2. Ward et al Statin Toxicity 329
risk in a range of patient populations (clinical atheroscle-
rotic CVD, diabetes mellitus, and hyperlipidemia), where the
greater the LDL-c reduction, the greater the subsequent risk
reduction, with recommendations to reduce levels by ≥50%.11
In addition to health-promoting behaviors, statins are the bed-
rock of all international guidelines on lipid management.
Mechanism of Action
Statins work by competitively blocking the active site of the
first and key rate-limiting enzyme in the mevalonate pathway,
HMG-CoA reductase. Inhibition of this site prevents substrate
access, thereby blocking the conversion of HMG-CoA to mev-
alonic acid. Within the liver, this reduces hepatic cholesterol
synthesis, leading to increased production of microsomal
HMG-CoA reductase and increased cell surface LDL receptor
expression. This facilitates increased clearance of LDL-c from
the bloodstream and a subsequent reduction in circulating
LDL-c levels by 20% to 55%.12
In addition to reducing LDL-c
and cardiovascular morbidity and mortality, statins may have
additional non–lipid-related pleiotropic effects. These include
improvements in endothelial function, stabilization of ather-
osclerotic plaques, anti-inflammatory, immunomodulatory
and antithrombotic effects, effects on bone metabolism, and
reduced risk of dementia. These additional benefits are prima-
rily thought to arise because of inhibition of the synthesis of
isoprenoid intermediates of the mevalonate pathway.12
Structural Characteristics and Pharmacokinetics of
Statins
The active component of statins is a modified 3,5-dihydroxy-
glutaric acid moiety, which is structurally similar to the en-
dogenous substrate, HMG-CoA, and the mevaldyl CoA
transition state intermediate. This active site binds to and in-
hibits HMG-CoA reductase activity in a stereoselective pro-
cess that requires the statin to have a 3R,5R configuration.
The molecular and clinical differences of statins arise from
the ring that is attached to the active moiety, which can be a
partially reduced naphthalene (lovastatin, simvastatin, pravas-
tatin), a pyrrole (atorvastatin), an indole (fluvastatin), a pyrim-
idine (rosuvastatin), a pyridine (cerivastatin), or a quinoline
(pitavastatin). The substituents on the ring define the solubility
and pharmacological properties of the statin. Hydrophilicity
(pravastatin and rosuvastatin) originates from the common
active site plus other polar substituents, whereas lipophilicity
(atorvastatin, lovastatin, fluvastatin, pitavastatin, simvastatin,
and cerivastatin) arises because of the addition of nonpolar
substituents.13,14
Statins differ in their pharmacokinetic characteristics due
in part to the form they are administered in and in part to their
lipophilicity (Table 1). Simvastatin and lovastatin are admin-
istered as an inactive lactone form that is converted to the
active form in the body. In contrast, atorvastatin, fluvastatin,
pravastatin, rosuvastatin, and pitavastatin are administered in
active acid form.15
Hydrophilic statins require carrier-mediat-
ed uptake into the liver, whereas lipophilic statins are able to
passively diffuse through the cell membrane, which decreases
their hepatoselectivity as they are also able to diffuse into other
tissues. Lipophilic statins are generally cleared via oxidative
biotransformation, whereas hydrophilic statins are excreted
unchanged. Metabolism occurs primarily through CYP3A4
for simvastatin, lovastatin, and atorvastatin, whereas fluvas-
tatin is metabolized mainly through CYP2C9. In addition, all
statins are substrates of several membrane transporters.14–16
Statin Toxicity
Statin toxicity or intolerance most commonly presents as
SAMSs.17,18
Other side effects of statin therapy, which can
be more serious, include new-onset type 2 diabetes melli-
tus, neurological and neurocognitive effects, hepatotoxicity,
renal toxicity, and other conditions.19
Currently, no univer-
sally accepted definition of statin toxicity/intolerance ex-
ists, with several groups attempting to define the condition
Nonstandard Abbreviations and Acronyms
ABC ATP-binding cassette
AKT protein kinase B
AMPK 5′ AMP-activated protein kinase
C/EBP CCAAT/enhancer binding protein
CK creatinine kinase
CVD cardiovascular disease
CYP450 cytochrome P450
FOXO Forkhead box protein O
GATM glycine amidinotransferase
GLUT glucose transporter
HMG-CoA hydroxymethylglutaryl-CoA
IGF insulin-like growth factor
IRS-1 insulin receptor substrate-1
JUPITER Justification for the Use of Statin in Prevention
LDL-c low-density lipoprotein cholesterol
MAFbx muscle atrophy F-box
MHC major histocompatibility complex
MRP multidrug resistance protein
MuRF-1 muscle RING-finger protein-1
OATP1B1 organic-anion-transporting polypeptide B1
PARP poly (ADP-ribose) polymerase
PCSK9 proprotein convertase subtilisin/kexin type 9
PDC pyruvate dehydrogenase complex
PDK pyruvate dehydrogenase kinase
PGC-1α peroxisome proliferator–activated receptor-γ coactivator
PI3K phosphoinositide 3-kinase
PKC protein kinase C
PPAR peroxisome proliferator–activated receptor
PRIMO Prediction of Muscular Risk in Observational
PROSPER Prospective Study of Pravastatin in the Elderly at Risk
RYR ryanodine receptor
SAMSs statin-associated muscle symptoms
SEARCH Study of the Effectiveness of Additional Reductions in
Cholesterol and Homocysteine
SNP single-nucleotide polymorphism
SPARCL Stroke Prevention by Aggressive Reduction in Cholesterol
Levels
STOMP Effect of Statins on Skeletal Muscle Function
UGTs UDP glucuronosyltransferases
ULN upper limit of normal
WOSCOPS West of Scotland Coronary Prevention Study
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3. 330 Circulation Research January 18, 2019
(Table 2). The prevalence of statin intolerance is also widely
debated, in part because of difficulties in identification and
diagnosis, particularly with respect to muscle symptoms.18
Observational studies suggest it occurs in 10% to 15% of pa-
tients,21,24
with clinic data putting it as high as 30%.17,22
In
randomized controlled trials, the incidence is thought to be
1.5% to 5% of patients, although this is believed to be an un-
derestimation as most studies exclude patients with a history
of statin intolerance either before randomization or during
the run-in period.18,21,25,26
True diagnosis of the condition re-
quires a systematic approach of dechallenge and rechallenge
to assess causation, multiple statin challenges to support di-
agnosis, and elimination of other underlying causes of the
described side effects.25,27
Despite the difficulties in identify-
ing and diagnosing statin toxicity, however, several interna-
tional organizations have identified statin intolerance to be of
major clinical importance that warrants further research and
investigation.20,28,29
Clinical Presentations of Statin Toxicity and
Their Proposed Mechanisms
Although the only reliably confirmed adverse events caused
by statins are said to be muscle-related, type 2 diabetes mel-
litus, and possibly hemorrhagic stroke,30,31
it is important to
consider all of the clinical manifestations of statin toxicity
and intolerance, which can significantly impact adherence to
therapy and subsequent cardiovascular risk. Mechanistically,
statin toxicity is thought to arise because of HMG-CoA re-
ductase inhibition effects, direct cellular and subcellular ef-
fects, or a combination of both.5
Other possible causes include
genetic factors, drug-drug interactions, vitamin D status, and
other metabolic or immune effects (Figure 1).21
Regardless of
the mechanistic pathway, the end result is a change in drug bi-
oavailability and activity, which can lead to nonadherence and
intolerance.32
Adverse side effects have generally been shown
to be class, dose, time, age, sex, and comorbidity dependent;
however, considerable variability exists. Although the mecha-
nisms are varied and likely because of multiple pathways, age
is considered the leading predisposing risk factor because of
the likely presence of multiple comorbidities (renal or liver
dysfunction), concomitant drug use that may interfere, de-
creased body mass, cognitive impairment, and a decreased re-
sistance to other stressors.23
Statin-Associated Muscle Symptoms
SAMSs are by far the most prevalent and important adverse
event, with up to 72% of all statin adverse events being muscle
related.33
These can present as myalgia, myopathy, myositis
with elevated CK (creatinine kinase), or at its most severe,
rhabdomyolysis, with some people reporting additional
joint and abdominal pain.17,34
Other skeletal-related side ef-
fects include tendinopathies and tendon disorders, as well as
Table 1. Statin Drug Characteristics
Drug Name Derivative Side Ring Solubility Form Administered Metabolism Clearance
Atorvastatin Synthetic Pyrrole Lipophilic Active hydroxy acid CYP3A4 Hepatic
Cerivastatin* Synthetic Pyridine Lipophilic Active hydroxy acid Various CYP3A Hepatic
Fluvastatin Synthetic Indole Lipophilic Active hydroxy acid CYP2C9 Hepatic
Lovastatin Fungal Naphthalene Lipophilic Inactive lactone CYP3A4 Hepatic
Pitavastatin Synthetic Quinoline Lipophilic Active hydroxy acid Non-CYP450
Limited CYP2C9/19
Hepatic
Pravastatin Fungal Naphthalene Hydrophilic Active hydroxy acid Non-CYP450 Hepatic and renal
Rosuvastatin Synthetic Pyrimidine Hydrophilic Active hydroxy acid Non-CYP450
Limited CYP2C9/8
Hepatic and renal
Simvastatin Fungal Naphthalene Lipophilic Inactive lactone CYP3A4 Hepatic
CYP indicates cytochrome.
*Withdrawn from the market.
Table 2. Definitions of Statin Intolerance
Group Year Definition
National Lipid
Association20
2014 Adverse effects relating to quality of life,
leading to decisions to decrease or stop
the use of an otherwise beneficial drug.
International
Lipid Panel21
2015 An inability to tolerate a dose of
statin required to reduce a person’s
cardiovascular risk sufficiently from
their baseline risk and could result from
different statin related side effects,
including; muscle symptoms, headache,
sleep disorders, dyspepsia, nausea,
rash, alopecia, erectile dysfunction,
gynecomastia, and arthritis.
European
Atherosclerosis
Society22
2015 The assessment of the probability of SAMS
being due to a statin take into account
the nature of the muscle symptoms,
the elevation in CK levels and their
temporal association with statin initiation,
discontinuation, and re-challenge.
