Risk Factors and Drug Interactions Predisposing to Statin-Induced

Risk Factors and Drug Interactions

Predisposing to Statin-Induced Myopathy

Implications for Risk Assessment, Prevention and Treatment

Yiannis S. Chatzizisis,

1,2

Konstantinos C. Koskinas,

Gesthimani Misirli,

Christos Vaklavas,

Apostolos Hatzitolios

and George D. Giannoglou

1 1st Cardiology Department, AHEPA University Hospital, Aristotle University Medical School,

Thessaloniki, Greece

2 Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

3 Department of Internal Medicine, University of Texas Medical School at Houston, Houston, TX, USA

4 1st Propedeutic Department of Internal Medicine, AHEPA University Hospital, Aristotle University

Medical School, Thessaloniki, Greece

Contents

Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171

1. Definition and Epidemiology of Statin-Induced Myopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173

2. Comparison between Statins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173

3. Mechanisms of Statin-Induced Myopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174

4. Physicochemical and Pharmacokinetic Properties of Statins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174

5. Risk Factors that Precipitate Statin-Induced Myopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175

5.1 Patient Characteristics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175

5.1.1 Demographic Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175

5.1.2 Genetic Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176

5.1.3 Co-Morbidities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177

5.2 Statin Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177

5.2.1 Dose-Dependent Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177

5.2.2 Physicochemical Properties of Statins: Lipophilicity versus Hydrophilicity. . . . . . . . . . . . . . . 178

5.3 Statin-Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178

5.3.1 Interactions with Non-Hypolipidaemic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179

5.3.2 Interactions with Other Hypolipidaemic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180

6. Recommendations for the Prevention and Management of Statin-Induced Myopathy . . . . . . . . . . 181

6.1 Prevention of Statin-Induced Myopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181

6.2 Management of Statin-Induced Myopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181

7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182

Abstract HMG-CoA reductase inhibitors (‘statins’) represent the most effective and

widely prescribed drugs currently available for the reduction of low-density

lipoprotein cholesterol, a critical therapeutic target for primary and second-

ary prevention of cardiovascular atherosclerotic disease. In the face of the

established lipid lowering and the emerging pleiotropic properties of statins,

the patient population suitable for long-term statin treatment is expected to

further expand. An overall positive safety and tolerability profile of statins

REVIEW ARTICLE

Drug Saf 2010; 33 (3): 171-187

0114-5916/10/0003-0171/$49.95/0

has been established, although adverse events have been reported. Skeletal

muscle-related events are the most common adverse events of statin treat-

ment. Statin-induced myopathy can (rarely) manifest with severe and po-

tentially fatal cases of rhabdomyolysis, thus rendering the identification of

the underlying predisposing factors critical.

The purpose of this review is to summarize the factors that increase the

risk of statin-related myopathy. Data from published clinical trials, meta-

analyses, postmarketing studies, spontaneous report systems and case reports

for rare effects were reviewed. Briefly, the epidemiology, clinical spectrum

and molecular mechanisms of statin-associated myopathy are discussed. We

further analyse in detail the risk factors that precipitate or increase the like-

lihood of statin-related myopathy. Individual demographic features, genetic

factors and co-morbidities that may account for the significant inter-

individual variability in the myopathic risk are presented. Physicochemical

properties of statins have been implicated in the differential risk of currently

marketed statins. Pharmacokinetic interactions with concomitant medica-

tions that interfere with statin metabolism and alter their systemic bioavail-

ability are reviewed. Of particular clinical interest in cases of resistant

dyslipidaemia is the interaction of statins with other classes of lipid-lowering

agents; current data on the relative safety of available combinations are

summarized. Finally, we provide an update of current guidelines for the

prevention and management of statin myopathy.

The identification of patients with an increased proclivity to statin-

induced myopathy could allow more cost-effective approaches of monitoring

and screening, facilitate targeted prevention of potential complications, and

further improve the already overwhelmingly positive benefit-risk ratio of

statins.

Atherosclerotic cardiovascular disease is the

most frequent cause of morbidity and mortality

in developed countries. Low-density lipoprotein

cholesterol (LDL-C) reduction attenuates the pro-

gression of atherosclerosis and reduces the risk

of cardiovascular events. Among hypolipidae-

mic medications, HMG-CoA reductase inhibitors

(‘statins’) have unequivocally revolutionized both

primary and secondary prevention of cardiovas-

cular disease, due to their lipid-lowering potential

and pleiotropic effects that beneficially affect

atherosclerotic plaque stability.

[1]

Statins are com-

petitive inhibitors of HMG-CoA reductase, the

rate-limiting enzyme in cholesterol biosynthesis

that converts HMG-CoA into mevalonate. They

lower plasma LDL-C through intracellular cho-

lesterol depletion and upregulation of the expres-

sion of LDL receptors in hepatocytes.

[2]

The

number of patients receiving statins, often in

combination with other classes of lipid-lowering

agents, has expanded with the implementation of

more aggressive goals for LDL-C lowering,

[3]

while the additional benefit attributed to intensive

statin therapy has resulted in higher dose statin

regimens.

[4]

Accumulating evidence from controlled trials

and clinical experience demonstrates that statins

are well tolerated medicines with a good safety

profile.

[5-8]

The major and most common com-

plication to their use is a variety of skeletal

muscle-related events, which represent a clinically

important cause of statin intolerance and dis-

continuation. Statins confer a small but definite

risk of myopathy, a dose-dependent adverse ef-

fect associated with all statins (cla ss effect).

[9]

Muscular adverse effects are usuall y mild and

reversible; however, these adverse effects may be

a prelude to rhabdomyolysis, a very rare but po-

tentially serious and even life-threatening clinical

condition. The association of statins with cases of

172 Chatzizisis et al.

severe myopathic events may have resulted in

excessive safety concerns for this revolutionary

class of medications.

[10]

Notwithstanding the

overall good safety profile, knowledge of the un-

derlying mechanisms and risk factors is required

for prompt identification and proper manage-

ment of adverse muscle events. The purpose of

this review is to investigate the risk factors that

precipitate statin-induced muscle adverse events,

and also to summarize current guidelines on the

administration of statins with regard to their

potential myotoxicity.

1. Definition and Epidemiology of

Statin-Induced Myopathy

In the present revie w the term ‘myopathy’ will

be used as a general term to describe all skeletal

muscle-related problems.

[11]

Several, often con-

troversial, terms have been used to describe the

clinical manifestations and laboratory findings of

statin-induced myopathy. The spectrum of myo-

pathy includes asymptomatic increase of creatine

kinase (CK), myalgia, myositis and rhabdomyo-

lysis, as summarized in table I. Rhabdomyolysis

represents the least frequent, though potentially

fatal, complication caused by skeletal muscl e

breakdown, which leads to the release of toxic

intracellular constituents into the blood circula-

tion and eventually causes acute renal failure.

The lack of consensus in the definition of

statin-induced muscle events hinders the precise

estimation of their true incidence. Because patients

with a considered high susceptibility to statin

toxicity are generally excluded from clinical trials

of statins, reported adverse event rates from con-

trolled trials may underestimate the true rate of

these adverse effects in an unselected patient po-

pulation. Complaints of muscle symptoms occur in

1.5–3.0% of clinical trial participants, while rates

widely range between 0.3% and 33% in routine

practice.

[12]

No conclusive evidence supports in-

creased myalgia associated with standard statin

doses,

[13]

although this has been reported in pa-

tients receiving higher doses.

[14]

The overall excess

risk of myopathy attributed to standard statin do-

ses is typically <0.01%.

[13]

Accordingtodatafrom

randomized clinical trials and cohort studies, the

incidence of myopathy is estimated at 5 patients

per 100 000 person-years and rhabdomyolysis at

1.6 patients per 100 000 person-years,

[15]

whereas

reporting rates in the US FDA Adverse Event

Reporting System datab ase (AERS) are 0.3–2.2

cases of myopathy and 0.3–13.5 cases of rhabdo-

myolysis per 1 000000 statin prescriptions.

[16]

recent, large-scale trial evaluating rosuvastatatin

20 mg daily reported comparable rates of myo-

pathy between recipients of drug and placebo

(0.1%).

[17]

Regarding higher dose statin regimens,

increased risk of myopathy has been reported for

simvastatin 80 mg daily

[18]

but not for higher doses

of atorvastatin (80 mg).

[4,19,20]

2. Comparison between Statins

Reports associating the use of all marketed

statins with the entire spectrum of myopathy

suggest that this is a class effect.

[21]

The safety

profiles of different statins at standard doses

seem comparable but not identical, as indicated

by the significantly greater risk and subsequent

withdrawal of cerivastatin,

[22,23]

while excess risk

seems to be clearly related to increased doses. On

the basis of current evidence, and in the absence

of randomized trials directly comparing the risk

of each available statin in comparable doses and

with standard definitions of myopathic events, no

definite conclusions on the relative myopathic

potential conferred by each of the currently

marketed statins can be drawn.

