Supplementary Information: Webtables
Webtable 1. Definitions of muscle effects attributed to statins used by different trials
and consensus groups
Webtable 2. Proposed statin myalgia clinical index score
Webtable 3. Possible mechanisms mediating statin-attributed muscle related symptoms
Webtable 4. The CoQ10 story
Webtable 5. Genetic variants affecting statin pharmacokinetics and statin adverse
effects.
1
Webtable 1. Definitions of muscle effects attributed to statins used by different trials and consensus groups
Reference
Tobert 1988 (1)
Myopathy
muscle pain or weakness plus
CK ≥10 X ULN
muscle symptoms plus CK >10
X ULN
Myositis
n/a
Myonecrosis
n/a
Rhabdomyolysis
n/a
Myalgia
n/a
n/a
n/a
myopathy with CK >40 X ULN
n/a
ACC/AHA/NHLBI
2002 (3)
general term referring to any
disease in muscles
muscle symptoms
with increased
CK levels
n/a
muscle ache or
weakness without
CK elevation
Ballantyne 2003 (4)
CK >10 x ULN with muscle
symptoms (myalgia, fatigue,
weakness)
n/a
n/a
muscle symptoms with marked CK
elevation (>10 X ULN) and creatinine
elevation (usually brown urine, urinary
myoglobin)
CK >10,000 U/L plus organ damage
(typically renal insufficiency)
FDA 2005 (5)
muscle aches and pains with
elevated CK >10 X ULN
n/a
n/a
“According to standard medical
textbooks, rhabdomyolysis is
characterised by severe muscle injury
with massive cell destruction, release
of myoglobin into the blood, and
consequent myoglobin-induced renal
failure."
n/a
NLA 2006 An
assessment of statin
safety by muscle
experts (6)
general term for all muscle
problems;
may be symptomatic or
asymptomatic (CK elevations
without symptoms or objective
weakness)
n/a
n/a
Clinically important rhabdomyolysis
should refer to muscle cell destruction
or enzyme leakage, regardless of CK,
considered causally related to a change
in renal function. The term
rhabdomyolysis should be replaced by
mild CK increase (CK above normal
and < 10 X ULN), moderate CK
increase (CK ≥ 10 X ULN and < 50 X
ULN), and marked CK increase (CK ≥
50 X ULN)
muscle pain
Heart Protection
Study Collaborative
Group 2002 (2)
2
muscle soreness or
pain
Webtable 1. Definitions of muscle effects attributed to statins used by different trials and consensus groups, contd.
Reference
NLA 2006 Final
Conclusions and
Recommendations
(7)
Myopathy
muscle pain, soreness,
weakness, and/or cramps plus
CK >10 X ULN
Myositis
n/a
Myonecrosis
n/a
Rhabdomyolysis
CK >10,000 IU/L or CK >10 X ULN
plus elevated serum creatinine or
medical intervention with intravenous
hydration therapy
Myalgia
muscle pain or
soreness
SEARCH
Collaborative Group
2008 and 2010 (8,9)
unexplained muscle symptoms
with CK >10 x ULN
n/a
n/a
myopathy with CK >40 X ULN plus
end organ damage (e.g. doubling of
plasma creatinine)
n/a
Canadian Working
Group Consensus
Conference 2011
(10) *
general term referring to any
disease of muscle: includes
myalgia, myositis and
rhabdomyolysis
muscle ache or
weakness with
CK >ULN
n/a
muscle ache or weakness with CK >10
X ULN (CK >10,000 IU/L); renal
dysfunction may result from
myoglobinuria
muscle ache or
weakness with
CK ≤ULN
ESC/EAS 2011 (11)
"an elevation of CK is the best
indicator, although not
unequivocal, of statin-induced
myopathy. The common
definition of a tolerable
elevation has been a rise of five
times the ULN of this enzyme
measured on two occasions."
n/a
n/a
not defined. Associated with marked
CK elevation
muscle pain
3
Webtable 1. Definitions of muscle effects attributed to statins used by different trials and consensus groups, contd.
Reference
NLA 2014 (12)
Myopathy
muscle weakness, not attributed
to pain and not necessarily
associated with elevated CK
Myositis
Muscle
inflammation
Rhabdomyolysis
Clinical rhabdomyolysis is severe
myonecrosis with myoglobinuria or
acute renal failure (increase in serum
creatinine ≥ 0.5 mg/dL)
Myalgia
unexplained muscle
discomfort with
normal CK levels
and includes muscle
aches, soreness,
stiffness, tenderness
and cramps with or
shortly after
exercise (not
nocturnal)
n/a
Myonecrosis
muscle
enzyme
elevations or
hyperCKemia
categorised as
mild (>3 fold
elevation);
moderate
(≥10 fold
elevation); or
severe (≥50
fold elevation)
in comparison
to baseline
untreated CK
levels or
normal upper
limit adjusted
for age, race,
sex
n/a
US Prescribing
Information for
atorvastatin (13),
fluvastatin (14,15),
pravastatin (16)
US Prescribing
Information for
lovastatin (17),
simvastatin (18) ϯ
EU Summary of
Product
Characteristics for
atorvastatin (19)
muscle aching or muscle
weakness with increases in CPK
values to >10 X ULN
n/a
n/a
muscle pain, tenderness or
weakness with CK >10 X ULN
n/a
n/a
n/a
n/a
n/a
n/a
n/a
markedly elevated creatine kinase (CK)
levels (> 10 times ULN),
myoglobinaemia and myoglobinuria
which may lead to renal failure
n/a
4
Webtable 1. Definitions of muscle effects attributed to statins used by different trials and consensus groups, contd.
Reference
EU Summary of
Product
Characteristics for
pravastatin (20)
Myopathy
n/a
Myositis
n/a
Myonecrosis
n/a
Rhabdomyolysis
an acute potentially fatal condition of
skeletal muscle which may develop at
any time during treatment and is
characterized by massive muscle
destruction associated with major
increase in CK (usually > 30 or 40 X
ULN) leading to myoglobinuria
n/a
Myalgia
n/a
EU Summary of
muscle pain, tenderness or
n/a
n/a
n/a
Product
weakness with creatine kinase
Characteristics for
(CK) above 10 X the upper limit
simvastatin (21, 22)
of normal
* The Canadian Working Group Consensus Conference 2011 (10) used the term “hyperCKemia” which was defined as follows: Mild (with or without myositis) grade 1, CK
>ULN, ≤5 X ULN; Mild (with or without myositis) grade 2, CK >5 X ULN and ≤10 X ULN ; Moderate (with/without rhabdomyolysis, with/without renal dysfunction), CK
