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REVIEW ARTICLE
Statin myopathies: pathophysiologic and clinical
perspectives
Steven K. Baker, MSc, MD
Mark A. Tarnopolsky, MD, PhD
From the Department of Medicine, Division of Neurology and Rehabilitation, McMaster University Medical
Centre, McMaster University, Hamilton, Ont.
Medical subject headings: anticholesteremic agents; arteriosclerosis; coenzymes; hydroxymethyl-CoA reductase inhibitors; hypercholesterolemia; lipids and antilipemic agents;
lovastatin; muscular disease; pravastatin; rhabdomyolysis;
simvastatin; ubiquinone
(Original manuscript submitted Aug. 21, 2001; received in revised form Aug. 23, 2001; accepted Aug. 28, 2001.)
Clin Invest Med 2001;24(5):258-72.
© 2001 Canadian Medical Association
Introduction
The sequelae of atherosclerotic vascular disease contribute significantly to the burden of illness in developed nations. In Canada an estimated 36% of all
deaths result from cardiovascular disease (CVD).1
Antilipemic agents have proven to be particularly
advantageous in both primary and secondary prevention of CVD sequelae.2–4 Among the various
lipid-lowering medications the 3-hydroxy-3methylglutaryl-coenzyme A (HMG-CoA) reductase
inhibitors, (HMGRI or “statins”) have emerged as
the dominant class for the treatment of hypercholesterolemia.5 In addition to their ability to lower serum
cholesterol by inhibiting a rate-limiting enzyme in
the cholesterol biosynthetic pathway, statins have
also been shown to target a variety of cellular
processes that modify endothelial function, inflammatory responses, plaque stabilization and thrombogenesis.6,7 Relevant to these functions are the findings that acute statin therapy decreases the incidence
of symptomatic ischemia in patients with acute coronary syndromes8 and may suppress recurrent transient ischemic attacks.9 These newly discovered
properties make statins particularly attractive agents
for the acute and long-term treatment of CVD be258
cause they target multiple pathways that ultimately
converge in atherothrombotic events. The use of
statins in the treatment of lipid-related disorders is
therefore expected to rise.
Generally, the statins have a benign side-effect profile and are well tolerated. The most serious adverse
effects arise from cell damage in liver and skeletal
muscle. Increases in serum transaminases of hepatic
origin are dose dependent and occur with a reported
frequency of approximately 1%, whereas myotoxicity, defined as myalgias and elevated serum creatine
kinase values (>10 times the upper limit of normal),
occurs in 0.1% of patients.5 Although hepatotoxicity
is more common, myotoxicity may pose a larger risk
for sarcolemmal disruption (i.e., rhabdomyolysis)
and can lead to myoglobinuria and acute renal failure.10–13 The incidence of myopathies is low, but the
increasing use of statins implies that more physicians
will encounter this clinical entity. Attempting to
understand the pathophysiology of statins is of particular importance given the withdrawal of cerivastatin
from the market in August 2001 owing to an unacceptable incidence of rhabdomyolysis and death.
This review will consider the potential etiologies of
statin myopathies in relation to altered cholesterol
biosynthesis and muscle physiology.
Clin Invest Med • Vol 24, no 5, octobre 2001
Statin myopathies
Pathophysiologic considerations
HMG-CoA reductase and statin biochemistry
Unique among lipid-lowering drugs, statins impair
cholesterogenesis by selectively targeting the ratelimiting enzyme, HMG-CoA reductase by reversible
competitive inhibition. This enzyme catalyzes the
conversion of HMG-CoA to mevalonate, an intermediate, which in turn gives rise to numerous metabolites (Fig. 1). Pharmacologic inhibition of HMG-
Acetate
Acetyl-CoA
CoA reductase results in reduced cholesterol synthesis and transcriptional upregulation of HMG-CoA
reductase (i.e., impaired feedback inhibition) and
may increase the expression of hepatic low-density
lipoprotein (LDL) receptors.14 This increases the
fractional catabolic rate of plasma LDL and therefore lowers serum cholesterol.14
Hormonal control of HMG-CoA reductase is exerted by 4 agents: (1) glucagon, which opposes insulin’s transcriptional effect and phosphorylates the
enzyme thereby reducing its activity; (2) thyroid
Acetoacetyl-CoA
HMG-CoA
Statins
Mevalonate-5-PP
CoQ10
Isopentyl-PP
Mevalonate-5-P
Prenylated
proteins
Geranylgeranyl-PP
Geranyl-PP
Mevalonate
Farnesyl-PP
Squalene
Dolichols
Cholestadien-3β-ol
*2
*3
Lathosterol
Desmosterol
Lanosterol
Squalene-2,3-epoxide
7-Dehydrocholesterol
Cholesterol
Fig. 1: The biosynthetic pathways for mevalonate and its distal metabolites. Statin drugs selectively impair the
rate-limiting enzyme, β-hydoxy-β-methylglutaryl-coenzyme A reductase, which decreases cholesterol production.
