500915

research-article2013
PMTXXX10.1177/8755122513500915Shannon et alJournal of Pharmacy Technology

Article
Journal of Pharmacy Technology

A Clinical Review of Statin-Associated

29(5) 219230
The Author(s) 2013
Reprints and permissions:
Myopathy sagepub.com/journalsPermissions.nav
DOI: 10.1177/8755122513500915
pharmatech.sagepub.com

Jennifer A. Shannon, PharmD1, Samuel M. John, PharmD1,

Harish S. Parihar, RPh, PhD1, Shari N. Allen, PharmD, BCPP1,
and Jenna J. Ferrara, PharmD, BCPS1

Abstract
Objective: To review the epidemiology, clinical features, proposed mechanisms, risk factors, and management of
statin-associated myopathy. Data Sources: Literature searches were conducted in PubMed (1948 to April 2013),
TOXLINE, International Pharmaceutical Abstracts (1970 to April 2013), and Google Scholar using the terms statin,
hydroxymethylglutaryl-coenzyme A reductase inhibitors, myopathy, myalgia, safety, and rhabdomyolysis. Results were
limited to English publications. Study Selection and Data Extraction: All relevant original studies, guidelines, meta-
analyses, and reviews of statin-associated myopathy and safety of statins were assessed for inclusion. References from
selected articles were reviewed to identify additional citations. Data Synthesis: The 3-hydroxy-3-methylglutaryl
coenzyme A reductase inhibitors remain one of the most effective medications for reducing low-density-lipoprotein
cholesterol. Statins are well tolerated by most patients; however, it is estimated that 10% to 15% of patients develop statin-
related muscle adverse effects known as statin-associated myopathy. Although clinicians may be aware of statin-associated
myopathy, they may not be aware of its clinical presentation. Providers should assess individual patient risk factors before
choosing the appropriate statin. A variety of skeletal muscle aches that may not present as a danger to the patient, may
affect patient adherence and quality of life. There are several steps that providers can take to properly treat and manage
patients with myalgia complaints. Conclusions: Statin-associated myopathy is a clinical problem that contributes to statin
therapy discontinuation. Patients who are statin intolerant may be treated with alternative treatment options such as low-
dose statins, switching statins, using alternative dosing strategies in statins with longer half-lives, non-statin lipid-lowering
agents, and complementary therapies.

Keywords
statin, hydroxymethylglutaryl-coenzyme A reductase inhibitors, myopathy, myalgia, safety, rhabdomyolysis

Introduction Statin-associated myopathy became more widely recog-

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)
reductase inhibitors (statins) remain an effective and widely
used medication class for the management of dyslipidemia
characterized by elevations in low-density lipoprotein cho-
lesterol (LDL-C).1,2 Statins have revolutionized the man-
agement of primary and secondary prevention of coronary
artery disease, and over the past 2 decades, the use of these
drugs has grown to more than 100 million statin prescrip-
tions per year.1,3 Statins are well tolerated by most patients;
however, observational studies estimate that 10% to 15% of
patients taking statins develop statin-related muscle adverse
effects known as statin-associated myopathy.1,4 Statin-
associated myopathy includes a broad spectrum of different
conditions that range from clinically benign myalgia to
more serious myositis, and in rare cases, may lead to life-
threatening rhabdomyolysis in approximately 0.04% to
0.2% of the population.2,5-7
nized term in 2001 following the withdrawal of cerivastatin,
after it was associated with approximately 100 rhabdomyol-
ysis-related deaths.2,5,8,9 These deaths associated with ceriv-
astatin treatment increased the awareness of statin-associated
myopathy. This phenomenon led to voluntary statin use ces-
sation by approximately 200 000 patients in the United
States.10 The overall reported incidence of clinically impor-
tant rhabdomyolysis is 0.15 deaths per 1 million prescrip-
tions, making its occurrence extremely rare; however,
cerivastatins unexpected outcome has led many clinicians
1
Philadelphia College of Osteopathic Medicine, Suwanee, GA, USA
Corresponding Author:
Jennifer A. Shannon, PharmD, School of Pharmacy, Philadelphia College
of Osteopathic Medicine, 625 Old Peachtree Rd NW, Suwanee, GA
30024, USA.
Email: jen@lilyrx.com
220 Journal of Pharmacy Technology 29(5)
to continue to use caution before prescribing statins.2,9 More
recently, the Food and Drug Administration (FDA) added
new safety recommendations for high-dose simvastatin, cit-
ing an increased risk of myopathy when using the 80 mg
dose.11 The potential impact of mild muscle-related
adverse effects should not be underestimated, as patients
who experience them are likely to discontinue therapy.12
Despite clinicians broad awareness of the possibility of
rhabdomyolysis, the knowledge of a variety of skeletal
muscle aches that do not present danger to the patient is not
forefront. However, any skeletal muscle aches caused by
statin medications may affect patient quality of life and
adherence to statin medications.2,5
The objective of this review is to discuss the epidemi-
ology, clinical features of statin-associated myopathy, and
review the proposed mechanisms. Additionally, we will
review clinical presentation and factors that place patients
at an increased risk of developing statin-associated myop-
athy. Finally, we identify screening and management
strategies for patients presenting with statin-associated
myopathy.
Definition
The general terminology in the literature that describes
statin-associated myopathy is difficult to interpret and often
inconsistent. The American College of Cardiology (ACC),
the American Heart Association (AHA), and National
Heart, Lung, and Blood Institute (NHLBI) helped standard-
ize the terminology used to describe statin-related muscle
toxicity, and the definition provided has become the most
widely recognized among clinicians. These organizations
define myopathy as a general term referring to any disease
of muscles that can be acquired or inherited.13 Myalgia is
described as muscle symptoms such as cramping, weak-
ness, or pain, without creatine kinase (CK) elevation.
Myositis is used to describe muscular symptoms with an
elevation of CK. Although clinically rhabdomyolysis is
referred to severe muscle breakdown and is usually associ-
ated with renal dysfunction, it exists whenever there is evi-
dence of muscle damage. The muscle damage can be
defined as muscular symptoms with marked CK elevation
more than 10 times the upper limit of normal (>10 ULN)
and the occasional presence of brown urine and urinary
myoglobin.13,14
The National Lipid Association (NLA) and the FDA also
provide definitions for muscle symptoms associated with
statins.14,15 The NLA defines myopathy as complaints of
myalgia (muscle pain or soreness), weakness, and/or cramps
in addition to CK elevation >10 ULN. The FDA defines
myopathy as a CK elevation of >10 ULN. It does not pro-
vide a definition for myalgia or myositis.5 Both organiza-
tions differ mainly in their definition of rhabdomyolysis and
the level of CK elevation that constitutes rhabdomyolysis.
The NLA defines rhabdomyolysis as a CK elevation of >10
000 IU/L or >10 ULN plus an elevation in serum creati-
nine or medical intervention with intravenous hydration
therapy.15 The FDA defines rhabdomyolysis as a CK eleva-
tion of >50 ULN plus evidence of organ damage such as
renal compromise.5 Throughout this review, myopathy will
be used as a broad term that includes myalgia, myositis, and
rhabdomyolysis, as defined by the ACC/AHA/NHLBI
guidelines.3
Epidemiology
The prevalence of statin-associated myopathy reported in
randomized controlled trials is often thought to be lower
than that observed in clinical practice. This may be due in
part to the exclusion of high-risk patients (who are identi-
fied later in this review), reliance on subjective reporting by
trial participants, and/or the lack of assessment for adverse
effects, such as muscle pain, being included in the trial
design. The lack of consistency with regards to statin, statin
dose, concomitant medications, and other risk factors for
statin-associated myopathy may contribute to differences in
the reported prevalence as well. Additionally, fewer patients
often receive the medication in clinical trials than when the
medication comes to market. A comparison of various statin
versus placebo clinical trials have been selected to demon-
strate the inconsistent rates of myopathy reported with dif-
ferent statins (Table 1).16-33
In addition to the trials listed in Table 1, the Prediction of
Muscular Risk in Observational conditions (PRIMO) was
the first large-scale, comprehensive investigation into risk,
causes, nature, and management of mild to moderate mus-
cular symptoms in patients receiving high-dose statin ther-
apy in clinical practice. Investigators defined muscular
symptoms as unexplained pain or cramps. This observa-
tional study examined muscular symptoms in 7900 patients
receiving various doses of statin therapy (fluvastatin 80 mg,
atorvastatin 40 or 80 mg, pravastatin 40 mg, or simvastatin
40 or 80 mg). Muscular symptoms were reported by 10.49%
of patients receiving high-dose statin therapy (832/7924),
with a median time of onset of 1 month following initiation
of statin therapy and titration to a higher dose. Fluvastatin
XL was associated with the lowest incidence of muscular
symptoms (5.1%) followed by pravastatin (10.9%), atorv-
astatin (14.9%), and simvastatin (18.2%).4 The results
reported with each statin, however, were not statistically
significant. The PRIMO trial was the first trial to raise
awareness of muscular symptoms; however, consistent with
problems in current practice, its definition of muscle symp-
toms remains inconsistent with alternative definitions used
in the literature, making it difficult to fully apply the results
to the general population.
The FDA continues to maintain the worlds largest post-
marketing surveillance public database for adverse effect
Shannon et al 221

