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-

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

© Adl s Internati onal Limited. All right s reserved. Drugs 1997 May; 53 (5)
 832 Lea & McTavish

@
Ca

Fig. 1. Structural formula of atorvastatin.

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

© Ad is Inte ma lio nal Umlted , All rig hts rese rved, Drug s 1997 May: 53 (5)
 Atorvastatin: A Review 833

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

multiple doses. Atorvastatin plasma concentrations not atorvastatin is taken with food is expected to
were analysed by an HMG-CoA reductase inhibi- have little effect on the clinical efficacy of the dru g.
tion assay for atorvastatin or its equivalents (active Elderly recipients of atorvastatin 20mg (mea n
metabolites of atorvastatin), or by a ga s chromatog- age 75 years) had a 43 % higher Cmax. 27 % greater
raph y/mass spectrometry assay for unmetaboli sed AUC and 36 % longer t Y2~ than younger recipi ent s
atorvastatin .l''?' (mean age 28 years). Additionally, in women C max
Multiple daily dosages of atorvastatin 2.5 to tended to be 18% higher, AUC 11% lower and t1/2 ~
80mg capsules produced maximum steady-state 20% shorter than in men. However, LDL-cholesterol
pla sma concentrations (C max) of 1.95 to 252 Ilg/L, reductions ob served in elderly patients and fem ale
time to C max (tmax) of 2 to 4 hours and area under patients were not significantly different from tho se
the plasma concentration-time curve (AUC) of seen in young patients at similar do sages (section
25.2 to 1293 ug/L • h.lsS] AUC increased in propor- 5) .l7,S9,60]
tion to dose of atorvastatin, atorvastatin equiva- The effects of hepatic and renal impairment
lents and active metabolites, but increases in C max on atorvastatin 10mg pharmacokinetic parameters
were greater than proportional to dose.l 49]The drug were studied.ls!' In comparison with tho se in
has an absolute bioavailability of 12% and is ~98 % healthy ind ividuals, atorvastatin C max and AUC
protein-bound in pla sma. F' Multiple-dose pharma- values were 5-fold greater in patients with Childs
cokinetic parameters of atorvastatin are predictable Pugh Cla ss A hepatic impairment, and 16- and 11-
from single-dose paramerers.P f fold gre ater, respecti vel y, in patients with Childs
Metabolism of atorvastatin, at lea st in part by Pugh Cla ss 8 impairment (section 5). Ren al im-
cytochrome P450 3A4,f7.57] produces ortho- and pairment had no effect on atorvastatin pharm aco-
para-hydrox ylated derivati ve s and various p- kinetic parameter s (section 5).
oxidation products.F' Two hydroxylated deri va- Since the major site of endogenous choles tero l
tives of atorvastatin, PD 152873 and PD 142542, sy nthes is is the liver, it ha s been sugges ted that
have been identified as acti ve metabolites in in inhibition of HMG-CoA exclu sivel y within the
vitro human liver microsomes, but their activity liver may be reg arded as the goal of HMG-CoA
ha s not been described in detaiJ.ls71ln vitro inhibi- reductase therapy. Al so, inhibition of chol esterol
tion of HMG-CoA reductase by ortho- and para- synthesis outside the liver by HMG-CoA redu ctase
hydroxylated metabolites is equivalent to that pro- inhibitors may be the cause of some adverse events
duced by arorvastatin.Fl 70 % of the HMG-CoA associated with the se agents.l 14,62] However, the se
reductase inhibition associated with atorvastatin are controversial issues, as the relevance of liver
ha s been attributed to its active metabolites.!"l selectivity to clinical efficacy or tolerability has yet
The me an terminal elimination half-life (t Y2~) of to be established.
atorvastatin is about 14 hours, but the half-life of Tissue disposition studies of atorvastatin hav e
HMG-CoA reductase inhibition is 20 to 30 hours been conducted in a number of in vitro, ex vivo and
as a result of long-lasting active metabolites. Pv'Pl in vivo animal models. Although HMG-CoA redu c-
Food significantly decreased the rate and extent tase inhibitors have differing tissue selec tivities,
of absorption of atorvastatin; C max and AUC de- results vary according to the models and meth od s
creased by 48 and 13% (both p < 0.05), respec- used. 114,62,63] Nevertheless, HMG-CoA redu ctase
tivel y, when the drug was taken after food .ISO]Time inhibitors with low calculated lipophilicity « 1.0)
to C max and t 1/2~ were not significa ntly altered by tended to ha ve high hepatic selec tiv ity.I'<' Al -
food intake.lsO] Thus, because the efficacy of though atorvastatin has a high calculated lip ophil-
HMG-CoA redu ctase inhibitors is rel ated more to icity (4. 06) in comparison with pra vastatin (0.57)
do se than plasma concentration,ISS.S8] whether or and lovastatin (3. 11), it has high hepatic selectiv ity,

© Adi s Inte rnational Umited . All righ ts reserved. Drugs 1997 Ma y: 53 (5)
 Atorvastatin: A Review 835

as it is extensively metabolised by the liver through LDL-cholesterollevels are considered to be a pri-

a first-pass mechanism.Uf mary risk factor for CHD, but more recently low
HDL-cholesterol and elevated triglyceride levels
2.1 Drug Interactions have been identified as important risk factors)69 ,70]
Atorvastatin, ethinyl estradiol and erythromy- Other risk factors include patient age, male sex,
cin are all cytochrome P450 3A4 substrates and cigarette smoking, diabetes mellitus, severe obe-
therefore may be expected to interact. Coad- sity, lack of physical exercise, hypertension and a
ministration of atorvastatin 40 mg/day with a con- family history of hyperlipidaemia or coronary ar-
traceptive pill containing ethinyl estradiol 35 tery disease.[67]
ug/day and norethisterone (norethindrone) I The goal of therapy in patients with dyslipid-
mg/day in 16 healthy women resulted in 30 and aemias is to normalise lipoprotein levels. In the
19% increases in ethinyl estradiol C max and AVC, first instance, nonpharmacological interventions
respectively, compared with ethinyl estradiol (diet/weight control, exercise and other lifestyle
alone. The t~·W of ethinyl estradiol was unchanged, modifications) should be initiated. Pharmacologi-
but the C max and AUC of norethisterone were in- cal intervention should be considered only if pa-
creased by 24 and 28%)64] tients fail to respond to these primary measures.
In the presence of erythromycin 500mg 4 times The US National Cholesterol Education Program
daily, the C max and AUC of atorvastatin or equiva- (NCEP), for example, has published comprehen-
lents were, respectively, 38 and 33% greater (sec- sive guidelines for the diagnosis and treatment of
tion 5»)64]
dyslipidaemia in patients with or without CHD (ta-
Coadministration of atorvastatin lOmg and a
ble II»)67] Similar guidelines are also available in
commonly available nonprescription antacid
other countries.[71 .72]
(Maalox TC®) resulted in the t max of atorvastatin
Evidence from several studies using lipid-low-
or equivalents increasing from 2.9 to 5.7 hours and
ering drugs , including HMG-CoA reductase inhib-
reductions in C max and AUC by 34% each . This
itors, has shown that lowering LDL-cholesterol
decreased rate and extent of atorvastatin absorp-
tion was not reported to have affected LDL- levels significantly reduces the risk of CHD mor-
cholesterol reductions in this study (no further in- tality and morbidity[73-77] and even total mortal-
formation provided»)65] ityP3,78] In the absence of such data, the clinical
The plasma concentration of atorvastatin is de- evaluation of newer antihyperlipidaemic agents
creased by 25% during coadministration with col- such as atorvastatin is based on lipid-lowering ef-
estipol .F' fects, an important surrogate marker of clinical ef-
ficacy .
3. Therapeutic Potential Atorvastatin has been evaluated mainly in pa-
tients with primary hypercholesterolaemia, but
Elevated plasma levels of lipoproteins, rich in
some data are available from patients with hyper-
cholesterol or triglycerides, can be caused by pri-
mary dietary and/or genetic factors , but can also be triglyceridaemia and combined hyperlipidaemia
secondary to diseases such as diabetes [both insu- (elevated cholesterol and triglyceride levels).
lin-dependent diabetes mellitus (IDDM) and non- Results of studies involving patients with hetero-
IDDM (NIDDM)],[66J hypothyroidism, nephrotic zygous familial hypercholesterolaemia will be de-
syndrome or other renal disorders)67.68] Patients scribed with those concerning nonfamilial (poly-
with dyslipidaemias (elevated non-HDL-cholesterol genic) hypercholesterolaernia, as many studies did
levels or low HDL-cholesterollevels) are at an in- not distinguish between these patient type s. How -
creased risk of developing atherosclerosis and sub- ever, patients with homozygous hypercholesterol-
sequent coronary heart disease (CHD). Elevated aemia are described separately.

