG <3.9 COL 10g bid NR ! 23 ts
ATO 10 + COL 10g bid NR ! 46 i 15
a To convert LDL-cholesterolto mg/dl. multiply mmoVL by 38.7; to convert TG to mg/dl, multiply by 88.6.
b Abstract.
c Division of patients between treatment groups was not stated.
d 70 atorvastatin and 67 simvastatin recipients received placebo for the first 16wk of this 52wk study.
e Patients had familial or polygenic hypercholesterolaemia.
f Number of colestipol daily dosages not stated. Patients received 16wk of colestipol monotherapy before addition of an HMG-CoA
reductase inhibitor.
Abbreviations and symbols: bid = twice daily; db = double-blind; C = cholesterol; HDL = high density lipoprotein; LDL = low density lipoprotein;
LOV = lovastatin; mc = multicentre; nb = nonblind; NR = not reported; PRA = pravastatin; r = randomised; SIM = simvastatin; TG = triglycerides;
T, ! and H indicate increases, decreases and no change in lipid levels; , p $;0.05 vs comparator; t p < 0.05 dose response; * p < 0.05 vs
the combination of colestipol and simvastatin.

© Adi s Inte rnational Umited. All rig hts re se rved . Drugs 1997 May; 53 (5)
 838
OWeek 16
. Week 52
I
I
I or simva statin (24 vs 64%») 59,83,84]
I LDL-cholesterol goals was analysed by CHD-risk
I
I
o 20 40 60
Patients reaching target LDL-C levels (%)
Fig. 2. Percentage of patients reaching US National Cholesterol
Education Program (NCEP) low density lipoprotein cholesterol
(LDL-C) goals after therapy with HMG-CoA reductase inhibi-
tors.l86] Patients received atorvastatin 10 to 20 mg/day, lova-
statin 20 to 40 mg/day , pravastatin 20 to 40 mg/day or
simvastatin 10 to 20 mg/day in large clinical trials.l59,83,84]
P :::':0.05) [table III]. HDL-cholesterollevels were
increased in all groups with no significant differ-
ences between atorvastatin and other HMG-CoA
reductase inhibitors)59,83,84]
Atorvastatin had a significantly greater effect on
apolipoprotein B levels than lovastatin (30 vs 22%
reduction from baseline),[59] pravastatin (30 vs
20%)[83] or simvastatin (34 vs 30%»)84] Similarly,
atorvastatin lowered VLDL-cholesterollevels to a
greater extent than lovastatin (16 vs 8%)[59] or
simvastatin (21 vs 12%»)84] Atorvastatin, lova-
statin and simva statin all raised HDL-cholesterol
levels by 7% and pravastatin induced a 10% rise in
HDL-cholesterollevels (table III) .
More patients reached NCEP LDL-cholesterol
goals (table II) after 16 and 52 week s of treatment
with atorvastatin than with pravastatin (both p <
0.00 I) and similar trends were observed with both
© Adis Intern ational Umited . All right s rese rved,
Lea & McTavish
lovastatin and simvastatin (statistical analysi s not
reported) [fig. 2]. Furthermore, patients receiving
atorvastatin were 1.3-fold more likely to reach
NCEP goals than lovastat in recipients in one trial
(p = 0.001»)59] As a result, fewer patients receiv ing
atorvastatin tended to require upward dosage titra-
tion after 16 weeks of treatment than those receiv-
ing lovastatin (48 vs 62%), pravastatin (27 vs 49 %)
The percentage of patients who reached NCEP
category in a study with 1049 patients.P'" 94 and
82 % of atorvastatin and lovastatin recipient s
categorised as low risk reached their LDL-choles-
terol goal of :::':4.2 mmol/L. For patients categorised
as medium risk (target :::.:3.4 mmol/L) or high risk
(target :::':2.6 mmol/L) the corresponding percent-
80
ages achieving NCEP LDL-cholesterol goal s were
72 and 58%, and 37% and II %.
3.1.3 In Combination with Colestipol
Combination therapy with atorv astatin and col-
estipol has been inve stigated in 2 studies (table III).