Table 1. Incidence of Statin-Associated Muscle Events Reported in Statin Versus Placebo Controlled Trials.16-33

Myositis/
Statin Trial Name Dose (mg) Patients (n) Myalgia (%) Rhabdomyolysis (%)
Pitavastatin LIVES 1 to 4 20 279 ND 4.5
Rosuvastatin STELLAR 10 to 80 10-73 per group 7.3 (80 mg); 2 (40 mg) 0
CT 40 153 3 1
II/III CT 5 to 40 12 400 3.1 0.03 (20 mg)
Atorvastatin ASCOT-LLA 10 10 305 ND ND
ASAP 80 280 6.4 0
MIRACL 80 3086 ND 0
Fluvastatin ER CT 80 48 0.021 0
EXPRESS FH 80 508 8.9 0.6
HPS 40 20 536 0.05 0.05
Simvastatin 4S 40 4444 ND 0.02
CT 10 to 80 433 0.2 0
A to Z (Z phase) 40 to 80 2265 0.31 0.13
Lovastatin AFCAPS/TexCaps 20 to 40 6605 0.003 0
PPP 40 19 592 0 0
PROSPER 40 5804 1.25 0
Pravastatin LIPID 40 9014 ND 0.001
PLAC-1 40 206 0 0

Abbreviations: ND, not determined; ASCOT, Anglo-Scandinavian Cardiac Outcomes Trial; ASAP, Atorvastatin versus Simvastatin on Atherosclerosis
Progression; A to Z, Aggrastat to Zocor; AFCAPS/TexCaps, Air Force/Texas Coronary Atherosclerosis Prevention Study; CT, clinical trial; ExPRESS
FH, The Examination of Probands and Relatives in Statin Studies with Familial Hypercholesterolemia; HPS, Heart Protection Study; LIVES, Livalo Effec-
tiveness and Safety Study; LIPID, Long-term Intervention with Pravastatin in Ischemic Disease; MIRACL, Myocardial Ischemia Reduction with Aggressive
Cholesterol Lowering; PLAC-I, Pravastatin Limitation of Atherosclerosis in Coronary Arteries; PPP, Prospective Pravastatin Pooling Project; PROSPER,
The Prospective Study of Pravastatin in the Elderly at Risk; STELLAR, Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvas-
tatin; 4S, Scandinavian Simvastatin Survival Study.

reports.34 The FDAs Adverse Event Reporting System
(AERS), known as Medwatch, collected data from 2005 to
2011 on approximately 320 million statin prescriptions.
During this time period, 147 789 suspected case reports for
muscle-related events were associated with statin therapy.
Among the commonly prescribed statins, in general, rosuv-
astatin appears to have the highest reported event rates of
various muscle symptoms including myalgia, myopathy,
myositis, rhabdomyolysis, joints and tendon pain, muscle
atrophy, and muscle coordination and weakness, with lov-
astatin and pravastatin linked to the lowest rates of report.35
However, data from the FDA Medwatch do come with limi-
tations secondary to the voluntary nature of reporting by
consumers leading to potential reporting bias. Additionally,
increased use of more recently approved statins poses dif-
ficulty when comparing statin outcomes, because older
statins do not have the same level as potency as more
recently developed statins.
Proposed Mechanisms of Muscle Injury
Despite the prevalence of statin myopathy, clinicians still
do not fully understand the mechanism behind the muscle
injury, making it difficult to manage. Leading theories
include decreased cholesterol content of skeletal muscle
membrane, depletion of isoprenoids or coenzyme Q10
(CoQ10), impaired mitochondrial function, vitamin D defi-
ciency, induction of apoptosis, and disturbed calcium
metabolism (Figure 1).1,6,36,37
Decreased Cholesterol Content of the Skeletal
Muscle Membrane
Cholesterol is an integral part of the membrane lipid bilayer.
Statin-associated myopathy was initially hypothesized to be
due to reduced sarcolemmal cholesterol content due to
statin therapy resulting in alterations in membrane fluidity
causing membrane destabilization, degradation, and necro-
sis.38-42 This concept is best supported by observations with
the administration of clofibrate and niacin over statin ther-
apy; however, there are key findings that make this explana-
tion unlikely for all of the aforementioned treatments.6,43-47
When cholesterol is decreased by inhibiting squalene syn-
thetase, a distal enzyme in the cholesterol synthesis path-
way, no increase in myotoxicity is demonstrated.6,48
Additionally, patients with genetic disorders of the choles-
terol synthesis have reduced cholesterol concentrations
without associated clinical myopathy.6,45 Thus, this theory
may be unlikely; however, it should be noted as a possible
mechanism.
222
Figure 1. Effect of statins on the cholesterol pathway and key
factors for myopathy.
(1) Statins inhibits HMG-CoA reductase, the rate-limiting step of choles-
terol synthesis. This leads to decreased production of all intermediate
biomolecules along with cholesterol. (2) Reduced cholesterol levels
result in alteration of sarcolemmal membrane fluidity causing membrane
destabilization, degradation, and necrosis. (3) Inhibition of isoprenylated
proteins, dolichol, and ubiquinone has been associated with impaired
mitochondrial function and apoptosis of myocytes. (4) Inhibition of
sqalene synthesis does not lead to increased myotoxicity. (5) It has been
proposed that reduced levels of 7-dehydrocholesterol may impair vita-
min D3 synthesis. Reduced levels of vitamin D have been associated with
muscles pains as well as impaired muscle strength and function.1,5,13,21
Sarcolemmal Membrane Excitability
Statins with higher lipophilicity and doses above the thera-
peutic level have led to altered sarcolemmal excitability.49-51
Sarcolemmal cholesterol modulates membrane fluidity
similar to other tissues. Decreased cholesterol concentra-
tion due to treatment with statin therapy may affect the cell
membrane integral proteins, especially ion channels such as
sodium, chloride, and potassium channels that can poten-
tially alter muscle membrane excitability.49,50 In particular,
chloride channels in skeletal muscles control resting mem-
brane potential and membrane repolarization. Muscle myo-
tonia, defined as delayed relaxation following muscle
contractility, as seen with impaired chloride conductance
has been observed in animals treated with statins.49,50
However, the sarcolemmal excitability varies based on the
lipophilicity and dosage of the statin drugs.51
Isoprenoid Depletion
Statin treatment causes apoptosis of the muscle cells. This
apoptotic effect is thought to be due to inhibition of isopren-
oid compounds such as farnesylated proteins, ubiquinone,
Journal of Pharmacy Technology 29(5)
and dolichol.52,53,54 Isoprenoids are lipids that are products
of the HMG-CoA reductase pathway.3,55 They serve as lipid
attachments for intracellular signaling molecules, and it is
proposed that many of the pleiotropic effects of statins
may be mediated by inhibition of isoprenoids.8 Farnesyl
pyrophosphate (F-PP) and geranylgeranyl pyrophosphate
(GG-PP) are important isoprenoids in the HMG-CoA reduc-
tase pathway. F-PP and GG-PP are linked to proteins by
processes known as farnesylation or geranylgeranylation. A
reduction in these processes is thought to increase cytosolic
calcium concentrations, which activate a cascade of events
that lead to apoptosis.1,6 This theory has been supported by
an in vitro study demonstrating that statin-induced cell
death or apopotosis may be prevented with supplementation
of F-PP and GG-PP.1,6,56
Ubiquinone or CoQ10 Inhibition and Impaired
Mitochondrial Function
Ubiquinone or CoQ10, which is also a product of the HMG-
CoA reductase pathway, is an isoprenoid that is a key cofac-
tor of the electron transport chain and important antioxidant
in the mitochondrial membranes.1,6,57 Various studies sug-
gest that statins play a role in impaired mitochondrial func-
tion by inhibiting the synthesis of mevalonate, a precursor
of CoQ10 and other isoprenoids. A reduction of this coen-
zyme may result in abnormal mitochondrial respiratory
function and ultimately lead to myopathy; however, this
theory has some limitations.1,6,58 Limitations to this theory
have been supported by studies that have demonstrated a
statins ability to reduce serum CoQ10 concentrations;
however, myocyte CoQ10 concentrations have not consis-
tently decreased with the use of statins1,6,59 Additionally, in
an in vitro study, cerivastatin induced cell death, but the cell
death did not correlate with CoQ10 concentrations.60,61
Strong, randomized, double-blind clinical trials are war-
ranted to determine if CoQ10 supplementation decreases
statin myopathy.
Disturbed Calcium Metabolism and Induction of
Apoptosis
The regulation of calcium is critical for normal function of
muscle cells.61 An additional theory has been proposed that
statins impair intracellular calcium homeostasis by inter-
rupting the mitochondrial respiratory chain, causing cal-
cium to be pumped into the cytoplasm. Although increased
cytoplasmic calcium concentrations have been associated
with myalgias, further investigation is necessary to deter-
mine whether increased expression of the receptors respon-
sible for higher calcium concentrations is a result of statin
therapy.1,6,62 Another theory is that statins induce the release
of calcium by the ryanodine receptors that leads to activa-
tion of caspase 3 and 9, causing apoptosis of muscle cells.63
Shannon et al 223