© Ad is International Limited. All righ ts reserved. 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 and triglyceride levels compared with placebo (ta-
diet for several weeks before initiation of drug treat- ble III).f8o-82 ] As with other HMG-CoA reductase in-
ment and were encouraged to maintain this diet hibitors, LDL-cholesterol levels were reduced in a
throughout the study.[79] Atorvastatin was adminis- nonlinear dose-dependent manner, with atorvastatin
tered once daily in the evening with or without food 2.5mg causing a 25% reduction, 5mg a 29% reduc-
and trials included men and women who met entry tion, IOmgreductions of 35 to 42%, 20mg reductions
criteria. As with other HMG-CoA reductase inhibi- of 42 and 44%, 40mg reductions of 50 and 50% and
tors, therapeutic response to atorvastatin correlates 80mg reductions of 59 and 61%.[80-82] Atorvastatin
better with dose than with blood concentration s.[55,58] 2.5 to 80 mg/day reduced apolipoprotein B levels by
17 to 50% compared with placebo.f8o ,8 1]
3.1 Primary Hypercholesterolaemia
Triglyceride levels were decreased by 10 to
3. 1. 1 Comparisons with Placebo 45 % after daily atorvastatin dosages of 2.5 to
In dose-response studies, atorvastatin signifi- 80mg.f 80 ,8 1] The effect of atorvastatin on HDL-
cantly reduced total chole sterol, LDL-cholesterol 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 20 to 40 mg/day and simvastatin 10 to 20 mg/day
maximum observed reduction in LDL-choIesterol in large double-blind trials of 1 year 's duration (ta-
levels wit h atorvastatin 2.5 to 80 mg/day was at- ble III). Patients initially received the lower dose
tained after 2 weeks of treatment.I'i' J of each drug, which was titrated to the higher dose
In postmenopausal women , atorvastatin 10 mg/ if LDL-cholesterol le vels did not reach NCEP
day (n = 20) reduced total chole sterol, LDL-choles- goal s (table II) after 16 weeks,! 59.83.84]
terol and triglyceride levels by 3 1, 43, and 7%, re- After 52 week s of treatment, reductions in LDL-
spectively, whereas placebo had little effect on these chol esterol levels were significa ntly greater with
parameters in a study of 12 weeks' duration ,!88]
atorvastatin than lovastatin (37 vs 29 %), prava-
statin (35 vs 23%) or simvastatin (38 vs 33%) [table
3.1.2 Comparisons with Other HMG-CoA
·Reduc tase Inhibitors III]. Total cholesterol and trigl yceride levels were
Atorvastatin 10 to 20 mg/day has been com- al so reduced more in atorvastatin groups than
pared with lovastatin 20 to 40 mg/day, pravastatin 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 Lea & McTavish

OWeek 16 lovastatin and simvastatin (statistical analysi s not

. Week 52 reported) [fig. 2]. Furthermore, patients receiving
atorvastatin were 1.3-fold more likely to reach
I
NCEP goals than lovastat in recipients in one trial
(p = 0.001»)59] As a result, fewer patients receiv ing
I
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 %)
I or simva statin (24 vs 64%») 59,83,84]
The percentage of patients who reached NCEP
I LDL-cholesterol goals was analysed by CHD-risk
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-
I
terol goal of :::':4.2 mmol/L. For patients categorised
as medium risk (target :::.:3.4 mmol/L) or high risk
I
(target :::':2.6 mmol/L) the corresponding percent-
o 20 40 60 80
ages achieving NCEP LDL-cholesterol goal s were
Patients reaching target LDL-C levels (%) 72 and 58%, and 37% and II %.
Fig. 2. Percentage of patients reaching US National Cholesterol
3.1.3 In Combination with Colestipol
Education Program (NCEP) low density lipoprotein cholesterol
(LDL-C) goals after therapy with HMG-CoA reductase inhibi- Combination therapy with atorv astatin and col-
tors.l86] Patients received atorvastatin 10 to 20 mg/day, lova- estipol has been inve stigated in 2 studies (table III).
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] In one trial,[85,86] atorvastatin 80 mg/day pro-
duced significantly larger reductions in LDL-
cholesterol, total cholesterol and triglyceride level s
P :::':0.05) [table III]. HDL-cholesterollevels were
than the combination of simvastatin 40 mg/day and
increased in all groups with no significant differ-
cole stipol 20 g/day. The combination of atorva-
ences between atorvastatin and other HMG-CoA
statin 40 mg/day and colestipol 20 g/day produced
reductase inhibitors)59,83,84]
similar reductions in LDL-cholesterol and total
Atorvastatin had a significantly greater effect on
cholesterol to atorvastatin 80 mg/day, but tended to
apolipoprotein B levels than lovastatin (30 vs 22%
reduction from baseline),[59] pravastatin (30 vs reduce triglyceride levels less than atorvastatin
monotherapy.[85,86]
20%)[83] or simvastatin (34 vs 30%»)84] Similarly,
atorvastatin lowered VLDL-cholesterollevels to a In a second trial ,[87] the combination of atorva-
greater extent than lovastatin (16 vs 8%)[59] or statin 10 mg/day and colestipol 20 g/day tended to
simvastatin (21 vs 12%»)84] Atorvastatin, lova- produce larger reductions in LDL-cholesterol lev-
statin and simva statin all raised HDL-cholesterol els and smaller reductions in triglyc eride levels
levels by 7% and pravastatin induced a 10% rise in than atorvastatin 10 mg/day monotherapy. Both
HDL-cholesterollevels (table III) . combined therapy and atorvastatin monother-
More patients reached NCEP LDL-cholesterol apy tended to cause larger reductions in LDL-
goals (table II) after 16 and 52 week s of treatment cholesterol levels and smaller reductions in trig-
with atorvastatin than with pravastatin (both p < lycer ide levels than monotherapy with cole stipol
0.00 I) and similar trends were observed with both 20 g/day [no statistical analysi s reported] .

© Adis Intern ational Umited . All right s rese rved,

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

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

 840 Lea & McTavish

respectively.P!' Atorvastatin 10 and 20 mg/day • Atorvastatin

produced reductions of 34 and 40% in this ratio, o Lovas tatin

whereas fenofibrate 300 mg/day reduced it by 31

to 32%.[92] Flatulence ~~DIIi:l• • • • • •L - --,
Dyspepsia rt· .. ,
3.3 Hypercholesterolaemia or Combined
Hyperlipidaemio Secondary to NIDDM Constipation liiiiiiijill••
I
In 25 patients with hypercholesterolaemia sec-
ondary to NIDDM, atorvastatin 10 mg/day pro-
duced significantly larger reductions than simva-
Pain ~iiiiiiiiiiiL=:
statin 10 mg/day in LDL-cholesterollevels (41 vs Headache ~iiiiiiiiiiii~------~
28%, p < 0.009) and total cholesterol levels (32 vs
22%, p < 0.002) in a nonblinded study of 4 weeks'
Asthenia .iiiiiiL~--,
duration.f 93] Back paln.,.. -,

