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The objective of this study was to evaluate the possible benefits of coenzyme Q and selenium supplementation administered to patients with statin-associated myopathy (SAM). Sixty eligible patients entered the pilot study. Laboratory examination (CoQ10, selenium, creatin kinase) and intensity of SAM (visual scale) were performed at baseline, after 1 month, and at the end of study at month 3. Plasma levels of CoQ10 increased from 0.81 ± 0.39 to 3.31 ± 1.72 μmol/L in the active group of patients treated by CoQ10, compared with the placebo (p = 0.001). Also, the symptoms of SAM significantly improved in the active group (p < 0.001): the intensity of muscle pain decreased from 6.7 ± 1.72 to 3.2 ± 2.1 (p < 0.01, -53.4 ± 28.2%); muscle weakness decreased from 7.0 ± 1.63 to 2.8 ± 2.34 (p < 0.01, -60 ± 24.0%); muscle cramps decreased from 5.33 ± 2.06 to 1.86 ± 2.42, p < 0.01, -65 ± 28%); tiredness decreased from the initial 6.7 ± 1.34 to 1.2 ± 1.32 (p < 0.01, -82 ± 22%). We did not observe any significant changes in the placebo group. In conclusion, supplementation of statin-treated patients with CoQ10 resulted in a decrease in the symptoms of SAM, both in absolute numbers and intensity. Additional selenium supplementation was not associated with any statistically significant decrease of SAM. However, it is not possible to draw any definite conclusions, even though this study was carried out in double-blind fashion, because it involved a small number of patients.
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ARTICLE
Coenzyme Q
10
and selenium in statin-associated myopathy treatment
Jan Fedacko, Daniel Pella, Petra Fedackova, Osmo Hänninen, Petri Tuomainen, Peter Jarcuska, Tomas Lopuchovsky, Lucia Jedlickova,
Lucia Merkovska, and Gian Paolo Littarru
Abstract: The objective of this study was to evaluate the possible benefits of coenzyme Q
10
and selenium supplementation
administered to patients with statin-associated myopathy (SAM). Sixty eligible patients entered the pilot study. Laboratory
examination (CoQ10, selenium, creatin kinase) and intensity of SAM (visual scale) were performed at baseline, after 1 month, and
at the end of study at month 3. Plasma levels of CoQ10 increased from 0.81 ± 0.39 to 3.31 ± 1.72 mol/L in the active group of
patients treated by CoQ10, compared with the placebo (p= 0.001). Also, the symptoms of SAM significantly improved in the active
group (p< 0.001): the intensity of muscle pain decreased from 6.7 ± 1.72 to 3.2 ± 2.1 (p< 0.01, –53.4 ± 28.2%); muscle weakness
decreased from 7.0 ± 1.63 to 2.8 ± 2.34 (p< 0.01, –60 ± 24.0%); muscle cramps decreased from 5.33 ± 2.06 to 1.86 ± 2.42, p< 0.01,
–65 ± 28%); tiredness decreased from the initial 6.7 ± 1.34 to 1.2 ± 1.32 (p< 0.01, –82 ± 22%). We did not observe any significant
changes in the placebo group. In conclusion, supplementation of statin-treated patients with CoQ10 resulted in a decrease in the
symptoms of SAM, both in absolute numbers and intensity. Additional selenium supplementation was not associated with any
statistically significant decrease of SAM. However, it is not possible to draw any definite conclusions, even though this study was
carried out in double-blind fashion, because it involved a small number of patients.
Key words: coenzyme Q10, selenium, statins, statins side effects, statin-associated myopathy, muscle pain, muscle cramps.