Finally, it has been observed that statins reduce muscle Table 2. Patient and Medication-Related Risk Factors
regenerative capacity by affecting myoblasts growth, Associated With Statin-Associated Myopathy.5,11,34,70
fusion, and differentiation.64 Major CK
Patient Characteristics Medications Interactions
Vitamin D Deficiency Advanced age High-dose statin therapy CYP 3A4
(>80 years)
Low serum vitamin D levels have been associated with leth-
Race Fibrates CYP 2C9
argy, muscle pain, and impaired muscle function.65,66
Sex (female > male) Nicotinic acid (rarely)
Vitamin D synthesis may be affected by statin treatment, as
Small body frame and Cyclosporine
7-dehydrocholesterol is a common precursor for both cho- frailty
lesterol and vitamin D. Various research reports have linked Alcoholism Azole antifungals
statin-associated myopathy to decreased biosynthesis of Family history of Macrolide antibiotics
vitamin D,67-69 whereas other reports70 show no statistical myopathy
correlation between statin-associated myopathy and low Unexplained cramps Protease inhibitors
vitamin D levels. Thus, further investigation is warranted Excessive physical Warfarin
before a link between the processes can be established. activity
Major surgery Verapamil
Genetic polymorphisms Amiodarone
Risk Factors of CYP450
isoenzymes
Data concerning risk for statin-associated myopathy are Renal disease Nefazodone
largely derived from studies on rhabdomyolysis and severe Hepatic disease Grapefruit juice
myositis rather than minor symptoms such as myalgia and (> 1 qt/day)
myositis with CK elevations <10 ULN, making it difficult Vitamin D deficiency
for clinicians to correlate symptoms to statin therapy.6,71
Nonetheless, several risk factors for statin-associated
myopathy have been identified, including medication char-
acteristics such as lipophilicity, pharmacokinetics, and risk of myopathy6,36,74 (Table 25,11,34,70). The choice of statin
dose, patient characteristics, and statin pharmacologic prop- requires close consideration of various factors including
erties, all of which should be taken into consideration before statin potency and renal clearance. However, statins that do
prescribing statin therapy (Table 25,11,34,70).4,6,13,36,72 not require CYP3A4 metabolism such as pravastatin (renal),
Use of higher to maximum doses of statin therapy is fluvastatin (CYP2C9), rosuvastatin (CYP2C9), and pitavas-
among the many statin characteristics identified as risk fac- tatin (minimally by CYP2C9 and CYP 2C8) may provide
tors for statin-associated myopathy.5,6,13,36,73 Therefore, it is an alternative for therapy in patients who are on multiple
recommended not to let doses of statin therapy exceed those medications that may interact with statins (Table 2).5,7 It
required to attain the patients ATP III goal, as only small should be noted that despite their potential to have a lower
gains in efficacy occur with higher doses compared with risk of myopathy, fluvastatin and rosuvastatin are not with-
increased risk of muscle-related symptoms.13,74 A statins out risk, and therefore risk should be evaluated prior to
ability to penetrate into peripheral tissues may be influ- statin initiation. For example, rosuvastatin is a non-3A4
enced by its lipophilicity, and lipophilic agents (atorvas- substrate and hydrophilic agent making it less likely to
tatin, fluvastatin, lovastatin, simvastatin) may be more cause myopathy, but due to its high potency, rosuvastatin
likely to produce muscular effects than hydrophilic agents may place a patient at an increased risk for developing
(pravastatin, rosuvastatin). However, the potency of rosuv- myopathy; thus, statin potency and dose administered
astatin demonstrates an exception to this theory.75 Thus, should be evaluated prior to initiation. Finally, moderate-to-
recognition of patients with increased risk may allow pro- severe renal disease should be considered when choosing a
viders to make more cost-effective decisions for therapy statin, as renal insufficiency is a risk factor for development
and prevent increasing a patients risk.6,72,76,77 of statin-associated myopathy.6,74
Among the pharmacologic properties associated with Statins are modestly effective at reducing triglycerides;
statin-associated myopathy is route of metabolism, as a therefore, many patients with mixed dyslipidemias require
common mechanism for drug interaction involves the cyto- the addition of a fibrate to statin therapy.78 Gemfibrozil and
chrome P-450 system. Approximately 50% of medications fenofibrate are the only FDA-approved fibrates in the United
(including most statins) are metabolized through the cyto- States. Selection of gemfibrozil over fenofibrate for combi-
chrome P-450 3A4 (CYP3A4) isoenzyme of the P-450 sys- nation therapy may result in an increased risk of myalgias, as
tem.5,7,74 Medications that are substrates for CYP3A4 gemfibrozil is an inhibitor of multiple components of statin
metabolism will likely increase the serum concentrations of metabolism (conjugation and biliary excretion), which can
a statin when given concomitantly leading to an increased increase statin concentrations leading to myalgias; however,
224 Journal of Pharmacy Technology 29(5)
fenofibrate does not carry the same risk.74 With the combina-
tion of fenofibrate and cerivastatin, the number of rhabdo-
myolysis cases reported to the FDA was 14 (an estimated
140 cases per 1 million prescriptions). Gemfibrozil and
cerivastatin combined led to 533 reported cases of rhabdo-
myolysis (an estimated 4600 cases per 1 million prescrip-
tions).74 An increase was also seen with other statins
combined with gemfibrozil with 57 reported cases to the
FDA (8.6 cases per 1 million prescriptions) compared to
statin-fenofibrate combinations with 2 reported cases (an
estimated 0.58 cases per 1 million prescriptions). Statins
undergo glucuronidation when metabolized, and gemfibro-
zil competes for enzymes required in glucuronidation. Thus,
if this process is inhibited, there is potential to see an increase
in serum statin concentrations.74,79 Caution is advised when
choosing fibrate therapy, as fibrates alone can cause myopa-
thy and rhabdomyolysis. When combined with a statin can
increase a patients risk for rhabdomyolysis by 10- to
15-fold.6,74,79 Therefore, if a patient requires statin therapy,
fenofibrate is the preferred agent over gemfibrozil for com-
bination therapy in patients with hypertriglyceridemia.
Clinical Features
The clinical presentation of statin-associated myopathy
may range from mild fatigue to hospitalization secondary to
rhabdomyolysis. Symptoms may include myalgia, lower
back pain, weakness, or aching.3,80,81 Kordas and col-
leagues80 reported in a survey of 1053 patients on statin
therapy with muscle complaints that 74% of patients com-
plained of fatigue, in addition to the 88% of patients who
presented with muscle pain as their chief complaint.
Additionally, in Cham and colleagues observational study
of 354 patients with self-reported muscle problems, adverse
effects occurred with all prescribed statins in the study.82
The PRIMO study participants described myalgia as heavi-
ness, stiffness, or cramping, occasionally associated with
weakness during exertion. Pain was widespread in the
majority of patients and generally affected the lower limbs
(thighs, calves). Tendonitis-associated pain was reported by
almost 25% of patients and affected multiple tendons in
more than 50% of cases. Approximately 74% of patients
with muscle symptoms reported intermittent pain lasting
only a few hours. The median time of symptom onset was 1
month following initiation of statin therapy; however,
symptoms could occur at any time following initiation of
therapy. More than 80% of patients had not experienced
similar symptoms prior to initiation of statin therapy.4
Screening and Monitoring
The ACC/AHA/NHLBI and the NLA have each proposed
methods to monitor for statin-associated myopathy.13,15
Along with these 2 proposed methods, an algorithm for the
diagnosis and management of statin-associated myopathy
was published, which included a third proposed method to
monitor for statin-associated myopathy.71 While these 3
methods have many similarities, they also have several
noteworthy differences, each of which was taken into con-
sideration when developing the new algorithm provided in
this review.13,15,71 This algorithm should aid clinicians in
screening and monitoring patients on statin therapy for
statin-associated myopathy (Figure 2).
The ACC/AHA/NHLBI recommendations include a
baseline CK measurement prior to initiating statin therapy;
however, they do not recommend routine CK monitoring in
all patients following initiation of statin therapy. Instead,
these recommendations include CK measurement only if a
patient experiences symptoms of myopathy, such as muscle
soreness, tenderness, or pain. Whether or not statin therapy
is recommended to be discontinued in patients with symp-
toms of myopathy is dependent on the CK level obtained. If
the CK level obtained is >10 ULN, statin therapy should
be discontinued. If the CK level obtained is <10 ULN,
including patients without CK elevations, statin therapy
may be continued with close monitoring of patient symp-
toms along with weekly of CK levels until there is no longer
a medical concern, or until CK levels rise to >10 ULN, at
which point statin therapy should be discontinued. If weekly
CK levels reveal progressive elevations, but have not risen
to >10 ULN, it may be prudent to reduce the statin dose or
temporarily discontinue statin therapy and rule out other
causes. Last, the ACC/AHA/NHLBI recommendations
emphasize the importance of counseling all patients begin-
ning statin therapy to immediately report clinical signs and
symptoms of myopathy, including muscle discomfort, mus-
cle weakness, and/or brown urine.13
The NLA recommendations do not assume baseline CK
level obtainment in all patients to be cost-effective. CK lev-
els should only be obtained in patients at high risk for statin-
associated myopathy and in patients reporting symptoms of
myopathy. The NLAs recommendation of cessation of
statin therapy in patients experiencing symptoms of myopa-
thy depends on both the CK level and symptom severity. If
other etiologies have been ruled out, and the patient devel-
ops intolerable muscle symptoms and/or rhabdomyolysis,
defined as CK level >10 000 IU/L or CK level >10 ULN
plus an elevation in serum creatinine and/or need for intra-
venous hydration therapy, statin therapy should be discon-
tinued. If a patient in whom other etiologies have been ruled
out and the CK level is <10 ULN, continue statin therapy
and symptoms can be used as a clinical guide as to whether
or not statin therapy may need to be discontinued in the
future. The NLA also emphasizes the need to educate
patients on the importance of immediately reporting symp-
toms of myopathy should they occur.15
The third and most recent proposed method to monitor
for statin-associated myopathy was included in a published
Shannon et al 225