>10 X ULN, ≤50 X ULN; Severe (with/without rhabdomyolysis, with/without renal dysfunction) CK > 50 X ULN.
ϯ Myopathy is not defined in the US Prescribing Information for pitavastatin or rosuvastatin.
Abbreviations: ACC American College of Cardiology; AHA American Heart Association; EAS European Atherosclerosis Society; ESC European Society of Cardiology;
EU European Union; FDA Food and Drug Administration; NHLBI National Heart Lung Blood Institute; NLA National Lipid Association; SEARCH Study of the
Effectiveness of Additional Reductions in Cholesterol and Homocysteine; CK creatine kinase; ULN upper limit of the normal range;
References
(1) Tobert JA. Efficacy and long-term adverse effect pattern of lovastatin. Am J Cardiol 1988;62:28J-34J.
(2) Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised
placebo-controlled trial. Lancet 2002;360:7-22.
(3) Pasternak RC, Smith SC Jr, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C; American College of Cardiology; American Heart Association; National Heart, Lung
and Blood Institute. ACC/AHA/NHLBI Clinical advisory on the use and safety of statins. J Am Coll Cardiol 2002;40:567-572.
(4) Ballantyne CM, Corsini A, Davidson MH, Holdaas H, Jacobson TA, Leitersdorf E, März W, Reckless JP, Stein EA. Risk for myopathy with statin therapy. Arch Intern
Med 2003;163:553-564.
5
(5) Stephen K. Galson Acting Director U.S. Food and Drug Administration Center for Drug Evaluation and Research. FDA Rejection of Citizen Petition. Letter dated 11
March 2005, Food and Drug Administration Docket No. 2004P-0113/CP1 accessed 27 June 2014.
(6) Thompson PD, Clarkson PM, Rosenson RS. An assessment of statin safety by muscle experts. (The National Lipid Association's Muscle Safety Expert Panel). Am J
Cardiol 2006;97(suppl):69C-76C.
(7) McKenney JM, Davidson MH, Jacobson TA, Guyton JR. Final conclusions and recommendations of the National Lipid Association Statin Safety Task Force. Am J
Cardiol 2006;97(suppl):89C-94C.
(8) SEARCH Collaborative Group, Link E, Parish S, Armitage J, Bowman L, Heath S, Matsuda F, Gut I, Lathrop M, Collins R. SLCO1B1 variants and statin-induced
myopathy--a genomewide study. N Engl J Med 2008;359: 789-799.
(9) Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group, Armitage J, Bowman L, Wallendszus K, Bulbulia
R, Rahimi K, Haynes R, Parish S, Peto R, Collins R. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12 064 survivors of myocardial
infarction: a double-blind randomized trial. Lancet 2010;376:1658-1669.
(10) Mancini GB, Baker S, Bergeron J, Fitchett D, Frohlich J, Genest J, Gupta M, Hegele RA, Ng D, Pope J. Diagnosis, prevention, and management of statin adverse effects
and intolerance: proceedings of a Canadian Working Group Consensus Conference. Can J Cardiol 2011;27:635-662.
(11) Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, Agewall S, Alegria E, Chapman MJ, Durrington P, Erdine S, Halcox J, Hobbs R, Kjekshus
J, Filardi PP, Riccardi G, Storey RF, Wood D. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the
European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011;32:1769-1818.
(12) Rosenson RS, Baker SK, Jacobson TA, Kopecky SL, Parker BA. An assessment by the statin muscle safety task force: 2014 update. J Clin Lipidol 2014;8:558-571.
(13) LIPITOR (atorvastatin) US Prescribing Information 2014. http://www.lipitor.com/ (20 January 2015)
(14) LESCOL (fluvastatin) US Prescribing Information 2012. https://www.pharma.us.novartis.com/product/pi/pdf/Lescol.pdf (20 January 2015)
6
(15) LESCOL XL (fluvastatin SL) US Prescribing Information 2012. https://www.pharma.us.novartis.com/product/pi/pdf/Lescol.pdf (20 January 2015)
(16) PRAVACHOL (pravastatin) US Prescribing Information 2012. http://packageinserts.bms.com/pi/pi_pravachol.pdf (20 January 2015)
(17) MEVACOR  (lovastatin) US Prescribing Information 2014. http://www.merck.com/product/usa/pi_circulars/m/mevacor/mevacor_pi.pdf (20 January 2015)
(18) ZOCOR  (simvastatin) US Prescribing Information 2014. http://www.merck.com/product/usa/pi_circulars/z/zocor/zocor_pi.pdf (20 January 2015)
(19) LIPITOR (atorvastatin) EU Summary of Product Characteristics 2014.
http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Lipitor_30/WC500125066.pdf (20 January 2015)
(20) LIPOSTAT (pravastatin) EU Summary of Product Characteristics 2013. http://www.medicines.org.uk/emc/medicine/356 (20 January 2015)
(21) INEGY (simvastatin) EU Summary of Product Characteristics 2013. https://www.medicines.org.uk/emc/medicine/15657 (20 January 2015)
(22) ZOCOR (simvastatin) EU Summary of Product Characteristics 2014. https://www.medicines.org.uk/emc/medicine/1201 (20 January 2015)
7
Webtable 2. Proposed statin myalgia clinical index score*
Clinical symptoms (new or increased unexplained symptoms)
Score
Regional distribution/pattern
Symmetric hip flexors/thigh aches
3
Symmetric calf aches
2
Symmetric upper proximal aches
2
Non-specific asymmetric, intermittent
1
Temporal pattern:
Symptoms onset <4 weeks
3
Symptoms onset 4-12 weeks
2
Symptoms onset >12 weeks
1
Dechallenge
Improves on withdrawal (<2 weeks)
2
Improves on withdrawal (2-4 weeks)
1
Does not improve on withdrawal (>4 weeks)
0
Challenge
Same symptoms occur on rechallenge <4 weeks
3
Same symptoms occur on rechallenge 4-12 weeks
1
Statin myalgia clinical index score
Probable
9-11
Possible
7-8
Unlikely
<7
From: Rosenson RS, Baker SK, Jacobson TA, Kopecky SL, Parker BA. An assessment by the statin muscle
safety task force: 2014 update. J Clin Lipidol 2014;8:558-571.
8
Webtable 3. Possible mechanisms mediating statin-attributed muscle related symptoms