Résumé : L'objectif de cette étude était d'évaluer les bénéfices possibles d'un supplément de coenzyme Q10 (CoQ10) et de
sélénium administré a
`des patients atteints d'une myopathie associée aux statines (MAS). Soixante patients éligibles ont été
recrutés dans l'étude pilote. Des examens de laboratoire (CoQ10, sélénium, créatine kinase) et de l'intensité de la MAS (échelle
visuelle) ont été réalisés au départ, après un mois et a
`la fin de l'étude après trois mois. Les niveaux plasmatiques de CoQ10
augmentaient de 0,81 ± 0,39 a
`3,31 ± 1,72 mol/L chez le groupe patients actifs traités a
`la CoQ10 comparativement au placébo
(p= 0,001). Les symptômes de MAS s'amélioraient aussi significativement chez le groupe actif (p< 0,001). L'intensité de douleur
musculaire diminuait de 6,7 ± 1,72 a
`3,2 ± 2,1 (p< 0,01, −53,4 ± 28,2 %). La faiblesse musculaire diminuait de 7,0 ± 1,63 a
`2,8 ± 2,34
(p< 0,01, −60 ± 24,0 %), les crampes musculaires diminuaient de 5,33 ± 2,06 a
`1,86 ± 2,42 (p< 0,01, −65 ± 28 %). La fatigue diminuait
de 6,7 ± 1,34 a
`1,2 ± 1,32 (p< 0,01, −82 ± 22 %). Dans le groupe placébo, aucun changement significatif n'était observé. En
conclusion, un supplément de CoQ10 donné a
`des patients traités aux statines a résulté en une diminution des symptômes de la
MAS en valeur absolue et en intensité. Un supplément additionnel de sélénium n'était pas associé de manière significative a
`une
diminution de la MAS. Il n'est pas possible de tirer des conclusions définitives, malgré le fait que cette étude ait été réalisée a
`
double-insu, car elle impliquait un faible nombre de patients. [Traduit par la Rédaction]
Mots-clés : coenzyme Q
10
, sélénium, statines, effets secondaires des statines, myopathie associée aux statines, douleur musculaire,
crampes musculaires.
Introduction
It has been found that many of the beneficial effects of statins
cannot be explained simply by the lowering of atherogenic lipids
alone. Some pleiotropic effects not related to the lipid lowering of
statins have been shown, which are likely responsible for this
additional benefit (Davignon 2004). Besides the positive pleiotro-
pic effects of statins, there are probably also unwanted effects like
inhibition of geranyl pyrophosphate synthesis and, subsequently,
dekaprenyl-4-benzoate, which is a precursor of coenzyme Q10
(CoQ10) (Ghirlanda et al. 1993). Moreover, statins inhibit endoge-
nous synthesis of several selenoproteins (cholesterol, CoQ10, and
the aforementioned selenoproteins share the same biosynthetic
pathway, which is inhibited by statins; Fig. 1)(Moosmann and Behl
2004a). This fact, plus the role of CoQ10 in mitochondrial energy
production, has prompted the hypothesis that statin-induced
CoQ10 deficiency is involved in the pathogenesis of statin
myopathy.
CoQ10 (ubiquinone) is one of the key substances in myocardial
energetic metabolism, and is also important for cell membrane
stability, and with CoQ10 deficiency, myocytes could be prone to
damage in the form of myopathy or myositis, or even rhabdomy-
olysis (Crane 2001). Although CoQ10 depletion does not appear to
play an etiopathogenic role in statin-induced myopathy, it is
highly probable that it is a critical predisposing factor, especially
in subjects for whom other CoQ10-depleting conditions coexist.
As mentioned, selenoproteins also play a very important role as
antioxidants, and their deficiency may lead to the development of
arterial hypertension, cardiomyopathy (Keshan disease), or pe-
ripheral muscle disease (Nawrot et al. 2007;Boosalis 2008).
The aim of our study was not to demonstrate that statin associ-
ated myalgia is caused by the deficiency of CoQ10 and (or) sele-
Received 11 April 2012. Accepted 6 November 2012.
J. Fedacko, D. Pella, P. Jarcuska, T. Lopuchovsky, L. Jedlickova, and L. Merkovska. Pavol Jozef Safarik University, 1st Department of Internal Medicine, Centre of
Excellency for Atherosclerosis Research, Trieda SNP 1, 041 90 Kosice, Slovakia.
P. Fedackova. Pavol Jozef Safarik University, Department of Experimental Medicine, Kosice, Slovakia.
O. Hänninen. University of Kuopio, Department of Physiology, Kuopio, Finland.
P. Tuomainen. University of Kuopio, Department of Cardiology, Kuopio, Finland.
G.P. Littarru. Marche Polytechnic University, Department of Odontostomatological and Clinical Sciences, Ancona, Italy.
Corresponding author: Jan Fedacko (e-mail: janfedacko@hotmail.com;jan.fedacko@upjs.sk).