Canadian
Consensus
Working Group23
2016 A clinical syndrome characterized by
significant symptoms and biomarker
abnormalities that is documented by
challenge/de-challenge/re-challenge using
at least 2 statins (including atorvastatin
and rosuvastatin) that is not due to drug-
drug interactions or untreated risk factors
for intolerance.
SAMS indicates statin-associated muscle symptoms.
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4. Ward et al Statin Toxicity 331
arthralgias, although these are rarely evaluated in large ran-
domized controlled trials.35
Since first reported in 2002, sev-
eral groups have worked to provide a unified definition and
diagnostic approach for SAMS.29,36
SAMS Phenotypes and Clinical Presentation
Regardless of the definition, SAMS usually presents as a sym-
metrical (bilateral) condition that affects the large proximal
muscles, particularly of the lower extremities. Symptoms
can occur at rest or shortly after exercise and usually oc-
cur within 1 month of initiation of therapy or an increase in
dose.5,21
Phenotypically, 7 progressively worse statin-related
myotoxicity phenotypes have been proposed. Beginning at a-
symptomatic CK elevation, they include tolerable and intoler-
able myalgia, myopathy, severe myopathy, rhabdomyolysis,
and autoimmune-mediated necrotizing myositis.37
However, it
is now recognized that muscle adverse events do not present
as a continuum that begins with myalgia and progresses to
more severe forms, thus requiring each event to be catego-
rized using standard definitions.36
Defining SAMS is further
compounded by no current consensus on the terminology to
be used, with myalgia, myositis, and myopathy often used in-
terchangeably.18,34
Furthermore, SAMSs can, and frequently
do, occur without elevations in CK, which must also be con-
sidered in definitions.38
From a clinical viewpoint, SAMSs can
be divided into 4 groups: (1) rhabdomyolysis characterized
by high CK concentrations (>100-fold the upper limit of nor-
mal [ULN]), myoglobinuria, and renal impairment; (2) myal-
gia or mild hyperCKemia (<5× ULN); (3) self-limited toxic
statin myopathy (CK levels between 10 and 100 ULN); and
(4) myositis or immune-mediated necrotizing myopathy with
HMG-CoA reductase antibodies and CK levels between 10
and 100× ULN.34
Additional classification includes 4 grades
of hypercreatinine kinase expressed relative to baseline val-
ues, with further consideration for sex and ethnicity.23
Muscle toxicity is classed as either toxic or immune re-
lated.5,19
Immune-related statin-induced muscle toxicity is
driven by both inflammatory and noninflammatory pathways.
Inflammatory myopathies, while rare, are characterized by
large increases in CK levels, a myopathic pattern on electro-
myogram and inflammatory infiltrates on muscle biopsy.19
Inflammation mainly comprised macrophages; however, cer-
tain immune-related features, including endothelial membrane
attack complex deposition in non-necrotic fibers and MHC
(major histocompatibility complex) class I, are additional fea-
tures.19,34
The condition usually resolves with discontinuation
of statin therapy and immunosuppressive therapy19
; however,
it has been associated with a specific immunogenetic back-
ground, with adults often showing the HLA-DRB1 (DRB1
beta chain)*11:01 and children HLA-DRB1*07:01.34
This is
Figure 1. Potential mechanisms for the development of statin toxicity. FPP indicates farnesyl pyrophosphate; GGPP geranylgeranyl pyrophosphate; GPP,
geranyl pyrophosphate; and HMG-CoA reductase, hydroxymethylglutaryl-coenzyme A reductase.
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5. 332 Circulation Research January 18, 2019
thought to be because of the upregulation of HMG-CoA reduc-
tase, with overexpression of this enzyme thought to facilitate
presentation of highly immunogenic HMG-CoA reductase au-
toantibodies by the leukocyte antigen. These may have a direct
pathogenic effect on muscle tissue expressing the HMG-CoA
reductase enzyme and trigger an autoimmune response that is
maintained by a feed-forward loop of autoimmunity.34,39–41
The
presence of these antibodies has been demonstrated to be asso-
ciated with both CK levels and limb strength in statin-exposed
patients, which were improved after immunosuppressive treat-
ment.42
Interestingly, these antibodies seem to be more selec-
tively expressed in regenerating myofibers coexpressing neural
cell adhesion molecule, which is a marker of muscle repair and
regeneration, supporting the notion that statins impact muscle
repair processes. In contrast, some studies have reported the
presence of these antibodies in statin-naive patients.23
Of further
note is the strong association between statin-induced immune-
mediated necrotizing myopathy and HLA-DRB1*11:01.40
Noninflammatory myopathy presents as muscle weakness/pain
with elevated CK, but no inflammation on biopsy, and has been
suggested to be caused by statin therapy exposing previously
restricted epitopes and triggering an autoimmune response.19
Pathological investigation of toxic myopathy reveals ne-
crosis and regenerating muscle fibers, with a negative re-
sponse to anti–HMG-CoA reductase autoantibodies.34
The
precise mechanisms behind toxic myopathy are unknown but
have been suggested to be aggravated by conditions that in-
crease statin levels in the blood, such as concomitant medica-
tions that interfere with statin metabolism via the CYPP450
enzymes, glucuronidation, or other processes.19
This is par-
ticularly relevant as skeletal muscle is 40× more sensitive to
HMG-CoA reductase inhibition than hepatocytes.5
A study
in skeletal muscle–specific HMG-CoA reductase knock-
out mice was shown to exhibit postnatal myopathy with el-
evated CK levels, mitochondrial impairment, and necrosis.
This was accompanied by upregulation of LDL receptor and
SREBP2 (sterol regulatory element-binding protein 2) mRNA
expression, suggestive of adaptations to sterol regulation.
Supplementation with mevalonic acid rescued this phenotype,
supporting the hypothesis that enzyme inhibition by statins
contributes to skeletal muscle toxicity.43
Prevalence and Risk Factors for SAMS
The prevalence of SAMS differs between statin classes, with
the highest risk associated with lipophilic statins such as sim-
vastatin, atorvastatin, and lovastatin because of their ability
to nonselectively diffuse into extrahepatic tissues such as
skeletal muscle.19,21
In contrast, hydrophilic statins such as
pravastatin and fluvastatin have less muscle penetration and
therefore lower risk of SAMS.21
Some reports suggest that up
to 60% of SAMS cases may be because of concomitant use
of statins with drugs metabolized by the same hepatic cyto-
chrome P450 isoforms.5
Others suggest that the strongest risk
factor for SAMS is a history of myopathy with other lipid-
lowering therapy, high-dose statin therapy, personal history of
unexplained cramps, a history of CK elevation, family history
of muscular symptoms with lipid-lowering therapy, and un-
treated hypothyroidism.44
Other risk factors include female
sex, old age (>80 years), small body frame and frailty, multi-
system disease (particularly, involving the liver and kidney),
alcoholism, high consumption of grapefruit juice, major sur-
gery, vitamin D deficiency, calcium disorders, Asian ethnicity,
low body mass index, and excessive physical activity.21,28
Proposed Mechanisms for the Development of
SAMS
Proposed mechanisms for SAMS include HMG-CoA reduc-
tase pathway-mediated effects, cellular and subcellular ef-
fects, genetic factors, and effects on skeletal muscle. These
can alter muscle cell membrane stability, fluidity, as well as
protein signaling and activity; impact mitochondrial func-
tion; and reduce membrane cholesterol content.5
Alterations
Figure 2. Potential mechanisms for the
development of statin-associated muscle
symptoms. AKT indicates protein kinase B;
Ca+2
, calcium; CYP, cytochrome P450; IGF-1,
insulin-like growth factor 1; LPL, lipoprotein
lipase; PI3K, phosphoinositide 3-kinase; and
UGTs, UDP glucuronosyltransferases.
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to statin uptake or metabolism can also result in increased
exposure of skeletal muscle to statins, which can lead to al-
tered mitochondrial function, calcium signaling, and cell cy-
cle pathways.45
Given the wide variation in the presentation of
SAMS and the inconsistent evidence with respect to treatment
of the condition, however, it is likely that >1 pathological
mechanism contributes (Figure 2).5,46
More detailed descrip-
tion of these proposed mechanisms is discussed below.
HMG-CoA Reductase Pathway-Mediated Effects
The highly conserved mevalonate pathway is an important
metabolic pathway, which plays a key role in many cellular
processes via the synthesis of sterol and nonsterol isopren-
oids (Figure 1). The sterol isoprenoid cholesterol is an im-
portant precursor of bile acids, lipoproteins, and steroid
hormones, whereas nonsterol isoprenoids such as dolichols
and ubiquinone (coenzyme Q10) play important roles in the
post-translational modification of proteins involved in intra-
cellular signaling and are essential for cell growth and dif-
ferentiation, gene expression, protein glycosylation, and
cytoskeletal assembly.5,12
Specifically, dolichols promote pro-
tein N-glycosylation, and inhibition of their formation can re-
sult in impairment in both receptor expression and production
of structural proteins.47
In addition, end products of the meva-
lonate pathway, which include farnesyl pyrophosphate and
geranylgeranyl pyrophosphate, play a role in cell maintenance
and growth and reducing apoptosis.19,45
These end products are
also involved in activating regulatory GTP-binding proteins
and the post-translational modification of GTPases and lam-
ins, both of which play an important role in cell maintenance
and chromatin organization. Dysprenylation of small GTPases
has been shown to result in apoptosis, whereas dysprenylation
of lamin results in fragile nuclear membranes, which induces
apoptosis.47
Other compounds also affected by inhibition of
the mevalonate pathway include prenylated proteins, electron
transport proteins, and heme A, which can result in down-
stream effects that include impaired cell membrane stability
and excitability, impaired signal transduction and intracellular
trafficking, and compromised protein structure and function,
all of which can lead to dysfunction of or a decrease in mem-
brane receptors, channels and transporters, as well as reduced
gene expression.5,47
Inhibition of HMG-CoA reductase can lead to alterations
to muscle protein signaling and activity can occur. These in-
clude impaired skeletal PI3k (phosphatidylinositol 3-kinase)/
Akt (protein kinase B), resulting in inductions in ubiquitin
and lysosomal proteolysis through upregulation of the FOXO
(Forkhead box protein O) downstream target genes of mus-
cle atrophy, which have been observed in cultured myotubes,
zebrafish, and mouse studies.48,49
These include cathepsin-L
mRNA, MuRF-1 (muscle RING finger-1) and MAFbx (mus-
cle atrophy F-box), and dephosphorylation of the FOXO1
and FOXO3 transcription factors.50
In vitro studies have
demonstrated upregulation of atrogin-1 (MAFbx) in muscle
cells exposed to statins. This was prevented by geranylgera-
nol, although inhibitors of the transfer of geranylgeranol iso-
prene units caused muscle damage and atrogin-1 induction.51
Others have suggested that suppression of IGF-1 (insulin-like
growth factor) signaling with statin treatment contributes as
this also leads to FOXO dephosphorylation, nuclear localiza-
tion, and transcription of the atrogin-1 gene.52
Furthermore,
these signaling effects were accompanied by distinct morpho-
logical changes to the muscle, including fiber damage, which
was prevented by overexpression of PGC-1α (peroxisome
proliferator–activated receptor-γ coactivator), a transcrip-
tional coactivator that induces mitochondrial biogenesis.49
This finding was also confirmed in an animal model of statin
myopathy, where simvastatin administration impaired PI3K/
Akt signaling and upregulated FOXO transcription factors and
downstream gene targets known to be implicated in protea-
somal- and lysosomal-mediated protein breakdown, muscle
carbohydrate oxidation, oxidative stress, and inflammation.