Reduced sarcolemmal and / or sarcoplasmic reticular cholesterol - Cholesterol is a critical
component of cellular membrane, including the sarcolemma. Reduced sarcolemmal cholesterol could
initiate breaching of the cellular membrane, releasing creatine kinase (CK) and other markers of
myocyte injury, and contributing to muscle pain. Similarly, cholesterol is a critical component of the
sarcoplasmic reticulum (SR), the membrane-like structure that releases and retrieves calcium ions,
initiating contraction and relaxation of the muscle, respectively. Statin mediated injury to the SR is
supported by the observation that even asymptomatic individuals on statins have small holes in the
T-tubular system and SR visible by electron microscopy.1 These possibilities seem unlikely, however,
since to our knowledge there is no correlation between reductions in low-density lipoprotein
cholesterol (LDL-C) with statins and myopathic events.

Reduced non-cholesterol end-products of the mevalonate pathway - Statins block hydroxyl-methylglutaryl CoA reductase at an early and rate-limiting step in the mevalonate pathway. This pathway
produces not only cholesterol, but also farnesyl pyrophate and geranylgenaryl pyrophosphate. These
prenylate other proteins to produce ubiquinone or co-enzyme Q10 (CoQ10), a member of the
mitochondrial electron transport pathway,2-3 as well as a variety of guanosine-5'-triphosphate (GTP)
binding proteins important in cell maintenance, growth and apoptosis.3 CoQ10 has been considered a
possible contributing factor because plasma levels decrease during statin therapy (see Webtable 4).