In one trial,[85,86] atorvastatin 80 mg/day pro-
duced significantly larger reductions in LDL-
cholesterol, total cholesterol and triglyceride level s
than the combination of simvastatin 40 mg/day and
cole stipol 20 g/day. The combination of atorva-
statin 40 mg/day and colestipol 20 g/day produced
similar reductions in LDL-cholesterol and total
cholesterol to atorvastatin 80 mg/day, but tended to
reduce triglyceride levels less than atorvastatin
monotherapy.[85,86]
In a second trial ,[87] the combination of atorva-
statin 10 mg/day and colestipol 20 g/day tended to
produce larger reductions in LDL-cholesterol lev-
els and smaller reductions in triglyc eride levels
than atorvastatin 10 mg/day monotherapy. Both
combined therapy and atorvastatin monother-
apy tended to cause larger reductions in LDL-
cholesterol levels and smaller reductions in trig-
lycer ide levels than monotherapy with cole stipol
20 g/day [no statistical analysi s reported] .
Drug s 1997 Ma y: 53 (5)
 Atorvastatin: A Review 839

Table IV. Summary of clinical trials comparing the efficacy of atorvastatin (ATO), placebo (PLA) and other lipid lowering agents in patients
with hypertriglyceridaemia (with or without hypercholesterolaemia). Study drugs were generally taken once daily in the evening
Reference Study design Lipid level No. of Dosage Percentage change in lipid levels from
and duration inclusion criteria evaluated (mg) baseline to treatment end-point
(wk) (rnrnott,") patients total C LDL-C HDL-C TG
Bakker-Arkema mc,db,r,2 TG ~4 .0 13 ATO 5 .J.20' .l.l r i9
et al.[231 16 ATO 20 .J.32,t .J.33, t i 13'
12 AT080 .J.43'!t .J.41, t i 12
14 PLA .J.l . 1 .1 i4
McKenney et al.(91) mc,nb,r,12 TG ~ .2to $9; 54 ATO 10 .J.26§ .J.30§ i4
total C ~5 . 2; 51 NIC 100·1000 tid .J.7 .J.2 i 25§
ApoB ~ .8
Ooi et a1.192)b mc,nb,r,24 TG ~ .3 ; 40 ATO 10 .J.27§ .J.30§ ill
total C ~5. 2 43 FEN 100 tid .J.16 .J.7 i24§
39 ATO 20 .J.33§ .J.38§ tro
35 FEN 100 tid .J.14 .J.6 i23§
a To convert total cholesterol and LDL-cholesterol to mg/dl, multiply mmol/L by 38.7; to convert TG to mg/dl, multiply by 88.6.
b There were 2 groups of patients in this study. One group received atorvastatin 10 mg/day for 12wk followed by atorvastatin 20 mg/day
for a further 12wk. The second group received fenofibrate 100mg 3 times daily for 24wk. Efficacy analyses were performed after
weeks 12 and 24.
Abbreviations and symbols: ApoB =apolipoprotein B; C =cholesterol; db =double-blind; FEN =fenofibrate; HDL =high density lipoprotein;
LDL =low density lipoprotein; mc =multicentre; nb =nonblind; NIC =nicotinic acid (niacin); r =randomised; TG =triglycerides; tid =3 times
*
daily; i and .J. indicate increases and decreases in lipid levels; , p < 0.05 vs placebo; t p < 0.05 vs atorvastatin 5 mg/day; p < 0.05 vs
atorvastatin 20 mg/day; § p < 0.05 vs comparator.

3.1.4 Homozygous Famifial
Hypercholesterolaemia
In 13 patient s with homozygous familial hyper-
chole sterolaemia, atorvastatin 80 mg/day reduced
LDL-cholesterol levels by 31 % (p < 0.005 )
compared with placebo .P'" Redu ctions in LDL-
cholesterol levels of 31 and 30 %, respecti vely,
were observed in 7 patients who received concom-
itant aphere sis and 3 patients who did not. Com-
bined use of aphere sis, once-daily ator vastatin
80mg and a bile acid sequestrant resulted in a 70%
reduction in LDL-cholesterol levels in a limited
number of patient s.