Interestingly, the statin-induced signaling effects preceded the
evidence of myopathy or change in muscle protein to DNA
ratio, implying the direct effect of the statin on this sequence
of events.48
The effect on the Akt pathway was also associated
with impaired phosphorylation of S6 kinase, ribosomal pro-
tein S6, 4E-binding protein 1, and FOXO3a, resulting in re-
duced protein synthesis, accelerated myofibrillar degradation
and atrophy of myotubes, as well as activation of apoptotic
caspases and PARP (poly (ADP-ribose) polymerase). In vitro
studies suggest differing effects on these signaling cascades in
response to different statins, with simvastatin and atorvastatin
cytotoxic at lower doses (10 μmol/L) compared with rosuvas-
tatin cytotoxicity at higher doses (50 μmol/L).53
The upstream effects of statins on the HMG-CoA–
mediated pathway relate to an increase in fatty acid synthesis.
Early in vitro studies revealed that micromolar concentrations
of lovastatin increased fatty acid synthesis and induced tria-
cylglycerol and phospholipid accumulation in lipid droplets
of cultured keratinocytes, which was associated with per-
oxisomal hyperplasia and increased catalase activity. These
effects were prevented by coincubation with LDL-c or
25-hydroxycholesterol.54
Direct Cellular and Subcellular Effects: Mitochondrial
Toxicity and Calcium Signaling
The direct effects on cellular and subcellular structures are
predominately responsible for statin-related mitochondrial
toxicity and calcium overload. These can result in increased
oxidative phosphorylation, which can lead to a decrease in
ATP levels, loss of mitochondrial membrane potential, ac-
tivation of mitochondria permeability transition, decreased
mitochondrial density and biogenesis, apoptosis, and calpain-
mediated cell death. In addition, these effects can trigger mas-
sive calcium release either via the RYR (ryanodine receptor)
in the sarcoplasmic reticulum or the permeability transition
pore and sodium-calcium exchanger in the mitochondria.5,19
Impaired calcium signaling can then result in mitochondrial
depolarization and calcium release, resulting in cytoplasmic
calcium waves and subsequent caspase activation and apop-
tosis. Increased cytosolic calcium can also increase calcium
and phospholipid-dependent PKC (protein kinase C) activity,
which promotes the closing of the chloride-1 channel, result-
ing in membrane hyperexcitability.47
In addition, muscle mitochondrial integrity is maintained
by multiple signaling pathways, including the IGF-1/Akt path-
ways. In vitro studies have revealed that simvastatin-treated
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myotubes had reduced mitochondrial respiration that was as-
sociated with reduced Akt phosphorylation and rescued with
IGF-1 treatment. In contrast, liver cells were not affected, with
the IGF-1/Akt signaling maintained.55
Other in vitro studies
have revealed that lactone forms of statins are more potent
than their acid counterparts because of their increased pas-
sive transport across muscle membranes where they lead to
decreased mitochondrial ATP production via direct effects
on production machinery. Specifically, this appears to in-
volve inhibition of the mitochondrial CIII complex at the Qo
binding site and appears to be more significant with the hy-
drophilic lactones. These findings were confirmed in muscle
biopsies from patients with statin-induced myopathy, which
revealed significant decreases in CIII activity and ATP pro-
duction.56
Simvastatin-treated patients were also found to have
decreased muscle coenzyme Q10 content, which was accom-
panied by decreased mitochondrial oxidative phosphorylation
capacity.57
More recent studies have demonstrated no major
effects on mitochondrial function after 2 weeks of simvastatin
treatment but an increase in mitochondrial substrate sensitiv-
ity, which may be indicative of early damage.58
Mitochondrial effects can also result from a reduction in
the formation of coenzyme Q10, an end product of the meval-
onate pathway.5
Coenzyme Q10 is an important component of
the electron transport chain of the inner mitochondrial mem-
brane where it facilitates electron transport between complex-
es I and II during oxidative phosphorylation. Inhibition of this
pathway results in abnormal mitochondrial respiratory func-
tion and subsequent mitochondrial dysfunction. Mitochondrial
dysfunction, typically at complex I in the respiratory chain,
increases mitochondrial NADH and the intracellular redox
potential (NADH/NAD+
ratio), activates PDK (pyruvate dehy-
drogenase kinase), and inhibits flux via the PDC (pyruvate de-
hydrogenase complex).50
Interestingly, although most studies
demonstrate a reduction in serum coenzyme Q10 levels with
statin treatment, this is thought to be predominately because
of a reduction in LDL-c, the main carrier of coenzyme Q10,
with tissue levels largely unaffected.19
Moreover, studies that
have examined the effect of coenzyme Q10 supplementation
in patients with statin-induced muscle effects found no dif-
ference in muscle pain or plasma CK between the placebo or
coenzyme Q10-treated groups.59
Genetic Factors
Organic Anion-Transporting Polypeptide 1B1 Influx
Transporter
SLCO1B1 encodes the OATP (organic anion-transporting
polypeptide)1B1 influx transporter, expressed on the baso-
lateral membrane of human hepatocytes.15,19
The transporter
regulates the hepatic uptake of statins from portal blood,
thus influencing their serum levels. Two common single-
nucleotide polymorphism (SNP) variants of the SLCO1B1
gene; c.388A>G (p.Asn130Asp; rs2306283) and c.521T>C
(p.Val174Ala; rs4149056) have been shown to affect
OATP1B1 transport function, although these are depend-
ent on their combination in individual haplotypes.15
When
rs2306283 exists alone (≈25%–30% in whites, 4%–60%
Asians, and 80% Africans/black), it is usually associated with
increased OATP1B1 activity and lower plasma concentration
of substrates. In contrast, rs4149056 reduces transport activ-
ity and increases plasma concentrations of the substrate, even
when present in combination with rs2306283.15
Although all
statins require hepatic transporters, the effect of SLCO1B1
polymorphisms appears to be dependent on the class of statin
used and are particularly relevant for the lipophilic statins.15,19
The largest effect of rs4149056 is seen with simvastatin, fol-
lowed by pitavastatin, atorvastatin, pravastatin, and rosuvas-
tatin, with no effect observed for fluvastatin. This difference
may be partly explained by varying contributions of other
OATPs to hepatic uptake.15
Genome-wide scans have revealed
strong associations between simvastatin-associated myopathy
and the rs4363656 SNP.60
This appears to be because of a non-
coding SNP in the SLCO1B1 gene that is in nearly complete
linkage disequilibrium with the rs4149056 SNP, which was
also associated with a slight reduction in the cholesterol-low-
ering efficacy of simvastatin.15
Ryanodine Receptors
RYRs are intracellular calcium release channels, expressed
in a range of tissues. Three genes encode the different iso-
forms with RYR1 expressed predominately in skeletal muscle
where it contributes to calcium signaling and muscle contrac-
tion. RYR3 expression has been shown to be upregulated in
the skeletal muscle of patients with statin-associated structural
muscle injury.61
In addition to variants in SLCO1B1, an in-
tronic variant in RYR2 gene, rs2819742, was identified as be-
ing linked with rhabdomyolysis associated with cerivastatin, a
drug that has now been withdrawn from the market.62
Leukocyte Immunoglobulin-Like Receptor
A variant in the leukocyte immunoglobulin-like receptor sub-
family-B gene (LILRB5) has been associated with lower CK
and lactate dehydrogenase levels, 2 common biomarkers that
are released from injured muscle tissue. The T>C:Asp247Gly;
rs12975366 variant was also associated with statin-intolerant
phenotypes, defined as either elevated CK and nonadherence
to therapy or intolerant to the lowest approved dose. It is pos-
tulated that this is via inhibition of immune-mediated repair
and regeneration of skeletal muscles, specifically suppression
of the accumulation of T regulatory cells, a process that is cru-
cial in the repair of damaged skeletal muscle.63,64
UDP Glucuronosyltransferase
UDP glucuronosyltransferases convert the lactone form of
statins to the acid form via a glucuronidation process. SNPs
in the UGT1A gene (UGT1A1*28(TA)7
) are associated with a
reduction in the systemic exposure to the atorvastatin lactone,
which has been associated with muscle toxicity.65
Glycine Amidinotransferase
Glycine amidinotransferase is an enzyme required for the syn-
thesis of creatinine that is encoded by GATM. Phosphorylation
of creatinine, the major downstream product of GATM (gly-
cine amidinotransferase) activity, is a major mechanism of
energy storage in muscle, which is mediated by CK, a bio-
marker of statin myopathy. Genome-wide eQTL analysis of
lymphoblastoid cell lines from simvastatin-treated partici-
pants has revealed a possible link between GATM and statin-
induced myopathy, as well as cellular cholesterol homeostasis
and energy metabolism. Although the link between GATM
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and myopathy appears to be independent of CK levels, mech-
anistically, it is believed to be because of metabolic effects in
the liver, including cholesterol depletion and subsequent ef-
fects on AMPK (5′ AMP-activated protein kinase) signaling.66
Despite this, however, a proposed protective SNP in GATM,
rs9806699 G>A, has not been replicated in a case-controlled
analysis of statin-induced myopathy.67
Genetic Predisposition to Pain Perception
A positive family history of statin myopathy is a common
risk factor for statin intolerance and may relate to an inherited
increased susceptibility to pain perception. Specifically, this
may be because of a genetic variation in serotonergic recep-
tors, supported by an early study looking at SNPs in genes
related to serotonergic neurotransmission, widely implicated