Increased myocellular fat and/or sterols– Increased myocyte fat can produce a skeletal myopathy.
Myocellular fat was higher during statin therapy in a small series of adults with statin myalgia 4 and
this could be due to reduced fat catabolism or increased cellular fat deposition. It is also possible that
elevated myocyte production of the LDL receptor could increase myocyte sterol content. We are
unaware of studies showing increased myocyte LDL receptor number or gene expression during statin
therapy, but there is at least one study showing increased cellular phytosterol content during
simvastatin and atorvastatin therapy.5

Alterations in muscle protein catabolism – Atrogin 1 is a muscle-specific ubiquitin ligase that
catabolises muscle protein, thus the name, reflecting the resultant muscle atrophy. 6 Some have
9
suggested that statin muscle injury does not occur or is reduced if atrogin is eliminated. 6 Others, in
contrast, suggest that statins reduce the increase in atrogin gene expression after muscle injury such as
that produced by physical exercise.7 These latter results imply that reduced removal of damaged muscle
protein ultimately leads to statin myopathy.

Vitamin D deficiency - Vitamin D deficiency itself can cause a skeletal myopathy and has been
postulated to contribute or cause statin myopathy.8 Vitamin D receptors have been demonstrated in
muscle, and D deficiency may contribute to statin myopathy in some patients. 8,9

Decreased myocellular creatine – Creatine phosphate (CP) is the immediate energy source for
contracting muscle. Creatine is made in the liver and proceeds to skeletal muscle where it is
synthesised to CP. The rate limiting enzyme for this synthesis is glycine amidinotransferase (GATM).
There is a genetic variant in GATM that reduces creatine synthesis. Remarkably this variant (and
presumably lower muscle creatinine concentrations) is associated with less rhabdomyolysis with statin
therapy in several clinical trials.10 Therefore it is possible that reduced creatine synthesis produces less
CP which forces the muscle to develop alternative energy pathways that protect the muscle during
statin therapy. If proven, this would suggest that defects in energy metabolism are the ultimate cause of
statin-related muscle injury.