Farnesyl-pyrophosphate (PP) gives rise to geranylgeranyl-PP, the compound responsible for donating 10 isoprenoid tail units to coenzyme Q (CoQ10). There are 3 nonenzymatic steps (*3) between lanosterol and cholestadien-3β-ol and 2 steps (*2) between this molecule and desmosterol. Overall, 14 steps (enzymatic + nonenzymatic) separate mevalonate from cholesterol, whether it is formed from desmosterol or 7-dehydrocholesterol.
This lack of propinquity to the targeted substrate causes pleiotropic metabolic effects in skeletal myocytes.
Clin Invest Med • Vol 24, no 5, October 2001
259
Baker and Tarnopolsky
hormone, which increases enzyme activity through
enhanced transcription and mRNA stability; (3) glucocorticoids, which destabilize; and (4) estrogen,
which stabilizes HMG-CoA reductase mRNA.15 Interestingly, hypothyroidism has been hypothesized
to potentiate the myotoxic effects of statins.16–18 Although there have been no reports on myopathic interactions between glucocorticoids and statins,
steroids may possibly contribute to muscle damage
in organ transplant recipients receiving combination
immunosuppresive and lipid-lowering therapy.19,20
Five drugs — atorvastatin, fluvastatin, lovastatin,
pravastatin and simvastatin — are currently marketed
in North America; a sixth, cerivastatin, has recently
been withdrawn. Lovastatin, pravastatin and simvastatin are all fungal derivatives and share the same hydronaphthalene ring structure. Simvastatin is a semisynthetic methylated analogue of lovastatin.
Pravastatin is a purified metabolite of mevastatin, the
original HMG-CoA reductase inhibitor that was never
marketed.21–25 Atorvastatin, cervistatin and fluvastatin
are synthetic.26 Each statin molecule has a moiety resembling hydroxymethylglutaric acid. The open, hydroxy acid, conformation is active whereas the closed,
lactone, conformation is inactive. Hepatic hydrolysis at
alkaline pH decyclizes and hence activates the lactone
prodrugs lovastatin, atorvastatin and simvastatin.27
Extensive first-pass metabolism limits the systemic bioavailability of the HMGRIs and accounts
for the rapid clearance of statins, excepting atorvastatin.2 (Atorvastatin undergoes hepatic metabolism to
active metabolites, which, together with the parent
compound, have a half-life of about 15 hours.) The
hepatic microsomal cytochrome P450 isoenzyme
system (CYP) is responsible for the complex metabolism of the HMGRIs. After hydrolysis, the lactone
prodrugs lovastatin,28 and simvastatin,28 cerivastatin,29
and atorvastatin 30 are primarily oxidized by
CYP3A4. Fluvastatin is predominately (50%–80%)
inactivated by CYP2C9, but recent evidence suggests that CYP3A4 and CYP2C8 also contribute to
its biotransformation.31 Cerivastatin is also partially
oxidized by CYP2C8.29 The multiple CYP isoenzyme pathways open to both cervistatin and fluvastatin may afford increased protection against potential myotoxic interactions when coadministered
drugs compete with or antagonize CYP isozymes.32
260
Cholesterol biosynthesis and the isoprenoids
The inhibition of HMG-CoA reductase by the HMGRIs is approximately 14 steps and 9 to 10 enzymatic
reactions removed from the terminal step(s) in cholesterologenesis (mediated by 7-dehydrocholesterol reductase and desmosterol reductase). Furthermore,
mevalonic acid, the immediate product of HMG-CoA
reductase, is a pivotal precursor intermediate which
gives rise to the vital isoprenoids en route to cholesterol. It is not surprising, therefore, that inhibiting this
important biosynthetic pathway causes pleiotropic
metabolic consequences33,34 (Fig. 1).
Prenylation is a fundamental element of posttranscriptional lipid modification of proteins and other
compounds and affects their function. Some of the
known isoprenoids include the following: (1)
isopentyladenosine, required for transfer RNA synthesis; (2) dolichols, required for glycoprotein synthesis;
(3) heme A, a polyisoprenoid component of the electron transport chain; and (4) ubiquinone, a polyisoprenylated quinoid cofactor of the electron transport
chain, which accepts electrons from complexes I and
II.6,35,36 The predominant form of coenzyme Q in human is coenzyme Q10, containing 10 isoprenoid units
in the tail, whereas the predominant form in rodents is
coenzyme Q9, with 9 isoprenoid units in the tail. The
covalent addition of either farnesyl (15-carbon) or
geranylgeranyl (20-carbon) isoprenoids to conserved
cysteine residues on the C-terminus of important regulatory proteins enables both membrane association
and protein–protein interactions.37 It is estimated that
over 1% of mammalian cellular proteins are isoprenylated.38 Isoprenylated proteins have been implicated in
smooth muscle cell migration and proliferation,33 and
skeletal muscle cell growth and differentiation.39–42
These conclusions were borne out of experiments in
which statin treatment impaired cell development in
culture, whereas the coapplication of mevalonate or
its distal metabolites (i.e., farnesol or geranylgeraniol)
reversed many of the inhibitory cellular effects of
statins.41,43 The identification of prenylated proteins involved in signal transduction and cell cycle progression (i.e., laminin B, ras proto-oncogene, Rho-related
proteins and the γ-subunit of heterotrimeric GTPbinding proteins) supports the dependency of these
processes on the mevalonate pathway.