In comparison with baseline, atorvastatin 20
to 80 mg/day produced reductions in LDL-
chole sterol levels of? to 53% (mean 20%) in 24 of
29 patients with homozygous familial hyperchol-
esterolaemia; the remaining 5 patient s experienced
LDL-chole sterol increases of 7 to 24%.[7]
3,2 Hypertriglyceridaemia or
Combined Hyperlipidaemia
Compared with placebo , atorvastatin 5, 20 or 80
mg/day significantly reduced levels of triglycer-
ides (26 to 46%), LDL-chole sterol ( 17 to 41%) and
total chole sterol (20 to 43%) in patients who had
mean baseline triglycerid e and LDL-chole sterol
levels of 6.8 mmol/L and 3.1 mmol/L , respectively
(table IV).[231 Atorvastatin 5 to 80 mg/day also re-
duced levels of VLDL-chole sterol by 34 to 58%
and apolipoprotein B by 17 to 42% compared with
baseline.Pf
In patient s with high levels of both triglycerides
and total cholesterol (combined hyperlipidaerni a),
atorva statin 10 to 20 mg/day produced greater re-
duction s in total chole sterol and LDL-cholesterol
than fenofibrate 300 mg/day or nicotinic acid (ni-
acin) 300 to 3000 mg/day (table IV)J 91 ,921 How-
ever, although atorvastatin reduced triglyceride
levels and increased HDL-cholesterol levels from
baseline , these change s were larger with fenofib-
rate or nicotinic acid (table IV)J91 ,921
The ratio of apolipoprotein B/HDL-ch olesterol
may be a useful measure with which to compare
the compo site effects of agent s with different lipid-
lowering profil esJ91,921 Apolipoprot ein B/HDL-
chole sterol ratios were reduced by 30 and 26% in
patients receiving atorvastatin and nicotinic acid,

© Ad is Interna tional Urnlted . All rights reserved. Drugs 1997 Ma y; 53 (5)

 840
respectively.P!' Atorvastatin 10 and 20 mg/day
produced reductions of 34 and 40% in this ratio,
whereas fenofibrate 300 mg/day reduced it by 31
to 32%.[92]
3.3 Hypercholesterolaemia or Combined
Hyperlipidaemio Secondary to NIDDM
In 25 patients with hypercholesterolaemia sec-
ondary to NIDDM, atorvastatin 10 mg/day pro-
duced significantly larger reductions than simva-
statin 10 mg/day in LDL-cholesterollevels (41 vs
28%, p < 0.009) and total cholesterol levels (32 vs
22%, p < 0.002) in a nonblinded study of 4 weeks'
duration.f 93]
In a 26-week randomised study, atorvastatin 10
to 20 mg/day caused a greater reduction in tri-
glyceride levels than simvastatin 10 to 20 mg/day
(24 vs 15%, p < 0.05) in 166 patients with com-
bined hyperlipidaemia secondary to NIDDM.f 94]
4. Tolerability
Like other HMG-CoA reductase inhibitors,
atorvastatin has been generally well tolerated in
clinical studies of up to 52 weeks' duration.f59.s3.s4]
The most common adverse events reported in the
largest study are shown in figure 3.[59] Gastrointes-
tinal adverse effects (including constipation, flatu-
lence, dyspepsia and abdominal pain) are most
common. In total, <2% of 2502 patients in clinical
trials withdrew because of adverse events associ-
ated with atorvastatin.Pl
The most serious tolerability concerns associ -
ated with HMG-CoA reductase inhibitors are pos-
sible hepatic dysfunction characterised by raised
serum aspartate (AST) or alanine (ALT) amino-
transferase levels and myopathy characterised by
myalgia and creatine phosphokinase levels > 10
times above the normal limit.P'" Myopathy occurs
infrequently «0.2%) in patients receiving other
HMG-CoA reductase inhibitors.f5.s.34.53] Although
atorvastatin has not been used as extensively as
other HMG-CoA reductase inhibitors, myopathy
has not been reported in patients receiving the drug .
Myalgia was reported in 3% of the atorvastatin
group (n = 132) in one study, but no patient had
© Adi s Internati onal limited . All rights reserved.