Present understanding of statin myopathy - These various possibilities cannot be easily reconciled,
but at present it is likely that statins both decrease mitochondrial function and increase muscle protein
degradation.

Mitochondrial oxidative phosphorylation (OXPHOS) is reduced in chronic simvastatin users
(mean±SD 5±5 years) vs untreated subjects.11 Mitochondrial number assessed by citrate synthase
activity (CSA) was not different in the two groups, but there was an increase in the ratio of
mitochondrial voltage-dependent anion channels (VDAC) to CSA suggesting more channels per
mitochondrion. VDAC helps regulate mitochondrial calcium (CA) content, and an increase in
mitochondrial CA content facilitates apoptosis. Other studies demonstrate reduction in post-exercise
phosphocreatine recovery,12 a measure of mitochondrial OXPHOS, during statin therapy and a decrease
10
in CSA activity in simvastatin-treated patients after exercise training,13 both consistent with reductions
in mitochondrial function during statin therapy.

There is also strong evidence for an increase in muscle protein catabolism during statin therapy.
Dephosphorylation of Akt (protein kinase B) reduces protein anabolism via the mTOR pathway and
accelerates proteosomal muscle protein catabolism via the forkhead box gene group O (FOXO) of
proteins including MAFbx (atrogin 1) and muscle ring finger 1 (MuRF 1). 14 Atrogin 1 is increased in
patients with statin myalgia6 and both Atrogin 1 and MuRF1 increase in an in vivo animal model of
statin myopathy.6,15 Cathepsin, a marker of lysosomal proteolysis is also increased,15 demonstrating
increases in both proteosomal and lysosomal protein catabolism with statin therapy. FOXO activation
also increases transcription of pyruvate dehydrogenase kinase (PDK) isoforms. 15 PDK inactivates the
muscle pyruvate dehydrogenase complex reducing carbohydrate oxidation, 15 thereby suggesting that
statin effects on FOXO contribute to both the myopathic and glucose metabolism side effects of statin
therapy.

Statins inhibit the production of prenylated proteins or GTPases, including Rho A.15 Decreases in
Rho A decrease phophorylation of Akt suggesting that reductions in Rho A could produce both the
muscle and metabolic side effects of statins. This hypothesis requires confirmation because changes in
Rho A during statin therapy have not yet been demonstrated to parallel the changes in Akt
phosphorylation.15

There is also some evidence that changes in calcium homeostasis may contribute to statin-induced
muscle dysfunction and injury. The ryanodine receptors (RyR) in the sarcoplasmic reticulum are
involved in calcium release into the cytoplasm, with the usual predominant isoform in adult skeletal
muscle being RyR-1. In a biopsy-based study, increased expression of RYR-3 mRNA was found in
patients with structural muscle damage indicating aberrant expression of RyR isoforms in statin
myopathy.16 Pathogenic vatiants in the RYR1 gene have also been identified in severe statin myopathy
cases.17
11