Signs and symptoms Signs and symptoms

of myopathy reported of myopathy resolved

Disconnue
stan therapy
Monitor signs
and symptoms
Hospitalizaon, Consider:
IV hydraon,and Consider Same stan with
treatment for Vitamin D dose reducon
rhabdomyolysis if supplementaon Alternave
CK level > 10x ULN necessary if decient stan
Consider OR intolerable symptoms Alternave
baseline CK OR signs and symptoms of stan dosing
level rhabdomyolysis strategy
Non-stan lipid
Yes
lowering therapy
Counsel paents Check CK level
Risk factors to report signs Evaluate
for stan- and symptoms of symptom severity
associated myopathy Screen for signs
myopathy Roune CK level and symptoms of
monitoring rhabdomyolysis
unnecessary Check Vitamin D
No level

Baseline CK
level CK level < 10x ULN
unnecessary AND tolerable symptoms
AND absence of Consider
rhabdomyolysis connuaon of
stan therapy, Consider
Connue to
consider dose Vitamin D
monitor signs and
reducon supplementaon
symptoms
Consider if decient
alternave stan
Monitor signs
and symptoms

Management of Dyslipidemia
Screening and Monitoring Management of Myopathy
following Myopathy resoluon

Figure 2. An algorithm for monitoring and management of statin-associated myopathy and treatment of dyslipidemia following
myopathy resolution.1-3,35,83-86