Clin Invest Med • Vol 24, no 5, octobre 2001
Statin myopathies
Statins and altered muscle physiology
Spectrum of myotoxic reactions to statin drugs
Various hypotheses have been proposed to explain
the relationship between statin therapy and the spectrum of muscle dysfunction manifested by myalgia,
myopathy and rhabdomyolysis. Although each
demonstrates unique merits none has sufficiently
elucidated the underlying pathophysiology, which
remains speculative.39,42,44–46
Myalgias are clinically defined by any combination
of muscle weakness, tenderness or pain either in a
proximal or regional pattern. Clinically, patients often
describe a cramping feeling in the muscle. The serum
creatine kinase (CK) activity can be normal or only
trivially elevated. In addition to myalgic complaints,
patients with HMGRI-related myopathy may have
CK activity values more than 10 times the upper limit
of normal for a given reference laboratory (i.e., >2200
U/L for males and >1500 U/L for females).47 Light
and electron microscopic histomorphometric features
of statin-induced myopathy are listed in Table 1.48 Altered myofibre architecture with evidence of necrosis
has been observed in experimental rodent models of
statin myopathy, where exposure to suprapharmacologic doses accelerates myotoxicity,48,49 and in humans
exposed to therapeutic doses.50–52
Rhabdomyolysis, an acute degeneration of skeletal
muscle, is a potentially fatal condition due to the
toxic effects of myoglobinemia/myoglobinuria on
the renal tubules. Nephrotoxicity is largely mediated
by the Fenton (Fe2+ + H2O2 → Fe3+ + OH• + OH–)
and Haber–Weiss (O2•– + H2O2 → O2 + OH• + OH–)
reactions as myoglobin provides ferrous iron, which
serves as a catalyst for the generation of harmful reactive oxygen species. Interestingly, reactive oxygen
species have also recently been implicated in the
pathophysiology of contrast-agent-induced renal
dysfunction,53–55 a condition in which N-acetylcysteine pre-supplementation (600 mg × 2 d) was
shown to be nephroprotective.56 Whether the acute
administration of antioxidants, at the onset of rhabdomyolysis, favourably alters the expression of renal
damage is unknown but deserves investigation.
Serum CK activity values are greatly elevated but
cannot be used to differentiate rhabdomyolysis from
Clin Invest Med • Vol 24, no 5, October 2001
myopathy. Possible complications arising from
rhabdomyolysis and consequent acute tubular
necrosis include hypocalcemia, hyperkalemia,
metabolic acidosis, hyperuricemia, disseminated
intravascular coagulation, cardiomyopathy and respiratory embarrassment.56
Ubiquinone and the development of statin myopathy
Much interest has focused on the role of ubiquinone
in the development of statin myopathy.57–63 This potential etiology has biologic rationale as coenzyme
Q10 is an essential cofactor of the electron transport
chain.56 Coenzyme Q10 is a lipophilic compound
composed of redox active quinoid moieties as well
Table 1: Histomorphologic changes in mammalian skeletal
muscle after pharmacologic doses of statins (lovastatin, 1
mg/g body weight for 30 days).
Microscopy
Change
Light
Increased variability in fibre diameter
Myofibre splitting
Increased numbers of internal nuclei
Perimysial fibrosis
Coarsening of intermyofibrillar membranous
network
Clumping of intermyofibrillar membranous
material
Diffuse decrease in NADH dehydrogenasestaining in non-necrotic myofibres
Myofibre necrosis with macrophage invasion
Hypercontracted fibres
Relative sparing of slow-twitch oxidative fibres
with earlier involvement of fast-twitch
glycolytic fibres
Electron
2 types of mitochondrial alterations:
• fragmented inner mitochondrial membrane
(IMM) or absent or effaced mitochondrial
cristae
± replacement of cristae with fine granular
material; outer mitochondrial membrane
(OMM) intact
• spared IMM and matrix; redundant and
thickened OMM ± circular loops formed by
OMM material
Myeloid figures in degenerating mitochondrial
membranes
Dilated cisterns of the sarcoplasmic reticulum
normal transverse tubules
Increased presence of vacuoles
Intermyofibrillar and subsarcolemmal
accumulations of abnormal mitochondria
Small zones of Z-band streaming
Adapted from Waclawik AJ, Lindal S, Engel AG. Experimental lovastatin myopathy. J
Neuropathol Exp Neurol 1993;52:542-9. Biopsies were taken from Lewis rat
gastrocnemius muscles on days 5, 10, 12, 14 and 30. Therefore, selected features
from the above list were not observed in each animal. Longer treatment was
associated with worsening disease.