Lea & McTavish
• Atorvastatin
o Lovas tatin
Flatulence ~~DIIi:l• • • • • •L - --,
Dyspepsia rt· .. ,
Constipation liiiiiiijill••
I
Pain ~iiiiiiiiiiiL=:
Headache ~iiiiiiiiiiii~------~
Asthenia .iiiiiiL~--,
Back paln.,.. -,
o 2 3 4
Incidence t% of patients)
Fig. 3. Adverse events associated with atorvastatin . Patients
with hypercholesterolaemia received either atorvastatin 10 to
20 mgJday (n = 789) or lovastatin 20 to 40 mg/day (n = 260) in
a double-blind randomised clinical trial of 1 year's duration . Only
adverse events with a ~2% incidence were included.!591
persistent increases in creatine phosphokinase lev-
els > 10 times normal Iimits .P'J
Mild asymptomatic elevations in serum trans-
aminase levels have been reported during treat-
ment with HMG-CoA reductase inhibitors.P?' In
clinical trials with atorvastatin, persistent eleva-
tions (>3 times the upper limit of normal on 2 or
more occasions) in serum transaminases occurred
in 0.7% of patients .F' The frequency of persistent
elevations in serum transaminases tended to in-
crease with atorvastatin dosage: 0.2, 0.6, 0.6 and
2.3% for dosages of 10,20,40 and 80 mg/day.Pl In
a large trial evaluating 1049 patients, the incidence
of abnormal transaminase level s was similar with
atorvastatin and lovastatin after 52 weeks of treat-
ment.[59]
High dosages of some HMG-CoA reductase in-
hibitors have been associated with lens opacities in
animal studies;[95] however, data from clinical
studie s involving HMG-CoA reductase inhibitors
have not reported lenticular opacities in patients
receiving long term treatment.f 5,S.34.53] No long
Drugs 1997 Ma y; 53 (5)
Atorvastatin: A Review
term tolerability data are available for atorvastatin,
but in studies of up to 1 year's duration (n = 1135) ,
no significant lenticular opacities have been re-
ported.l s9,83,841 Therefore, routine eye examina-
tions are not necessary.P?'
In 3 trials in which 1135 patients received
atorvastatin, pancreatitis was reported in 1 pa-
tient.[S9,83,84]
In comparative trials, atorvastatin had a similar
adverse event profile to that of lovastatin (fig , 3),
pravastatin and simvastatin.l s9,83,841 Atorvastatin
10 mg/day and nicotinic acid 100 to 1000mg 3
times daily were considered to be associated with
adverse events in 11 and 66%, respectively, of 105
patients with hypertriglyceridaemia. Gastrointesti-
nal adverse events were most common with ator-
vastatin and vasodilation-related events with nico-
tinic acid.l 911
5. Dosage and Administration
Oral atorvastatin 10 to 80 mg/day may be used
to lower lipid levels of patients with primary
hypercholesterolaemia (heterozygous familial or
nonfamilial) or combined dyslipidaemia, who do
not respond to life-style measures (including a
standard cholesterol-lowering diet). For patients
with homozygous familial hypercholesterolaemia
who require apheresis, atorvastatin 10 to 89
mg/day may be used as an auxiliary treatment, or
by itself if apheresis is not available.l7,96J
Lipid levels should be analysed within 2 to 4
weeks of treatment onset or titration and the dosage
of atorvastatin should be tailored according to re-
sponse (table II). Liver function tests should be
performed before initiating treatment with ator-
vastatin, 6 and 12 weeks after treatment onset or
dosage titration and approximately twice yearly
thereafter.[71
Atorvastatin may be taken at any time of day,
(at the same time every day)17] although in clinical
trials it was usually taken in the evening (section
3) . Atorvastatin may also be taken with or without
food (section 2).l71
As atorvastatin does not undergo significant re-
nal excretion, dosage adjustments should not be
© Adi s International Limited. All right s reserv ed.
841
necessary in older patients or in patients with renal
impairment. However, in patients with hepatic in-
sufficiency, dosage reductions may be required
(section 2).