[21]

An overall

Table I. The clinical spectrum of statin-induced myopathy

[11]

Condition Definition

Myopathy General term to describe all skeletal

muscle-related adverse effects

Asymptomatic CK elevation CK elevation without muscle

symptoms

Myalgia Muscle pain or weakness without

CK elevation

Myositis Muscle symptoms with CK

elevation typically <10 · ULN

Rhabdomyolysis Muscle symptoms with CK

elevation typically >10 · ULN, and

with creatinine elevation (usually

with brown urine and urinary

myoglobin)

CK = creatine kinase; ULN = upper limit of normal.

Statin-Induced Myopathy: Risk Factors and Drug Interactions 173

higher risk of rhabdomyolysis has been asso-

ciated with simvastatin 80 mg, whereas the lowest

incidence apparently occurs with fluvastatin and

pravastatin, presumably associated with their

weaker HMG-CoA reductase inhibitor capa-

city.

[12,15,24,25]

According to a meta-analysis

of trials comparing standard doses of all cur-

rently marketed statins except rosuvastatin,

atorvastatin was associated with the relatively

highest risk and fluva statin with the lowest risk of

adverse events in general, and muscular events in

particular.

[26]

A recently published meta-analysis

of randomized controlled trials comparing differ-

ent doses of atorvastatin (10–80 mg) and rosu-

vastatin (5–40 mg) revealed no significant difference

in adverse muscul ar events between these two

statins at any dose ratio.

[27]

3. Mechanisms of Statin-Induced

Myopathy

The pathogenetic mechanisms of statin-induced

myopathy have been thoroughly reviewed by

Vaklavas et al.

[28]

and are presented briefly in this

review. The interruption of the HMG-CoA re-

ductase biosynthetic pathway and the consequent

intracellular depletion of downstream intermediate

metabolites (i.e. isopentenylated proteins geranyl

pyrophosphatase and farnesyl pyrophosphatase)

and end products (i.e. cholesterol, dolichols, ubi-

quinone) are considered the cornerstone of the

myotoxic effects of statins. Reduction of pre-

nylated proteins can result in dysprenylation of

proteins, including lamins and small guanosine

triphosphatases, thereby causing an imbalance in

the intracellular signalling cascades and enhancing

apoptosis. Sarcolemmal cholesterol deficiency, as a

result of the dynamic equilibrium between mem-

brane and plasma lipids, may adversely modify

membrane physical properties, integrity and fluid-

ity, thus resulting in membrane destabilization.

[29]

Inhibition of dolichol synthesis has been impli-

cated in defective N-linked glycosylation of plasma

membrane proteins and impaired response to

growth factors.

[28]

Ubiquinone or coenzyme Q10 (CoQ10) is a re-

cognized constituent of oxidative phosphorylation

and adenosine triphosphate production in mito-

chondria required to maintain cell integrity.

[30]

Consistently, the decreased CoQ10 biosynthesis

and thus energy depletion mediated by statins has

been postulated to account for the potential myo-

toxicity of statins. Statin-mediated reduction of

circulating, but not intramuscular,

[31]

CoQ10 levels

has been reported, while no direct association

between decreased intramuscular CoQ10 levels

and mitochondrial myopathy has been established.

Accordingly, CoQ10 deficiency may represent

a predisposing rather than etiopathogenic factor

of statin mediated myopathy, possibly in a syner-

gistic manner with coexisting CoQ10-depleting

conditions.

[32]

The equilibrium between intramuscular statin

transport and efflux may be a critical regulator

of intramuscular drug concentration and con se-

quently the risk of myopathy. Organic anion

transporting polypeptide (OATP) 2B1, a re-

cognized hepatic uptake transporter for statins,

has also been identified in skeletal myofibres,

[33]

and the OATP inhibitor estrone sulphate pro-

tected the skeletal myofibres against pravastatin-

and fluvastatin-induced toxicity. Furthermore,

isoforms -1, -4 and -5 of the multidrug resistance-

associated protein (MRP), a well characterized

statin efflux transporter, are highly expressed in

skeletal muscle, and the inhibition of MRP with

probenecid precipitates skeletal muscle toxicity in

rats treated with rosuvastatin,

[34]

implying that

MRP-1 may be involved in statin efflux at the

myocyte level.

4. Physicochemical and

Pharmacokinetic Properties of Statins

The physicochemical propert ies of statins,

which determine their bioavailability and thereby

affect the risk of myopathy, are summarized in

table II. Water solubility affects statin perme-

ability through cellular membranes of non-hepa-

tic (including muscular) cells and their ability to

cross the blood-brain barrier. Pravastatin, rosu-

vastatin and to some extent fluvastatin exhibit

hydrophilic properties, as opposed to the lipo-

philicity of the other statin molecules (i.e. ator-

vastatin, simvastatin and lovastatin).

[35]

174 Chatzizisis et al.

The hepatic cytochrome P450 enzyme (CYP)

system is responsible for the metabolism of many

drugs, including statins to some extent with the

exception of pravastatin.

[36]

Lovastatin, simvas-

tatin and, to a lesser extent, atorvastatin are

metabolized by the CYP3A4 isozyme. Coadminis-

tration of the previously mentioned statins with

medications or food that either inhibit or are

substrates of CYP3A4 decreases the statins’ first-

pass metabolism, thereby resulting in increased

bioavailability.

[37]

Fluvastatin is mainly meta-

bolized by CYP2C9, and to a much lesser

extent by CYP3A4 and CYP2C8, and conse-

quently does not interact with CYP3A4 inhibi-

tors. Pravastatin is metabolized through several

pathways, including isomerization, sulfation,

glutathione conjugation and oxidation, and only

to a small extent (1%) by the CYP enzyme system;

it is the only statin with a significant renal excre-

tion (approximately 60% of the absorbed quan-

tity), in keeping with its hydrophilic nature.

[38]

This theoretically renders it safer as far as its

potential drug interactions are concerned.

[9]

Ro-

suvastatin undergoes minimal metabolism via the

CYP2C9 isoenzyme,

[39]

while 90% is eliminated

as the parent compound in the faeces.

The systematic bioavailability of statins is

quite low. All statins present a high affinity

with blood proteins (95%), except pravastatin

(approximately 50%). Atorvastatin and rosuvas-

tatin are the two statins with longer half-lives

(13–16 hours) and this property is most probably

linked to their higher lipid-lowering efficacy.

5. Risk Factors that Precipitate

Statin-Induced Myopathy

When administering statins, physicians should

take into consideration a series of factors that

potentially increase the risk of myopathic events.

As summarized in figure 1, a constellation of

factors are associated with the risk of statin-

associated myopathy development, including

(i) patient characteristics (demographic character-

istics, co-morbidit ies, genetic factors); (ii) drug

properties (specific statin molecule, dose, phar-

macokinetic properties); and (iii) concomitant

interacting medications. Systemic exposure

is considered to play a pivotal role in statin-

associated myopathy, and risk factors that enhance

the respective risk may do so, at least partly, by

increasing either statin systemic bioavailability or

the sensitivity to increased statin blood levels.

5.1 Patient Characteristics

5.1.1 Demographic Characteristics

Certain demographic characteristics have

been associated with an increased risk of statin-

induced myopathy. It has been observed

epidemiologically that advanced age (particularly

>80 years), female sex, small body frame and

frailty increase the myopathic effect of

Table II. Physicochemical and pharmacokinetic properties of statins

Characteristic Lovastastin Simvastatin Pravastatin Fluvastatin Atorvastatin Rosuvastatin

Daily dosage (mg) 20–80 10–80 20–80 40–80 10–80 10–40

Origin Fungi Semisynthetic Fungi Synthetic Synthetic Synthetic

Prodrug Yes Yes No No No No

Solubility Lipophilic Lipophilic Hydrophilic Intermediate Lipophilic Hydrophilic

CNS permeation Yes Yes No No No No

Effect of food intake on

absorption

Increased

absorption

None Decreased

absorption

None None None

First-pass metabolism CYP3A4 CYP3A4 Multiple ways CYP2C9 CYP3A4 Limited CYP2C9

Protein binding (%)9595 50989090

Half-life (hours) 2–32–31–20.5–213–16 19

Hepatic excretion (%)69 79 46 >68 Not available 63

Renal excretion (%)30 13 60 <6 <210

CYP = cytochrome P450 enzyme.

Statin-Induced Myopathy: Risk Factors and Drug Interactions 175

statins.

[11,13,40]

Myopathic symptoms may be

hard to differentiate from muscular complaints

commonly experienced in elderly patients. Poly-

pharmacy and age-related impairment of renal

function may in part account for the increased

risk of myopathy among elderly individuals. A

greater risk has been attributed to Chinese or

Japanese descent, although this concept is

inadequately supported by current evidence. Typi-

cally, Asians achieve similar benefits to Cauca-

sians at lower statin doses. Plasma levels of

rosuvastatin in particular have been shown to be

2-fold higher in Asian than in Caucasian in-

dividuals receiving similar rosuvastatin doses.

[41]

The smaller body mass index in Asians has been

postulated as the underlying cause of the differ-

ences in drug response in some

[42,43]

but not all

comparable studies.