Immune-mediated effects of statins Statin use has been associated with a variety of inflammatory
myopathies including polymyositis, dermatomyositis, and necrotising autoimmune myopathy (NAM).18
Autoantibodies to HMG CoA reductase have been detected in NAM patients. Regenerating muscle
cells express high levels of HMGCoA reductase,19 raising the possibility that the muscle regeneration
process prolongs statin-induced NAM. This may explain why CK levels remain elevated even when
the statins are stopped,19 and why treatment usually requires immunosuppressive therapy. 18
The clinical relevance of these mechanisms remains unclear.
12
References
1. Draeger A, Monastyrskaya K, Mohaupt M, Hoppeler H, Savolainen H, Allemann C, Babiychuk EB. Statin
therapy induces ultrastructural damage in skeletal muscle in patients without myalgia. J Pathol 2006;210:94102.
2. Marcoff L, Thompson PD. The role of coenzyme Q10 in statin-associated myopathy: a systematic review. J
Am Coll Cardiol 2007;49:2231-2237.
3. Coleman ML, Olson MF. Rho GTPase signalling pathways in the morphological changes associated with
apoptosis. Cell Death Differ 2002;9:493-504.
4. Phillips PS, Haas RH, Bannykh S, Hathaway S, Gray NL, Kimura BJ, Vladutiu GD, England JD; Scripps
Mercy Clinical Research Center. Statin-associated myopathy with normal creatine kinase levels. Ann Intern Med
2002;137:581-585.
5. Päivä H, Thelen KM, Van Coster R, Smet J, De Paepe B, Mattila KM, Laakso J, Lehtimäki T, von Bergmann
K, Lütjohann D, Laaksonen R.. High-dose statins and skeletal muscle metabolism in humans: a randomized,
controlled trial. Clin Pharmacol Ther 2005;78:60-68.
6. Hanai J, Cao P, Tanksale P, Imamura S, Koshimizu E, Zhao J, Kishi S, Yamashita M, Phillips PS, Sukhatme
VP, Lecker SH. The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity
1. J Clin Invest 2007;117:3940-3951.
7. Urso ML, Clarkson PM, Hittel D, Hoffman EP, Thompson PD. Changes in ubiquitin proteasome pathway
gene expression in skeletal muscle with exercise and statins. Arterioscler Thromb Vasc Biol 2005;25:25602566.
8. Gupta A, Thompson PD. The relationship of vitamin D deficiency to statin myopathy. Atherosclerosis
2011;215:23-29.
9. Mergenhagen K, Ott M, Heckman K, Rubin LM, Kellick K. Low vitamin D as a risk factor for the
development of myalgia in patients taking high-dose simvastatin: a retrospective review. Clin Ther
2014;36:770-777.
10. Mangravite LM, Engelhardt BE, Medina MW, Smith JD, Brown CD, Chasman DI, Mecham BH, Howie B,
Shim H, Naidoo D, Feng Q, Rieder MJ, Chen YD, Rotter JI, Ridker PM, Hopewell JC, Parish S, Armitage J,
Collins R, Wilke RA, Nickerson DA, Stephens M, Krauss RM. A statin-dependent QTL for GATM expression
is associated with statin-induced myopathy. Nature 2013;502:377-380.
13
11. Larsen S, Stride N, Hey-Mogensen M, Hansen CN, Bang LE, Bundgaard H, Nielsen LB, Helge JW, Dela F..
Simvastatin effects on skeletal muscle: relation to decreased mitochondrial function and glucose intolerance. J
Am Coll Cardiol 2013;61:44-53.
12. Wu JS, Buettner C, Smithline H, Ngo LH, Greenman RL. Evaluation of skeletal muscle during calf exercise
by 31-phosphorus magnetic resonance spectroscopy in patients on statin medications. Muscle Nerve 2011;43:7681.
13. Mikus CR, Boyle LJ, Borengasser SJ, Oberlin DJ, Naples SP, Fletcher J, Meers GM, Ruebel M, Laughlin
MH, Dellsperger KC, Fadel PJ, Thyfault JP. Simvastatin impairs exercise training adaptations. J Am Coll
Cardiol 2013;62:709-714.
14. Hoffman EP, Nader GA. Balancing muscle hypertrophy and atrophy. Nat Med 2004;10:584-585.
15. Mallinson JE, Constantin-Teodosiu D, Sidaway J, Westwood FR, Greenhaff PL. Blunted Akt/FOXO
signalling and activation of genes controlling atrophy and fuel use in statin myopathy. J Physiol 2009;587:219230.
16. Mohaupt MG, Karas RH, Babiychuk EB, Sanchez-Freire V, Monastyrskaya K, Iyer L, Hoppeler H, Breil F,
Draeger A. Association between statin-associated myopathy and skeletal muscle damage. CMAJ 2009;181:E11–
E18.
17. Vladutiu GD, Isackson PJ, Kaufman K, Harley JB, Cobb B, Christopher-Stine L, Wortmann RL. Genetic
risk for malignant hyperthermia in non-anesthesia-induced myopathies. Molec Genet Metab 2011;104:167-173.
18. Padala S, Thompson PD. Statins as a possible cause of inflammatory and necrotizing myopathies.
Atherosclerosis 2012;222:15-21.
19. Mammen AL, Chung T, Christopher-Stine L, Rosen P, Rosen A, Doering KR, Casciola-Rosen LA.
Autoantibodies against 3-hydroxy-3-methylglutaryl-Coenzyme A reductase in patients with statin-associated
autoimmune myopathy. Arthritis Rheum 2011;63:713-721.
14
Webtable 4. The CoQ10 story
Coenzyme Q10 (CoQ10, also known as ubiquinone), an end product of the mevalonate pathway, is a component
of the mitochondrial electron transport system. It participates in electron transport during oxidative
phosphorylation in mitochondria and is an essential coenzyme in mitochondrial respiration, facilitating the
transfer of electrons between complex I and II of the respiratory chain. 1 A reduction in CoQ10 could cause
abnormal mitochondrial respiratory function and result in mitochondrial dysfunction and myopathy. 2