In a 26-week randomised study, atorvastatin 10 o 2 3 4

to 20 mg/day caused a greater reduction in tri- Incidence t% of patients)
glyceride levels than simvastatin 10 to 20 mg/day
(24 vs 15%, p < 0.05) in 166 patients with com- Fig. 3. Adverse events associated with atorvastatin . Patients
bined hyperlipidaemia secondary to NIDDM.f 94] 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
4. Tolerability adverse events with a ~2% incidence were included.!591

Like other HMG-CoA reductase inhibitors,

atorvastatin has been generally well tolerated in persistent increases in creatine phosphokinase lev-
clinical studies of up to 52 weeks' duration.f59.s3.s4] els > 10 times normal Iimits .P'J
The most common adverse events reported in the Mild asymptomatic elevations in serum trans-
largest study are shown in figure 3.[59] Gastrointes- aminase levels have been reported during treat-
tinal adverse effects (including constipation, flatu- ment with HMG-CoA reductase inhibitors.P?' In
lence, dyspepsia and abdominal pain) are most clinical trials with atorvastatin, persistent eleva-
common. In total, <2% of 2502 patients in clinical
tions (>3 times the upper limit of normal on 2 or
trials withdrew because of adverse events associ-
more occasions) in serum transaminases occurred
ated with atorvastatin.Pl
in 0.7% of patients .F' The frequency of persistent
The most serious tolerability concerns associ -
elevations in serum transaminases tended to in-
ated with HMG-CoA reductase inhibitors are pos-
crease with atorvastatin dosage: 0.2, 0.6, 0.6 and
sible hepatic dysfunction characterised by raised
serum aspartate (AST) or alanine (ALT) amino- 2.3% for dosages of 10,20,40 and 80 mg/day.Pl In
transferase levels and myopathy characterised by a large trial evaluating 1049 patients, the incidence
myalgia and creatine phosphokinase levels > 10 of abnormal transaminase level s was similar with
times above the normal limit.P'" Myopathy occurs atorvastatin and lovastatin after 52 weeks of treat-
infrequently «0.2%) in patients receiving other ment.[59]
HMG-CoA reductase inhibitors.f5.s.34.53] Although High dosages of some HMG-CoA reductase in-
atorvastatin has not been used as extensively as hibitors have been associated with lens opacities in
other HMG-CoA reductase inhibitors, myopathy animal studies;[95] however, data from clinical
has not been reported in patients receiving the drug . studie s involving HMG-CoA reductase inhibitors
Myalgia was reported in 3% of the atorvastatin have not reported lenticular opacities in patients
group (n = 132) in one study, but no patient had receiving long term treatment.f 5,S.34.53] No long

© Adi s Internati onal limited . All rights reserved. Drugs 1997 Ma y; 53 (5)
Atorvastatin: A Review 841

term tolerability data are available for atorvastatin, necessary in older patients or in patients with renal
but in studies of up to 1 year's duration (n = 1135) , impairment. However, in patients with hepatic in-
no significant lenticular opacities have been re- sufficiency, dosage reductions may be required
ported.l s9,83,841 Therefore, routine eye examina- (section 2).
tions are not necessary.P?' In patients who have active hepatic disease or
In 3 trials in which 1135 patients received unexplained persistent elevations in serum trans-
atorvastatin, pancreatitis was reported in 1 pa- aminases, are pregnant or are breast feeding,
tient.[S9,83,84] atorvastatin is contraindicated.Pl
In comparative trials, atorvastatin had a similar As with other HMG-CoA reductase inhibitors,
adverse event profile to that of lovastatin (fig , 3), concomitant therapy of atorvastatin with cyclo-
pravastatin and simvastatin.l s9,83,841 Atorvastatin sporin, nicotinic acid, fibric acid derivatives,
10 mg/day and nicotinic acid 100 to 1000mg 3 erythromycin or azole antifungals is likely to in-
times daily were considered to be associated with crease the risk of adverse events such as myopathy
adverse events in 11 and 66%, respectively, of 105 and rhabdomyolysis, and such combinations
patients with hypertriglyceridaemia. Gastrointesti- should be avoided where possible.l7,97-991
nal adverse events were most common with ator-
vastatin and vasodilation-related events with nico- 6. Potential Place of Atorvastatin in the
tinic acid.l 911 Management of Hyperlipidaemias

5. Dosage and Administration In the US and Europe, approximately 15% of

adults are at increased risk of experiencing cardio-
Oral atorvastatin 10 to 80 mg/day may be used vascular events because of elevated blood lipid
to lower lipid levels of patients with primary levels ,[lOO,IOII Large primary and secondary pre-
hypercholesterolaemia (heterozygous familial or vention studies in patients with hypercholesterol-
nonfamilial) or combined dyslipidaemia, who do aemia have demonstrated that lowering LDL-
not respond to life-style measures (including a cholesterol levels leads to significant reductions in
standard cholesterol-lowering diet). For patients coronary mortality and morbidity[73-77,102-1041 and
with homozygous familial hypercholesterolaemia total mortality.F'J Despite this abundant evidence,
who require apheresis, atorvastatin 10 to 89 many patients still do not receive appropriate treat-
mg/day may be used as an auxiliary treatment, or ment. The need to vigilantly screen and treat pa-
by itself if apheresis is not available.l7,96J tients according to recommended guidelines must
Lipid levels should be analysed within 2 to 4 be emphasised.I'P'"
weeks of treatment onset or titration and the dosage The relationship between elevated triglyceride
of atorvastatin should be tailored according to re- levels and CHD is less clear. In several epidemio-
sponse (table II). Liver function tests should be logical studies, elevated triglyceride levels have
performed before initiating treatment with ator- been associated with increased risk of CHD.l 106,107]
vastatin, 6 and 12 weeks after treatment onset or Indeed, in the Stockholm Prospective Study, raised
dosage titration and approximately twice yearly triglyceride levels were an independent and
thereafter.[71 stronger predictor of myocardial infarction than in-
Atorvastatin may be taken at any time of day, creased levels of total cholesterol.U'<' The rela-
(at the same time every day)17] although in clinical tionship between triglyceride levels and CHD is
trials it was usually taken in the evening (section more pronounced in women, younger patients and
3) . Atorvastatin may also be taken with or without those with increased insulin resistance.l70,109,IIOJ
food (section 2).l71 However, after adjusting for HDL-cholesterol,
As atorvastatin does not undergo significant re- LDL-cholesterol and/or total cholesterol in multi-
nal excretion, dosage adjustments should not be factorial analyses, the independent effect of tri-

© Adi s International Limited. All right s reserv ed. Drugs 1997 May ; 53 (5)
 842 Lea & McTavish