in pain detection and processing in the brain, spinal cord, and
peripheral tissues. In hypercholesterolemic statin-treated pa-
tients, a significant association was observed between myalgia
and 2 SNPs (rs2276307 and rs1935349) in the genes HTR3B
and HTR7, which encode serotonin receptors. There was no
association with CK levels, suggesting that statin myopathy
may be a collection of independent syndromes encompassing
various genetic pathways.68
This finding is also supported by
clinic data, with statin myopathy commonly seen in associa-
tion with personal or family history of nonspecific myalgia,
higher scores on hospital anxiety and depression scales and fi-
bromyalgia. Furthermore, patients with preexisting conditions
associated with muscle symptoms, including fascioscapular
muscular dystrophy, malignant hyperthermia, polymyosi-
tis and polymyalgia rheumatica, often report a worsening of
symptoms with statin therapy.17
Gene Array Analysis
Analysis of gene expression in patients experiencing SAMS
suggests an association with a molecular signature of mito-
chondrial stress, cell senescence, and apoptosis, including a
host of differentially expressed genes with greater than ex-
pected enrichment in 5 canonical pathways. These pathways
include IGF/PI3k/Akt signaling, cell cycle, nerve growth fac-
tor signaling, and cholesterol biosynthesis I and II. Specific
genes within these pathways included upregulation of cal-
modulin (CALM1), a calcium sensor protein that interacts
with RYR1 calcium channel to mediate calcium release dur-
ing muscle contraction. In contrast, the inositol 1,4,5-trispho-
sphate receptor 2 (ITPR2), which triggers calcium release
allowing mitochondrial calcium accumulation and cell se-
nescence, was downregulated. Within the cell cycle pathway,
genes that include the protein BARD1, thought to be involved
in muscle wasting via apoptosis and protein degradation, and
histone deacetylase, involved in muscle atrophy, were upregu-
lated. Disruption of genes associated with cholesterol biosyn-
thesis and related to downstream proteins of the mevalonate
pathway were postulated to reflect a compensatory upregula-
tion in response to statin-induced inhibition. Increased expres-
sion of these distal pathways is also suggestive of a complete
blockade of the pathway because of increase statin exposure
and sensitivity.45
The authors further suggest that persistent
myalgia originates from cellular stress that affects the struc-
tural integrity and performance of skeletal muscle and its re-
sponse to postinflammatory repair and regeneration.45
Structural Effects of Statins on Skeletal Muscles
Skeletal muscle consists of fast and slow twitch muscle fibers,
which have different compositions and different responses to
external compounds such as statins. Animal studies have con-
sistently shown that statin treatment results in massive necro-
sis of muscle containing fast twitch, glycotic type IIB fibers,
with the slow twitch oxidative type I fibers spared.5
These
changes were accompanied by ultrastructural changes to the
muscle mitochondria, including swollen mitochondria with
disrupted cristae and increased vacuolation or degeneration
resulting in vesicular bodies accumulating in the subsarcolem-
mal space.5
Human studies have also observed vacuolization
of the T-tubular system in statin-treated patients.61,69
Other structural effects may relate to an inability to re-
place damaged muscle protein via the ubiquitin pathways. A
small study investigating the effect of atorvastatin and exer-
cise on muscle damage observed differences in gene expres-
sion in the combination statin and exercise group compared
with either treatment alone. Specifically, this combination
had the greatest effect on genes related to transcription fac-
tors and those involved in the ubiquitin proteasome path-
way, including protein folding and catabolism, which is
responsible for the recognition and degradation of proteins
in skeletal muscle.
In addition, cholesterol is a key component of the struc-
ture and function of all cell membranes, including skeletal
muscles. Increased sensitivity of skeletal muscle to HMG-
CoA reductase inhibition can lead to a reduction in the cho-
lesterol content in skeletal muscle cell membranes, rendering
them unstable and altering fluidity and excitability of ion
channels.5,19,35
This can modulate the function of sodium, po-
tassium, and chloride channels, leading to myocyte damage
and myopathy.47
Previous mouse studies have also demon-
strated an increase in skeletal muscle mitochondria, choles-
terol accumulation, and lipid droplets in statin-treated mice
overexpressing lipoprotein lipase. This was also associated
with increased plasma creatinine phosphokinase, indica-
tive of muscle damage.70
More recently, statins have been
shown to have toxic effects on immature muscle cells via
multiple mechanisms. The lactone forms of statins signif-
icantly impaired complex III activity in C2C12 myoblasts,
reducing mitochondrial respiration and inducing apoptosis.
When investigated in a clinical setting, patients presenting
with SAMS also had reduced complex II activity, which was
most pronounced in those with rhabdomyolysis, the most se-
vere form of muscle damage.56
Disturbances in the acid/base
balance, for example, in the setting of acidosis and alkalosis
can also affect the conversion of the inactive lactone forms of
simvastatin and pravastatin to their active hydroxy acid form.
Acidic environments appear to maintain the statins in their
lactone form, facilitating greater uptake by C2C12 skeletal
muscle cells because of the increased lipophilicity, which re-
sults in myotoxicity.71
This process was exacerbated in the
presence of hyperlipidemia because of the enhanced associ-
ation between simvastatin and nonpolar lipoprotein fractions
and uptake via a lipoprotein lipase–mediated process.72
In
addition, in vitro and animal studies have demonstrated that
statin exposure can result in impaired muscle regeneration73
and cell cycle arrest.74
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9. 336 Circulation Research January 18, 2019
Clinical Studies Investigating SAMS
The PRIMO (Prediction of Muscular Risk in Observational)
conditions study, a general practice survey in France, re-
vealed that 10.5% of hyperlipidemic patients receiving
high-dose statins (predominately simvastatin) reported
mild-to-moderate muscle symptoms.44
In the United States,
a large internet-based survey of current and former statin us-
ers (USAGE) reported muscle-related side effects in 60% of
current and 25% of former users, with side effects the pri-
mary reason for statin discontinuation (62%).75
The STOMP
(Effect of Statins on Skeletal Muscle Function) was a large
randomized controlled trial assessing the effect of high-dose
atorvastatin on muscle performance in healthy, statin-naive
participants. Despite no effect on muscle strength or exercise
performance after 6-month treatment, there was a significant
increase in CK levels among both asymptomatic participants
and those with myalgia after treatment with atorvastatin.76
The SEARCH (Study of the Effectiveness of Additional
Reductions in Cholesterol and Homocysteine) demonstrated
a dose effect on development of myopathy, where 80 mg
daily of simvastatin produced a 10-fold higher rate than a 20
mg dose77
or the 40 mg used in the HPS (Heart Protection
Study), with risk higher when it occurred in combination with
elevated CK levels.78
A recent review has suggested that the excess rate
of symptomatic muscle pain and other muscle-related
problems is ≈10 to 20 cases yearly per 10 000 treated in-
dividuals, with only one of those cases associated with
substantially elevated CK requiring cessation of statin treat-
ment. Furthermore, treatment of 10 000 patients for 5 years
with an effective regime (40 mg atorvastatin daily) has been
suggested to yield 5 cases of myopathy of which one might
progress to rhabdomyolysis if treatment was not stopped.30
Importance must be given, however, to how SAMSs are re-
ported in studies, with a previous meta-analysis suggesting
that only 62% of clinical trials report the frequency of mus-
cle problems with only one of those studies systematically
querying participants about muscle problems. Although the
incidence of SAMS in the trials that reported these events
did not differ between statin and placebo groups, 98% of the
studies did not define muscle problems, nor did the majority
of them enquire about muscle problems or report the effect
of statin therapy on CK levels.79
New-Onset Type 2 Diabetes Mellitus
Incidence of new-onset type 2 diabetes mellitus with statin
treatment appears to be more common in patients with pre-
existing risk factors, including elevated body massive index
and glycated hemoglobin or impaired fasting glucose. It has
been observed for both hydrophilic and lipophilic statins and
appears to occur more frequently in older patients and those
on high-dose statin therapy.21
Mechanistically, the incidence
of new-onset type 2 diabetes mellitus is not known but may
be related to both on-target and off-target action, including
effects on body weight, body mass index, adipocyte differen-
tiation, blood glucose homeostasis via gluconeogenesis and
the insulin signaling cascade, changes in circulating free fatty
acids or hormones such as adiponectin and leptin, as well as
impaired β-cell function.16,23,80,81
Proposed Mechanisms for Statin-Induced New-
Onset Type 2 Diabetes Mellitus
In the pancreas, insulin secretion is initiated by an increase
in intracellular calcium controlled by voltage-gated calcium
channels, with changes in these channels significantly affect-
ing glucose homeostasis.16
In vitro studies have shown that
simvastatin inhibited glucose-induced calcium signaling in rat
pancreatic islet β-cells via direct blockage of L-type calcium
channels, although this was not seen with pravastatin, sug-
gesting that effects are related to lipophilicity.82
In addition,
reductions in endogenous pancreatic cholesterol levels have
also been proposed to contribute to impaired calcium channel