[44,45]

Genetic differences in

statin metabolism involving the CYP450 enzymes

and the OATPs are more likely to account for the

heightened response to statins in Asians.

[46-48]

Although the increased systemic bioavailability

achieved with similar statin doses

[41]

has not been

clearly related to a higher myopathic risk in

Asians, rosuvastatin is labelled for lower doses

in Asians

[49]

and none of the statins are approved in

Japan at the highest doses approved in the US.

[50]

5.1.2 Genetic Factors

Genetic predisposition and interindividual

variability in susceptibility to statin-induced ad-

verse muscular events have been reported. A

number of candidate gene variants that encode

statin metabolizing enzymes and receptors,

[51,52]

OATPs

[53]

and CoQ10

[54]

have been implicated.

Genetic polymorphisms may result in variant

expression of the CYP isoenzymes both in the li-

ver and small intestine. Low hepatic or intestinal

expression of the CYP3A4 isoenzyme (‘poor

metabolizers’) results in decreased first-pass me-

tabolism for lovastatin, simvastatin and atorv-

astatin, which increases their bioavailability. In

a recently published study that performed a

genome-wide scan in patients with definite or in-

cipient myopathy receiving simvastatin 80 mg

daily, common variants in solute carrier organic

anion transporter (SLCO) 1B1 on chromosome

12, which encodes the OATP and thereby the

hepatic uptake of most statins, were linked to a

substantial excess risk of statin myopathy, with

60% of all myopathy cases attributable to one

specific common variant (rs4149056 C). Hetero-

zygotes for this variant displayed a 4-fold in-

crease in the incidence of myopathy, whereas the

homozygotes had a 17-fold increase.

[55]

Notably,

Dose

Pharmacokinetic properties

water solubility

first-pass metabolism

protein binding

Drug properties Patient characteristics Concomitant medications

Demographic characteristics

age

race

sex

Genetic predisposition

transporting polypeptides

CYP isoenzymes

Co-enzyme Q10 depletion

Co-morbidites

systemic diseases

infectious diseases

alcoholism/drug addiction

major surgical operations

myopathy

hereditary

acquired

Pharmacokinetic interactions

CYP metabolism

CYP3A4

CYP2C9

glucuronidation

Pharmacodynamic interactions

synergic myotoxicity

Increased systemic bioavailability

Enhanced susceptibility to elevated blood levels of statins

Myopathy

Fig. 1. Risk factors for statin-induced myopathy. CYP = cytochrome P450 enzyme.

176 Chatzizisis et al.

these associations were demonstrated among

patients receiving high doses of simvastatin

(80 mg daily), indicating that genotypic control

could optimize tailored therapeutic adjustments

in patients under high-dose regimens and with

coexisting risk factors.

5.1.3 Co-Morbidities

The incidence of statin-induced rhabdomyo-

lysis may be higher in patients with existing

myopathies, either hereditary (e.g. carnitine pal-

mityl transferase II deficiency, McArdle’s diseas e

and myoadenylate deaminase deficiency) or ac-

quired (e,g. postpolyomyelitis syndrome).

[56,57]

Statins have also been implicated in the potential

aggravation of myasthenia gravis.

[58]

Further-

more, an underlying metabolic predisposition

consisting of biochemical abnormalities in mito-

chondrial or fatty acid metabolism in myocytes

may render some apparently healthy individuals

more susceptible to the development of statin-

induced myopathic outcomes than others.

[59]

Underlying chronic systemic diseases may

serve as non-modifiable risk factors that decrease

statin metabolism and excretion, and thereby in-

crease their syst emic bioavailability. These fac-

tors render some patients more suscept ible to

myopathy and increase the probability of adverse

muscle events, whi ch may ensue at any time

during the administration of a statin. Although

limited data suggest a beneficial cardiovascular

effect of statins in patients with moderate renal

impairment,

[60]

coexisting renal failure increases

the risk of statin-induced myopathic events.

[13]

Diabetes mellitus constitutes a further myopathic

risk factor in patients receiving statins, particu-

larly combined with advanced age and chronic

renal fail ure,

[11]

although there is no consensus of

opinion.

[61]

Enhanced risk of statin-induced

myopathy with excessive alcohol consumption

cannot be conclusively supported by data from

randomized trials as alcoholism is an exclusion

criterion in most trials. However, increased al-

cohol intake per se confers a myotoxic poten-

tial

[62]

and alcohol abuse could raise the blood

levels of statins.

[12]

Untreated hypothyroidism is

considered to increase the risk of statin myo-

pathy,

[11,25,63]

and statins may aggrava te the

muscle symptoms and CK elevation caused by

occult hypothyroidism. Liver dysfunction has

been considered a risk factor for statin myo-

pathy,

[11,64-66]

mainly due to the involvement of

the hepatobiliary system in the metabolism and

excretion of most statins. Although hepatic dys-

function has been associated with statin-induced

rhabdomyolysis in reports by regulatory autho-

rities,

[67]

the exclusion of patients with hepatic

failure from randomized controlled trials pre-

vents the establishment of a direct link between

impaired liver function and height ened risk of

myopathy.

[4,6,17]

Furthermore, acutely acting factors predis-

pose to myopathy independently, and may trig-

ger the development of severe myopathy, even

rhabdomyolysis, in statin-receiving individuals.

Such precipitating conditions include the use of

addictive drugs (e.g. amfetamines, cocaine,

heroin, LSD, ecstasy),

[62]

serious viral

[68]

or bac-

terial infection,

[69,70]

major trauma and intense

muscle activity. Statins can exacerbate exercise-

induced skeletal muscle injur y, as reported in an

observational study in patients receiving high-

dose statins

[25]

and as suggested by the greater

CK response to exercise in statin- compared with

placebo-treated patients.

[71]

Statin-related myo-

pathy has been reported in the setting of extensive

surgical operations;

[72,73]

therefore, a short-term

withdrawal of statins during hospitalization

for major surgery is recommended.

[11]

In the case

of vascular surgery in particular, including cor-

onary bypass procedures, statins should not be

discontinued

[74]

in light of their beneficial plaque-

stabilizing effect, wi th the exception of preopera-

tive muscular sympto ms, marked perioperative

tissue compression or prolonged postoperative

energy deprivation.

[75]

5.2 Statin Properties

5.2.1 Dose-Dependent Effects

While the therape utic benefit from statin

therapy is related to the achieved LDL-C reduc-

tion,

[76]

the risk of adverse muscular events ap-

pears to be a dose-dependent adverse effect

[21]

regardless of the degree of LDL-C decrease.

[15]

However, there does not ap pear to be a linear

Statin-Induced Myopathy: Risk Factors and Drug Interactions 177

relationship between plasma levels achieved by a

certain drug dose and the risk of adverse muscular

events. Increased myopathic risk has been de-

monstrated with higher than currently marketed

doses of simvastatin (160 mg)

[76]

and pravastatin

(160 mg).

[77]

An increased incidence of myopathy

has also been shown in patients with acute cor-

onary syndromes receiving simvastatin 80 mg daily

compared with placebo or simvastatin 20 mg.

[18]

higher incidence of statin-related myalgia was at-

tributed to atorvastatin 80 mg compared with

simvastatin 20 mg

[14]

but notably this did not occur

when atorvastatin 80 mg was compared with either

atorvastatin 10 mg

[19]

or placebo.

[20]

5.2.2 Physicochemical Properties of Statins:

Lipophilicity versus Hydrophilicity

In vitro research data indicate that pravastatin,

which is water soluble, is less myotoxic in relation

to lovastatin and simvastatin.

[78]

Although the in-

hibition of hepatocellular cholesterol synthesis was

comparable between these three statins, the effect

of pravastatin was 85 times weaker in rat myo-

cytes. Moreover, pravastatin was 100-200 times

(in an inversely dose-dependent mode) less myo-

toxic.

[78]

Overall, different statins seem to exert di-

verse dose-dependent effects on the HMG CoA

reductase activity of non-hepatic cells in vitro.The

decreased myotoxicity of pravastatin appears to be

related to its decreased penetration of the cell

membrane and thus uptake by extra-hepatic tis-

sues, presumably associated with the hydro-

philicity of the molecule. Pravastatin is taken up by

the hepatic cells via a sodium-independent bile

acid transporter, the OATP,

[79]

which, along with

sodium-dependent taurocholate cotransporting

polypeptide, also mediates the active hepatic up-

take of the hydrophilic rosuva statin molecule. The

lipid-rich membranes of non-hepatic cells, such as

muscle cells, lack OATP so that they function as a

barrier to hydrophilic statins while allowing pas-

sive diffusion to lipophilic statins. However, the

hydrophilicity of some statins per se has not been

proven to offer clinically significant muscular pro-

tection

[12]

and no clinical evidence supports a direct

association between the degree of lipophilicity

and the myotoxic potential

[9]

since cases of

rhabdomyolysis have also been attributed to hy-

drophilic statins.

5.3 Statin-Drug Interactions

The interaction of statins with other categories

of medications can enhance their myotoxic po-

tential (table III). Indeed, approximately 60% of

cases of statin-related rhabdomyolysis are related

to drug interactions.