Patients receiving statin therapy have been shown to have decreased serum concentrations of CoQ10
(from 16% to 49%).3 Since CoQ10 in the serum is mainly carried by low-density lipoprotein (LDL)
and some by high-density lipoprotein (HDL), very low-density lipoprotein (VLDL) and intermediatedensity lipoprotein (IDL), most of the reduction of CoQ10 by statins is caused by lowering LDL. 4

Several studies have reported a discrepancy between serum CoQ10 levels and muscle CoQ10 levels
after statin treatment.3

Statin-induced ubiquinone depletion could lead to abnormal mitochondrial function and contribute to
the aetiology of statin-induced myopathy.5 Decreased skeletal muscle CoQ10 content was accompanied
by a reduction in maximal mitochondrial oxidative phosphorylation in statin-treated patients.6

Preliminary pharmacogenetic studies suggest that COQ2 gene variants are associated with severe
inherited myopathies and statin intolerance, which manifests primarily through muscle symptoms. 7-9

Around 50% of ubiquinone is thought to be obtained through fat ingestion and the other 50% through
endogenic synthesis.10 Oral CoQ10 is slowly absorbed from the gastrointestinal tract and has a
relatively long plasma half-life of 34 h.11 Several studies have reported that oral supplementation
with CoQ10 reverses the decrease in serum CoQ10 levels by statins;12-18 However, trials on
supplementation of CoQ10 in statin-associated myopathy found conflicting results.16,19-22

There is no definitive answer whether depletion of CoQ10 in muscle mitochondria causes myopathy
and can be treated by CoQ10 supplementation.
15