165
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nium, but to confirm that in such statin-treated patients
(susceptible to myopathy usually with coexisting predisposing
risk factors) supplementation with CoQ10 and (or) selenium (in
reasonable doses) may have a clinical benefit.
Up to now, no previous clinical study has been reported testing
the efficacy and safety of both CoQ10 and selenium supplementa-
tion in statin-treated patients who present mild adverse effects
(mild to moderate statin-associated myopathy). The background
of our pilot, double blind, randomized single centre prospective
3-month study using2×2factorial design (200 mg CoQ10/day
compared with 200 ug selenium/day, compared with their combi-
nation, compared with a placebo administered to statin-treated
patients with mild side effects, but not leading to treatment with-
drawal) was to evaluate possible benefits of CoQ10 and selenium
supplementation.
Materials and methods
Study population
We screened 1142 patients, treated with statins following the
current guidelines, at the outpatient cardiology clinic in Kosice,
Slovakia, during the period from January 2006 to December 2007.
Of that number, we selected 60 eligible patients reporting statin-
associated myopathy (muscle pain, muscle weakness, tiredness,
or muscle cramps) with or without increased plasma levels of
creatine kinase. The local ethical committee approved the study
protocol, and written informed consent was obtained from all
patients.
Patients were randomly divided among study subgroups: ran-
domization 1, 200 mg CoQ10 daily or the corresponding placebo;
randomization 2, 200 ug selenium daily or the corresponding
placebo. Four subgroups were studied: (i) group Q10Se, 200 mg of
CoQ10 (active) + 200 ug of selenium (active) (daily);(ii) group
Q10SePla, 200 mg CoQ10 (active) + selenium placebo (daily);
(iii) group Q10PlaSe, CoQ10 placebo + 200 g selenium (active)
(daily);and (iv) group Q10PlaSePla, CoQ10 placebo and selenium
placebo.
The inclusion criteria were as follows: statin-treated patients
with muscle pain, and (or) muscle weakness, and (or) tiredness,
and (or) muscle cramps, with or without elevated levels of crea-
tine kinase (less than 10-times over upper limit of the normal
value range) not leading to statin withdrawal.
The exclusion criteria shared by the 2 components of the study
(CoQ10 and selenium) were (i) known hypersensitivity to study
treatments; (ii) conditions that in the opinion of the investigator
would be associated with poor adherence to the protocol; (iii) any
serious noncardiac morbidity (e.g., cancer, muscle disease) or any
acute disease that may influence plasma CoQ10 or selenium lev-
els. In addition to the above mentioned criteria, patients were
excluded if their background therapy during last 3 months in-
cluded CoQ10 or selenium supplements.
Study procedures
At the beginning of the study, all patients underwent a physical
examination and a laboratory examination (plasma level of CoQ10
and selenium, lipid profile, liver enzymes, creatine kinase, glycae-
mia, BUN (blood urea nitrogen), creatinine, uric acid, sodium, and
potassium levels). Physical and laboratory examinations were re-
peated after 1 month and at the end of study. The presence and
severity of adverse effects from statin therapy was checked at all
study visits, and when needed during the duration of the study
duration. For qualification of statin-associated myopathy (muscle
pain, muscle weakness, tiredness, or muscle cramps) we used a
visual scale scoring system (10 is given to the worst pain ever, and
0 is given to no pain at all) at baseline, after 1 month, and at the
end of the study at month 3.
In each phase of the study, blood was withdrawn from the
cubital vein and coagulated in heparin. Plasma was separated and
kept at –80 °C until the analytical procedure was to be performed.