glycerides often becomes insignificant or is weak- receiving atorvastatin. Data on the effect of atorva-
enedp3,I06,107,11I-1I 3] In part, this may be caused by statin in the primary and secondary prevention of
physiological relationships between plasma tri- CHD are not yet available. However, a 4-year study
glyceride levels and LDL-cholesterol levels, obes - investigating the effects of atorvastatin 10 mg/day
ity and, more importantly, HDL -cholesterol lev- in 2250 patients (aged $.75 years) with NIDDM,
els.[70,l14] In addition, large short term variations in with or without a prior myocardial infarction, is
triglyceride levels, as a result of diet , alcohol intake under way in North America, Europe, Australia and
and other factors, may disguise the true nature of the South AfricaJ I331
relationship between triglyceride levels and CHD in Patients with heterozygou s familial hyperchol-
multifactorial analyses.F't' Nevertheless, a recent esterolaemia generally have higher cholesterol lev-
study has found that raised triglyceride levels are an els than patients without this auto somal dominant
independent predictor of myocardial infarction, par- mutation and therefore require larger percentage
ticularly when total cholesterol levels are also reductions in lipid levels to dimini sh the risk of
raised,[691 and a second study found that elevated tri- atherosclerosis.I'<l Although there is no conclusive
glyceride levels are an independent predictor of ma- evidence that greater reductions in cholesterol lev-
jor coronary events, especially when the ratio of els are of benefit in this small, but high risk patient
LDL-cholesterol to HDL-cholesterol is >5J1151 group, atorvastatin may be regarded as the HMG-
Aside from the possible risk of CHD , patients CoA reductase inhibitor of choi ce, as it is more
with very high triglyceride level s (> 11.3 mmol/L) likely to achieve the current target lipid level s for
have an increased risk of pancreatitis and chylo- primary and secondary prevention. For patients
micronaemia syndrome.F'l with homozygous familial hypercholesterolaemia
Several large studies have demonstrated the ef- who require apheresis, atorvastatin may be used as
fectiveness of other HMG -CoA reductase inhibi- an auxiliary treatment, or by itself if apheresis is
tors (pravastatin and simvastatin) in the primary not available.F'
and/or secondary prevention of CHD in patients In contrast to the other HMG-CoA reductase in-
with hypercholesterolaemia alone (patients with hibitors, which have a limited effect on triglyceride
hypertriglyceridaemia were excluded from these level s, atorvastatin significantly reduced triglycer-
trial s).l73,74.76,771 In addition, regression studies ide level s in patients with hypertriglyceridaemia or
have shown that lovastatin, simvastatin and combined hyperlipidaemia. Although ator vastatin
pravastatin slow the progression of atherosclerosis reduced total cholesterol and LDL-cholesterol to a
and lower the risk of coronary events in patients greater extent than fenofibrate or nicotinic acid ,
with mild to moderately severe hypercholesterol - these latter agents produced larger reductions in
aemia.l116-1 311 Furthermore, lovastatin reduces the triglyceride levels.
progression of atherosclerosis in grafts of patients It has been suggested that atorvastatin reduces
who have undergone saphenous vein coronary ar- triglyceride levels as a result of its more pro-
tery bypass graftsJl 321 With this weight of evi- noun ced inhibitory effect on cholesterol synthesis
dence, HMG-CoA reductase inhibitors are consid- compared with other HMG-CoA reducta se inhibi-
ered effective and appropriate pharmacotherapy tors at currently recommended dosages.Ff How-
for the treatment of hypercholestero laemia.I'Pl ever, it can also be argued that all HMG-CoA
Like other HMG-CoA reductase inhibitors, reductase inhibitors are qualitatively similar, and
atorvastatin reduces LDL-cholesterol and total therefore , that HMG-CoA redu cta se inhibitors
cholesterol level s in patients with hypercholester- other than atorvastatin would also reduce triglycer-
olaemia. Indeed, in clinical trials reductions ide levels if given at sufficiently high dosesJ 5,8,34-36]
achieved with the more established agents in this Currently, single-agent pharmacological treat -
drug class were matched or exceeded in patients ment in patients with combined hyperlipidaemia

© Adis Internatl onal Umited . All rights reserved . Drugs 1997 Ma y; 53 (5)
Atorva statin: A Review 843

involves use of a fibric acid derivative or nicotinic suitable for patients with heterozygou s or homo -
acid.l 89] Monotherapy with nicotinic acid effec- zygous fam ilial hypercholesterolaemia. Further-
tively reduces triglyceride and LDL-cholesterol more, bec ause of its trigl yceride-lowering proper-
levels, but treatment-related adver se effects often ties, atorvastatin may be an appropriate therapeuti c
limit the use of this drug; in addition, the risk of option for patient s with combined hyperlipidaemia
ad ve rse events is greater still in patients with or hypertriglyceridaemia.
NIDDM .[89] Monotherapy with fibric acid deri va-
tive s effectively reduces triglyceride level s and References
rai ses HDL-cholesterollevels, but may not achieve I. Blum CBB. Comparison of properties of four inhibitors of 3-
hydroxy-3-methylglutaryl-coenzyme Areductase. Am JCar-
desired reductions in LDL-cholesterol levels.l 89] diol 1994; 73 Suppl. D: 3D-l ID
Thu s, combination therapy with an HMG -CoA re- 2. Rackley CEoMonotherapy with HMG-CoA reductase inhibi-
torsandsecondaryprevention incoronaryarterydisease.Clin
ductase inhibitor and either a fibric acid derivative Cardiol 1996 Sep; 19: 683-9
or nicotinic acid is often necessary to achieve sat- 3. Alberts AW. Effectsof HMG CoA reductase inhibitors oncho-
lesterol synthesis. Drug Invest1990; 2 Suppl. 2: 9-17
isfactory reductions in lipid levels. However, such 4. O'Connor P. Feely J. Shepard J. Lipid lowering drugs. BMJ
combinations may be associated with increased in- 1990Mar 10; 300: 667-72
cidences of myopathy, acute renal failure, occa- 5. HariaM. McTavish D. Pravastatin: areappraisalof its pharma-
cological properties and therapeutic useinthe management
sional rhabdomyolysis and liver function abnor- of coronary heart disease. Drugs 1997; 53 (2): 299-336
malities.l89.97-99]An HMG-CoAreductase inhibitor 6. Conde K. Vergara-Jinenez M. Krause BR, etal. Hypercholes-
terolemic actions of atorvastatin are associated with alter-
that markedly lowers triglyceride level s, such as ations on hepatic cholesterol metabolism and lipoprotein
ator vastatin , may allow more patients to be treated composition intheguineapig.J LipidRes 1996; 37: 2372-82
7. Lipitor" (atorvastatin calcium) tablets. Data sheet. Parke-
with monotherapy, thereby pos sibly avoiding the Davis. Division ofWarner-Lambert Company, Morris Plains.
adver se event s associated with combination ther- NJ 07950. USA. 1996. (Dataon file)
apy. 8. Plosker GL. WagstaffAJ. Fluvastatin: a reviewofits pharma-
cology anduse in the managementofhypercholesterolaemia.
The choice of which HMG-CoA reductase in- Drugs 1996 Mar; 51: 433-59
hibitor to use for a particular patient depends on 9. KearneyAS.CrawfordLF.MehtaSC.etal.Theinterconversion
kinetics. equilibrium. and solubilities of the lactone and
the degree of cholesterol-lowering that is desired hydroxyacidforms ofthe HMG-CoA reductase inhibitor. CI-
and the acquisition cost of the do se nece ssary to 98 1. Pharm Res 1993 Oct; 10: 1461-5
10. Ferguson E. McNally W. Bocan TMA. et al. Measurementof
achieve this reduction. At currently recommended sterol synthesis and tissue distribution of a liver selective
dosage s, atorvastatin offers the largest reductions HMG-CoAreductase inhibitor. CI-981 [abstract]. FASEB J
in cholesterol level s and thu s may become the 1991 Mar 15; 5: AI253
II. Newton RS. AreallHMG-CoA reductase inhibitors(vastatins)
agent of choice for patients with severe hyperchol- alike? [abstract]. In: 66th Congress of the European Athero-
esterolaemia. However, for patients with less se- sclerosis Society Abstract Book: 1996 Jul 13-17; Florence
(Italy), 31
vere hypercholesterolaemia, other HMG-CoA re- 12. ShawMK. Newton RS. Sliskovic DR. etal. Hep-G2cells and
ductase inhibitors with lower acquisition costs may primary rat hepatocytes differ in their response to inhibitors
of HMG-CoA reductase. Biochem Biophys Res Commun
be able to reduce a patient's lipid level s to within 1990; 170 (2): 726-34
recommended limits. 13. Auerbach BJ. Bousley RF. Stanfield RL, et al. Mechanism of
Thus, although clinical data with atorvastatin cholesterol lowering in casein-fed rabbits treated with
atorvastatin [abstract]. Atherosclerosis 1994 Sep 15; 109:
are limited at present , the drug appears to have the 164-5
potential to claim a place alongside other HMG- 14. Sliskovic DR. Roth BD. Bocan TMA. Tissue selectivity of
HMG-CoAreductase inhibitors. Drug News Perspect 1992;
CoA reductase inhibitors as a first-line pharmaco- 5 (9): 517-33
therapy for patients with hypercholesterolaemia, if 15. Bocan TMA. Mazur MJ. MuellerSB. et al. Antiatherosclerotic
activity of inhibitors of 3-hydroxy-3-methylglutaryl coen-
changes in lipid levels with atorvastatin result in zyme Areductase in cholesterol-fed rabbits: a biochemical
reductions in CHD mortality and morbidity. As a and morphological evaluation. Atherosclerosis 1994 Nov;
111: 127-42
result of the marked reductions in LDL-cholesterol 16. KrauseBR. NewtonRS.Lipid-loweringactivity ofatorvastatin
observed with atorvastat in, it may be part icularly and lovastatin in rodent species: triglyceride-lowering in rat