Current evidence, as well as recent guidelines for the treatment of dyslipidaemia, do not support
CoQ10 supplementation in patients with statin-induced myopathy or to improve adherence to the
treatment.23-25
References
1. Parker BA, Gregory SM, Lorson L, Polk D, White CM, Thompson PD. A randomized trial of coenzyme Q10
in patients with statin myopathy: rationale and study design. J Clin Lipidol 2013;7:187–193.
2. Bitzur R, Cohen H, Kamari Y, Harats D. Intolerance to statins: mechanisms and management. Diabetes Care
2013;36 Suppl 2:S325-S330.
3. Marcoff L, Thompson PD. The role of coenzyme Q10 in statin-associated myopathy: a systematic review. J
Am Coll Cardiol 2007;49:2231-2237.
4. Laaksonen R, Jokelainen K, Laakso J, Sahi T, Harkonen M, Tikkanen MJ, Himberg JJ. The effect of
simvastatin treatment on natural antioxidants in low-density lipoproteins and high-energy phosphates and
ubiquinone in skeletal muscle. Am J Cardiol 1996;77:851-854.
5. Vladutiu GD, Simmons Z, Isackson, PJ, Tarnopolsky M, Peltier WL, Barboi AC, Sripathi N,Wortmann RL,
Phillips PS. Genetic risk factors and metabolic myopathies associated with lipid-lowering drugs. Muscle Nerve
2006;34:153-162.
6. Larsen S, Stride N, Hey-Mogensen M, Hansen CN, Bang LE, Bundgaard H, Nielsen LB, Helge JW, Dela F.
Simvastatin effects on skeletal muscle: relation to decreased mitochondrial function and glucose intolerance. J
Am Coll Cardiol 2013;61:44-53.
7. Emmanuele V, López LC, Berardo A, Naini A, Tadesse S, Wen B, D'Agostino E, Solomon M, DiMauro S,
Quinzii C, Hirano M. Heterogeneity of coenzyme Q10 deficiency: patient study and literature review. Arch
Neurol 2012;69:978-983.
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Webtable 5. Genetic variants affecting statin pharmacokinetics and statin adverse effects
Adapted from: Needham M, Mastaglia FL. Statin myotoxicity: a review of genetic susceptibility factors. Neuromuscul Disord 2014;24:4-15.
Ref
Statin
Outcomes
Genes investigated
SNP or allele associated with outcome
1,2
Pravastatin
Pharmacokinetics (plasma
SLC01B1
c.521CC genotype of SLC01B1 affects
Statin
Fluvastatin
concentration)
pharmacokinetics of pravastatin
transporter
protein
3
Simvastatin
Drug discontinuation,
CYP2D6, CYP2C8,
SLC01B1*5 allele (most significant for simvastatin)
Atorvastatin
myalgia, hyperCKaemia
CYP2C9, CYP3A4,
Pravastatin
SLC01B1
4
Simvastatin
Pharmacokinetics of
SLC01B1
c.521CC genotype of SLC01B1 affects
simvastatin acid
pharmacokinetics of simvastatin acid
5
Simvastatin
Myopathy and cholesterol
Genome wide study with rs4149056 SNP (in the C allele) in SLCO1B1.
lowering effects
>300,000 markers,
CYP3A4/SLC01B1
6
Multiple (most
Statin intolerance and
SLC01B1
rs4149056 (Val174Ala) associated with higher
simvastatin)
cholesterol lowering effect
intolerance; rs230683 (Asp130Asn) associated with
lower intolerance
7
Simvastatin
Reduction in serum
CYP3A4, CYP3A5,
1236T allele and 2677G>A/T SNP in ABCB1 gene
cholesterol and LDLs
ABCB1
had more significant reductions in serum cholesterol
and LDL
Presence of myalgia
Reduced frequency of 1236T, 2677 non-G, and
3435T haplotypes in patients with myalgia
19
Webtable 5. Genetic variants affecting statin pharmacokinetics and statin adverse effects, contd.
Statin
metabolism
genes
Ref
8
Statin
Simvastatin
Outcomes
Discontinuation of therapy
due to adverse events
(gastrointestinal >myalgia)
and efficacy of cholesterol
lowering
Genes investigated
CYP2D6
SNP or allele associated with outcome
CYP2D6*4 (G1934 mutation)
CYP2D6*3 (A2637 deletion)
CYP2D6*5 (CYP2D6 gene deletion) (associated with
‘poor metaboliser’ phenotype). Homozygosity
associated with highest incidence of intolerability and
stronger decrease in serum cholesterol
9
Atorvastatin,
simvastatin
CYP2D6 (388 SNPS
investigated)
*4 allele associated with muscle events
10
Atorvastatin
Frequency of muscle
events (myalgia, CK
elevation, rhabdomyolysis)
Elevated CK and presence
of myalgia
CYP3A
CYP3A5*3 allele (no increase in incidence of
myopathy but higher CK rises in homozygotes
experiencing myalgia)
Abbreviations: CK creatine kinase; LDL low-density lipoprotein; SNP single nucleotide polymorphism
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21