[24]

The underlying mechan-

ism usually has a pharmacokinetic basis invol-

ving intestinal absorption, distribution, metabo-

lism, protein binding or excretion of statins. The

majority of reported cases pertain to competition

at the level of hepatic metabolism,

[80]

considering

that over half of currently available drugs are

metabolized by the CYP3A4 isoenzyme; inhibi-

tion of the CYP activity by co administered drugs

increases the risk of myopathic events. Simvas-

tatin and lovastatin appear to be more susceptible

to the inhibiting effect of other CYP3A4 sub-

strates than atorvastatin. Similarly, the inter-

action between fluvastatin and CYP2C9 inhibitors

or competitive substrates may be of clinical im-

portance, whereas CYP450 isoenzymes are mini-

mally involved in rosuvastatin clearance.

Table III. Substances that may precipitate statin-induced myopathy

Non-hypolipidaemic medicines

Ciclosporin

Macrolide antibacterials (erythromycin, clarithromycin)

Azole antifungals (itraconazole, ketoconazole, fluconazole)

Calcium channel antagonists (diltiazem, verapamil)

Nefazodone

HIV protease inhibitors (ritonavir, nelfinavir, indinavir)

Warfarin

Histamine H

receptor antagonists (cimetidine, ranitidine)

Omeprazole

Amiodarone

Hypolipidaemic medicines

Fibrates (gemfibrozil > bezafibrate, clofibrate, fenofibrate)

Niacin

Other substances

Grapefruit juice

Over-the-counter medications (Chinese red rice fungus)

178 Chatzizisis et al.

Other sites of potential pharmacokinetic

interactions include inhibition of metabolism

by intestinal wall isoenzymes of the CYP system,

prevention of the OATP-mediated hepatocel-

lular uptake, blocking of biliary excretion and

inhibition of the renal elimination of hydrophilic

metabolites.

[80]

Pharmacodynamic interactions involving sta-

tins are less common because of the high selectivity

of statins as HMG-CoA reductase inhibitors.

The concomitant administration of agents with an

independent myotoxic effect, such as fibrates, can

synergistically increase the risk of statin-associated

myopathy. In that case, a pharmacokinetic com-

ponent may also come into play.

5.3.1 Interactions with Non-Hypolipidaemic Agents

Pharmacokinetic Interactions with Cytochrome

P450 Enzyme (CYP) 3A4 Inhibitors and Competing

Substrates

Inhibitors of CYP3A4 isoenzyme decrease

statin metabolism and thus increase their serum

levels and the likelihood of myopathy. Such en-

zymatic inhibitors include azole antifungals

(itraconazole, ketoconazole, fluconazole),

[37,81,82]

macrolide antibacterials (erythromycin, clari-

thromycin),

[83,84]

calcium channel antagonists

diltiazem

[85,86]

and verapamil, the antidepressant

nefazodone and the consumption of grapefruit

juice exceeding approximately 1 L daily. Grape-

fruit juice contain s 6

-dihydroxybergamottin,

which acts as an inhibi tor of the intestinal

CYP3A4 isoenzyme resulting in decreased meta-

bolism and thereby enhanced bioavailability of

statins.

[80]

HIV protease inhibitors (ritonavir, nelfinavir,

indinavir) are recognized CYP3A4 inhibitors and

this property renders the myotoxic potential of

their combination with statins high risk,

[87]

particular those statins that rely to a large extent

on the CYP3A4 isoform for their metabolism. Of

clinical interest is the adverse effect of HIV pro-

tease inhibitors on the lipid profile,

[88]

which may

increase the risk of cardiovascular disease and

pancreatitis and often requires the administration

of lipid-lowering agents.

[89]

Statins are the most effective medicines for the

treatment of hypercholesterolaemia in patients

who have undergone transplantation,

[90]

and

their immunomodulatory properties appear to

provide general protection for the graft. How-

ever, ciclosporin (cyclosporine) inhibits both in-

testinal and hepatic CYP3A4 activity and can

therefore lead to increased bioavailability of sta-

tins metabolized by this cytochrome.

[91]

The more

lipophilic the stat in and the greater the systemic

exposure to unbound active statin compound, the

greater the potential for myopathy.

[73,92]

Pravas-

tatin and fluvastatin are less likely to interact

with ciclosporin on a pharmacokinetic basis.

However, ciclosporin has been reported to in-

crease serum levels of pravastatin.

[93]

Competi-

tion at the level of biliary clearance resulting in

reduced pravastatin removal through the bile

duct and prevention of the P-glycoprotein trans-

fer are considered the main pathomechanisms,

indicating that CY P3A4 is not the only site in-

volved in clinically relevant ciclosporin-statin

interactions.

The combination of statins with warfarin is

likely to increase the serum levels of warfarin,

thereby potentiating its anticoagulant effect.

[94]

Regular anticoagulation control and possibly

warfarin dose adjustment may thus be required.

However, the potentiating effect of warfarin on

statin levels has not been studied sufficiently.

[95]

A hypothesis has been articulated that as war-

farin constitutes the substrate of CYP2C9, and

partly of CYP3A4, it could compete with statins

in their enzymatic conversion.

Pharmacokinetic Interactions with CYP2C9

Inhibitors and Competing Substrates

Azole antifungal agents are recognized in-

hibitors of CYP2C9, as well as the previously

mentioned CYP3A4. This necessitates a higher

index of suspicion when they are administered in

patients receiving fluvastatin. For example, flu-

conazole has been reported to increase fluvastatin

bioavailability,

[96]

although no cases of rhab-

domyolysis attributable to such a combination

are known. Furtherm ore, histamine H

receptor

antagonists cimetidine and ranitidine, and the

proton pump inhibitor omeprazole, which are

Statin-Induced Myopathy: Risk Factors and Drug Interactions 179

also substrates of CYP2C9, enhance fluvastatin’s

systemic exposure, but without particular clinical

significance. Of note, omeprazole also appears to

possess a CYP3A4 induction capacity, poten-

tially increasing the biotransformation and thus

decreasing levels of statins that are substrates of

the CYP3A4 isoenzyme.

[37]

5.3.2 Interactions with Other Hypolipidaemic

Agents

Fibrates

In many cases of mixed dyslipidaemia, in dia-

betic patients or in patients with high triglycer-

ides despite the achieve ment of the desirable

LDL-C goal, the coadministration of statins with

fibrates is an attractive therape utic option. Ac-

cording to data from epidemiological studies and

clinical trials, the combination of any statin with

fibrates increases the risk of myopathy, which is

usually observed within the first 12 weeks by the

initiation of treatment. The incidence of myo-

toxicity with this combination is 0.12%.

[97]

Even

if most reports involve gemfibrozil,

[98,99]

other

fibrates (bezafibrate, clofibrate, fenofibrate) have

also been implicated in cases of rhabdomyolysis

when used alone and have an additive myotoxic

potential when combined with statins.

[99]

The

presence of gemfibrozil in most cases of rhabdo-

myolysis is partly explained by its wider clinical

use than other fibrates; however, the differential

safety profile of fibrates seems to remain even

after correction for the wider prescription of

gemfibrozil.

[100]

Since fibrates do not interfere with CYP-

mediated statin elimination, the additive adverse

effect when combined with statins appears to

have a predominantly pharmacodynamic basis

(synergy). The incidence of hospitalized patients

with rhabdomyolysis prescribed fibr ate mono-

therapy has been reported to be more than

5 times higher than with atorvastatin, pravastatin

or simvastatin monotherapy.

[101]

Pharmacoki-

netic parameters are also believed to account to

some degree for the observed interactions. Statin

glucoronidation is an intermediate step in the

conversion of active acid forms to lactones, which

in turn are metabolized by the hepatic P450 sys-

tem.

[102]

The inhibition of statin hydroxy acid

glucoronidation mediated by gemfibrozil

[103]

but

not fenofibrate and subsequent increased bio-

availability of statins is believed to partly account

for the increased myopathic risk associated with

the combination of statins with fibrates. Further-

more, statin-fibrate interactions may in part be

mediated through the activation of the peroxi-

some proliferator-activated family of nuclear re-

ceptors,

[104]

which have been shown to affect

CYP regulation. Moreover, gemfibrozi l has been

reported to reduce the renal clearance of pravas-

tatin by competitively acting at the transport

proteins

[105]

and it increases pravastatin and ro-

suvastatin concentrations by impeding their bili-

ary excretion.

[37]

Niacin

The addition of niacin in a statin-receiving

patient can yield complementary benefits in

achieving a comprehensive lipid control. The

concomitant administration of statins with high

doses of niacin has been associated with rhabdo-

myolysis in a limited number of anecdotal

reported c ases

[106]

through a mechanism that re-

mains unknown but appears to be unrelated to

statin serum levels. Niacin is not implicated as a

strong precipitating factor for statin-induced

myopathy, and the combination of statin and

niacin is considered to carry a lower risk than

statin-fibrate coadministration.