261
Baker and Tarnopolsky
as a hydrophobic prenylated tail that provides the
physiochemical properties enabling mobility within
the phospholipid bilayer of the inner mitochondrial
membrane. Coenzyme Q10 is found in complexes I
and II of the electron transport chain (ETC) where it
undergoes 2 sequential 1 electron reductions by
flavoproteins, first to the semiubiquinone radical and
then to ubiquinol. 6,35,36 Ubiquinol reduces cytochromes b and c of complex III and so provides
the necessary electron carrier system for reduced
nicotinamide adenosine dinucleotide (NADH)- and
reduced flavin adenosine dinucleotide (FADH2)linked substrates to aerobically generate ATP, the
universal cellular energy currency. Coenzyme Q10
also serves as an important antioxidant in both mitochondria and lipid membranes.64,65 Apoptosis, which
can be induced by statins in cultured myoblasts66,67 is
inhibited by coenzyme Q10.68 Additionally, coenzyme Q10 decreases oxidative DNA damage in human lymphocytes.56 Further evidence of the potential
utility of coenzyme Q10 for the treatment of statin
myopathy derives from studies demonstrating both
biochemical and clinical efficacy of quinone supplementation in patients with primary69–72 and secondary
(i.e., cardiomyopathy)56,73–75 coenzyme Q10 deficiency states and other forms of mitochondrial disorders.76 Given the preponderance of evidence supporting the therapeutic efficacy of coenzyme Q10 in
various conditions, the question is not whether coenzyme Q10 supplementation benefits patients who are
ubiquinone-deficient, but whether statin therapy induces such a secondary deficiency state.
Shortly after the development of selective inhibitors of HMG-CoA reductase experimental evidence accrued demonstrating impaired ubiquinone
synthesis in various cell types.77,78 Clinical reports
describing the efficacy of coenzyme Q10 supplementation in patients with statin myopathy soon followed.79,80 The first case described a physically active 48-year-old physician who experienced fatigue
and proximal myalgias and had elevated CK levels
(1400 U/L) 2 to 3 weeks after starting lovastatin (20
mg OD). Despite withdrawal of the drug, his symptoms persisted for 6 months, at which time he began
taking low-dose coenzyme Q10 (30 mg OD).
Within a few days his symptoms abated, and he resumed strenuous activities without difficulty.80 The
262
second case report described a 63-year-old woman
who required hospital admission 8-months after
starting simvastatin (20 mg OD) for a constellation
of symptoms and laboratory abnormalities that resembled a MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) syndrome. Her clinical findings included diffuse
muscle weakness, bilateral ptosis, external ophthalmoplegia, cognitive dysfunction and mild aphasia.
Laboratory investigations revealed rhabdomyolysis
(CK >20 000 U/L), hyperlacticacidemia (5.1
mmol/L; normal <2.2 mmol/L) and ragged-red fibres with abundant pleiomorphic mitochondria and
a reduced muscle coenzyme Q10 concentration
([Q10]) (13.1 mg/g; normal 15.5–21.7 mg/g)81–83 on
skeletal muscle biopsy. A 3-month trial of oral
coenzyme Q10 (250 mg OD) ameliorated weakness
and ophthalmoplegia, renormalized muscle [Q10]
and eliminated ragged-red fibres.79 Interestingly,
consecutive etofibrate and clofibrate treatment provoked a mitochondrial myopathy5 and valproate, an
antiepileptic agent that inhibits mitochondrial fatty
acid oxidation, reportedly triggered a MELAS syndrome in a woman who was later found to harbour
the A3243G transition mutation.84 Although this 63year-old did not have the A-to-G substitution at nucleotide 3243 it is quite conceivable that she harboured another defect since none of the other
mutations (>50) were sought. These observations
raise the possibility that pharmacologic inhibitors of
mitochondrial metabolism may unmask latent mitochondrial dysfunction and manifest overt disease.
Coenzyme Q10 improved the lactate/pyruvate
(L/P) ratios in some patients with mitochondrial myopathies and increased oxygen consumption in a patient with MELAS.76,85,86 Related to this, De Pinieux
and colleagues,57 found increments in the L/P ratios
of patients treated with statins compared to hyperand normocholesterolemic controls (19.0 v. 15.9 and
13.1, respectively). The statin group was not supplemented with coenzyme Q10 to determine if blood
lactate levels could be restored to normal. The high
lactate levels were presumed to be secondary to a
statin-induced alteration of ubiquinone biosynthesis
and thus (ETC) function. Significantly, serum
ubiquinone was lower in the statin group than the
hypercholesterolemic controls but unchanged comClin Invest Med • Vol 24, no 5, octobre 2001
Statin myopathies
pared to the healthy controls (0.75 v. 0.69 mg/L)
who had normal L/P ratios. The etiologic importance
of ubiquinone was therefore questionable.