algorithm by Jacobson and colleagues for evidence-based
management of statin-associated myopathy. The algorithm
recommends obtaining baseline CK levels only in patients
at high risk for developing statin-associated myopathy or in
patients experiencing symptoms of myopathy. If patients
experience symptoms at the time of CK level obtainment,
other etiologies should also be ruled out. Whether or not
statin therapy should be discontinued in these patients expe-
riencing symptoms of myopathy is dependent on both the
CK level obtained and the severity of symptoms. If a patient
develops intolerable symptoms, statin therapy should be
discontinued regardless of CK level. If a patient develops
tolerable muscle symptoms, but the CK level obtained is
>10 ULN or the patient is also experiencing symptoms of
rhabdomyolysis, such as elevated serum creatinine or the
need for intravenous hydration, statin therapy should be dis-
continued. If a patient develops tolerable muscle symptoms
and the CK level obtained is <10 ULN, statin therapy can
be continued and symptoms can be used as a clinical guide
to stop or continue statin therapy from that point forward.
Furthermore, like the ACC/AHA/NHLBI and the NLA, the
algorithm also emphasizes the importance of patient education
and counseling regarding the need to immediately report
symptoms of myopathy.71
Management of Myopathy
Depending on severity of symptoms and magnitude of CK
level elevation, management of statin-associated myopathy
includes monitoring for symptom improvement with or
without discontinuation of statin therapy, hospitalization,
and intravenous hydration, as mentioned above. Two com-
plementary therapies have been proposed for the manage-
ment of statin-associated myopathynamely, CoQ10 and
vitamin D.71
CoQ10 deficiency is one theory behind statin-associated
myopathy, and therefore, supplementation with CoQ10 has
been proposed for the treatment of statin-associated myopa-
thy.2 Although the role of CoQ10 supplementation in this
setting has yet to be clearly defined, several studies have
revealed its potential benefit in patients experiencing statin-
associated myopathy; however, the results of these studies
evaluating CoQ10 were limited in their design due to small
sample sizes and duration. Additionally, there has been no
226 Journal of Pharmacy Technology 29(5)
correlation between intramuscular CoQ10 levels and statin-
associated myopathy.83 However, the use of CoQ10 in
patients with statin-associated myopathy continues to be
highly debated and popular among the general public;
therefore, further studies evaluating the role of CoQ10 sup-
plementation in statin-intolerant patients are warranted.
Additionally, the NLA does not currently endorse the use of
CoQ10 as a treatment option.58,87,88
Also previously mentioned, vitamin D deficiency has
been linked with myalgias, as well as with statin-associated
myopathy. Therefore, vitamin D supplementation has been
proposed for the management of statin-associated myopa-
thy. Again, although the role of vitamin D supplementation
in patients with statin-associated myopathy has not been
clearly defined, it has been evaluated for its potential bene-
fits in this setting.67
A prospective study performed by Ahmed and col-
leagues67 included 621 patients on statin therapy; of the total,
128 of whom had symptomatic myalgia had a vitamin D defi-
ciency screening that revealed 62% (82/128) of the patients
with myalgia to be vitamin D deficient (vitamin D levels less
than 32 ng/mL). These patients with myalgia and vitamin D
deficiency were treated with 50 000 units of ergocalciferol
once weekly and followed prospectively for 12 weeks. Mean
vitamin D levels increased from 20.4 7.3 ng/mL to 48.2
17.9 ng/mL (P < .0001), and 92% (35/38) of these patients
became free of myalgia.67 Additionally, a second study
assessed 68 patients intolerant to statin therapy secondary to
myalgia, also with vitamin D deficiency (vitamin D levels
less than 32 ng/mL), to determine whether resolution of vita-
min D deficiency would result in myalgia-free statin toler-
ance. After 12 weeks of 50 000 units of twice-weekly
ergocalciferol, mean vitamin D levels increased from 22 7
ng/mL to 43 13 ng/mL (P < .0001), and 91% (62/68) of the
patients were statin tolerant and free of myalgia.68
Limitations to the above study include a small sample
size, nonstandardized statin therapy, subjective reporting of
myopathy symptoms, as well as the lack of a double-blind,
placebo-controlled design. Along with prospective studies,
several case reports and case series have also supported the
use of vitamin D supplementation in patients with statin-
associated myopathy.69,89 Although the current evidence
lends support to the use of vitamin D in this setting, double-
blind and placebo-controlled trials are necessary to clearly
delineate the role of vitamin D supplementation in vitamin
Ddeficient patients with statin-associated myopathy.
Management of Dyslipidemia
Following Myopathy Resolution
In patients requiring discontinuation of statin therapy sec-
ondary to myopathy, the benefits and risks of reinitiation of
statin therapy following myopathy resolution should be
carefully considered. If patients develop statin-associated
myopathy after trials of multiple statins at multiple doses
and cannot tolerate non-statin lipid lowering therapies, life-
style modifications should be intensified and alternative
options should be considered.71
Once symptoms of myopathy have resolved, there are
several options to consider for the treatment of dyslipid-
emia in patients with a history of statin-associated myopa-
thy. These include reinitiating statin therapy at a lower dose,
treatment with an alternative statin, treatment with statin
therapy using an alternative dosing strategy, and treatment
with non-statin lipid-lowering therapies, such as ezetimibe,
colesevelam, and Chinese red yeast rice (RYR). If RYR is
used, it should be done so with caution as it does contain a
statin and may have similar effects as lovastatin.71
Before choosing alternative medications, strong consid-
eration of reinitiating statin therapy should be given to
patients with history of myopathy, and special consideration
should be given to patients with increased risk for a cardio-
vascular event, history of coronary artery disease, or patients
with cardiovascular risk equivalents. One approach to this is
reinitiating the same statin at a lower dose, as higher doses
have been correlated with increased risk of myopathy, a con-
cept previously discussed. Another approach is initiating an
alternative statin as some patients may tolerate alternative
statin therapy despite a history of statin-associated myopa-
thy.90,91 A third approach to reinitiating statin therapy is
using an alternative dosing strategy. Several studies have
evaluated the efficacy of these alternative dosing strategies,
but fewer studies have evaluated these alternative dosing
strategies that include twice-weekly atorvastatin and rosuv-
astatin, in addition to rosuvastatin dosed every other day in
patients with a history of statin intolerance and/or statin-
associated myopathy.92-94 Atorvastatin and rosuvastatin have