e Adis Internaffonal Lim ited . All rights reserved. Drug s 1997 Ma y; 53 (5)
 844 Lea & McTavish

correl ates with efficac y in LDL anima l models. Atherosclero- 33. Ma PTS . Gil G. Siidhof TC , et al. Me vinolin , an inhib itor of
sis 1995 Oct; 117: 237-44 choleste rol synthesis, induces mRNA for low density lipop ro-
17. Au erbach BJ. Krause BR. Bisgaier CL. Comp arative effects of tein recept or in liver s of ham sters and rabbit s. Proc Natl Acad
HMG-CoA reductase inhibit ors on apo B produ ction in the Sc i USA 1986; 88: 8370-4
casein-fed rabbit : atorvastatin versus lovastatin. Atheroscl e- 34. Plosker G L. McTavish D. Simvastatin : a reappr aisal of its phar-
ros is 1995 Jun ; 115: 173- 80 macology and ther apeut ic efficacy in hypercholesterolaem ia.
18. Parker TS . McNamara OJ. Brown CD. et al. Plasma me valon ate Drugs 1995 Aug; 50 : 334-63
as a measure of choles tero l biosynth esis in man. J Clin Invest 35 . Davidson MH, Ste in EA, Dujo vne CA . et al. The efficacy and
1984; 74: 795-804 six-week tolerability of simvasta tin 80 and 160 mg/day. Am
19. Naoum ova RP. Mar ais AD. Mountn ey J. et al. Plasm a mevalo- J Cardiol 1997; 79 (I ): 38-42
nic ac id. an index of choles tero l synthes is in vivo. and respon- 36. Merck to file for ex tended rele ase Zocor in 1998; high dose is
sive ness to HMG-CoA redu ct ase inhibitor s in familial one strategy to combat atorvastatin launch: Zocor HMG-CoA
hyperch olesterol aemi a. Ath ero sclerosis 1996 Jan 26 ; 119 : market share is 29.9%. FOC Rep Pink Sheet 1996 Dec 23: 5
203- 13 37. Vaughan CJ. Murph y MB . Buckley BM . Statins do more than
20. Naoumov a RP. Mar ais AD . Firth JC. et al. Aph eresis plus ju st lower choles terol. Lancet 1996 Oct 19; 348: 1079-82
atorvas tatin: a hard act for gene ther apy to follow ? [abstra ct] .
38 . Corsini A. Raiteri M. Soma MR . et al. Si mvastatin but not
66th Congress of the European Atheroscle rosis Society Ab-
pra vastatin has a direct inhibitory effect on rat and hum an
strac t Book . JuI13-17. 1996. Florence Italy : 24 myocyte proliferation . Clin Biochem 1992; 25: 399 -400
21. Cili a Jr DO. Gib son OM . Whitfield LR. et al. Pharm acodynamic
39. Weissber g PL. Cles ham GJ. Bennett MR . Is vascular smooth
effe cts and pharmacokinetics of atorvastatin after administra-
muscle ce ll proliferation beneficial ? Lancet 1996 Feb 3; 347:
tion to norm ocholesterolemic subjects in the morn ing and
305 -7
evening. J Clin Pharmacol 1996 Jul ; 36: 604-9
40 . Negre-Aminou P. van Erck M. Cohen LH. Ant i-proliferati ve
22. Le N-A . Li Xlnnis-Whitehouse W. et al. Lipid and apolip oprot-
potencies of 6 vastatins in cultured human cells ; involvem ent
ein levels and distribution in patient s with hypertri glyceride-
of the ras-medi ated signalling pathw ay [abstract] . In: 66 th
mi a: effect of atorv ast atin . Parke-Davi s. Ann Arb or.
Congress of the European Atherosclerosis Society Abstract
Michi gan. USA. (Data on file)
Book : 1996 Jul 13-17 ; Floren ce (Italy). 120
23 . Bakker-Ark em a RG. David son MH. Gold stein RJ. et al. Effi-
41 . Ortego M, Bustos C, Hern andez-Presa M. et al, Th e HMG-CoA
cacy and safety of a new HMG -CoA redu ctase inhibitor.
reductase inhibitor atorvastatin red uces NF -kB activation and
atorvas ta tin, in patients with hyp ertri glycerid emi a. JAM A
1996 Jan 10; 275: 128-33 MCP- I gene expressio n in vasc ular smoo th muscle ce lls and
mononucl ear cells [abstract] . In: 66th Congress of the Eu-
24. Th omp son G R. Nao umova RP. Watts GF, et al. Role of choles-
ropean Atheroscler osis Societ y Ab stract Book: 1996 Jul 13-
terol in regulating apoli poprotein B sec retion by the liver. J
17; Florence (Italy). 66
Lipi d Res 1996; 37: 439-47
42. Som a M. Piliego T, Seregni R, et al. Effect of atorvas tatin on
25 . Kasim SE. LeBoeu f RC. Khiln ani S. et al. Mechani sms of tri-
intimal caro tid th ickening indu ced by perivascular man ipula-
glyce ride-lowering effect of HMG- CoA reductase inhibitors
in a hypert riglycerid emi c anima l model. the Zucker obese rat. tion in norm ocholesterolemi c rabbits [abstract] . In: 66 th Co n-
J Lipid Res 1992; 33: 1-7 gress of the European Athe rosclerosis Societ y Abs tract Book:
1996 Jul y 13-17, Florence Italy, 231
26 . Go h EH, Heim burg M. Effects of free fatt y acids on activity of
hepatic microsomaI 3-h ydro xy-3-meth ylglut aryl coe nzy me A 43. Dujovne CA, Harri s WS, Altm an R, et al. Changes in hemorh eo-
redu ctase and on secretion of triglyceride and choles terol by logy and atherot hrombotic parameters by improving serum
liver. J Bioi Chern 1977 Ma y 10; 252 (9) : 2822-6 lipids in atorvas tatin-trea ted hyperlipidem ics [abstr act) . In:
27. Watts GF. Cummings MH, Umpleby M, et al. Sim vastatin de- 66th Co ngress of the Europ ean Ath eroscle rosis Society Ab-
creases the hepatic secretion of very-low-d ensity lipoprotein stract Book : 1996 Jul 13-17 ; Florence (Italy). 169
apo lipoprotein B-IOO in heterozyg ou s famili al hyperchol- 44 . Alf6n J, Pueyo C, Badim on L. Regul ation by atorvas tatin, a
es tero laemia: path ophysiologi cal and therapeut ic impli ca- novel HMG CoA redu ctase inhibitor. of plasm a lipids and
tions. Eur J Clin Invest 1995 ; 25: 559-67 thrombotic risk in atherosclerotic rabbit s [abstract]. In: 66 th
28. Cianfl one KM. Yasruel Z. Rodriguez MA. et al. Regul ation of Con gress of the European Atherosclerosis Societ y Abstract
apoB secr etion from HepG2 cell s: evid ence for a critical role Book: 1996 Jul y 13-17. Florence Italy. 20 I
for ch olesteryl ester synthesis in the response to a fatty acid 45 . Dost al LA. Sch ardein JL . Anderson JA . Developm ent al toxicity
challen ge . J Lipid Res 1990; 31: 2045 -55 of the HMG -CoA reductase inhibitor. ator vastatin, in rats and
29 . Watts GF, Naoumova R, Cummings MH . et al. Direct correla- rabbit s. Teratology 1994 Dec ; 50 : 387-94
tion between cholesterol synthesis and hepatic secretion of 46 . Do stal LA. Whitfi eld LR. Anderson JA . Fertility and general
apolipoprotein B-100 in normolipidemic subjects. Met abo- reproduction studies in rats with the HMG -CoA reductase in-
lism 1995; 44 (8): 1052-7 hibit or. atorvas tatin. Fund am Appl Toxicol 1996; 32: 285 -92
30. Sch aefer EJ. Le vy RI. Path ogene sis and management of 47 . Ciaravi no V. Kropk o ML, Rothwell CEoet al. The gcnotox icity
lipoprotein disord ers. N Engl J Med 1985 May 16; 312 (20): profil e of ato rvastatin, a new drug in the treat ment of
1300 -10 hypercholesterolem ia. Mut at Res Genet Toxicol 1995 Jun;
3 I. McNeil JJ. Sloman JG . Cardiovascul ar Disorders. In: Speight 343: 95-10 7
TM , edi tor. Avery's dru g treatm ent . 3rd ed. Auckland : Ad is 48. Walsh KM. Albassa m MA. Clarke DE. Subchro nic toxicity of
Intern ational. 1987: 591-675 atorvastatin, a hydroxymethylglut aryl-coe nzyme A reductase
32. Grun dy SM. HMG-CoA reductase inhib itors: clinical applica- inhibit or, in beag le dogs. Toxicol Pathol 1996; 24 (4) : 468 -76
tions and the rapeuti c potenti al. In: Rifk ind BM, editor. Drug 49. Yang B-B. Sm ithers JA. Stern RH, et al. Pharmacokin et ics and
treatm ent of hyperlipidemi a. New York . New York : Merce! dose proporti onal ity of atorvastati n and its active metabolites
Dekk er Inc., 1991: 139-67 [abstract]. Pharm Res 1996; 13 (9) Supp l.: S437