[21]

Based on cur-

rent evidence, no excessive risk of myopoat hy as a

result of a statin-niacin combination, compared

with that expected by adding one agent to the

other, can be supported.

[107]

Ezetimibe

Combined inhibition of intestinal cholesterol

absorption mediated by ezetimibe and hepatic

cholesterol synthesis via statins has emerged as a

challenging therapeutic option. Anecdotal reports

of myopathy attributed to the combination of sta-

tin plus ezetimibe

[108,109]

have not been confirmed

in the setting of randomized controlled trials. An

enhanced lipid-lowering effect and comparable

safety profile was shown when ezetimibe was ad-

ded to statins in patients with hypercholester-

olaemia.

[110]

The incidence of muscle-related events

was not higher in patients taking simvastatin

alone than the combination of simvastatin plus

180 Chatzizisis et al.

ezetimibe according to pooled data from 17 re-

lative randomized clinical trials.

[111]

In recent stud-

ies, the addition of ezetimibe 10 mg resulted in

greater lipid-lowering efficacy than, and equal

safety and tolerability to, uptitration of atorvasta-

tin 20–40mg in patients at moderately high risk

[112]

and to the doubling of atorvastatin 40–80 mg in

patients at high risk for coronary heart disease.

[113]

Overall, current evidence cannot support enhanced

risk for statin-related myopathy by the coadmi-

nistration of ezetimibe.

[21]

6. Recommendations for the Prevention

and Management of Statin-Induced

Myopathy

6.1 Prevention of Statin-Induced Myopathy

Prevention and early recognition are the best

approaches to managing statin-related myopathy

and averting serious sequelae. Statin treatment

should begin with low doses that can be pro-

gressively increased; if necessary, the anticipated

clinical benefit should be weighed against the

increased myopathic risk. Coadministration of

interacting medications should be avoided

whenever possible. When a high-risk combina-

tion is necessary, small doses of the presumably

safest statin for any given combination should be

prescribed.

Patients should be counselled on the risk and

warning signs of myopathy, and on the possibility

of drug interactions. Any unexplained muscle

symptoms should be reported immediately to the

attending physician. Patients at high risk should

be followed up clinically, especially during the

first months of treatment. When acute clinical

conditions that can precipitate rhabdomyoly-

sis coexist, it is advisable to interrupt statins

temporarily.

Routine measurement of pretreatment CK

levels is not recommended because of the rarity of

myopathy when statins are prescribed at usual

doses in the general population. However, CK

should be measured in patients at high risk for

myopathy, at baseline and regularly during the

course of statin therapy.

[21]

If a statin-fibrate combination is required,

fenofibrate is the preferred option over gemfi-

brozil.

[80,100,114]

Thestatindosesshouldremain

below the maximal levels. Fluvastatin may be ap-

propriate for combination with gemfibrozil.

[115]

Particular attention is required for patients with

increased CK levels, and renal and hepatic

dysfunction.

On the basis of current evidence, routine CoQ10

supplementation cannot be recommended to pre-

vent statin-related myopathic events.

[21]

CoQ10

supplementation might be considered in the setting

of CoQ10-depleting conditions, such as advanced

age or multisystem diseases.

[30]

6.2 Management of Statin-Induced

Myopathy

Statin-induced myopathy is usually mild and

reversible upon statin discontinuation; however,

in very rare cases it may evolve towards severe

muscle damage, even rhabdomyolysis. If statin-

related myopathy is suspected, more common

causes of symptoms and/or CK elevation should

be ruled out by thorough history taking, physical

examination and laboratory tests. Other etiolo-

gies of muscle symptoms include unusual phy si-

cal activity, trauma, falls, accidents, seizures,

alcohol, drugs (corticosteroids, antipsychotics,

cocaine, amfetamines), occult hypothyroidism,

infections and autoimmune disorders (polymyo-

sitis, dermatomyositis, rheumatic polymyal-

gia).

[116]

Initial tests include CK levels, serum

thyroid-stimulating hormone levels, and renal

function with urinalysis if rhabdomyolysis is

suspected. In rare cases of persistent symptoma-

tology despite statin discontinuation, further in-

vestigations including electromyography and

muscle biopsy may be required, in consultation

with experts in muscle diseases.

[116]

The intensity of clinical symptoms along with

the magnitude of CK elevation should guide

clinical management, as summarized in figure 2.

In the case of CK levels <10 · the upper limit of

normal, without or with tolerable muscle symp-

toms, the statin may be continued at the same or

a smaller dose.

[116]

In the presence of tolerable

symptoms with CK serum elevation >10 · the

Statin-Induced Myopathy: Risk Factors and Drug Interactions 181

upper limit of normal, or if frank rhabd omyolysis

develops, statins should be discontinued. Rhab-

domyolysis prompts in-hospital supportive treat-

ment consisting of intravenous hydration and

monitoring for potential complications.

[117]

Intolerable muscle symptoms, regardless of CK

levels, require temporary statin interruption.

Once symptoms resolve, the same or lower dose

of the same or a different statin can be restarted.

Alternative statin regimens with an ostensibly

lower myopathic potential may include fluvasta-

tin extended release,

[118]

low-dose rosuvastatin,

[119]

and non-daily regimens with atorvastatin

[120-122]

or rosuvastatin.

[123-126]

If symptoms reoccur,

statin suspension should be permanent. Non-

statin lipid-lowering agents that have shown ef-

ficacy and safety in patien ts intolerant to statins

include ezetimibe,

[118,127]

alone or in combination

with bile acid-binding resin.

[128]

7. Conclusions

Statins represent the most effective class of

medications for reduction of LDL-C and there-

fore for the prevention of cardiovascula r athero-

sclerotic disease. Although myopathy is their

most common adverse effect, severe muscle-

related complications are very rare and should

not deter physicians from prescribing these gen-

erally safe and well tolerated agents. Several fac-

tors that may predispose to, or trigger, myopathic

events in statin-receiving patients have been

well characterized. Individual risk stratification,

taking into consideration patient characteristics,

Suspected statin-induced myopathy

Asymptomatic CK elevation

Exclude other causes

Measure CK levels

CK <10 × ULN CK >10 × ULN

CK <10 × ULN

CK >10 × ULN

CK >10 × ULN and renal function impairment

Normal

Myalgia

Myositis

TolerableIntolerable

RhabdomyolysisAssess symptom severity

Assess CK levels

Elevated

Yes

Continue statin

(same/reduced dose)

Treatment adjustment

based on CK monitoring

Continue statin

(same/reduced dose)

Treatment adjustment

based on symptoms

Restart statin once

symptoms resolve

(same/different statin,

same/reduced dose)

Symptoms recurrence?

Discontinue

statin

Discontinue statin Discontinue statin

Muscle-related symptoms ± CK elevation

Fig. 2. Assessment and management of statin-induced myopathy. CK = creatine kinase; ULN = upper limit of normal.

182 Chatzizisis et al.

coadministered medications and statin pharma-

cological properties, should determine clinical

decision making. Considering the dose-dependen t

nature of statin-related myopathy, physicians

should start cautiously with lower doses in the

presence of predisposing conditions and weigh

the benefit of lipid lowering versus the potential

of excess risk when uptitrating doses. Combina-

tion therapy with other classes of hypolipidaemic

agents may be opted for when aggressive lipid-

lowering therapy is required. Since most patients

eligible for statins receive multiple concomitant

medications, often sharing the metabolic path-

way of the CYP system, recognition of potential

drug interactions is critical. Knowledge of the

pharmacokinetic properties of currently available

statins may allow the identification of the statin

at the presumably lowest risk for drug inter-

actions. In the clinical setting, counselling patients

on the risk and warning signs of myopathy will

increase awareness and allow prompt recogni-

tion and appropriate management of myopathic

events. In order to accurately estimate the true

incidence of statin-induced myopathy and en-

hance our understanding of potential risk factors,

a more complete and formal reporting of the

entire spectrum of muscle-related events attribu-

table to statins is required.

Acknowledgements

No sources of funding were used to assist in the prepara-

tion of this review. The authors have no conflicts of interest

to declare. Y.S. Chatzizisis and K.C. Koskinas contributed

equally to this work.

References

1. Chatzizisis YS, Jonas M, Beigel R, et al. Attenuation of

inflammation and expansive remodeling by valsartan

alone or in combination with simvastatin in high-risk

coronary atherosclerotic plaques. Atherosclerosis 2009;

203: 387-94

2. Istvan ES, Deisenhofer J. Structural mechanism for statin

inhibition of HMG-CoA reductase. Science 2001; 292

(5519): 1160-4

3. Grundy SM, Cleeman JI, Merz CN, et al., for the Co-

ordinating Committee of the National Cholesterol Edu-

cation Program and Endorsed by the National Heart,

Lung, and Blood Institute, American College of Cardiol-

ogy Foundation, and American Heart Association.