In patients who have active hepatic disease or
unexplained persistent elevations in serum trans-
aminases, are pregnant or are breast feeding,
atorvastatin is contraindicated.Pl
As with other HMG-CoA reductase inhibitors,
concomitant therapy of atorvastatin with cyclo-
sporin, nicotinic acid, fibric acid derivatives,
erythromycin or azole antifungals is likely to in-
crease the risk of adverse events such as myopathy
and rhabdomyolysis, and such combinations
should be avoided where possible.l7,97-991
6. Potential Place of Atorvastatin in the
Management of Hyperlipidaemias
In the US and Europe, approximately 15% of
adults are at increased risk of experiencing cardio-
vascular events because of elevated blood lipid
levels ,[lOO,IOII Large primary and secondary pre-
vention studies in patients with hypercholesterol-
aemia have demonstrated that lowering LDL-
cholesterol levels leads to significant reductions in
coronary mortality and morbidity[73-77,102-1041 and
total mortality.F'J Despite this abundant evidence,
many patients still do not receive appropriate treat-
ment. The need to vigilantly screen and treat pa-
tients according to recommended guidelines must
be emphasised.I'P'"
The relationship between elevated triglyceride
levels and CHD is less clear. In several epidemio-
logical studies, elevated triglyceride levels have
been associated with increased risk of CHD.l 106,107]
Indeed, in the Stockholm Prospective Study, raised
triglyceride levels were an independent and
stronger predictor of myocardial infarction than in-
creased levels of total cholesterol.U'<' The rela-
tionship between triglyceride levels and CHD is
more pronounced in women, younger patients and
those with increased insulin resistance.l70,109,IIOJ
However, after adjusting for HDL-cholesterol,
LDL-cholesterol and/or total cholesterol in multi-
factorial analyses, the independent effect of tri-
Drugs 1997 May ; 53 (5)
 842
glycerides often becomes insignificant or is weak-
enedp3,I06,107,11I-1I 3] In part, this may be caused by
physiological relationships between plasma tri-
glyceride levels and LDL-cholesterol levels, obes -
ity and, more importantly, HDL -cholesterol lev-
els.[70,l14] In addition, large short term variations in
triglyceride levels, as a result of diet , alcohol intake
and other factors, may disguise the true nature of the
relationship between triglyceride levels and CHD in
multifactorial analyses.F't' Nevertheless, a recent
study has found that raised triglyceride levels are an
independent predictor of myocardial infarction, par-
ticularly when total cholesterol levels are also
raised,[691 and a second study found that elevated tri-
glyceride levels are an independent predictor of ma-
jor coronary events, especially when the ratio of
LDL-cholesterol to HDL-cholesterol is >5J1151
Aside from the possible risk of CHD , patients
with very high triglyceride level s (> 11.3 mmol/L)
have an increased risk of pancreatitis and chylo-
micronaemia syndrome.F'l
Several large studies have demonstrated the ef-
fectiveness of other HMG -CoA reductase inhibi-
tors (pravastatin and simvastatin) in the primary
and/or secondary prevention of CHD in patients
with hypercholesterolaemia alone (patients with
hypertriglyceridaemia were excluded from these
trial s).l73,74.76,771 In addition, regression studies
have shown that lovastatin, simvastatin and
pravastatin slow the progression of atherosclerosis
and lower the risk of coronary events in patients
with mild to moderately severe hypercholesterol -
aemia.l116-1 311 Furthermore, lovastatin reduces the
progression of atherosclerosis in grafts of patients
who have undergone saphenous vein coronary ar-
tery bypass graftsJl 321 With this weight of evi-
dence, HMG-CoA reductase inhibitors are consid-
ered effective and appropriate pharmacotherapy
for the treatment of hypercholestero laemia.I'Pl
Like other HMG-CoA reductase inhibitors,
atorvastatin reduces LDL-cholesterol and total
cholesterol level s in patients with hypercholester-
olaemia. Indeed, in clinical trials reductions
achieved with the more established agents in this
drug class were matched or exceeded in patients
© Adis Internatl onal Umited . All rights reserved .