© Adi s Inte rna tiona l Umlte d . All rig hts rese rved . Drugs 1997 Ma y: 53 (5)
Atorvastatin: A Review 845

50 . Radulovic LL. Cilia DD. Posvar EL. Effect of food on the bio- lence, detecti on . and eva luation. Circulation 1994 Mar; 89:
availability of ator vastatin, an HMG-CoA redu ctase inhibitor. 1344 -63. 1432-45
J Clin Pharm acol 1995 Oct; 35: 990-4 68 . Ex pert Panel on Dete ction . Evaluation. and Treatment of High
51 . Davignon J. Dufour R. Montigny M . Atorv astatin: wh at do we Blood Chole sterol in Adults. National C ho lestero l Education
know ? [abstra ct] . In: 66th Con gress of the European Athero- Pro gram . Second report of the Exp ert Panel on Detection.
sclerosis Society Ab stract Book : 199 6 Jul 13-7 : Florence Evaluation. and Tre atment of Hi gh Blood Ch olesterol in
(Ital y). 31 Adult s (Adult Treatm ent Panel II): IV. Spe cial issue s. Circu-
52. Cili a Jr DD . Radul ovic LL. Whit field LR . et al. Safet y. toler- lation 1994 Mar; 89 : 1420-45
ance and ph arm acokinetic (P K) profiles followin g single- 69. Stam pfer MJ. Krauss RM. Ma J. et al. A pro specti ve study of
doses of C I-98 1. a potent HMG-CoA reductase inhibitor trig lyceride level. low-d en sity lipop rotein particl e diameter.
[abs tract] . Pharm Res 1993; 10 Suppl.: S332 and risk of myocard ial infarctio n. JAM A 1996 Sep 18; 276
53 . Henwood JM . Heel RC. Lovastat in: a prel iminary review of its (II ): 882-8
ph arm acod ynamic properties and therapeuti c use in 70 . Pyorala K. De Backer G. Graham I. et al. Prevent ion of coro-
hyperlipidaemi a. Dru gs 1988; 36: 429-54 nary heart di sease in cl inica l practice: recommendations of
54 . Mauro VF. Clinical pharmaco kinet ics and practi cal applica - the Task Force of the Euro pean Soc iet y of Ca rdiology. Euro-
tion s of simvas tatin. Clin Pharm acokin et 1993 ; 24 : 195-202 pean Athe roscl ero sis Societ y and European Society of Hyper -
55. Cilia Jr DD. Whitfi eld LR. Gib son DM . et al. Multipl e-d ose tension . Ath erosclero sis 1994 Oct; 110: 121-61
pharmacokinetic s. pharmacodynamic s. and safety of atorva- 71 . DiBianco R. Hyperchole sterolaemia man agement guidelines. S
statin , an inhibit or of HMG-CoA reductase. in health y sub - Afr Med J 1992 Feb 15; 81 Suppl. : 4-9
jects. Pharmacol Ther 1996 ; 60 : 687-95 72 . Bett erid ge DJ. Dod son PM . Du rrin gton PM . et al. Man agem ent
56. Whitfield LR. Cilia Jr DD . Posvar EL . et al. Sin gle - and multi - of hyperlipidaemi a: guide lines of the Brit ish Hyperlipidae-
ple-dose pharm acokin eti cs of CI -981. a potent HMG- CoA mia Associ ation . Postgrad Med J 1993; 69: 359-69
redu ctase inhibitor [abstract] . Pharm Res 1993; 10 Suppl.: 73 . Scandin avian Sim vast atin Surviv al Stud y Group. Rand omi sed
S340 trial of cholesterol lower ing in 4444 patients with co ronary
57. Michniewicz BM. Black AE . Sinz MW. et al. In vitro and in heart disease: the Sca ndi navian Sim vast atin Sur vival Study
vivo met abol ism of ator vastatin (C I-98 1) [abstract] . ISSX Group (4S). Lancet 1994 ; 344 : 1383-9
Pro c 1994 ; 6: 93 74 . Sack s FM . Pfeffer M A. Moye LA. et al. Th e effect of
58 . Illingw orth DR. Tobert JA . A review of clin ical trials co mpar- pravastatin on co ronary e vents afte r myocardi al infarc tio n in
ing HMG-CoA redu cta se inh ibitors. Clin Th er 1994 ; 16 (3) : patients with aver age cho lesterol level s. N Engl J Med 1996;
366-85
335: 1001-9
59. Davidson MM. McK enney JM . Stein EA . et al. Long-t erm ef- 75 . Frick MH . Elo O. Haapa K. et al. Hel sinki heart study : primary-
ficacy and safety of atorvastatin co mpared to lovastatin in
preventi on trial with gemfibrozil in middle-aged men with
hypercholesterolemi c patients. Am J Cardiol 1997. In pres s
dy slipidemia. N Engl J Med 1987 ; 317 (20 ): 1237 -45
60 . Gib son DM . Bron NJ. Richen s A. et al. Effect of age and gender
76 . Sheperd J. Cobbe SM . Ford I. et al. Prevention of co ronary heart
on pharmacokinetics of atorv astatin in hum ans [437340] . J
disease with pravastatin in men with hyper chole sterolemia.
Cli n Pharmacol 1996; 36: 242 -6
N Engl J Med 1995; 333 (20) : 1301 -7
6 1. G ibso n DM . Yang B-B. Abel RB . et al. Effect s of hepatic and
77 . West of Scotland Coronary Prevention Group . West of Scotl and
renal imp airm ent on pharmacokineti cs (P K) and pharm aco-
Coronary Preventi on Stud y: identificat ion of high-risk
dyn ami cs (PD) of atorvastatin [abstract]. Pharm Res 1996 ; 13
gro ups and co mpari son wit h other car diovasc ular interven-
(9 Su ppl ).: S428
tion trials. Lancet 1996 Nov 16; 34 8: 1339-42
62 . Bocan TM A. Ferguso n E. McNall y W. et al. Hep atic and non -
78. van Boven AJ . Briigem ann J. de Grae ff PA. Th e 4S study : im-
hepa tic stero l synthesis and tissue di stribution follow ing ad-
plications for prescr ibin g. Dru gs 1996 Apr; 51 : 507-14
ministr ati on of a liver se lec tive HMG-C oA redu ctase
inhibitor. C I-98 I: co mparison with se lec ted HMG -CoA re- 79 . Expert Panel on Detection . Evaluation . and Treatment of High
duct ase inhibitors. Biochim Bioph ys Acta 1992 Jan 24; 1123 : Blood Cho les tero l in Ad ults. National Ch olesterol Educatio n
133-44 Program . Sec ond report of the Expert Panel on Detecti on.
63. Duggan DE. Vickers S. Physiological disposition ofHMG-CoA- Eva luation. and Treatm ent of High Blood Cholesterol in
reductase inhibitor s. Drug Met ab Rev 1990 ; 22 (4 ): 333-62 Adults (Adult Tre atment Pane l II ): II. Dietary therapy and
64 . Yang B-B . Sm ither s JA . Siedlik PH. et al. Atorvastatin ph arm a- ph ysi cal activity. Circul ation 1994 M ar ; 89 : 1364-404.
co kinetic interactions with other C YP3A 4 substrates : eryth- 1432-45
rom ycin and ethinyl estradiol [abstr act] . Pharm Res 1996; 13 80 . Gme rek A. Yang R. Bays H. et al. Ator vastatin causes a dose-
(9) Suppl.: S437 depen dent redu cti on in LDL- C and triglycerid es [abstra ct] .
65 . Yang B-B . Smithers JA . Abel RB. e t al. Effect s of Maalox TC® In: 66th Congress of the Euro pea n Atheroscleros is Societ y
on pharmacokin etics and ph ar macodyn amic s of atorvas tatin Abstrac t Book: 1996 Jul 13-7 : Floren ce (Italy). 2 12
[ab str act ]. Pharm Res 1996 ; 13 (9) Suppl.: S437 81. Nawrocki JW. Weiss SR . Davidson MH . et al. Redu cti on of
66. Oki Jc. Dysl ipid emi as in patients with diabetes mellitu s: cl as- LDL cho lestero l by 25 % to 60% in patients w ith primary
sific ation and risks and benefits of therap y. Pharm acoth erap y hypercholesterolemi a by atorvasta tin, a new HMG-CoA re-
1995 ; 15 (3): 3 17-3 7 du cta se inhibitor. Art Th rombosis Vasc BioI 1995 May; 15:
67 . Expert Panel on Detection . Evaluation. and Treatment of High 678 -82
Blood Chol esterol in Adults. Nati onal Ch olesterol Educati on 82. Hein onen TM . Stein E. We iss SR . et al. Th e lipid-l owerin g
Program. Second Report of the Expert Panel on Detection . effe cts of atorv astatin , a new HMG-CoA redu ctase inhibitor:
Evaluation . and Treatment of High Blood Cholesterol in result s of a double-masked stud y. Clin Th er 1996 ; 18 (5):
Adults (Ad ult Tre atment Panel II ). l. Cla ssific ation . pre va- 853 -63