Total CoQ10 concentration was measured by the HPLC–UV
method already described (Littarru et al. 2004). Briefly 200 Lof
plasma was supplemented with 50 L of 1.4 benzoquinone solu-
tion (2 mg/mL), vortexed for 10 s, and extracted with 1 mL
n-propanol. The benzoquinone treatment fully oxidizes CoQ10
present in the sample; the propanol extract was then directly
injected into the HPLC apparatus. The mobile phase was ethanol–
methanol (65%:35%), and the flux was 1 mL/min. The analytical
column was a Supelcosil LC18 (Supelco, Milano Italy), 25 cm ×
0.46 cm, inner diameter 5 m. Detection was performed at 275
nm, which quantifies oxidized CoQ10. Interassay precision
showed a day-to-day CV% close to 2. The inductively coupled
plasma – mass spectrometry method was used to quantify the
selenium content (Dr. Bayer Laboratory, Bopserwaldstraße 26, D
70184 Stuttgart, Germany).
Study interventions
All participants were randomly distributed among the test
groups in a double-blind manner, and given either a combination
of 200 mg/day CoQ10 capsules (Bio-Quinon 100 mg B.I.D, Pharma
Nord, Vejle, Denmark) and 200 g/day of organic selenium yeast
tablets (SelenoPrecise 200 g, Pharma Nord, Vejle, Denmark), or
an equivalent amount of placebo. The study supplements were
taken in addition to regular medication. All study medication
capsules (active drug and placebo) not consumed were returned
and counted. The selenium source was a patented pharmaceutical
grade selenium yeast, SelenoPrecise
®
, with a documented batch-
to-batch stability in its composition of selenium species (Larsen
et al. 2003,2004;Bugel et al. 2008). Previous results from the
Precise pilot studies showed low levels of adverse effects and good
absorption (Larsen et al. 2004) in doses up to 300 g/day. It has
been approved as a pharmaceutical drug in Denmark by the Dan-
ish Medicines Agency for many years (appr. No. 6233603). The
CoQ10 preparations have shown good absorption and efficacy in
previous controlled trials (Folkers et al 1994;Weis et al. 1994) and
the capsules were identical to medicinal quality capsules regis-
tered for treatment of heart failure in a European Union Member
State (Myoqinon
®
, authorization No. OGYI 11494-2010).
Statistical analysis
Statistical analysis for testing the hypothesis was performed
with either a t-test or ANOVA. A non-parametric t-test or paramet-
ric t-test was used where appropriate. Where a normal (Gaussian)
Fig. 1. Cholesterol (mevalonate) synthesis pathway. PP, pyrophos-
phate; CoA, coenzyme A; HMG, hydroxyl methyl glutaryl; 4-OH,
4-hydroxy.
Acetyl CoA
HMG-CoA
HMG-CoA reductase
mevalonate
isopentanyl- PP → selenoproteins
geranyl-PP→ dekaprenyl-PP→ dekaprenyl 4-OH benzoate→ CoQ10
squalene farnesyl-PP farnesylated proteins
cholesterol geranylated proteins
166 Can. J. Physiol. Pharmacol. Vol. 91, 2013
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distribution was expected, non-parametric Mann Whitney Uor
Wilcox parametric test was used. For testing mean values of more
groups, a 1-way ANOVA was used with a post-hoc LSD test. For
testing of influence of different factors (CoQ10, Se), a 2-way
ANOVA was used. The data are expressed as the mean ± SD. The
statistical analysis of symptoms was performed with
2
test or
Fisher's exact test.
Results
During the 2 year period from January 2006 to December 2007
we screened 1142 patients treated with statins. Tables 1aand 1b
show that the study population was comparable among the
2 groups of patients. Most of them were treated with atorvastatin
457 (40%), followed by fluvastatin 342 (29.9%), rosuvastatin 229
(20.1%), and simvastatin 114 (9.98%). Of that number, we randomly
selected 60 patients with statin-associated myopathy (5.25%). Ad-
verse effects of statins were most common with the simvastatin-
treated group (n= 14; 12.2%), followed by rosuvastatin-treated
group; (n= 16; 6.98%), then the atorvastatin treated (n= 25; 5.47%),
and least for the group treated with fluvastatin (n= 5; 1.46%).
Plasma levels of CoQ10 in the CoQ10 active group increased
from baseline 0.81 ± 0.39 mol/L to 3.31 ± 1.72 mol/L at month 3
(p= 0.001) without any significant alteration in the placebo group
(Table 2). Comparison of all 4 study subgroups of patients revealed
a statistically significant increase of CoQ10 plasma levels in both
CoQ10-active group of patients. The rise in CoQ10 was more pro-
nounced in the group where the active form of selenium was
supplemented simultaneously with CoQ10, compared with the
selenium placebo group; however, it did not reach statistical sig-
nificance (p= 0.106). Selenium plasma levels in the active group of
patients increased from 70.45 ± 12.90 g/L to to 145.42 ± 22.01 g/L
(month 3) in comparison with the placebo group 73.15 ± 19.20 g/L
(comparison of both examinations of the placebo group; p= 0.001).