extended half-lives (14 hours and 19 hours, respectively)
and therefore offer a unique advantage for alternative dosing
strategies with regard to their pharmacokinetic properties.
Although these alternative dosing strategies are not approved
by the FDA and larger, prospective, randomized, double-
blind, placebo-controlled trials are needed, these alternative
strategies may be of benefit to patients who would not other-
wise be treated with statin therapy and would therefore lose
the advantage of their superior efficacy.
If statin therapy is not reinitiated or is not tolerated on
reinitation, treatment with non-statin lipid-lowering thera-
pies should be considered; however, many do not have the
ability to reduce cardiovascular events. Non-statin LDL-C
lowering therapies for patients with a history of statin-
associated myopathy largely consist of ezetimibe and bile
acid sequestrants, such as colesevelam. Though both
options have been shown to be well tolerated in patients
with a history of statin-associated myopathy, statin efficacy
remains superior in LDL reduction.91,95,96
Although limited in data, the use of complementary ther-
apies, most notably vitamin D, offer a novel approach to
Shannon et al 227
those patients intolerant to statin therapy suffering from
myopathy. Therefore, as previously mentioned, an algo-
rithm has been provided to aid clinicians in screening and
monitoring patients on statin therapy for statin-associated
myopathy, as well as in the management of myopathy in
statin-treated patients, and the management of dyslipid-
emias characterized by elevated LDL-C in patients with a
history of statin-associated myopathy. This algorithm has
been adapted from the algorithm created by Jacobson and
colleagues, while also taking into account additional more
recent data published after the creation of the algorithm by
Jacobson and colleagues (Figure 2).13,15,67-69,71,89,97
Another option for patients who cannot tolerate statin
therapy may be Chinese RYR, which has been used for its
LDL-C lowering effects. The active ingredient is monacolin
K, which is a natural form of lovastatin. Confusion remains
among patients purchasing RYR as the amount of monaco-
lin K varies among the different brands that are available.98
Clinical trials evaluating the use of RYR have been limited
in their design and duration. Further clinical studies with
larger sample sizes and outcomes evaluating long-term
effects are warranted considering the favorability of this
agent among clinicians and patients alike. The use of RYR
could be considered an alternative option once patients
have demonstrated intolerance to statins or possibly after a
trial of a non-statin lipid-lowering therapy.6
Conclusion
Statins continue to play a vital role in the prevention of ath-
erosclerotic disease and remain an effective treatment option
for patients with dyslipidemia. Although considered a minor
adverse effect, clinicians continue to be challenged by statin-
associated myopathy. Providers should conduct an assess-
ment of each patients risk factors before selecting a statin to
reduce the risk of statin-associated myopathy. Patients with
risk factors for statin myopathy should be treated with a low-
dose statin and which should be titrated slowly.
There are various theories behind the cause of statin-
associated myopathy; however, it is important to rule out
secondary causes prior to choosing a management strategy.
Options available for management include decreasing the
statin dose, switching statins, alternative dosing schedules,
use of alternative lipid-lowering agents, complementary
supplements, or cessation of therapy. Although develop-
ment of statin-associated myopathy may require discontinu-
ation of statin therapy, clinicians should weigh the
benefit-to-risk ratio in the context of cardioprotective ben-
efits before cessation of therapy and when considering rein-
itiation of statin therapy on resolution of myopathy.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
References
1. Abd TT, Jacobson TA. Statin-induced myopathy: a review
and update. Expert Opin Drug Saf. 2011;10:373-387.
2. Thompson PD, Clarkson P, Karas RH. Statin-associated
myopathy. JAMA. 2003;289:1681-1690.
3. Harper CR, Jacobson TA. The broad spectrum of statin myop-
athy: from myalgia to rhabdomyolysis. Curr Opin Lipidol.
2007;18:401-408.
4. Bruckert E, Hayem G, Dejager S, Yau C, Begaud B. Mild to
moderate muscular symptoms with high-dosage statin therapy
in hyperlipidemic patientsthe PRIMO study. Cardiovasc
Drugs Ther. 2005;19:403-414.
5. Sewright KA, Clarkson PM, Thompson PD. Statin myopa-
thy: Incidence, risk factors, and pathophysiology. Curr
Atheroscler Rep. 2007;9:389-396.
6. Harper CR, Jacobson TA. Evidence-based management of
statin myopathy. Curr Atheroscler Rep. 2010;12:322-330.
7. Omar MA, Wilson JP, Cox TS. Rhabdomyolysis and HMG-
CoA reductase inhibitors. Ann Pharmacother. 2001;35:1096-
1107.
8. Radcliffe KA, Campbell WW. Statin myopathy. Curr Neurol
Neurosci Rep. 2008;8:66-72.
9. Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal
rhabdomyolysis. N Engl J Med. 2002;346:539-540.
10. Maggini M, Raschetti R, Traversa G, et al. The cerivastatin
withdrawal crisis: a post-mortem analysis. Health Policy.
2004;69:151-157.
11. US Food and Drug Administration. FDA announces new safety
recommendations for high-dose simvastatin. http://www.fda.
gov/NewsEvents/Newsroom/PressAnnouncements/ucm258338.
htm. Published June 8, 2011. Accessed June 10, 2012
12. Bruckert E, Simonetta C, Giral P. Compliance with fluvas-
tatin treatment characterization of the noncompliant popula-
tion within a population of 3845 patients with hyperlipidemia.
CREOLE study team. J Clin Epidemiol. 1999;52:589-594.
13. Pasternak RC, Smith SC Jr, Bairey-Merz CN, et al. ACC/
AHA/NHLBI clinical advisory on the use and safety of
statins. J Am Coll Cardiol. 2002;40:567-572.
14. Thompson PD, Clarkson PM, Rosenson RS; National Lipid
Association Statin Safety Task Force Muscle Safety Expert
Panel. An assessment of statin safety by muscle experts. Am J
Cardiol. 2006;97:69C-76C.
15. McKenney JM, Davidson MH, Jacobson TA, Guyton JR;
National Lipid Association Statin Safety Assessment Task
Force. Final conclusions and recommendations of the national
lipid association statin safety assessment task force. Am J
Cardiol. 2006;97:89C-94C.
16. Teramoto T. The clinical impact of pitavastatin: comparative
studies with other statins on LDL-C and HDL-C. Expert Opin
Pharmacother. 2012;13:859-865.
17. Jones PH, Davidson MH, Stein EA, et al. Comparison of the
efficacy and safety of rosuvastatin versus atorvastatin, simv-
astatin, and pravastatin across doses (STELLAR* trial). Am J
Cardiol. 2003;92:152-160.
228 Journal of Pharmacy Technology 29(5)
18. Ballantyne CM, Miller E, Chitra R. Efficacy and safety of
rosuvastatin alone and in combination with cholestyramine
in patients with severe hypercholesterolemia: a randomized,
open-label, multicenter trial. Clin Ther. 2004;26:1855-1864.
19. Shepherd J, Hunninghake DB, Stein EA, et al. Safety of rosu-
vastatin. Am J Cardiol. 2004;94:882-888.
20. Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary
and stroke events with atorvastatin in hypertensive patients