Implications of recent clinical trials for the National

Cholesterol Education Program Adult Treatment Panel

III Guidelines. Circulation 2004; 110: 227-39

4. Cannon CP, Braunwald E, McCabe CH, et al. Intensive

versus moderate lipid lowering with statins after acute

coronary syndromes. N Engl J Med 2004; 350: 1495-504

5. Schwarz GG, Olsson AG, Ezekowitz MD, et al. Effects of

atorvastatin on early recurrent ischemic events in acute

coronary syndromes. The MIRACLE study: a rando-

mized controlled trial. JAMA 2001; 285: 1711-8

6. Heart Protection Study Collaborative Group. MRC/BHF

Heart Protection Study of cholesterol lowering with sim-

vastatin in 20,536 high-risk individuals: a randomised

placebo-controlled trial. Lance t 2002; 360 (9326): 7-22

7. Shepherd J, Blauw GJ, Murphy MB, et al., PROSPER

study group. Pravastatin in elderly individuals at risk of

vascular disease (PROSPER): a randomised controlled

trial. PROspective Study of Pravastatin in the Elderly at

Risk. Lancet 2002; 360: 1623-30

8. Sever PS, Dahlof B, Poulter NR, et al., ASCOT in-

vestigators. Prevention of coronary and stroke events with

atorvastatin in hypertensive patients who have average or

lower-than-average cholesterol concentrations, in the

Anglo Scandinavian Cardiac Outcomes Trial – Lipid

Lowering Arm (ASCOT-LLA): a multicentre randomised

controlled trial. Lancet 2003; 361: 1149-58

9. Evans M, Rees A. Effects of HMG-CoA reductase in-

hibitors on skeletal muscle: are all statins the same? Drug

Saf 2002; 25 (9): 649-63

10. Bolego C, Baetta R, Bellosta S, et al. Safety considerations

for statins. Curr Opin Lipidol 2002; 13 (6): 637-44

11. Pasternak RC, Smith SC Jr, Bairey-Merz CN, et al., and

Writing Committee Members. ACC /AHA/NHLBI clin-

ical advisory on the use and safety of statins. Circulation

2002; 106: 1024-8

12. Bays H. Statin safety: an overview and assessment of the

data: 2005. Am J Cardiol 2006; 97 Suppl. 8A: 6-26C

13. Armitage J. The safety of statins in clinical practice. Lancet

2007; 370: 1781-90

14. Pedersen TR, Faergeman O, Kastelein JP, et al. High-dose

atorvastatin vs usual-dose simvastatin for secondary pre-

vention after myocardial infarction. The IDEAL study: a

randomized controlled trial. JAMA 2005; 294: 2437-45

15. Law M, Rudnicka AR. Statin safety: evidence from the

published literature. Am J Cardiol 2006; 97 Suppl. 8A:

52-60C

16. Davidson MH, Clark JA, Glass LM, et al. Statin safety: an

appraisal from the Adverse Event Reporting System

(AERS). Am J Cardiol 2006; 97 Suppl. 8A: 32-43C

17. Ridker PM, Danielson E, Fonseca FA, et al., JUPITER

Study Group. Rosuvastatin to prevent vascular events in

men and women with elevated C-reactive protein. N Engl

J Med 2008; 359 (21): 2195-207

18. de Lemos JA, Blazing MA, Wiviott SD, et al. Early in-

tensive vs. a delayed conservative simvastatin strategy in

patients with acute coronary syndromes: phase Z of the A

to Z trial. JAMA 2004; 292: 1307-16

19. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid

lowering with atorvastatin in patients with stable cor-

onary disease. N Engl J Med 2005; 352: 1425-35

Statin-Induced Myopathy: Risk Factors and Drug Interactions 183

20. The Stroke Prevention by Aggressive Reduction in

Cholesterol Levels (SPARCL) Investigators. High-dose

atorvastatin after stroke or transient ischemic attack.

N Engl J Med 2006; 355: 549-59

21. Thompson PD, Clarkson PM, Rosenson RS. An assess-

ment of statin safety by muscle experts. Am J Cardiol

2006; 97 Suppl.: 69-76C

22. US Food and Drug Administration. Office of Drug Safety

annual report 2001 [online]. Available from URL: http:

//www.fda.gov/AboutFDA/CentersOffices/CDER/ucm16

9925.htm. [Accessed 2009 Aug 5]

23. Staffa JA, Chang J, Green L. Cerivastatin and reports of

fatal rhabdomyolysis. N Engl J Med 2002; 346 (7): 539-40

24. Kashani A, Phillips CO, Foody JA, et al. Risks associated

with statin therapy: a systematic overview of randomized

clinical trials. Circulation 2006; 114: 2788-97

25. Bruckert E, Hayem G, Dejager S, et al. Mild to moderate

muscular symptoms with high-dosage statin therapy in

hyperlipidemic patients: the PRIMO study. Cardiovasc

Drugs Ther 2005; 19: 403-14

26. Silva MA, Swanson AC, Gandhi PG, et al. Statin-related

adverse events: a meta-analysis. Clin Ther 2006; 28: 26-33

27. Wlodarczyk J, Sullivan D, Smith M. Comparison of bene-

fits and risks of rosuvastatin versus atorvastatin from a

meta-analysis of head-to-head randomized controlled

trials. Am J Cardiol 2008; 102 (12): 1654-62

28. Vaklavas C, Chatzizisis YS, Ziakas A, et al. Molecular

basis of statin-associated myopathy. Atherosclerosis 2009

Jan; 202 (1): 18-28

29. Morita I, Sato I, Ma L, et al. Enhancement of membrane

fluidity in cholesterol-poor endothelial cells pre-treated

with simvastatin. Endothelium 1997; 5 (2): 107-13

30. Marcoff L, Thompson PD. The role of coenzyme Q10 in

statin-associated myopathy: a systematic review. J Am

Coll Cardiol 2007; 49: 2231-7

31. Laaksonen R, Jokelainen K, Sahi T, et al. Decreases in

serum ubiquinone concentrations do not result in reduced

levels in muscle tissue during short-term simvastatin

treatment in humans. Clin Pharmacol Ther 1995; 57: 62-6

32. Chatzizisis YS, Vaklavas C, Giannoglou GD. Coenzyme

Q10 depletion: etiopathogenic or predisposing factor in

statin associated myopathy [letter]? Am J Cardiol 2008

Apr 1; 101 (7): 1071

33. Sakamoto K, Mikami H, Kimura J. Involvement of or-

ganic anion transporting polypeptides in the toxicity of

hydrophilic pravastatin and lipophilic fluvas tatin in rat

skeletal myofibres. Br J Pharmacol 2008; 154: 1482-90

34. Dorajoo R, Pereira BP, Yu Z, et al. Role of multi-drug

resistance-associated protein-1 transporter in statin in-

duced myopathy. Life Sci 2008; 82: 823-30

35. Hamelin BA, Turgeon J. Hydrophilicity/lipophilicity: re-

levance for the pharmacology and clinical effects of

HMG-CoA reductase inhibitors. Trends Pharmacol Sci

1998; 19 (1): 26-37

36. Shitara Y, Sugiyama Y. Pharmacokinetic and pharmaco-

dynamic alterations of 3-hydroxy-3-methylglutaryl co-

enzyme A (HMG-CoA reductase inhibitors: drug-drug

interactions and interindividual differences in transporter

and metabolic enzyme functions. Pharmacol Ther 2006;

112: 71-105

37. Bellosta S, Paoletti R, Corsini A. Safety of statins: focus on

clinical pharmacokinetics and drug interactions. Circula-

tion 2004; 109 Suppl. III: III50-7

38. Haria M, McTavish D. Pravastatin: a reappraisal of its

pharmacological properties and clinical effectiveness in

the manag ement of coronary heart disease. Drugs 1997;

53 (2): 299-336

39. White CM. A review of the pharmacologic and pharma-

cokinetic aspects of rosuvastatin. J Clin Pharmacol 2002;

42: 963-70

40. Schech S, Graham D, Staffa J, et al. Risk factors for statin-

associated rhabdomyolysis. Pharmacoepidemiol Drug Saf

2007; 16 (3): 352-8

41. Lee E, Ryan S, Birmingham B, et al. Rosuvastatin phar-

macokinetics and pharmacogenetics in white and Asian

subjects residing in the same environment. Clin Pharma-

col Ther 2005; 78 (4): 330-41

42. Tan C-E, Ma S, Wai D, et al. Can we apply the National

Cholesterol Education Program Adult Treatment Panel

definition of the metabolic syndrome to Asians? Diabetes

Care 2004; 27: 1182-6

43. Matsuzawa Y, Kita T, Mabuchi H, et al., for the J-LIT

Study Group. Sustained redu ction of serum cholesterol in

low-dose 6-year simvastatin treatment with minimum side

effects in 51 321 Japanese hypercholesterolemic patients:

implication of the J-LIT study, a large scale nationwide

cohort study. Circ J 2003; 67: 287-94

44. Morales D, Chung N, Zhu J-R, et al. Efficacy and safety

of simvastatin in Asian and non-Asian coronary heart

disease patients: a comparison of the GOALLS and

STATT studies. Curr Med Res Opin 2004; 20: 1235-43

45. Tan CE, Loh LM, Tai ES. Do Singapore patients require

lower doses of statins? The SGH Lipid Clinic experience.