Numerous investigations have confirmed that
statins reduce serum ubiquinone concentrations.57,60,62,87–89 Circulating lipoproteins appear to be
the predominant carrier proteins for ubiquinone in
both animals90 and humans.91,92 Laaksonen and associates 88 found reductions in serum and LDL
ubiquinone approximately proportional to reductions
in serum LDL cholesterol after 4 weeks of statin
treatment. In contrast, another study found that
whereas short-term (4-wk) statin treatment did not
change serum ubiquinone-to-LDL ratios, long-term
treatment (12 wk) caused a significant decrement in
serum LDL (–25%) relative to serum coenzyme Q10
(–52%). Whether long-term statin treatment increases the likelihood of secondary ubiquinone deficiency is not entirely clear, but this seems unlikely as
a subsequent study found no differences in serum
ubiquinone-to-LDL ratios after 6 months of simvastatin therapy (i.e., 0.49 before v. 0.50 after).87 In fact,
one study reported an elevated serum ubiquinone-toLDL ratio after HMGRI treatment.56
Of greater theoretical importance is the effect of
statins on intramuscular coenzyme Q10 content for
biosynthetic alterations in this tissue should provide
a more precise index of deranged metabolism. Only
one study has found depleted muscle ubiquinone,
which appeared to be commensurate with the extent
of muscle damage.79 Paradoxically, in the few muscle biopsy studies performed to date, ubiquinone
concentrations were increased after HMGRI treatment in rodents 56 and humans. 87,88 These results
suggest that HMGRIs do not cause physiologically
significant perturbations in muscle coenzyme Q10
synthesis. However, none of the patients in whom
muscle biopsies were performed experienced any
symptoms of myotoxicity. It is tempting to speculate
that only those patients who express a latent mitochondriopathic diathesis or partial defect in coenzyme Q10 synthesis will become clinically symptomatic with the administration of statin drugs. This
notion is supported by the finding that lovastatin
while impairing the incorporation of [3H]acetate and
[14C]tyrosine into ubiquinone failed to impair the
activities of succinate-cytochrome c reductase and
Clin Invest Med • Vol 24, no 5, October 2001
succinate dehydrogenase in murine neuroblastoma
cells. Additionally, polarographic measurements of
oxygen consumption in state 3 (i.e., electron transport chain saturation) and in an uncoupled state in
both muscle homogenate and isolated mitochondria
were normal.93 Therefore, even in the context of
quantified decreases in ubiquinone synthesis mitochondrial respiration was preserved. However, this
was an acute treatment effect in vitro and may not
parallel chronic in vivo changes. Laaksonen and colleagues87 confirmed this with measurements of highenergy phosphates in skeletal muscle. Both ATP and
creatine phosphate levels were unaffected by therapeutic doses of simvastatin. Recently, simvastatin
treatment was associated with a reduction in blood
ATP levels even though tissue ATP concentration
([ATP]) 7was not affected.94 Considering that muscle, by virtue of its mass and metabolic activity, is a
major contributor to the blood ATP pool it is unclear
what causes the fall in [ATP]. One possibility may
be that statins cause membrane destabilization resulting in functional impairment of the ATP binding
cassettes (i.e., ATP transport proteins) and decreased
egression of ATP. Therefore, constrained ATP
synthesis coupled with decreased membrane ATP
transport may account for reduced blood [ATP] with
paradoxically normal tissue [ATP]. This requires
experimental confirmation.
Ubiquinone is an important antioxidant in biological systems. 6,95 Statins reduce concentrations of
lipophilic antioxidants (i.e., α-tocopherol, β-carotene
and lycopene) found in LDL particles.87 As with
coenzyme Q10, this effect is thought to be mediated
by a primary drop in serum lipoproteins.56 Lankin and
associates96 found that pravastatin intensified in vivo
free radical oxidation of LDL particles in patients
with myocardial ischemia and that ubiquinone supplementation suppressed lipid peroxidation. Ischemia
is a potent generator of free radicals 97,98 and
ubiquinone has been well described as an antiischemic cardioprotectant;99–103 therefore it is unclear
to what extent exogenous coenzyme Q10 attenuated
ischemia- or statin-related oxidative stress.
The contribution of ubiquinone to the development
of statin myopathy is unclear. This is because definitive experiments correlating mitochondrial respiratory chain enzymology to muscle coenzyme [Q10]
263
Baker and Tarnopolsky
and indices of oxidative stress (i.e., malondialdehyde, 8-iso-prostaglandinF 2α , 8-hydroxy-2′deoxyguanosine) in patients with and without statin
myopathy is lacking.
Effects of statins on membrane function
and calcium regulation
Statins have been reported to affect skeletal muscle
K+
¯
Cl
PIP
Na
+
Ca
2+
↑Na+
PLCγ1
P
membrane physiology not only through changes in
cholesterol content,94 which alters membrane fluidity,2
but also through changes in (1) membrane electrical
properties (which appears to be a secondary phenomenon),2,104,105 (2) Na+-K+ pump density,106 (3) excitationcontraction coupling,107 and (4) cell surface receptor
signal transduction cascades.66,108 Fig. 2 provides a
composite summary of the hypothetical multifactorial
etiopathogenesis of statin-induced myotoxicity.