function, either through incorrect sorting of membrane-bound
lipid raft proteins or changes in the conformation of channel
subunits.83
A recent in vitro study has also suggested that mi-
tochondria isolated from rat pancreas and treated with statins
had reduced complex II activity that was accompanied by ox-
idative stress, mitochondrial swelling, and reduced membrane
potential.84
Within adipose tissue and skeletal muscle, glucose uptake
is facilitated by the GLUT4 (glucose transporter 4), which is
initiated by insulin-receptor tyrosine kinase phosphorylation,
facilitating recruitment of GLUT4 from intracellular storage
to the plasma membrane.16
In vitro studies have shown an at-
tenuation of adipocyte maturation and a decrease in GLUT4
expression in both differentiating and mature adipocytes with
atorvastatin treatment because of inhibition in the formation
of isoprenoids. In addition, a reduction in caveolin-1, an im-
portant plasma membrane protein associated with GLUT4
translocation, was observed. These findings were associated
with impaired insulin sensitivity in mice with type 2 diabe-
tes mellitus and elevated HbA1c (glycated hemoglobin) in a
small patient population.85
Attenuation of the adipocyte dif-
ferentiation process is also critical as preadipocytes do not
secrete insulin-sensitizing hormones, a requirement for in-
itiation of the signaling cascade. This inhibition is thought
to be because of a decrease in the expression of 2 important
transcription factors, PPARγ (peroxisome proliferator–acti-
vated receptor γ) and C/EBP (CCAAT/enhancer-binding pro-
tein).16
Other studies have shown that several statins decrease
glucose uptake in skeletal muscle because of conforma-
tional changes in the glucose transporter GLUT1 or reduced
GLUT4 expression.86
The IRS-1 (insulin-receptor substrate) is also critical for
insulin signaling, with its phosphorylation activating the PI3K
pathway, Akt phosphorylation, and subsequent GLUT4 trans-
location.16
In vitro studies have demonstrated a reduction in
the IRS-1–mediated signaling cascade and subsequent glu-
cose uptake after treatment with atorvastatin. This effect was
dose-dependent and due to inhibited lipid modification of var-
ious proteins involved in the signal cascade, as well as altered
cellular distribution of some small G proteins.87
Genome-wide association studies suggest that lipid frac-
tions, including LDL-c, appear to have contrasting asso-
ciations with CVD and diabetes mellitus.88
LDL-c–lowering
genetic variants on or near the HMGCR gene have also been
shown to be associated with a higher risk of type 2 diabetes
mellitus, similar to the increased incidence observed in ran-
domized controlled trials.89,90
Alleles that lower LDL-c via the
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10. Ward et al Statin Toxicity 337
HMGCR gene are also associated with increased body mass
index and fasting insulin, suggestive of an effect on insulin re-
sistance that is mediated via the LDL-c receptor.91
This is sup-
ported by cross-sectional analysis revealing a lower incidence
of diabetes mellitus in patients with familial hypercholester-
olemia compared with their unaffected relatives, with varia-
bility by mutation type revealing a lower prevalence in those
with a LDL-c receptor gene mutation. This receptor-mediated
effect has been hypothesized to be because of statin-induced
increases in LDL receptors facilitating cholesterol entry into
and damage of pancreatic cells.92
Clinical Studies Investigating Statin-Induced New-
Onset Type 2 Diabetes Mellitus
The JUPITER trial (Justification for the Use of Statin in
Prevention) revealed that participants with ≥1 diabetes melli-
tus risk factors randomized to 20 mg daily rosuvastatin were
at increased risk (28%) of developing diabetes mellitus, de-
spite reductions in LDL-c levels and cardiovascular events
and mortality.93
The CARDS study found that low-dose (10
mg) atorvastatin caused small but significant glycemia pro-
gression in diabetic participants, but this did not increase with
duration nor impact the CVD risk reduction.94
Meta-analysis
has shown that intensive-dose statin therapy is associated with
an increased risk of new-onset type 2 diabetes mellitus com-
pared with moderate dose,95
whereas high-dose (80 mg) ator-
vastatin is associated with increased risk with baseline fasting
glucose and metabolic syndrome features predictive of risk.96
Subsequent meta-analysis of 13 randomized controlled trials
suggests that statin therapy is associated with a slightly in-
creased risk of developing diabetes mellitus, but this risk is
low when compared with the reduction in coronary events.97
A larger meta-analyses of 17 trials revealed different class,
and doses of statins have differing effects on the incidence of
diabetes mellitus. Pravastatin was associated with the lowest
risk, and atorvastatin had an intermediate risk, whereas rosu-
vastatin was associated with a 25% increased risk.98
Increased
risk with intensive dose statin compared with moderate dose
was further confirmed in pooled analysis of 5 randomized
controlled trials.95
More recent meta-analysis of observational
trials confirms and reinforces the increased risk of diabetes
mellitus with statin use.99
Although it has been suggested that
treatment of 10000 patients for 5 years with an effective re-
gime (40 mg atorvastatin daily) would yield 50 to 100 cases
of new-onset type 2 diabetes mellitus, this is far outweighed
by the beneficial effects of statins on CVD, even among high-
risk patients and those who already have diabetes mellitus.30,81
Neurological and Neurocognitive Conditions
Neurological conditions that have been associated with statin
use include hemorrhagic stroke, cognitive decline, peripheral
neuropathy, depression, confusion/memory loss and aggres-
sion, and personality changes.19
It is unclear whether these are
because of the direct action of statins given the blood-brain
barrier’s selective permeability to substrates and the brain’s
self-sufficiency when it comes to endogenous cholesterol syn-
thesis.81
Lipophilic statins are thought to have a higher risk
because of their increased ability to cross the blood-brain bar-
rier13
; however, it should be noted that these effects may not be
specific to statins per se and instead a result of low cholesterol
levels.
Proposed Mechanisms for Development of
Neurological and Neurocognitive Conditions
Several mechanisms for neurological effects have been pro-
posed, most of which focus on the important role lipids play
in brain function. Reductions in serum lipid levels have been
proposed to negatively affect the formation of neuronal cell
membranes, myelin sheath, and nerve synapses. Reduced cho-
lesterol availability for neurons can then contribute to lower
serotonin activity through reduced receptor expression, which
can result in changes in behavior control and adverse psychi-
atric effects.100
Clinical Studies Investigating Statin-Induced
Ischemic and Hemorrhagic Stroke
Observational studies suggest an inverse relationship between
cholesterol levels and rates of hemorrhagic stroke, particularly
at low concentrations of cholesterol in people with hyperten-
sion.30
The SPARCL trial (Stroke Prevention by Aggressive
Reduction in Cholesterol Levels) demonstrated a definite re-
duction in ischemic stroke with 80 mg daily of atorvastatin,
but a probable increase in hemorrhagic stroke,101
which was
confirmed in meta-analysis.102
Recent analysis of randomized
controlled trials has suggested that treatment of 10000 pa-
tients for 5 years with an effective regime (40 mg atorvastatin
daily) would yield a probable 5 to 10 cases of hemorrhagic
stroke.30
More recently, however, a large systematic review
and meta-analysis has investigated statin use in patients with
previous ischemic stroke or intracerebral hemorrhage. In pa-
tients with a previous intracerebral hemorrhage, statin use did
not increase the risk of a recurrent event. In patients with a pre-
vious ischemic stroke, however, although statins reduced the
risk of a recurrent ischemic stroke, they did nonsignificantly
increase the risk of intracerebral hemorrhage. Irrespective of
stroke type, statins did show clear benefits in reducing mor-
tality and improving functional outcome, although these find-
ings were predominately based on observational data, limiting
their interpretation.103
Clinical Studies Investigating Statin-Induced
Dementia and Alzheimer Disease
Both the PROSPER (Prospective Study of Pravastatin in the
Elderly at Risk) and Heart Protection Studies demonstrated
no effect of pravastatin or simvastatin on cognitive decline or
impairment or the development of dementia.78,104
Similarly, no
effect of statins on cognitive outcomes in patients with mild-
to-moderate Alzheimer disease has been observed, with either
atorvastatin105
or simvastatin.106
This is supported by a recent
meta-analysis of 31 studies, which actually found a reduced
risk of dementia with statin use.107
A population-based co-
hort study also observed a decrease in the risk of dementia
in stroke patients who were receiving statin therapy, which
was further enhanced with high-potency, lipophilic statins
and a prolonged exposure time.108
In contrast, a recent popu-
lation-based retrospective study observed an increased risk of
Alzheimer disease in patients receiving fungus-derived statins
compared with synthetic statins. Lipophilic statins were also
associated with a higher risk compared with hydrophilic
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statins, whereas statin potency did not seem to have an ef-
fect.109
A recent systematic review and meta-analysis has also
demonstrated that statin use may reduce the risk of all-type
dementia, Alzheimer disease, and mild cognitive impairment,
with no apparent effect on vascular dementia.110
A more re-
cent community-based observational study has observed that
older patients on long-term statin therapy (>5 years) showed
no difference in neuroimaging biomarkers of Alzheimer di-
sease compared with non–statin-treated (<3 months) adults.