who have average or lower-than-average cholesterol con-
centrations, in the Anglo-Scandinavian Cardiac Outcomes
TrialLipid Lowering Arm (ASCOT-LLA): a multicentre
randomised controlled trial. Lancet. 2003;361:1149-1158.
21. Smilde TJ, van Wissen S, Trip MD, Stalenhoef AF, Kastelein
JJ. Effect of aggressive versus conventional lipid lowering
on atherosclerosis progression in familial hypercholesterol-
emia (ASAP): a prospective, randomized, double-blind trial.
Lancet. 2001;357:577-581.
22. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of
atorvastatin on early recurrent ischemic events in acute coro-
nary syndromes: the MIRACL study: a randomized controlled
trial. JAMA. 2001;285:1711-1718.
23. Derosa G, Cicero AE, Bertone G, Piccinni MN, Ciccarelli L,
Roggeri DE. Comparison of fluvastatin + fenofibrate combi-
nation therapy and fluvastatin monotherapy in the treatment
of combined hyperlipidemia, type 2 diabetes mellitus, and
coronary heart disease: a 12-month, randomized, double-
blind, controlled trial. Clin Ther. 2004;26:1599-1607.
24. de Sauvage Nolting PR, Buirma RJ, Hutten BA, Kastelein JJ;
Dutch ExPRESS Investigator Group. Two-year efficacy and
safety of simvastatin 80 mg in familial hypercholesterolemia
(the examination of probands and relatives in statin studies
with familial hypercholesterolemia [ExPRESS FH]). Am J
Cardiol. 2002;90:181-184.
25. The Heart Protection Study Collaborative Group. MRC/BHF
Heart Protection Study of cholesterol lowering with simvas-
tatin in 20,536 high-risk individuals: a randomised placebo-
controlled trial. Lancet. 2000;360:7-22.
26. Randomised trial of cholesterol lowering in 4444 patients
with coronary heart disease: The Scandinavian Simvastatin
Survival Study (4S). Lancet. 1994;344:1383-1389.
27. Masana L, Mata P, Gagne C, et al. Long-term safety and,
tolerability profiles and lipid-modifying efficacy of ezeti-
mibe coadministered with ongoing simvastatin treatment: a
multicenter, randomized, double-blind, placebo-controlled,
48-week extension study. Clin Ther. 2005;27:174-184.
28. de Lemos JA, Blazing MA, Wiviott SD, et al. Early intensive
vs a delayed conservative simvastatin strategy in patients with
acute coronary syndromes: phase Z of the A to Z trial. JAMA.
2004;292:1307-1316.
29. Downs JR, Clearfield M, Tyroler HA, et al. Air Force/Texas
Coronary Atherosclerosis Prevention Study (AFCAPS/
TEXCAPS): additional perspectives on tolerability of long-term
treatment with lovastatin. Am J Cardiol. 2001;87:1074-1079.
30. Pfeffer MA, Keech A, Sacks FM, et al. Safety and tolerability of
pravastatin in long-term clinical trials: Prospective Pravastatin
Pooling (PPP) project. Circulation. 2002;105:2341-2346.
31. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in
elderly individuals at risk of vascular disease (PROSPER): a
randomised controlled trial. Lancet. 2002;360:1623-1630.
32. Prevention of cardiovascular events and death with pravas-
tatin in patients with coronary heart disease and a broad range
of initial cholesterol levels. The Long-Term Intervention with
Pravastatin in Ischaemic Disease (LIPID) study group. N Engl
J Med. 1998;339:1349-1357.
33. Pitt B, Mancini GB, Ellis SG, Rosman HS, Park JS, McGovern
ME. Pravastatin limitation of atherosclerosis in the coronary
arteries (PLAC I): reduction in atherosclerosis progression
and clinical events. PLAC I investigation. J Am Coll Cardiol.
1995;26:1133-1139.
34. Davidson MH, Clark JA, Glass LM, Kanumalla A. Statin
safety: an appraisal from the adverse event reporting system.
Am J Cardiol. 2006;97:32C-43C.
35. Hoffman KB, Kraus C, Dimbil M, Golomb BA. A survey
of the FDAs AERS database regarding muscle and tendon
adverse events linked to the statin drug class. PLoS One.
2012;7:e42866.
36. Joy TR, Hegele RA. Narrative review: statin-related myopa-
thy. Ann Intern Med. 2009;150:858-868.
37. Venero CV, Thompson PD. Managing statin myopathy.
Endocrinol Metab Clin North Am. 2009;38:121-136.
38. Pierce LR, Wysowski DK, Gross TP. Myopathy and rhabdo-
myolysis associated with lovastatin-gemfibrozil combination
therapy. JAMA. 1990;264:71-75.
39. London SF, Gross KF, Ringel SP. Cholesterol-lowering agent
myopathy (CLAM). Neurology. 1991;41:1159-1160.
40. Waclawik AJ, Lindal S, Engel AG. Experimental lovastatin
myopathy. J Neuropathol Exp Neurol. 1993;52:542-549.
41. Smith PF, Eydelloth RS, Grossman SJ, et al. HMG-CoA
reductase inhibitor-induced myopathy in the rat: cyclosporine
A interaction and mechanism studies. J Pharmacol Exp Ther.
1991;257:1225-1235.
42. Nakahara K, Kuriyama M, Yoshidome H, et al. Experimental
simvastatin-induced myopathy in rabbits. J Neurol Sci.
1992;113:114-117.
43. Langer T, Levy RI. Acute muscular syndrome associated with
administration of clofibrate. N Engl J Med. 1968;279:856-
858.
44. Smals AG, Beex LV, Kloppenborg PW. Clofibrate-induced
muscle damage with myoglobinuria and cardiomyopathy. N
Engl J Med. 1977;296:942.
45. Baker SK. Molecular clues into the pathogenesis of statin-
mediated muscle toxicity. Muscle Nerve. 2005;31:572-580.
46. Westwood FR, Bigley A, Randall K, Marsden AM, Scott RC.
Statin-induced muscle necrosis in the rat: distribution, devel-
opment, and fibre selectivity. Toxicol Pathol. 2005;33:246-
257.
47. Morita I, Sato I, Ma L, Murota S. Enhancement of membrane
fluidity in cholesterol-poor endothelial cells pre-treated with
simvastatin. Endothelium. 1997;5:107-113.
48. Flint OP, Masters BA, Gregg RE, Durham SK. Inhibition of
cholesterol synthesis by squalene synthase inhibitors does
not induce myotoxicity in vitro. Toxicol Appl Pharmacol.
1997;145:91-98.
49. Pierno S, De Luca A, Tricarico D, et al. Potential risk of
myopathy by HMG-CoA reductase inhibitors: a comparison
of pravastatin and simvastatin effects on membrane electri-
cal properties of rat skeletal muscle fibers. J Pharmacol Exp
Ther. 1995;275:1490-1496.
Shannon et al 229
50. Pierno S, Didonna MP, Cippone V, et al. Effects of chronic
treatment with statins and fenofibrate on rat skeletal muscle: a
biochemical, histological and electrophysiological study. Br J
Pharmacol. 2006;149:909-919.
51. Pierno S, De Luca A, Beck CL, George AL Jr, Conte Camerino
D. Aging-associated down-regulation of ClC-1 expression
in skeletal muscle: phenotypic-independent relation to the
decrease of chloride conductance. FEBS Lett. 1999;449:12-16.
52. Nishimoto T, Tozawa R, Amano Y, Wada T, Imura Y,
Sugiyama Y. Comparing myotoxic effects of squalene syn-
thase inhibitor, T-91485, and 3-hydroxy-3-methylglutaryl
coenzyme A (HMG-CoA) reductase inhibitors in human
myocytes. Biochem Pharmacol. 2003;66:2133-2139.
53. Yamazaki H, Suzuki M, Aoki T, et al. Influence of 3-hydroxy-
3-methylglutaryl coenzyme A reductase inhibitors on ubiqui-
none levels in rat skeletal muscle and heart: relationship to
cytotoxicity and inhibitory activity for cholesterol synthe-
sis in human skeletal muscle cells. J Atheroscler Thromb.
2006;13:295-307.
54. Sakamoto K, Honda T, Yokoya S, Waguri S, Kimura J. Rab-
small GTPases are involved in fluvastatin and pravastatin-
induced vacuolation in rat skeletal myofibers. FASEB J.
2007;21:4087-4094.
55. Dirks AJ, Jones KM. Statin-induced apoptosis and skeletal
myopathy. Am J Physiol Cell Physiol. 2006;291:C1208-C1212.