↓ GCl–
DAG
+
IP3
↑[Ca ]i
2+
Ca2+
Ca2+
Ca2+
Transverse
tubule
↓ Q10 → ? ↓ ATP → E dysFx → ROS
Ca
? ↑ O2•–
2+
SR
↓ Chol/PL ratio
Sarcomere
Fig. 2: A comprehensive schematic diagram of the proposed mechanisms of statin myopathy. Decreased chloride conductance (GCl–) potentially destabilizes membrane electrical potential and increases susceptibility to
myotonic afterdepolarizations, which may elevate intracellular calcium ([Ca2+]i) through increased sarcoplasmic reticulum (SR) Ca2+ release. Furthermore, [Ca2+]i may be augmented from increased activity of the Na+Ca2+ exchanger as a secondary response to increased intracellular [Na+], which accrues as a result of decreased Na+-K+ pump density. SR Ca2+ ATPase function may be impaired by statins therefore impairing the
reuptake of free sarcoplasmic Ca2+. Statins induce the phosphorylation (P) of the γ1 subunit of phospholipase
C (PLCγ1) causing phosphodiesterase activation and the conversion of phosphatidylinositol 4,5-bisphosphate
(PIP) to diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). Receptors on the SR for IP3 mediate Ca2+
release (Note, the IP3 receptors predominate in the junctional SR but are depicted in the longitudinal SR for
clarity). Decrements in the membrane cholesterol-to-phospholipid (Chol/PL) ratio may also contribute to
disruption of integral membrane protein function. Decreased synthesis of ubiquinone (Q10) may lead to both
decreased ATP production and reduced free radical scavenging. E dysFx = energy dysfunction, ROS = reactive oxygen species.
264
Clin Invest Med • Vol 24, no 5, octobre 2001
Statin myopathies
Cholesterol’s role in membrane chloride conductance was first evidenced in patients treated with
clofibrate who presented with acute muscular syndromes characterized by muscle cramping, weakness, stiffness and myopathic changes.109,110 Clofibrate produces electrophysiologic myotonia in rats,
an effect completely attributable to a drug-induced
decline in membrane chloride conductance.56 In experiments by Pierno and colleagues104,105 pravastatin
was shown to have no effect on electromyographic
activity or membrane chloride conductance whereas
simvastatin caused dose-dependent reductions in the
latter. Furthermore, decreased action potential amplitudes were recorded in simvastatin-treated rats, suggestive of decreased sodium channel function, and
glybenclamide attenuated the increased potassium
channel conductance, suggestive of reduced flux
through the ATP-sensitive K+ channel. The latter
finding was hypothesized to be attributable to decreased muscle ubiquinone and ATP, leading to
channel opening; however, as discussed above, this
remains inconclusive.
Sarcolemmal Na+–K+ ATPase activity is partly determined by the cholesterol environment in which it
is expressed.111,112 Reductions in membrane cholesterol impair pump function whereas elevated cholesterol levels augment pump function.113 Lovastatin,
through mechanisms unrelated to changes in membrane cholesterol, decreased sarcolemmal Na+–K+
ATPase density and pump current in skeletal and
cardiac muscle.106 This was accompanied by a coordinated rise in sarcoplasmic Na+ concentration. Parenteral administration of mevalonate reversed these
effects. Although unsubstantiated, increased intracellular Na+ could invoke Ca2+ influx via the Na+–Ca2+
antiport and cause myofibre necrosis or apoptosis.56
Excitation-contraction coupling is the process by
which a sarcolemmal action potential is propagated
down the transverse tubules and converted into a calcium release signal through the interaction between
L-type calcium channel dihydropyridine receptors
and sarcoplasmic reticulum (SR) ryanodine receptors at the triadic junctions.4 A second messanger
signal from inositol 1,4,5-trisphosphate (IP3) is also
involved in modulating SR Ca2+ release in skeletal
muscle.114,115 Simvastatin significantly reduced the
mechanical threshold of rat skeletal muscle in a
Clin Invest Med • Vol 24, no 5, October 2001
dose-dependent fashion.99 The voltage threshold for
contraction is made more negative (closer to the resting potential) by any process, either physiologic or
pharmacologic, that increases cytosolic Ca2+ concentration ([Ca2+]).56 Either increased SR Ca2+ release or
decreased SR Ca2+ATPase (SERCA) activity can be
responsible for elevated cytosolic [Ca2+]. High concentrations of simvastatin in rat L6 myoblasts caused
transient elevations in cytosolic [Ca2+] and eventual
membranolysis.56 Parallel findings were recorded in
cultured rat skeletal muscle satellite cells superfused
with simvastatin.116 In this study, neither mevalonic
acid nor cholesterol could abolish simvastatin’s
effect, and membrane lipid composition was unchanged, suggesting that the effect was not mediated
through an inhibition of HMG-CoA reductase. Simvastatin caused similar increases in intracellular
[Ca2+] in cardiomyocytes.84 Recently, tyrosine phosphorylation of the γ1 subunit of phospholipase C
(PLC) has been inculpated as a critical step in cell
death signalling in L6 myoblasts.108 Tyrosine phosphorylation of PLC-γ1 stimulates catalytic activity,
causing coordinated increments in IP3 and intracellular [Ca2+]. Interestingly, aging is associated with decreased SERCA activity.117,118 Aging is also coupled
to the accumulation of mitochondrial DNA mutations, leading to impaired ETC function and the generation of reactive oxygen and nitrogen species.119
The SERCA2 isoform appears to be relatively resistant to oxidative damage,2,56 whereas the fast-twitch
isoform, SERCA1, is particularly vulnerable to oxidative modification at targeted cysteine residues.56 If
statins do increase the oxidative burden in skeletal
muscle, the SERCA1 protein may be susceptible and
thus contribute to the deranged Ca2+ homeostasis.