© Ad is Int e rna tional Umite d . All rights reserved. Drugs 1997May: 53 (5)
 846 Lea & McTavish

83. Bertolini S, Bittolo Bon G, Campbell LM, et al. Efficacy and 99. Garne ll WR. Interactions with hydroxymeth ylglutaryl-coen-
safety of atorvastatin comp ared to pravastatin in patients with zyme A redu ctase inhibitors . Am J Health System Pharm
hypercholesterolemia. Atherosclerosis 1997. In press 1995; 52: 1639-45
84. Dart A. Jerum s G. Nicholson G. et al. A multicenter. double- 100 . Schucker B. Willes JT. Santanello NC. et al. Change in cho les-
blind . one-yea r study co mpa ring safe ty and efficacy of terol awareness and action: result s from national physician
atorvas tatin versus simvastatin in patient s with hypercholes- and public surveys . Arch Intern Med 1991 ; 15 I: 666- 73
tero lemia . Am J Cardi ol 1997 . In press 10 I. Theile DS. Epidemiology of hyper cholesterolemia and Euro-
85. Heinonen T. Stein E. Issacsohn J. et al. Atorvastatin in the treat- pean management guidelines. Cardi ology 1990; 77 Suppl. 4:
ment of severe hypercholesterol emi a [abstract) . In: 66th Con- 2-7
gress of the European Athero scle rosis Socie ty Abstrac t Book : 102. Multipl e Risk Factor Inter venti on Trial Research Group. Mul-
1996 July 13-17. Florence Italy. 2 14 tiple risk fac tor inter venti on trial. JAM A 1982; 148 ( 12):
86. Heinonen T. Black D. Atorvastat in monotherapy and co mbina- 1465-77
tion therapy in the treatment of severe hypercholesterolemia 103. Th e Lipid Research Clinics Coro nary Prim ary Prevention Trial
results: II. The relationship of reducti on in incidence of coro -
[abstract]. Atherosclerosis 1995 Jun ; 115 Suppl.: S20
nary heart disease to cholesterol lowering. JAMA 1984; 25 1:
87. Hein onen T. Schroll H. McKenn ey J. et al. The lipid-lowering
365-74
effects of atorvastatin and cole stipol used as monothe rapie s
104. The Lipid Research Clini cs Coronary Primary Prevention Trial
and in combination [abstract] . Athero scle rosis 1994 Sep 15;
results. I. Reduction in incidence of coronary heart disease.
109: 314
JAMA 1984 ; 251 : 35 1-64
88. Hein on en T, Schroll H, Bro yles F. et al. The effects of
105. ASPIRE Steerin g Group. A British Cardi ac Socie ty survey of
atorvas tatin in postmenopausal women [abstract] . In: 66th the potential for the secondary prev ention of coro nary d is-
Congress of the European Athero sclerosis Society Abstract ease: ASPIR E (Action on Secondary Pre vention thro ugh In-
Book : 1996 Jul 13-7; Florence (Italy), 56 terven tion to Redu ce Events). Heart 1996; 75: 334-42
89. Expert Panel on Detec tion. Evaluation . and Treatment of High 106. Austin MA. Plasma triglyceride and coron ary heart disease. Art
Blood Cholesterol in Adult s. National Cholesterol Education Th romb osis Vase Bioi 1991; II : 2-14
Program. Second report of the Expert Panel on Detection. 107. Criqui MH. Heiss G. Cohn K. et al. Plasma triglyceride le vel
Evalu ati on . and Tre atment of High Blood Cho les tero l in and mortality from coro nary artery disease. N Engl J Med
Adults (Adult Treatment Panel II): III. Drug treatment. Cir- 1993 Apr 29; 328: 1220-5
culation 1994 Mar; 89 : 1405- 19. 1432-45 108. Carlson LA. BOlliger LE. Ahfeldt poE. Risk factors for myocar-
90. Naoum ova RP. Marais D. Firth JC. et al. Atorvas tatin augments dia l infarction in the Stoc kholm Prospective Study. A 14-year
therapy of homozygous famil ial hypercholesterol emi a by in- follow-up focusing on the role of plasma triglycerides and
hibiting upregulation of cholesterol synthesis after apheres is cholesterol. Acta Med Sca nd 1979; 206 : 35 I-60
and bile acid sequestrants [abstract). Circulatio n 1996; 94 (8 109. Tenkanen L. Pietila K. Mannin en V. et al. Th e triglyceride issue
Suppl ).: 1-583 revisited. Findings from the Helsinki Heart Study. Arch Intern
91. McKenn ey JM. McCorm ick LS, Kafonek S. et al. Lipid lower- Med 1994 Dec 12-26; 154: 27 14-20
ing effects of atorvas tatin, a new HMG-CoA redu ctase inhib- 110. Castelli WP. T he triglycer ide issue revisited: a view from Fra-
ito r. and niacin in patients with co mbined or iso lated mingham . Am Heart J 1986; I 12 (2) : 432-7
hypertriglyceridemia. Park e-D avis. An n Arbo r. Michigan. I II . Hulley SB. Rosenm an RH. Bawol RD. et al. Epidemiology as
USA . (Data on file) a guide to cli nical dec isio ns: the assoc iation betwee n tri-
92 . Ooi TC. Heinonen T. Alaupovic P. et al. Efficacy and safety of glyceride and coronary heart disease. N Engl J Med 1980;
a new HMG-CoA reducta se inhib itor. atorvas tatin, in patients 302 : 1383-9
with co mbined hyperlip idemi a: co mparison with fenofibrate. 112. Pyorala K. De Backer G, Graham I, et al. Prevention of coro nary
Art Th romb osis Vase Bioi 1997. In press heart disease in clini cal practi ce: recom mendations of the
93. Best JD. Nicholson GC, O'Neal DN. et al. Atorvastatin and Task Force of the Europea n Societ y of Ca rdiology, Europea n
simvas tatin redu ce elevated chole sterol in non- insulin de- Atherosclerosis Society and European Society of Hyper ten-
sion. Eur Heart J 1994 Oct ; 15: 1300-31
pend ent diabete s]. Diabete s Nutr Met ab 1996; 9 (2): 74-80
113. Assmann G. Schulte H. Relation of high-d ensity lipopr otein
94. Naw rocki J, Schwartz S. Fayyad R. et al. Atorvastatin, a new
cholesterol and triglycerides to incidence of atherosclerotic
HM G-C oA reductase inhibitor is safe and effective in
coro nary artery disease (the PROCAM experience). Am J
NIDDM pat ient s with hyperlipidemia [abstract) . In: 66th
Card iol 1992; 70 : 733-7
Congress of the European Atherosclerosis Societ y Abstract
114. Havel RJ, Rapaport E. Management of primar y hyperlipi dem ia.
Book : 1996 Jul 13-7; Florenc e (Italy). 222 N Engl J Med 1995; 332 (22) : 1491-8
95 . Gerso n RJ. MacDonald JS. Alberts AW. et al. On the etiology 115. Ass mann G, Schulte H, von Eckardstein A. Hypertriglyceride-
of subcapsular lenticular opacities produ ced in dogs receiving mia and elevated lipoprotein (a) are a risk for major coronary
HMG- CoA reductase inhibitors. Exp Eye Res 1990; 50: 65-78 eve nts in middle-aged men . Am J Cardiol 1996; 77 : 11 79-84
96. Warner-Lambert Lipitor is first statin ind icated for reduction of 116. Byington RP. Jukerna JW, Salonen JT. et al. Reduction in car-
trigl ycer ides; co -promotions with Pfizer to tout head-to-head diovascular even ts dur ing pra vastatin therapy. Pooled analy-
co mparisons with competitors. FDC Rep Pink Sheet 1996 sis of cl inical eve nts of the pravastatin atheroscle ros is
Dec 23: 3-4 intervention program . Circulation 1995; 92 (9): 2419 -25
97. Newm an TJ . Kassler-Taub KB. Gelarden RT. et al. Safety of 117. Salonen R. Nyyssonen K. Porkkala E, et al. Kuopio Athero scle-
pravastatin in long-term trials co nducted in the United States. rosis Prevention Study (KAPS). A population-based primary
J Drug Dev 1990; 3 Suppl. I: 275-8 1 preventive trial of the effec t of LDL lowering on atheroscle-
98. Tho mpson GR. Adverse reacti ons profile: 10. Simvastatin and rotic progression in carot id and femoral arteries. Ci rcu lation
pravastatin . Prescr J 1990; 33 : 2 17-20 1995; 92 (7): 1758-64