Singapore Med J 2003; 44: 635-8

46. Kim K, Johnson JA, Derendorf H. Differences in drug

pharmacokinetics between East Asians and Caucasians

and the role of genetic polymorphisms. J Clin Pharmacol

2004; 44: 1083-105

47. Wang A, Yu BN, Luo CH, et al. Ile 118Val genetic poly-

morphism of CYP3A4 and its effects on lipid-lowering

efficacy of simvastatin in Chinese hyperlipidemic patients.

Eur J Clin Pharmacol 2005; 60: 843-8

48. Liao JK. Safety and efficacy of statins in Asians. Am J

Cardiol 2007; 99 (3): 410-4

49. Food and Drug Administration Center for Drug Evaluation

and

Res

earch. FDA Public Health Advisory on Crestor

(rosuvastatin) [online]. Available from URL: http://www.

fda.gov/Drugs/DrugSafety/PublicHealthAdvisories/ucm051

756.htm [Accessed 2009 Aug 1]

50. Saito M, Hirata-Koizumi M, Urano T, et al. A literature

search on pharmacokinetic drug interactions of statins

and analysis of how such interactions are reflected in

package inserts in Japan. J Clin Pharm Ther 2005; 30:

21-37

51. Vermes A, Vermes I. Genetic polymorphisms in cyto-

chrome P450 enzymes: effect on efficacy and tolerability

of HMG-CoA reductase inhibitors. Am J Cardiovasc

Drugs 2004; 4: 247-55

52. Mulder AB, van Lijf HJ, Bon MA, et al. Association of

polymorphism in the cytochrome CYP2D6 and the effi-

184 Chatzizisis et al.

cacy and tolerability of simvastatin. Clin Pharmaco l Ther

2001; 70: 546-51

53. Morimoto K, Ueda S, Seki N, et al. OATP-

C(OATP01B1)*15 is associated with statin-induced

myopathy in hypercholesterolemic patients. Clin Phar-

macol Ther 2005; 77: P21

54. Oh J, Ban MR, Miskie BA, et al. Genetic determinants of

statin intolerance. Lipids Health Dis 2007; 6: 7

55. The SEARCH Collaborative Group. SLCO1B1 variants

and statin-induced myopathy: a genomewide study.

N Engl J Med 2008; 359 (8): 789-99

56. Leung NM, Ooi TC, McQueen MJ. Use of statins and

fibrates in hyperlipidemic patients with neuromuscular

disorders. Arch Intern Med 2000; 132: 418-9

57. Franc S, Bruckert E, Giral P, et al. Rhabdomyolysis in

patients with preexisting myopathy, treated with anti-

lipemic agents. Presse Med 1997; 26: 1855-8

58. Oh SJ, Dhall R, Young A, et al. Statins may aggravate

myasthenia gravis. Muscle Nerve 2008; 38: 1101-7

59. Vladutiu R, Isackson P, Peltier W, et al. Genetic risk fac-

tors and metabolic abnormalities associated with lipid

lowering therapies. Muscle Nerve 2006; 34 (2): 153-62

60. Fried LF, Orchard TJ, Kasiske BL. Effect of lipid reduc-

tion on the progression of renal disease: a meta-analysis.

Kidney Int 2001; 59: 260-9

61. Nichols GA, Koro CE. Does statin therapy initiation in-

crease the risk for myopathy? An observational study of

32 225 diabetic and nondiabetic patients. Clin Ther 2007;

29 (8): 1761-70

62. Giannoglou GD, Chatzizisis YS, Misirli G. The syndrome

of rhabdomyolysis: pathophysiology and diagnosis. Eur J

Intern Med 2007; 18: 90-100

63. Bar SL, Holmes DT, Frohlich J. Asymptomatic hypo-

thyroidism and statin induced myopathy. Can Fam Phy-

sician 2007; 53 (3): 428-31

64. Sathasivam S, Lecky B. Statin induced myopathy. BMJ

2008; 337: a2286

65. Davidson MH, Robinson JG. Safety of aggressive lipid

management. J Am Coll Cardiol 2007; 49: 1753-62

66. Thompson PD, Clarkson P, Karas RH. Statin-associated

myopathy. JAMA 2003; 289 (13): 1681-90

67. Ronaldson KJ, O’Shea JM, Boyd IW. Risk factors for

rhabdomyolysis with simvastatin and atorvastatin. Drug

Saf 2006; 29 (11): 1061-7

68. Wong WM, Wai-Hung Shek T, Chan KH. Rhabdomyo-

lysis triggered by cytomegalovirus infection in a heart

transplant patient on concomitant cyclosporine and

atorvastatin therapy. Gastroenterol Hepatol 2004; 19 (8):

952-3

69. Finsterer J, Zuntner G. Rhabdomyolysis from simvastatin

triggered by infection and muscle exertion. South Med J

2005; 98 (8): 827-9

70. Betrosian A, Thireos E, Kofinas G, et al. Bacterial sepsis-

induced rhabdomyolysis. Intensive Care Med 1999; 25:

469-74

71. Thompson PD, Zmuda JM, Domalik LJ, et al. Lovastatin

increases exercise-induced skeletal muscle injury. Meta-

bolism 1997; 46: 1206-10

72. Wilhelmi M, Winterhalter M, Fisher S, et al. Massive post-

operative rhabdomyolysis following combined CABG/

abdominal aortic replacement: a possible association with

HMG-CoA reductase inhibitors. Cardiovasc Drugs Ther

2002; 16 (5): 471-5

73. East C, Alivizatos PA, Grundy SM, et al. Rhabdomyolysis

in patients receiving lovastatin after cardiac transplanta-

tion. N Engl J Med 1988; 318 (1): 47-8

74. Schouten O, Kertai MD, Bax JJ, et al. Safety of perio-

perative statin use in high-risk patients undergoing major

vascular surgery. Am J Cardiol 2005; 95 (5): 658-60

75. Antons KA, Williams CD, Baker SK, et al. Clinical per-

spectives of statin-induced rhabdomyolysis. Am J Med

2006; 119: 400-9

76. Davidson MH, Stein EA, Dujovne CA, et al. The efficacy

and six-week tolerability of sim vastatin 80 and

160 mg/day. Am J Cardiol 1997; 257 (79): 38-42

77. Rosenson RS, Bays HE. Results of two clinical trials on the

safety and efficacy of pravastatin 80 and 160 mg per day.

Am J Cardiol 2003; 91: 878-81

78. Masters BA, Palmoski MJ, Flint OP, et al. In vitro myotoxi-

city of the 3-hydroxy-3-methylglutaryl coenzyme A re-

ductase inhibitors, pravastatin, lovastatin and simvastatin,

using neonatal rat skeletal myocytes. Toxicol Appl Phar-

macol 1995; 131: 163-74

79. Ziegler K, Stunkel W. Tissue-selective action of pravastatin

due to hepatocellular uptake via sodium-independent bile

acid transporter. Biochem Biophys Acta 1992; 1139: 203-9

80. Bottorff MB. Statin safety and drug interactions: clinical

implications. Am J Cardiol 2006; 97 Suppl.: 27-31C

81. Lees RS, Lees AM. Rhabdomyolysis from the coadminis-

tration of lovastatin and the antifungal agent itracona-

zole. N Engl J Med 1995; 333: 664-5

82. Neuvonen PJ, Kantola T, Kivisto KT. Simvastatin but not

pravastatin is very susceptible to interaction with the

CYP3A4 inhibitor itraconazole. Clin Pharmacol Ther

1998; 63: 332-4

83. Kantola T, Kivisto KT, Neuvonen PJ. Erythromycin and

verapamil considerably increase serum simvastatin and

simvastatin acid concentrations. Clin Pharmacol Ther

1998; 64: 177-82

84. Lee AJ, Maddix DS. Rhabdomyolysis secondary to drug

interaction between simvastatin and clarithromycin. Ann

Pharmacother 2001; 35: 26-31

85. Mousa O, Brater DC, Sunblad KJ, et al. The interaction of

diltiazem with simvastatin. Clin Pharmacol Ther 2000; 67:

267-74

86. Lewin JJ, Nappi JM, Taylor MH. Rhabdomyolysis with

concurrent atorvastatin and diltiazem. Ann Pharmaco-

ther 2002; 36: 1546-8

87. Penzak SR, Chuck SK, Stajich GV. Safety and efficacy of

HMG-CoA reductase inhibitors for treatment of hyper-

lipidemia in patients with HIV infection. Pharmaco-

therapy 2000; 20: 1066-71

88. Lenhard JM, Croom DK, Weiel JE, et al. HIV protease

inhibitors stimulate hepatic triglyceride synthesis. Arter-

ioscler Thromb Vasc Biol 2000; 20: 2625-9

89. Chuk SK, Penzak SR. Risk-benefit of HMG-CoA re-

ductase inhibitors in the treatment of HIV protease

Statin-Induced Myopathy: Risk Factors and Drug Interactions 185

inhibitor-related hyperlipidaemia. Expert Opin Drug Saf

2002; 1 (1): 5-11

90. Gazi IF, Liberopoulos EN, Athyros VG, et al. Statins

and solid organ transplantation. Curr Pharm Des 2006;