Whether oxidative factors are related to the statinmediated early and selective mitochondrial swelling
and fibre necrosis commonly observed in type II fibres (i.e., fast-twitch fibres)48,56 is not known.
Drug interactions and 3-hydroxy-3-methylglutaryl
CoA-reductase inhibitor therapy
The concomitant administration of HMGRIs with
other medications poses a significant risk for the development of myotoxicity. As already discussed,
CYP3A4 is the predominant isoform responsible for
265
Baker and Tarnopolsky
HMGRI biotransformation. Current evidence suggests that the muscle damage is precipitated through
inhibition of CYP3A4 with secondary elevations in
serum HMGRI levels. 81,120–122 For example, erythromycin,121,122 azole antifungals,4,56 cyclosporin A
(CsA),56 mibefradil2 and nefazadone3 are all oxidized by CYP3A4 and have been associated with
myopathy or rhabdomyolysis when taken with
lipophilic HMGRIs (Table 2). Indeed, the pharmacokinetics of pravastatin, a hydrophilic HMGRI
with non-CYP450-dependent metabolism and fluvastatin, which relies on the CYP2C9 isoform for
biotransformation, are only modestly affected by
the co-administration of CsA.31,123 CsA is unique in
that it augments serum statin levels via 2 mechanisms. First, CsA competitively inhibits the
CYP3A4 isozyme and increases blood levels of lovastatin, simvastatin and cervistatin. Fluvastatin is
less affected by CsA due to alternative metabolism.
Notably, HMGRIs tend not to affect the pharmacokinetics of CsA since CsA has a greater affinity for
CYP3A4 and since its serum concentrations are approximately 10-fold higher.4 Second, CsA is known
to induce cholestasis in humans.56 Smith and colleagues124 demonstrated that the cholestatic effect of
CsA increased muscle HMGRI levels (up to 13-
fold) and resulted in light microscopic changes including myofibre necrosis, interstitial edema and inflammatory cell infiltration. Interestingly, periodic
acid-Schiff staining revealed decreased glycogen
content in type IIb fibres, which were most sensitive
to the myotoxic effects of HMGRIs. Decreased
availability of glycolytic substrate and increased reliance on β-oxidation, in aerobically deficient cells,
compounded by the possible statin-mediated impaired ETC function (i.e., decreased ubiquinone
synthesis) may suppress myocyte viability. Mevalonate but not coenzyme Q10 supplementation ameliorated the myopathy suggesting that the toxic effect was not due to deficiency of the latter. 124
Interestingly, HMGRIs in certain experimental situations can induce apoptosis,66 and CsA inhibits the
mitochondrial permeability transition pore (MPT)
by preventing the binding of cyclophilin-D to the
adenine nucleotide transporter (a component of
the MPT).125,126 Therefore, it appears that, in the
appropriate physiologic condition(s), the deleterious
effects of HMGRIs overwhelm the protective effects CsA. Alternatively, HMGRI-mediated myofibre necrosis may not proceed through an MPTmediated pathway. Furthermore, CsA independently causes muscle dysfunction, characterized by
Table 2: Various drugs metabolized by the human cytochrome P450 mixed oxidase isoenzyme system
CYP1A2
CYP2C9
CYP2C19
CYP2D6
CYP2E1
Acetominophen
Alprenolol
Diazepam
Amitriptyline
Chloroxazone
Caffeine
Diclofenac
Ibuprofen
Bufaralol
Ethanol
Clozapine
Mephenytoin
Codeine
Halothane
Fluvastatin
Phenacetin
N-DMDZP
MethylPB
Debrisoquine
Paracetamol
Theophylline
Tolbutamide
Omeprazole
Desipramine
(S)-Warfarin
Proguanil
Dextromethorphan
Phenytoin
Encainide
Flecainide
Imipramine
Metoprolol
Mibefradil
Nortriptyline
Perhexiline
Perphenazine
Propafenone
Propranolol
Sparteine
Thioridazine
Timolol
CYP3A4
Atorvastatin
Cervistatin
CsA
Erythromycin
Felodipine
Lidocaine
Lovastatin
Mibefradil
Midazolam
Nefazodone
Nifedipine
Quinidine
Simvastatin
Triazolam
Verapamil
(R)-Warfarin
N-DMDZP = N-desmethyldiazepam, MethylPB = methylphenobarbital, CsA = Cyclosporin A, (S)- and (R)-Warfarin = enantiomers of warfarin. Note, azole antifungals (itraconazole,
fluconazole, ketoconazole and miconazole), the selective serotonin reuptake inhibitors (fluvoxamine, fluoxetine and sertraline) and cimetidine inhibit both the CYP2C and CYP3A4
isoforms. Quinidine, non-dihydropyridine calcium channel blockers and grapefruit inhibit the CYP3A4 isozyme. Trimethoprim-sulfamethoxazole, omeprazole, and amiodarone
impair 2C activity. Rifampin and phenobarbitol induce CYP2C and CYP3A4. Carbamazepine and phenytoin also induce CYP3A4.
Modified from Corsini A, Bellosta S, Baetta R, Fumagalli R, Paoletti R, Bernini F. New insights into the pharmacodynamic and pharmacokinetic properties of statins. Pharmacol Ther
1999;84:413-28, with permission from Elsevier Science.