Long-term statin therapy was associated with a worse white
matter structural integrity; however, this was thought to be re-
flective of the increased cerebrovascular and cardiovascular
risk factor burden within this patient group. These results were
not related to statin lipophilicity.111
Clinical Studies Investigating Statin-Induced
Psychiatric Effects
There is some evidence to show that low cholesterol and
statin use have been linked to neuropsychiatric effects in-
cluding aggression, agitation, irritability, mood changes, vi-
olent ideation, sleep problems, and suicidal tendencies.112,113
A retrospective cohort study investigating depression in hy-
drophilic and lipophilic statin users found a nonsignificant
increase in the risk of depression in patients taking lipophilic
statins. These results were unchanged when patients were
analyzed by subgroup, including patients initiating statin use
for primary prevention, for secondary prevention, or in those
with a history of psychiatric comorbidities. The highest in-
cidence of depression was seen with simvastatin, followed
by lovastatin, atorvastatin, pravastatin, and rosuvastatin,
with the simvastatin group the only statin to reach statistical
significance.114
Hepatotoxicity
Early clinical trials of statins revealed elevations in amino-
transferases in up to 2% of patients despite only rare obser-
vation of clinically apparent liver injury.115
Asymptomatic
rises in hepatic enzyme activity, with elevated aminotrans-
ferase activity >3× the ULN, is a common side effect that
normally resolves with dose reduction21
and is not associ-
ated with histopathology changes or liver toxicity in the
absence of increased bilirubin or dysfunction. When com-
bined with increased bilirubin, statin discontinuation and
monitoring of liver function is necessary.23
More serious,
but rare hepatotoxicity, may present as asymptomatic ele-
vation in serum transaminases, hepatitis, cholestasis, and
acute liver failure. Although liver function panels are rec-
ommended before commencement of statin therapy and at
initial follow-up, further monitoring is only recommended
if concerns emerge. In patients with chronic liver disease,
including nonalcoholic fatty liver disease, chronic hepati-
tis, and primary biliary cirrhosis, follow-up of liver func-
tion is warranted, although these patients are not at higher
risk of hepatotoxicity than patients with normal liver tests
pretreatment.23,115
Current evidence suggests statin ther-
apy to be safe in patients with nonalcoholic fatty liver
disease and may confer more efficient treatment of viral
hepatitis and reduced risk of cirrhosis and hepatocellular
carcinoma.23
Proposed Mechanisms of Stain-Induced
Hepatotoxicity
The mechanisms of statin-induced hepatocellular injury are
unclear, although animal studies suggest that the reduction in
mevalonate or one of its sterol intermediates may be associ-
ated with an elevation in liver enzymes. In addition, asympto-
matic rises without histopathologic changes may result from
changes in hepatocyte membrane lipid composition, leading
to increased permeability and leaking of the liver enzymes.32
Statin-induced hepatotoxicity may also arise from extensive
hepatic metabolism and lipophilicity, with a high oral daily
dose associated with an increased risk of drug-induced liver
injury.115
A recent study using the LDLr−/−
mouse found that
pravastatin can induce liver mitochondrial redox imbal-
ance, which may also account for adverse hepatic effects.
Interestingly, these effects were reversed with either coenzyme
Q10 or creatine cotreatment, suggesting that the negative he-
patic effects of statins are not solely because of inhibition of
the mevalonate pathway.116
Clinical Studies Investigating Statin-Induced
Hepatotoxicity
Recent data from the Spanish Hepatotoxicity Registry reveal
that statins are the most frequent drug type associated with
chronic liver injury.117
Atorvastatin appears to be the most im-
plicated statin, although hepatotoxicity has also been observed
in patients taking simvastatin, and to a lesser extent, fluvas-
tatin, pravastatin, and rosuvastatin. Prognosis after statin dis-
continuation is generally favorable, with liver-related fatalities
only having been observed in patients treated with atorvastatin
and simvastatin.115
Three prospective studies have shown that
most patients (87%) with statin-induced hepatotoxicity were
symptomatic with hepatocellular rather than cholestatic or
mixed liver injury. Cholestatic/mixed liver injury appeared to
be more predominant in patients taking atorvastatin.115
Drug-
induced autoimmune hepatitis has also been observed in statin
users, particularly those receiving atorvastatin, with a similar
clinical, biochemical, and histological pattern as non–drug-
induced autoimmune hepatitis.115
Renal Toxicity
Controversy still exists about the effects of statins on renal
function. With the exception of hydrophilic statins (pravas-
tatin and rosuvastatin), other statins are metabolized by the
liver and minimally cleared by the kidney.81
Mild transient
proteinuria is sometimes seen with high-dose statin treatment,
but this is not associated with impaired renal function.81
Proposed Mechanisms for Statin-Induced Renal
Toxicity
Mechanistically, these effects are thought to be related to
HMG-CoA reductase inhibition. Renal proximal tubule cells
are responsible for the reabsorption of proteins, a process that
involves receptor-mediated endocytosis and certain GTP-
binding proteins. Inhibition of HMG-CoA reductase by statins
results in reductions in isoprenoid pyrophosphates, which are
required for the prenylation and normal function of GTP-
binding proteins. In vitro studies have shown that statins in-
hibit the uptake of albumin via receptor-mediated endocytosis
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in a dose-dependent manner with no effects on cellular tox-
icity. The effects on uptake were associated with the degree
of HMG-CoA reductase inhibition and related to depletion of
mevalonate metabolites other than cholesterol.118,119
Clinical Studies Investigating Statin-Induced Renal
Toxicity
A large Italian population nested cohort study revealed that
high-potency statins were more likely to result in hospitali-
zation for acute kidney injury at 6 months compared with
low-potency statins, although there was no evidence for risk
of chronic kidney disease.120
Retrospective cohort analysis re-
vealed a higher crude incidence rate of severe renal failure
(composite of hemodialysis, peritoneal dialysis, and kidney
transplant) in high-potency statin initiators compared with
low potency.121
Several meta-analysis, however, have revealed
no change in the risk of acute renal impairment or increase
in serious adverse renal events with statin therapy. In chronic
kidney disease patients, there was no increase in disease pro-
gression or adverse events with statins.81
Statin therapy did
not affect the risk of kidney failure events in adults not receiv-
ing dialysis, but was observed to modestly reduce proteinuria
and decline in glomerular filtration rate.122
Interestingly, use
of atorvastatin has been proposed to reduce inflammation and
improve kidney function after transplantation.123
Other Statin-Mediated Adverse Events
Other statin-mediated adverse events include cataracts, gas-
trointestinal effects, urogenital health effects, gynecomastia,
and reproductive effects, most of which have been purported
to be as a result of reduced production of intermediate and
end products of the mevalonate pathway. Thyroid disease,
while not thought to be because of statin toxicity per se, may
contribute to statin intolerance, particularly with respect to
SAMS.23
Although it remains debatable as to the role statins
play in these proposed adverse effects, meta-analysis has re-
vealed no significant effect of statins or cholesterol lowering
with a statin on the development or prevention of cataracts.124
Indeed, in vitro studies have shown that atorvastatin promotes
phagocytosis and reduces inflammation in retinal pigment ep-
ithelium, which may protect against the development of age-
related macular degeneration.125
Statins may be associated with reductions in androgens as
they inhibit production of the substrate required for local syn-
thesis. An early meta-analysis highlighted the testosterone-
lowering effect of statins in both men and women,126
whereas
a recent case-control study has revealed an increased risk of
developing gynecomastia with statin use.127
Fetal exposure to
statins may also result in adverse effects, and this is partic-
ularly relevant when considering patients with familial hy-
percholesterolemia who require lipid-lowering therapy from
an early age. A recent cohort analysis of pregnant women
found that statin exposure during the first trimester was as-
sociated with an increased risk of fetal ventricular septal de-
fect, and there was a higher incidence of congenital cardiac
abnormalities in pregnancies exposed to statin therapy.128
Of
further potential clinical importance is a recent animal study,
which revealed significant adverse effects of atorvastatin, but
not pravastatin, on cardiac muscle integrity, which effected
cardiac mitochondrial structure and function, as well as car-
diac cytoarchitecture.129
Off-Target Statin-Induced Effects
Genetic Variants
Common and rare genetic variants may contribute to statin
toxicity via mutations in genes that encode proteins regulat-
ing statin pharmacokinetics (drug receptors, transporters,
and metabolizing enzymes) and pharmacodynamics (muscle
enzymes).23
These can include polymorphisms or mutations
in genes encoding the CYP450 (cytochrome P450) enzymes,
coenzyme Q, myophosphorylase, glycine amidinotransfer-
ase, UDP glucuronosyltransferase, palmitoyltransferase 2,
myoadenylate deaminase, ATP-binding cassette sub-family
B, multidrug resistance protein 1, and multidrug resistance–
associated protein 2 efflux transporters.15,19,23,41,65
Genetic dif-
ferences in the activity of CYP450 enzymes can affect statin
interactions with other drugs, whereas genetic differences in
membrane transporters can alter first pass hepatic uptake and
thus residual circulating concentrations and peripheral tis-
sue exposure.81
In addition, mouse studies have revealed that
statin therapy may also alter gene expression, including he-
patic genes related to lipid and glucose homeostasis, such as
Pparα, Trib3, and Slc2a2, which may also contribute to their
adverse side effects.130
The importance of the HMG-CoA pathway–mediated
effects can also be inferred from Mendelian randomization
studies. Such analysis, which constructs a genetic score that
mimics the action of statins by targeting variants in the HMG-
CoA reductase gene (HMGCR), reveals that individuals with
higher scores have lower LDL-c levels and a reduced risk of
myocardial infarction or death from coronary heart disease.
This was additive when combined with high scores for vari-
ants in the PCSK9 gene.90
Other studies, which have inves-
tigated over 50 genes that are associated with lower LDL-c,
are also associated with a lower risk of coronary heart di-
sease.3
In contrast, a high HMGCR score was associated with
an increased risk of diabetes mellitus, which appeared to be
dose dependent, additive when combined with a high PCSK9
score, and higher in those with an impaired fasting glucose at
baseline.90
Drug-Drug Interactions
Drug-drug interactions occur when the pharmacokinetic or
pharmacodynamics of 1 drug is altered by prior or concomi-
tant administration of another drug, resulting in an effect dif-
ferent from the expected effects of each drug given alone. This
can result in a change in drug efficacy or toxicity for one or
both drugs in an additive, synergistic, or antagonistic fashion,
as well as alterations to absorption, distribution, metabolism,
or excretion of a drug. Most clinically significant drug-drug
interactions are pharmacokinetic in origin and often because
of induction or inhibition of drug-metabolizing enzymes and
transporters.131
Most statins undergo extensive microsomal
metabolism by the CYP450 isoenzymes in addition to being
recognized by drug transporters in the liver, gut, and kidney.131
The risk of statin toxicity is increased by drug interactions that
increase the concentration of statins in the plasma, with up to
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13. 340 Circulation Research January 18, 2019
50% of statin-mediated adverse events thought to be because
of drug-drug interactions.23,132
These interactions are depend-
ent on the pharmacokinetic profile of the statin prescribed and
can occur because of competing metabolism with CYP3A4 or
the (OATP)1B1 transporter.132
Inhibitors of (OATP)1B1 can de-
crease the hepatic uptake and therapeutic index of many statins.