56. Guijarro C, Blanco-Colio LM, Ortego M, et al. 3-Hydroxy-
3-methylglutaryl coenzyme a reductase and isoprenylation
inhibitors induce apoptosis of vascular smooth muscle cells in
culture. Circ Res. 1998;83:490-500.
57. Owczarek J, Jasinska M, Orszulak-Michalak D. Drug-
induced myopathies. An overview of the possible mecha-
nisms. Pharmacol Rep. 2005;57:23-34.
58. Marcoff L, Thompson PD. The role of coenzyme Q10 in
statin-associated myopathy: a systematic review. J Am Coll
Cardiol. 2007;49:2231-2237.
59. Laaksonen R, Jokelainen K, Sahi T, Tikkanen MJ, Himberg JJ.
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;57:62-66.
60. Johnson TE, Zhang X, Bleicher KB, et al. Statins induce
apoptosis in rat and human myotube cultures by inhibiting
protein geranylgeranylation but not ubiquinone. Toxicol Appl
Pharmacol. 2004;200:237-250.
61. Bowser DN, Minamikawa T, Nagley P, Williams DA. Role
of mitochondria in calcium regulation of spontaneously con-
tracting cardiac muscle cells. Biophys J. 1998;75:2004-2014.
62. Sirvent P, Mercier J, Vassort G, Lacampagne A. Simvastatin
triggers mitochondria-induced Ca2+ signaling altera-
tion in skeletal muscle. Biochem Biophys Res Commun.
2005;329:1067-1075.
63. Sacher J, Weigl L, Werner M, Szegedi C, Hohenegger M.
Delineation of myotoxicity induced by 3-hydroxy-3-methyl-
glutaryl CoA reductase inhibitors in human skeletal muscle
cells. J Pharmacol Exp Ther. 2005;314:1032-1041.
64. Sirvent P, Mercier J, Lacampagne A. New insights into
mechanisms of statin-associated myotoxicity. Curr Opin
Pharmacol. 2008;8:333-338.
65. Erkal MZ, Wilde J, Bilgin Y, et al. High prevalence of vitamin
D deficiency, secondary hyperparathyroidism and general-
ized bone pain in Turkish immigrants in Germany: identifica-
tion of risk factors. Osteoporos Int. 2006;17:1133-1140.
66. Bischoff-Ferrari HA, Dietrich T, Orav EJ, et al. Higher
25-hydroxyvitamin D concentrations are associated with bet-
ter lower-extremity function in both active and inactive per-
sons aged > or =60 y. Am J Clin Nutr. 2004;80:752-758.
67. Ahmed W, Khan N, Glueck CJ, et al. Low serum 25 (OH)
vitamin D levels (<32 ng/mL) are associated with revers-
ible myositis-myalgia in statin-treated patients. Transl Res.
2009;153:11-16.
68. Glueck CJ, Budhani SB, Masineni SS, et al. Vitamin D defi-
ciency, myositis-myalgia, and reversible statin intolerance.
Curr Med Res Opin. 2011;27:1683-1690.
69. Lee P, Greenfield JR, Campbell LV. Vitamin D insuffi-
ciencya novel mechanism of statin-induced myalgia? Clin
Endocrinol (Oxf). 2009;71:154-155.
70. Riphagen IJ, van der Veer E, Muskiet FA, Dejongste MJ.
Myopathy during statin therapy in the daily practice of an out-
patient cardiology clinic: prevalence, predictors and relation
with vitamin D. Curr Med Res Opin. 2012;28:1247-1252.
71. Jacobson TA. Toward pain-free statin prescribing: clinical
algorithm for diagnosis and management of myalgia. Mayo
Clin Proc. 2008;83:687-700.
72. Bruckert E. A new approach to decrease serum cholesterol
levels. Cardiovasc Drugs Ther. 2006;20:157-158.
73. Talbert RL. Safety issues with statin therapy. J Am Pharm
Assoc. 2006;46:479-488.
74. Bottorff MB. Statin safety and drug interactions: clinical
implications. Am J Cardiol. 2006;97:27C-31C.
75. Rosenson RS. Current overview of statin-induced myopathy.
Am J Med. 2004;116:408-416.
76. Armitage J. The safety of statins in clinical practice. Lancet.
2007;370:1781-1790.
77. Ballantyne CM, Corsini A, Davidson MH, et al. Risk for
myopathy with statin therapy in high-risk patients. Arch
Intern Med. 2003;163:553-564.
78. Shek A, Ferrill MJ. Statin-fibrate combination therapy. Ann
Pharmacother. 2001;35:908-917.
79. Jones PH, Davidson MH. Reporting rate of rhabdomyolysis
with fenofibrate + statin versus gemfibrozil + any statin. Am J
Cardiol. 2005;95:120-122.
80. Kordas KC, Phillips PS, Golomb BA. Clinical characteristics
of 1053 patients with statin associated muscle complaints.
Arterioscler Thromb Vasc Biol. 2004;24:e51-e136.
81. Toth PP, Harper CR, Jacobson TA. Clinical characterization
and molecular mechanisms of statin myopathy. Expert Rev
Cardiovasc Ther. 2008;6:955-969.
82. Cham S, Evans MA, Denenberg JO, Golomb BA. Statin-
associated muscle-related adverse effects: a case series of 354
patients. Pharmacotherapy. 2010;30:541-553.
83. Vaughan CJ, Gotto AM Jr. Update on statins: 2003.
Circulation. 2004;110:886-892.
84. Fernandez G, Spatz ES, Jablecki C, Phillips PS. Statin myop-
athy: a common dilemma not reflected in clinical trials. Cleve
Clin J Med. 2011;78:393-403.
230 Journal of Pharmacy Technology 29(5)
85. Foley KA, Simpson RJ Jr, Crouse JR 3rd, Weiss TW, Markson
LE, Alexander CM. Effectiveness of statin titration on low-
density lipoprotein cholesterol goal attainment in patients at
high risk of atherogenic events. Am J Cardiol. 2003;92:79-81.
86. Ansell BJ, Fonarow GC, Maki KC, Dicklin MR, Bell M,
Davidson MH; NEPTUNE II Steering Committee. Reduced
treatment success in lipid management among women with
coronary heart disease or risk equivalents: results of a national
survey. Am Heart J. 2006;152:976-981.
87. Caso G, Kelly P, McNurlan MA, Lawson WE. Effect of coen-
zyme q10 on myopathic symptoms in patients treated with
statins. Am J Cardiol. 2007;99:1409-1412.
88. Young JM, Florkowski CM, Molyneux SL, et al. Effect of
coenzyme Q(10) supplementation on simvastatin-induced
myalgia. Am J Cardiol. 2007;100:1400-1403.
89. Bell DS. Resolution of statin-induced myalgias by correcting
vitamin D deficiency. South Med J. 2010;103:690-692.
90. Hansen KE, Hildebrand JP, Ferguson EE, Stein JH. Outcomes
in 45 patients with statin-associated myopathy. Arch Intern
Med. 2005;165:2671-2676.
91. Stein EA, Ballantyne CM, Windler E, et al. Efficacy and
tolerability of fluvastatin XL 80 mg alone, ezetimibe 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;101:490-496.
92. Athyros VG, Tziomalos K, Kakafika AI, Koumaras H,
Karagiannis A, Mikhailidis DP. Effectiveness of ezetimibe
alone or in combination with twice a week atorvastatin
(10 mg) for statin intolerant high-risk patients. Am J Cardiol.
2008;101:483-485.
93. Reddy KJ, Singh M, Batsell RR, et al. Efficacy of combina-
tion drug pulse therapy in maintaining lipid levels in patients
intolerant of daily statin use. J Clin Hypertens (Greenwich).
2009;11:766-768.
94. 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;42:341-346.
95. Gazi IF, Daskalopoulou SS, Nair DR, Mikhailidis DP. 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;23:2183-2192.
96. Rivers SM, Kane MP, Busch RS, Bakst G, Hamilton RA.
Colesevelam hydrochloride-ezetimibe combination lipid-
lowering therapy in patients with diabetes or metabolic
syndrome and a history of statin intolerance. Endocr Pract.
2007;13:11-16.
97. Glueck CJ, Abuchaibe C, Wang P. Symptomatic myositis-
myalgia in hypercholesterolemic statin-treated patients with
concurrent vitamin D deficiency leading to statin intoler-
ance may reflect a reversible interaction between vitamin D
deficiency and statins on skeletal muscle. Med Hypotheses.
2011;77:658-661.
98. Becker DJ, Gordon RY, Halbert SC, French B, Morris PB, Rader
DJ. Red yeast rice for dyslipidemia in statin-intolerant patients: a
randomized trial. Ann Intern Med. 2009;150:830-839.