266
Clin Invest Med • Vol 24, no 5, octobre 2001
Statin myopathies
reduced muscle capillary density, mitochondrial
respiration and endurance capacity.56
The other major HMGRI drug interaction occurs
with hypolipemic agents such as fibric acid derivatives127–129 and niacin.47,128 Although fibrates can impair hepatic function the interaction appears to be
more pharmacodynamic than pharmacokinetic.32 A
plausible mechanism may be attributed to dual
membrane-cholesterol lowering effects that result in
increased sarcolemmal fluidity and subsequent
destabilization.130,131
Conclusions and clinical approach
From the current literature there are a few conclusions that can be made regarding the use of statins
and myopathy. First, myalgias and cramps are the
most frequent muscle-related side effects of statin
therapy, while true myopathy is much less common
(approximately 0.1 %). Second, there are several
medications in which the potential for myotoxic interactions with statins is increased (i.e., CsA, erythromycin, fibric acid derivatives, niacin). Third,
there are a few pre-existing conditions in which
statins should not be used, such as untreated hypothyroidism, muscle coenzyme Q10 deficiency, mitochondrial cytopathies (except with coenzyme Q10
supplementation) and in patients in whom myopathy
was documented with a statin (not absolute — see
below). Fourth, the exact mechanism of action of the
statins causing myopathy is unclear but may involve
any or all of the following; coenzyme Q10 depletion,
altered excitation-contraction coupling, decreased
membrane fluidity, decreased sarcolemmal ionic
flux and altered Ca2+ modulation. Currently there is
insufficient evidence with which to propose a definitive clinical pathway for the care of patients with
muscle symptoms who are taking statins; however,
there are some guidelines that may be of benefit to
the clinician as outlined below.
In clinical practice, there are several scenarios that
may arise in patients treated with statins; asymptomic
hyperCKemia, myalgias with normal CK activity;
myalgias with hyperCKemia; and the use of statins in
patients with pre-existing neuromuscular disease.
Prior to starting statin therapy it is important to
measure baseline CK activity, thyroid-stimulating
Clin Invest Med • Vol 24, no 5, October 2001
hormone level and liver enzymes at least once. In the
absence of symptoms, there is no evidence to suggest that routine monitoring of plasma CK activity is
of benefit. However, this is occasionally done in
asymptomatic people and found to be elevated. In
such a case, if the CK is less than 3 times the upper
limit of normal and the physical examination and
routine blood chemistry values are normal (complete
blood count, thyroid-stimulating hormone and electrolytes levels), further evaluation is usually not revealing. In the case of myalgias or cramps (or both)
associated with normal CK activity the clinician
must consider other causes, and a physical examination and some blood tests (above tests plus measurement of plasma magnesium and calcium) may reveal
a cause. If no cause is found, then the patient and the
clinician must decide whether the symptoms warrant
a discontinuance of therapy. Analgesics or antiinflammatory agents or even a brief trial of coenzyme Q10 (60 mg twice daily for 2 mo) may be considered. In the case of myalgias with hyperCKemia
(assuming the baseline CK was normal), it is important to consider that another acquired myopathy may
have developed and investigations may include a history, physical examination, blood chemistry measurements (thyroid-stimulating hormone, electrolytes, antinuclear antibody, complete blood count)
and electromyography and nerve-conduction studies.
Consideration may be given to a neuromuscular disease consult and possible a muscle biopsy, depending on the scenario. If the CK is greater than 10
times the upper limit of normal, screening for rhabdomyolysis and renal function is indicated, including
measurement of uric acid, urine myoglobin, potassium, creatinine, bicarbonate and blood urea nitrogen. If renal dysfunction is found, the patient should
be admitted to hospital and the nephrology department consulted. If there is no renal dysfunction, the
statin therapy should be stopped and the patient
should be followed up clinically and biochemically
until resolution. At this point, the decision to switch
to a hydrophilic statin (pravastatin) or another agent,
or to avoid hypocholesterolemic medications requires careful assessment of the risk:benefit ratio of
each decision. The role for coenzyme Q10 in treatment and prophylaxis is unclear; however, the case
reports mentioned above suggest that at least in a
267
Baker and Tarnopolsky
subgroup of patients, this may be of benefit. In general, the only patients with neuromuscular disorders
who should not be given statins are those with untreated hypothyroidism, a rare form of myopathic
coenzyme Q10 deficiency (6 cases reported worldwide) and patients with mitochondrial cytopathies76
(although treatment may be considered if simultaneous coenzyme Q10 is given in the latter group).85
With the recent interest in the rhabdomyolysis attributed to cerivastatin, it is hoped that further research into statin-induced myotoxicity will ensue and
that more definitive clinical guidelines and a deeper
understanding of the pathogenesis will emerge.
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Reprint requests to: Dr. Mark A. Tarnopolsky, Department of Medicine (Neurology and Rehabilitation), Rm. 4U4, McMaster University Medical Center, Hamilton ON L8N 3Z5; fax 905 521-2656,
[email protected]
Clin Invest Med • Vol 24, no 5, octobre 2001