Lea & McTavish
receiving atorvastatin. Data on the effect of atorva-
statin in the primary and secondary prevention of
CHD are not yet available. However, a 4-year study
investigating the effects of atorvastatin 10 mg/day
in 2250 patients (aged $.75 years) with NIDDM,
with or without a prior myocardial infarction, is
under way in North America, Europe, Australia and
South AfricaJ I331
Patients with heterozygou s familial hyperchol-
esterolaemia generally have higher cholesterol lev-
els than patients without this auto somal dominant
mutation and therefore require larger percentage
reductions in lipid levels to dimini sh the risk of
atherosclerosis.I'<l Although there is no conclusive
evidence that greater reductions in cholesterol lev-
els are of benefit in this small, but high risk patient
group, atorvastatin may be regarded as the HMG-
CoA reductase inhibitor of choi ce, as it is more
likely to achieve the current target lipid level s for
primary and secondary prevention. For patients
with homozygous familial hypercholesterolaemia
who require apheresis, atorvastatin may be used as
an auxiliary treatment, or by itself if apheresis is
not available.F'
In contrast to the other HMG-CoA reductase in-
hibitors, which have a limited effect on triglyceride
level s, atorvastatin significantly reduced triglycer-
ide level s in patients with hypertriglyceridaemia or
combined hyperlipidaemia. Although ator vastatin
reduced total cholesterol and LDL-cholesterol to a
greater extent than fenofibrate or nicotinic acid ,
these latter agents produced larger reductions in
triglyceride levels.
It has been suggested that atorvastatin reduces
triglyceride levels as a result of its more pro-
noun ced inhibitory effect on cholesterol synthesis
compared with other HMG-CoA reducta se inhibi-
tors at currently recommended dosages.Ff How-
ever, it can also be argued that all HMG-CoA
reductase inhibitors are qualitatively similar, and
therefore , that HMG-CoA redu cta se inhibitors
other than atorvastatin would also reduce triglycer-
ide levels if given at sufficiently high dosesJ 5,8,34-36]
Currently, single-agent pharmacological treat -
ment in patients with combined hyperlipidaemia
Drugs 1997 Ma y; 53 (5)
Atorva statin: A Review
involves use of a fibric acid derivative or nicotinic
acid.l 89] Monotherapy with nicotinic acid effec-
tively reduces triglyceride and LDL-cholesterol
levels, but treatment-related adver se effects often
limit the use of this drug; in addition, the risk of
ad ve rse events is greater still in patients with
NIDDM .[89] Monotherapy with fibric acid deri va-
tive s effectively reduces triglyceride level s and
rai ses HDL-cholesterollevels, but may not achieve
desired reductions in LDL-cholesterol levels.l 89]
Thu s, combination therapy with an HMG -CoA re-
ductase inhibitor and either a fibric acid derivative
or nicotinic acid is often necessary to achieve sat-
isfactory reductions in lipid levels. However, such
combinations may be associated with increased in-
cidences of myopathy, acute renal failure, occa-
sional rhabdomyolysis and liver function abnor-
malities.l89.97-99]An HMG-CoAreductase inhibitor
that markedly lowers triglyceride level s, such as
ator vastatin , may allow more patients to be treated
with monotherapy, thereby pos sibly avoiding the
adver se event s associated with combination ther-
apy.
The choice of which HMG-CoA reductase in-
hibitor to use for a particular patient depends on
the degree of cholesterol-lowering that is desired
and the acquisition cost of the do se nece ssary to
achieve this reduction. At currently recommended
dosage s, atorvastatin offers the largest reductions
in cholesterol level s and thu s may become the
agent of choice for patients with severe hyperchol-
esterolaemia. However, for patients with less se-
vere hypercholesterolaemia, other HMG-CoA re-
ductase inhibitors with lower acquisition costs may
be able to reduce a patient's lipid level s to within
recommended limits.
Thus, although clinical data with atorvastatin
are limited at present , the drug appears to have the
potential to claim a place alongside other HMG-
CoA reductase inhibitors as a first-line pharmaco-
therapy for patients with hypercholesterolaemia, if
changes in lipid levels with atorvastatin result in
reductions in CHD mortality and morbidity. As a
result of the marked reductions in LDL-cholesterol
observed with atorvastat in, it may be part icularly
e Adis Internaffonal Lim ited . All rights reserved.
843
suitable for patients with heterozygou s or homo -
zygous fam ilial hypercholesterolaemia. Further-
more, bec ause of its trigl yceride-lowering proper-
ties, atorvastatin may be an appropriate therapeuti c
option for patient s with combined hyperlipidaemia
or hypertriglyceridaemia.
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Correspondence: DonnaMcTavish, Ad is International lim-
ited, 41 Centorian Drive , Private Bag 65901, Mairangi Bay,
Auckland 10, New Zeala nd .
E-ma il: de mai l@adis.co.nz
Drugs 1997 May: 53 (5)