12 (36): 4771-83

91. Pichard L, Domergue J, Fourtanier G, et al. Metabolism of

the new immumosuppresor cyclosporin G by human liver

cytochrome P450. Biochem Pharmacol 1996; 51 (5): 591-8

92. Norman DJ, Illingworth DR, Munson J, et al. Myolysis

and acute renal failure in a heart-transplant recipient re-

ceiving lovastatin. N Engl J Med 1988; 318: 46-7

93. Park JW, Siekmeier R, Merz M, et al. Pharmacokinetics

of pravastatin in heart-transplant patients taking

cyclosporin A. Int J Clin Pharmacol Therapeut 2002; 40:

439-50

94. Corsini A, Bellosta S, Baetta R, et al. New insights into the

pharmacodynamic and pharmacokinetic properties of

statins. Pharmacol Ther 1999; 84: 413-28

95. Moguorosi A, Bradley B, Showealter A, et al. Rhabdo-

myolysis and acute renal failure due to combina tion

therapy with simvastatin and warfarin. J Intern Med

1999; 246: 599-602

96. Kantola T, Backman JT, Niemi M, et al. Effect of fluco-

nazole on plasma fluvastatin and pravastatin concentra-

tions. Eur J Clin Pharmacol 2000; 56: 225-9

97. Shek A, Ferrill MJ. Statin-fibrate combination therapy.

Ann Phermacother 2001; 35: 908-17

98. Murdock DK, Murdock AK, Murdock RW, et al. Long-

term safety and efficacy of combination gemfibrozil and

HMG-CoA reductase inhibitors for the treatment of

mixed lipid disorders. Am Heart J 1999; 138: 151-5

99. Jones PH, Davidson MH. Reporting rate of rhabdomyolysis

with fenofibrate+statin versus gemfibrozil+any statin. Am J

Cardiol 2005; 95: 120-2

100. Franssen R, Vergeer M, Stroes ES, et al. Combination

statin-fibrate therapy: safety aspects. Diabetes Obes Me-

tab 2009 Feb; 11 (2): 89-94

101. Graham DJ, Staffa JA, Shatin D, et al. Incidence of hospi-

talized rhabdomyolysis in patients treated with lipid-

lowering drugs. JAMA 2004; 292: 2585-90

102. Prueksaritanont T, Subramanian R, Fang X, et al. Glu-

curonidation of statins in animals and humans: a novel

mechanism of statin lactonization. Drug Metab Dispos

2002; 30: 505-12

103. Prueksaritanont T, Zhao JJ, Ma B, et al. Mechani-

stic studies on metabolic interactions between gemfi

brozil and statins. J Pharmacol Exp Ther 2002; 301:

1042-51

104. Schoonjans K, Steals B, Auwerx J. Role of peroxisome

proliferator activated receptor in mediating effects of

fibrates and fatty acids on gene expression. J Lipid Res

1996; 37: 907-25

105. Kyrklund C, Backman JT, Neuvonen M, et al. Gemfibrozil

increases plasma pravastatin concentrations and reduces

pravastatin renal clearance. Clin Pharmacol Ther 2003;

73: 538-44

106. Reaven P, Witztum JL. Lovastatin, nicotinic acid, and

rhabdomyolysis. Ann Intern Med 1988; 109: 597-8

107. Bays H. Safety of niacin and simvastatin combination

therapy. Am J Cardiol 2008; 101 Suppl.: 3-8B

108. Fux R, Morike K, Gundel UF, et al. Ezetimibe and statin-

associated myopathy. Ann Intern Med 2004; 140: 671-2

109. Simard C, Poirier P. Ezetimibe-associated myopathy in

monotherapy and in combination with a 3-hydroxy-

3-methylglutaryl coenzyme A reductase inhibitor. Can J

Cardiol 2006; 22 (2): 141-4

110. Pearson TA, Denke MA, McBride PE, et al. A community-

based, randomized trial of ezetimibe added to statin

therapy to attain NCEP ATP III goals for LDL choles-

terol in hypercholesterolemic patients: the ezetimibe add-

on to statin for effectiveness (EASE) trial. Mayo Clin Proc

2005 May; 80 (5): 587-95

111. Davidson MH, Maccubbin D, Stepanavage M, et al. Stri-

ated muscle safety of ezetimibe/simvastatin (Vytorin). Am

J Cardiol 2006 Jan 15; 97 (2): 223-8

112. Conard SE, Bays HE, Leiter LA, et al. Efficacy and

safety of ezetimibe added on to atorvastatin (20 mg) ver-

sus uptitration of atorvastatin (to 40 mg) in hyper-

cholesterolemic patients at moderately high risk for

coronary heart disease. Am J Cardiol 2008 Dec 1; 102

(11): 1489-94

113. Leiter LA, Bays H, Conard S, et al. Efficacy and safety of

ezetimibe added on to atorvastatin (40 mg) compared with

uptitration of atorvastatin (to 80 mg) in hypercholester-

olemic patients at high risk of coronary heart disease. Am

J Cardiol 2008; 102: 1495-501

114. Davidson MH, Armani A, McKenney JM, et al. Safety

considerations with fibrate therapy. Am J Cardiol 2007;

99 Suppl.: 3-18C

115. Spence JD, Munoz CE, Hendricks L, et al. Pharmaco-

kinetics of the combination of fluvastatin and gemfibrozil.

Am J Cardiol 1995; 76 Suppl.: 80-3A

116. McKenney JM, Davidson MH, Jacobson TA, et al. Final

conclusions and recommendations of the National Lipid

Association Statin Safety Assessment Task Force. Am J

Cardiol 2006; 97 Suppl.: 89-94C

117. Chatzizisis YS, Misirli G, Hatzitolios AI, et al. The syn-

drome of rhabdomyolysis: complications and treatment.

Eur J Intern Med 2008; 19 (8): 568-74

118. Stein EA, Ballantyne CM, Windler E, et al. Efficacy

and tolerability of fluvastatin XL 80 mg alone, ezeti-

mibe alone, and the combination of fluvastatin XL 80 mg

with

ezetimibe

in patients with a history of muscle-related

side effects with other statins. Am J Cardiol 2008; 101:

490-6

119. Glueck CJ, Aregawi D, Agloria M, et al. Rosuvastatin

5 and 10 mg/d: a pilot study of the effects in hypercholes-

terolemic adults unable to tolerate other statins and reach

LDL cholesterol goals with nonstatin lipid-lowering

therapies. Clin Ther 2006; 28: 933-42

120. Matalka MS, Ravnan MC, Deedwania PC. Is alternate

daily dose of atorvastatin effective in treating patients

with hyperlipidemia? The Alternate Day Versus Daily

Dosing of Atorvastatin Study (ADDAS). Am Heart J

2002; 144: 674-7

121. Juszczyk MA, Seip RL, Thompson PD. Decreasing LDL

cholesterol and medication cost with every-other-day

statin therapy. Prev Cardiol 2005; 8: 197-9

122. Athyros VG, Tziomalos K, Kakafika AI, et al. Effective-

ness of ezetimibe alone or in combination with twice a

186 Chatzizisis et al.

week atorvastatin (10 mg) for statin intolerant high-risk

patients. Am J Cardiol 2008; 101 (4): 483-5

123. Backes JM, Venero CV, Gibson CA, et al. Effectiveness

and tolerability of every-other-day rosuvastatin dosing in

patients with prior statin intolerance. Ann Pharmacother

2008; 42: 341-6

124. Backes JM, Moriarty PM, Ruisinger JF, et al. Effects of

once weekly rosuvastatin among patients with a prior

statin intolerance. Am J Cardiol 2007; 100: 554-5

125. Mackie BD, Satija S, Nell C, et al. Monday, Wednesday,

and Friday dosing of rosuvastatin in patients previously

intolerant to statin therapy [letter]. Am J Cardiol 2007;

99: 291

126. Gadarla M, Kearns A, Thompson PD. Efficacy of

rosuvastatin (5 mg and 10 mg) twice a week in patients

intolerant to daily statins. Am J Cardiol 2008; 10 (12):

1747-8

127. Gazi IF, Daskalopoulou SS, Nair DR, et al. Effect of

ezetimibe in patients who cannot tolerate statins or cannot

get to the low density lipoprotein cholesterol target

despite taking a statin. Curr Med Res Opin 2007; 23:

2183-92

128. Rivers SM, Kane MP, Busch RS, et al. Colesevelam

hydrochloride-ezetimibe combination lipid-lowering

therapy in patients with diabetes or metabolic syndrome

and a history of statin intolerance. Endocr Pract 2007; 13:

11-6

Correspondence: Professor George D. Giannoglou, 1st

Cardiology Department, AHEPA University Hospital,

Aristotle University Medical School, 1 St Kyriakidi Street,

54636 Thessaloniki, Greece.

E-mail: [email protected]

Statin-Induced Myopathy: Risk Factors and Drug Interactions 187