Potent inhibitors of CYP3A4 can significantly increase the
plasma concentration of the active forms of atorvastatin, sim-
vastatin, and lovastatin. Fluvastatin, which is metabolized by
CYP2C9, is less prone to pharmacokinetic interactions, whereas
pravastatin, rosuvastatin, and pitavastatin are not susceptible to
any CYP450 inhibition.133
In addition, genetic variations in he-
patic, gut, and muscle transporters may also contribute to drug-
drug interactions through alterations to statin bioavailability,
metabolism, and clearance, as well as tissue concentration.15
ABC (ATP-binding cassette) transporters including
ABCB1 (ATP-binding cassette subfamily B member 1) are
expressed on the canillicular membrane of hepatocytes
and are thought to mediate the excretion of statins into
the bile. Variation in the ABCB1 gene, which encodes the
P-glycoprotein MRP2 (multidrug resistance protein), has
been associated with myalgia.41,134
ABCG2, which encodes
the ABCG2 (ATP-binding cassette G2) efflux transporter,
is expressed in the apical membranes of intestinal epithe-
lial cells, hepatocytes, renal tubule cells, and the endothelial
cells of the blood-brain barrier. Most statins are substrates
of the ABCG2 transporter, and it is thought to limit intes-
tinal absorption and tissue penetration as well as enhance
renal and hepatic elimination of its substrates.15
Mutations
in the ABCG2 gene impact plasma concentrations of statins,
with carriers also reported to have increased risk of statin-
associated adverse drug reactions.41,134
One relatively com-
mon SNP is c.421C>A (p.Gln141Lys; rs2231142), which
reduces the transport function of ABCG2, predominately
affecting rosuvastatin, followed by the inactive form of
simvastatin, atorvastatin, and fluvastatin. It appears to have
no effect on atorvastatin or pitavastatin. The SNP results
in an increase in the plasma concentration because of in-
creased bioavailability as a result of decreased intestinal
efflux.15
More recently, the rs717620 (-24C>T) SNP in the
ABCC2 gene, which encodes a transmembrane transporter,
has been shown to alter response to simvastatin and atorv-
astatin. Interestingly, female Chinese patients carrying this
SNP appeared to have a reduced benefit from simvastatin,
whereas male patients did not. In contrast, Chilean male but
not female patients had an attenuated response to atorvas-
tatin with this SNP, highlighting the contribution of both
gender and ethnicity.135,136
The most common drugs associated with statin drug in-
teractions are glucocorticoids, antipsychotics, HIV protease
inhibitors, azole antifungal agents, immunosuppressive drugs,
macrolides, calcium channel blockers, and lipid-modifying
drugs like gemfibrozil. Additional interactions can also occur
with alcohol, opioid, and cocaine abuse.5
Despite this, vari-
ation in the disposition of statins, including the role of me-
tabolizing enzymes and transporters, as well as interindividual
variations in the activity of CYP450 enzymes and transport
proteins, makes predicting statin drug-drug interactions
difficult.131
Vitamin D Status
Vitamin D is a steroid hormone that plays an important role
regulating the body’s levels of calcium and phosphorus, as well
as in bone mineralization. Vitamin D is produced when 7-de-
hydrocholesterol (synthesized from cholesterol) is converted
to cholecalciferol by UV B light.137
Low vitamin D is asso-
ciated with many disease states, including muscle weakness
and myopathy.138
Skeletal muscle contains vitamin D recep-
tors and the molecular mechanisms of vitamin D within this
tissue are both genomic and nongenomic. The genomic path-
way effects are initiated by the binding of bioactive vitamin
D (calcitriol) to its nuclear receptor, resulting in alterations in
gene transcription and subsequent protein synthesis. This can
have effects on muscle calcium uptake, phosphate transport
across muscle cell membranes, as well as muscle cell prolifer-
ation and differentiation. Vitamin D is also known to regulate
calcium uptake through modulation of calcium pump activity,
which then affects intracellular calcium levels and subsequent
muscle contraction, relaxation, and function. Effects on phos-
phate transport can impact cell structure and ATP availability,
whereas proliferation effects can alter the synthesis of certain
cytoskeletal proteins.137
It remains debatable whether vitamin D insufficiency
leads to statin-induced myalgia or statins contribution to vi-
tamin D deficiency. There is speculation that insufficient vi-
tamin D status may complicate and confound the adverse
effects of statins, possibly because of a preferential shunting
of the CYP3A4 enzyme toward hydroxylation of vitamin D,
reducing the enzyme’s availability for statin metabolism and
thus increasing circulating statin levels.32,137,138
Conversely,
high vitamin D status may also cause enhanced CYP450
activity, increasing statin metabolism and reducing drug
bioavailability.138
Although the exact interaction between vitamin D and
statins is unclear, vitamin D status does appear to play a
role in the lipid-lowering response to statins, with vitamin
D–deficient patients having no response to low (10–20 mg)
or high-dose (40–80 mg) atorvastatin.139
Interestingly, supple-
mentation with vitamin D was shown to enhance the effects of
atorvastatin, which is unexpected given both are metabolized
by CYP3A4.138
Biopsies of skeletal muscle in adults with vi-
tamin D deficiency show type II muscle fiber atrophy with
enlarged interfibrillar spaces and infiltration of fat, fibrosis,
and glycogen granules.140
Retrospective, cross-sectional, and
meta-analysis reveal an association between low vitamin D
levels and myalgia in patients on statin therapy,141–143
although
normalization of serum vitamin D levels has been shown to
facilitate successful statin rechallenge in ≈88% of patients
previously intolerant because of SAMS.144
A recent secondary
analysis trial has shown that monthly vitamin D supplemen-
tation results in improved adherence to statin medication in
older adults on long-term statin therapy.145
Microbiome-Mediated Effects
The microbiome plays an important role in our physiology,
immune system development, digestion, and overall health.146
While extremely dynamic, the microbiota composition and
structure can be influenced by a number of factors includ-
ing medication. Recent studies have demonstrated a role for
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14. Ward et al Statin Toxicity 341
statins in modulating microbiome composition, with statin
therapy resulting in profound remodeling of the gut micro-
biota, hepatic gene deregulation, changes in bile acid pool
size and composition, as well as metabolic alterations in mice
through a pregnane X receptor–dependent mechanism.130
Hypolipidemic response to rosuvastatin has also been shown
to be dependent on microbiome composition, diversity, and
taxa,147,148
whereas simvastatin has been shown to influence
gut-derived metabolites which may impact response to the
drug, as well as the development of adverse events.149
Stem Cell–Mediated Effects
Statin effect on stem cells is another potential mechanism
contributing to their adverse effects. Mesenchymal stem cells
isolated from adipose tissue and exposed to physiologically
relevant doses of statins have been shown to experience in-
creased cell senescence and apoptosis via upregulation of p16,
p53, and various caspases. Accompanying this was impaired
expression of DNA repair genes as well as impaired differen-
tiation ability.150
In vitro and animal studies have also demon-
strated a reduced proliferative capacity of stem cell–derived
mesodermal precursors after statin exposure.151
Cardiovascular Sequelae of Statin Intolerance
From Observational and Trial Data
Statins are commonly prescribed to reduce total and LDL cho-
lesterol levels, and their clinical benefits are widely accepted
in both primary and secondary prevention.7
Meta-analysis
has highlighted the benefits of LDL-c reduction, with every
1 mmol/L (38.7 mg/dL) reduction associated with signifi-
cant reductions in major vascular and coronary events.7
The
Cholesterol Treatment Trialists Collaboration has demonstrat-
ed a consistent relative risk reduction in major vascular events
per change in LDL-c level to as low as 0.5 mmol/L (21 mg/
dL) with no observed adverse events, suggesting that lower-
ing beyond current targets would further reduce CVD risk.8
As
a result, statin discontinuation and nonadherence represents a
significant clinical problem. Estimates suggest that 40% to 75%
of patients discontinue their statin therapy within 1 year of ini-
tiation, with rates higher for primary versus secondary preven-
tion, in older patients (>75 years), in women, in patients taking
concomitant medication, and in patients with higher medica-
tion copayments.152
Data from the National Cardiovascular
Data Registry suggest that among coronary artery disease out-
patients, over one-third fail to receive their optimal combina-
tion of secondary prevention medication, including statins.153
More recent analysis suggests that more than half of all stable
coronary artery disease patients are still considered at extreme
risk with only ≈5% achieving recommended LDL-c targets
(<55 mg/dL).154
Reports from the United Kingdom reveal only
79% of patients with established CVD were reported to be re-
ceiving statins, with only 31% of those receiving high-dose
statins as recommended by clinical guidelines.155
In primary prevention, retrospective analysis reveals that
patients with ≥90% statin adherence over 1 year had signifi-
cantly fewer nonfatal coronary artery disease events compared
with those who were <90% adherent with their statin.156
In pa-
tients with a prior acute myocardial infarction, the risk of mor-
tality was significantly increased in low adherence statin users
compared with high adherence users (24% versus 16%).157
Retrospective cohort analysis revealed that statin intolerance
was also associated with a 36% increase in recurrent myocar-
dial infarction and a 43% increase in coronary heart disease
events compared with high statin adherence patients.158
Meta-
analysis of secondary prevention statin trials revealed large
variability in the reduction of lipoprotein levels with statin
therapy. Furthermore, >40% of patients failed to reach guide-
line-recommended LDL-c targets despite high-dose statin
therapy. Those who did achieve very low LDL-c levels had
significantly lower risk of cardiovascular events than those
who achieved moderately low levels.159
Reinitiating Statin Therapy: More Than Just
Reducing Cardiovascular Risk
Meta-analysis reveals several sociodemographic, medical, and
healthcare utilization characteristics, including sex, income
level, out-of-pocket costs, and level of lipid testing as factors
that impact statin adherence.160
The economic significance of
this also needs to be considered, as patients with hyperlipi-
demia already have substantial economic and clinical burden
from cardiovascular events up to 3 years after their first event,
which continues to increase with subsequent events.161,162
A
decrease in the use of statin therapy, either in primary or sec-
ondary prevention, can arise as a result of several issues. First,
statin underuse may be because of a physician’s failure to