© Adi s lnremo ttonol Urnite d . All rig hts reserved . Drug s 1997 Ma y: 53 (5)
Atorvastatin: A Review 847

118. Pill B. Ellis SG. Mancini GBJ. et al. Design and recruitment in randomised controlled clinical trial. Ann Intern Med 1996;
the United States of a multicenter quantitat ive angiographic 124 (6): 548-56
trial of pra vastatin to limit atherosclerosis in the coronary 127. Probstfield JL. Margitic SE. Byington RP. et al. Results of the
arteries (PLAC I). Am J Cardiol 1993 Jul I; 72: 31-5 prim ary outco me measure and clinic al events from the
119. Pill B. Mancini BJ. Ellis SG. et al. Pravastatin limitation of Asymptomatic Carotid Artery Progression Study. Am J Car-
atherosclerosis in the coro nary arterie s (PLAC I): reduction diol 1995; 76 (9): 47C -53C
in atherosclerosis progression and clinical events. J Am Coli 128. Furberg CD. Adams Jr HP. Applegate WB. et al. Effect of
Cardiol 1995; 26 (5): 1133-9 lovastatin on early carotid atherosclerosis and cardiovascular
120. Byington RP. Furberg CD. Crouse III JR. et al. Pravastatin, event s: Asymp tomatic Caro tid Artery Progression Study
lipids. and atherosclerosis in the carotid arteries (PLAC-II). (ACAPS) Research Group. Circulation 1995; 90 (4): 1679-87
Am J Cardiol 1995 Sep 28; 76: 54C-9C 129. MAAS Investigators. Effect of simvastatin on coronary ather-
121. Crouse III JR. Byington RP. Bond MG, et al. Pravastatin. lipids. oma: the Multicentre Anti-Atheroma Study (MAAS). Lancet
and atherosclerosis in the carotid arteries (PLAC-II). Am J 1994 Sep 3; 344 (8923): 633-8
Cardiol 1995 Mar I; 75: 455-9 130. Water D. Higginson L. Gladstone P. et al. Effects of monother-
122. Barth JD. Zonjee MMB. The REGRESS Research Group. Re- apy with an HMG-CoA reductase inhibitor on the progression
gression growth evaluation statin study (REGRESS): Study of coronary atherosclerosis as assessed by serial quantitative
des ign and baseline characteristics in 600 patients. Can J Car- arteriograp hy: the Canadian Coro nary Atherosclerosis Inter-
diol 1992 Nov; 8 (9): 925-32 vention Trial. Circulation 1994; 89 (3): 959-68
123. de Gro ot E. Jukema JW. van Bove n AJ. et al. Effec t of 131. Blankenhorn DH, Azen SP. Kramsch OM. et al. Coronary an-
pravastatin on progression and regression of coronary athero- giographic changes with lovastatin therapy: the Monitored
sclerosis and vessel wall changes in carotid and femoral ar- Atherosclerosis Regression Study (MARS). The MARS Re-
teries: a report from the Regression Grow th Evaluation Statin search Group. Ann Intern Med 1994; 119 (10): 969-76
Study. Am J Cardiol 1995 Sep 28; 76: 4OC-6C 132. The Post Coronary Artery Bypass Graft Trial Investigators. The
124. JukemaJW. Bruschke AVG. van Boven AJ. et al. Effects of lipid effect of aggressive lowering of low-density lipoprotein cho-
lowering by pravastatin on progression and regression of cor- lesterol levels and low-dose anticoagu lation on obstructive
onary artery disease in symptoma tic men with normal to mod- changes in saphenous vein graft coro nary artery bypass
erately elevated serum chole stero l leve ls. The Regression grafts. N Engl J Med 1997 Jan 16; 336: 153-62
Grow th Evaluatio n Statin Study (REG RESS). Circu lation 133. Parke-Davis. Ann Arbor. Michigan. USA. (Data on file)
1995; 91 ( 10): 2528-40
125. Kroon AA. Aenge vaeren WR. van der Werf T. et al. LDL-
Apheresis Atherosclerosis Regression Study (LAARS). Ef-
fect of aggress ive vers us conventional lipid lowe ring
Correspondence: DonnaMcTavish, Ad is International lim-
treatment on coronary atherosclerosis. Circulation 1996; 93
( 10) : 1826-35 ited, 41 Centorian Drive , Private Bag 65901, Mairangi Bay,
126. Hodis HN. Mack WJ, LaBree L. et al. Reduction of carotid Auckland 10, New Zeala nd .
arterial wall thickness using lovastatin and dietary therapy: a E-ma il: de mai [email protected]

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