initiate or intensify treatment or a patient’s reluctance to in-
itiate treatment because of concerns about toxicity. Second,
it may be due to the development of statin resistance, which
occurs when a patient has a substantially lower response to
a given dose of statin than what would be predicted. Third,
due to statin intolerance, when a patient cannot tolerate statin
therapy either at a necessary dose or at all, and finally statin
nonadherence because of poor patient compliance with statin
medication.152
A recent survey of US adults prescribed statins
revealed that provider-patient communication about statin
therapy is inadequate, which may play a pivotal role in statin
adherence.163
Retrospective analysis of statin reattempt after
an adverse event revealed that the nature and timing of the
adverse event, medical history, and the medication prescribed,
including adverse reactions to nonstatin therapy, all affect the
success rate of reattempting statin therapy, supporting the
need for a patient-centered approach when attempting to re-
start statin treatment.164
The REGARDS study (Reasons for Geographic and
Racial Differences in Stroke) found that 15% of those sur-
veyed reported stopping their statin treatment. Within this
group, the major reasons for discontinuation included statin
side effects (66%), perceived lack of need for a statin (31%)
and cost (3%). Overall, 37% of patients who had ceased statin
treatment were willing to reinitiate statin therapy, with this
being highest in the group who reported cost as the primary
reason for discontinuation. Those with elevated LDL-c and
reported side effects were less willing, highlighting the need
for health providers to discuss the benefits of statin treatment
with respect to long-term cardiovascular risk reduction.165
A large retrospective study of >100000 patients found that
after discontinuation, most patients (92%) could be rechal-
lenged with a new statin that was tolerated for ≥12 months,
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15. 342 Circulation Research January 18, 2019
suggestive of a reversible pattern of statin toxicity in most
cases.166
It is therefore important that when a patient presents
with statin intolerance and other causes have been ruled out,
a step-by-step approach to future treatment, including that
reinitiating statin therapy is essential. This must include an
accurate clinical assessment, listening to patient concerns,
reviewing past adverse events and possible contributing fac-
tors, providing evidence-based counseling about the potential
for adverse events as well as the cardiovascular benefits of
statin therapy, and shared decision making with the patient
when reintroducing therapy.18,33
Treatment and management
algorithms have been developed to aid both diagnosis and
management of SAMS in a bid to standardize nomenclature
and phenotypes, as well as the type of data that should be col-
lected from each patient.37
Development was based on 2012
Therapeutic Guidelines: Cardiovascular and 2016 European
Society of Cardiology/European Atherosclerosis Society
Guidelines for the management of dyslipidemias, with input
from experts (Figure 3).23,29,36
Recently released 2018 American Heart Association
and American College of Cardiology Guidelines for the
Management of Blood Cholesterol recommend a comprehen-
sive approach to patients who experience statin-associated
symptoms, with the clinician reassessing, rediscussing, and
encouraging rechallenge as the initial approach unless side
effects are severe. Reassessment and rechallenge should be
addressed by modified dosing regimen, an alternate statin or
in combination with nonstatin therapy to achieve a maximal
LDL-c–lowering effect. Ongoing communication is seen as
integral to patient care, along with regular monitoring to check
for adherence, adequacy of response, new associated symp-
toms, and reaffirmation of clinical benefits. Measurement
of CK is only recommended for those who experience se-
vere SAMS or objective muscle weakness. Coenzyme Q is
not recommended for either routine use or the treatment of
SAMS. Patients with increased risk of type 2 diabetes mel-
litus are recommended to continue statin therapy with added
emphasis given to net clinical benefit and adoption of life-
style changes including increased physical activity, a healthy
diet, and moderate weight loss. If hepatotoxicity symptoms
are present, liver transaminases, total bilirubin, and alkaline
phosphatase are recommended. In patients with stable liver
disease (including nonalcoholic fatty liver disease), statins can
be used after obtaining baseline measurements and determin-
ing a safety monitoring schedule.11
Biomarkers of Statin Toxicity
The lack of universal definitions of statin toxicity, particularly
with respect to SAMS, means potential biomarkers identify-
ing either risk of developing adverse events or confirming
their presence have not been identified. In extreme cases of
necrotizing myopathy, patients do present with significantly
elevated CK levels (>1000 IU/L) and prominent myofiber ne-
crosis on biopsy, whereas patients with autoimmune myopathy
Figure 3. Statin-associated muscle
symptoms (SAMS) management algorithm.
CK indicates creatinine kinase; LDL-c,
low-density lipoprotein cholesterol; LLT,
lipid-lowering therapy; and ULN, upper limit
of normal. Figure derived from www.nps.
org.au and 2012 Therapeutic Guidelines:
Cardiovascular and 2016 European Society
of Cardiology/European Atherosclerosis
Society Guidelines for the management of
dyslipidemias.23,29,36
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16. Ward et al Statin Toxicity 343
will also present with anti–HMG-CoA reductase autoantibod-
ies. However, less severe SAMS do not always include a path-
ogenic response and, in some instances, can include normal
CK levels. Further investigation of the STOMP trial revealed
no association between CK levels and skeletal muscle func-
tion, nor did CK predict muscle complaints after high-dose
atorvastatin treatment.167
Conversely, elevated CK levels can
also be observed in the absence of myopathy, such as after
strenuous exercise, further confounding the problem.5,41,81
The National Lipid Association has developed guidelines
for both diagnosing and managing SAMS.36
Recently renamed
the SAMS Clinical Index to reflect the diversity of symptoms,
the score aims to define the spectrum of statin-associated mus-
cle events to include, in increasing order of severity, myalgia
(described as flu-like symptoms), myopathy (muscle weak-
ness), myositis (muscle inflammation), myonecrosis (muscle
enzyme elevation or increase in CK), and clinical rhabdo-
myolysis.168
SAMS clinical index uses 4 scales relating to
location, pattern, timing of symptom onset, and timing of im-
provement after statin withdrawal (Table 3).169
Although this
index appears to confirm true SAMS in a small study of statin
myopathy, its use still requires validation in larger, long-term
studies.29
Genome-wide association studies have identified several
genetic variants associated with statin toxicity; however, these
are suggestive and their associations have not always been
widely replicated. Furthermore, this type of investigation pre-
dominantly looks at common variants in the genome and may
not detect rare variants.41
In addition, it is unknown whether
statins play a causal role in unmasking a phenotype or whether
development of an adverse event is a natural progression of
the underlying condition, indicating that further understand-
ing of the molecular mechanisms underlying statin toxicity
is required. This is particularly relevant with SAMS, given
the diverse nature of muscular conditions that are reported.
Pharmacogenomics of statin therapy has generally focused on
genes involved in pharmacodynamics and pharmacokinetics
(SLCO1B1 and CYP3A4) or those linked to lipoprotein metab-
olism pathways (HMGCR, LDLR, APOE, APOB, PCSK9). In
general, these common genetic variations do not appear to be
a major determinant of statin response, with relatively modest
effect sizes and inconsistent replication in larger studies. The
exception to this is SLCO1B1 and risk of myopathy, with
SLCO1B1 521C clinically relevant to simvastatin-induced
myopathy.170,171
Animal studies have revealed increased serum and u-
rinary excretion of 1- and 3-methylhistidine in response to
cerivastatin-induced mytotoxicity.172
Elevated skeletal mus-
cle phosphodiesters are also related to muscle disorders, and
these have been observed to be higher in statin users compared
with nonstatin users,173
although further work is required to
establish a link between either of these markers and muscle
function and myopathy. Other potential biomarkers include
lactate/pyruvate ratio, which may reflect a dysfunction in the
mitochondrial respiratory chain and myotoxicity. An early
study revealed higher lactate/pyruvate ratios in statin-treated
hypercholesterolemic patients compared with untreated pa-
tients or healthy controls.174
In contrast, a study in healthy
subjects treated with simvastatin observed statin-induced
mitochondrial dysfunction compared with those treated with
placebo, with no difference observed for lactate/pyruvate
ratio.175
The Nocebo Effect: Is Statin Toxicity All in the
Mind?
The issue of statin toxicity, particularly with respect to
the development of SAMS, remains a contentious issue.
Randomized controlled trials suggest a low incidence (<5%)
of statin toxicity; however, some feel this is an underestima-
tion as most studies exclude patients with a history of statin
intolerance either before randomization or during the run-in
period. Furthermore, patients more likely to develop statin in-
tolerance are often underrepresented in trials, those enrolled in
trials often underreport side effects, and there is a lack of valid
questionnaires, standard definitions, relevant biomarkers, and
toxicity outcomes included in trial design.5,19
Others maintain
that randomized controlled trials do not reflect clinical prac-
tice and thus fail to reliably assess adverse effects.176
A much debated topic is the so-called nocebo effect,
caused by negative expectations about the effects of treatment
because of information provided by clinicians, drug package
inserts, the media, and a patient’s own internet searches about
possible side effects, leading to higher than expected adverse
event reporting.21,81,177
Both the placebo and nocebo effect re-
flect normal human neuropsychology and not drug efficacy
or toxicity.178
Two large-scale trials have observed develop-
ment of SAMS in statin-intolerant patients randomized to
either PCSK9 inhibitors or ezetimibe, drugs that operate via
Table 3. Statin-Associated Muscle Symptom Clinical Index36,170
Clinical Symptoms Score
Regional distribution/pattern
Symmetrical hip flexors/thigh aches 3
Symmetrical calf aches 2
Symmetrical upper proximal aches 2
Nonspecific asymmetrical, intermittent 1
Temporal pattern
Symptom onset <4 wk 3
Symptom onset 4–12 wk 2
Symptom onset >12 wk 1
Dechallenge
Improves upon withdrawal <2 wk 2
Improves upon withdrawal 2–4 wk 1
Does not improve upon withdrawal >4 wk 0
Challenge
Same symptoms reoccur upon rechallenge <4 wk 3
Same symptoms reoccur upon rechallenge 4–12 wk 1
Statin myalgia clinical index score
Probable 9–11
Possible 7–8
Unlikely <7
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