Creatine kinase plasma levels decribed in Table 1 were not associ-
ated with the severity of statin-associated pain, and CoQ10 had no
statistically significant impact on its change.
Statin-associated myopathy showed significant improvement
in the CoQ10 active group without any benefit in the placebo
group (Table 3). Selenium supplementation showed no beneficial
effects (Table 4). Because there was no effect from selenium sup-
plementation, we decided to present the following data for statin-
associated myopathy related to the CoQ10 active treatment group
compared with the CoQ10 placebo group only.
The intensity of muscle pain was statistically significantly
higher in the CoQ10-active treatment group of patients compared
with the placebo group at baseline (6.7 ± 1.72 vs. 5.3 ± 1.60,
p< 0.05). After 3 months of active treatment, the intensity of
muscle pain decreased to 3.2 ± 2.1 (p< 0.01), and already after
1 month of treatment the change was statistically significant (5 ±
1.8, p< 0.01). After 3 months of treatment with the placebo, mus-
cle pain intensity remained unchanged (Table 5). Absolute
decrease in muscle pain intensity after 3 months for the CoQ10-
active treatment group was significantly greater, compared with
the placebo group (–3.5 ± 1.87 vs. –0.1 ± 0.7, p< 0.01).
Table 1. Data for the study population and statin treatment showing that the study population was comparable
among the 2 groups of patients (treatment with coenzyme Q10 (CoQ10) or selenium).
Baseline End of study
Placebo CoQ10 pPlacebo CoQ10 p
a.Study population
No. of patients 26 34 NS 26 34 NS
Men/women 7/19 12/22 NS 7/19 12/22 NS
Age (years) 55.4±12.4 59.6±8.9 NS 56.3±13.1 60.1±9.7 NS
BMI (kg/m
2
) 27.2±4.1 29.0±6.1 NS 27.3 ±4.4 29.2±6.5 NS
Treatment with statins (months) 18.3±16.4 15.0±14.5 NS 21.3±16.4 18.0±14.5 NS
Plasma levels of CoQ10 (mol/L) 0.74±0.31 0.81±0.39 NS 0.68±0.31 3.31±1.72 <0.001
TCH (mmol/L) 5.15±1.1 4.8±1,0.4 NS 5.3±1.2 4.9±1.2 NS
LDL (mmol/L) 2.97±1.97 2.61±0.97 NS 3.13±1.14 2.60±0.93 NS
HDL (mmol/L) 1.53±0.36 1.43±0.31 NS 1.5±0.4 1.4±0.3 NS
TG (mmol/L) 1.41±0.67 1.62±0.73 NS 1.5±0.9 1.7±1.0 NS
Glycaemia (mmol/L) 5.59±1.67 5.55±1.56 NS 5.63±1.94 5.66±1.89 NS
CK (kat/L) 2.20±1.21 3.51±2.96 0.04 2.15±0.98 3.1±4.77 NS
AST (kat/L) 0.43±0.30 0.40±0.11 NS 0.39±0.17 0.39±0.10 NS
ALT (kat/L) 0.43±0.28 0.40±0.16 NS 0.45±0.28 0.41±0.22 NS
GMT (kat/L) 0.49±0.29 0.61±0.61 NS 0.56±0.39 0.60±0.44 NS
ALP (kat/L) 1.10±0.30 1.18±0.31 NS 1.10±0.30 1.2±0.4 NS
Urea (mmol/L) 4.87±1.31 5.01±1.27 NS 5.0±1.41 5.27±1.61 NS
Creatinine (mol/L) 85.70±13.52 86.47±16.03 NS 86.08±10.32 88.21±15.78 NS
sBP (mm Hg) 130.12±16.11 128.79±13.39 NS 130.2±11.7 128.2±12.7 NS
dBP (mm Hg) 82.04±8.88 79.12±6.69 NS 82.2±9.1 79.2±6.9 NS
b. Statin treatment
No. of patients 26 34 NS 26 34 NS
Type of statin
Atorvastatin (n)1114NS1114NS
Mean dose (mg/day) 16.7±8.7 18.1±9.1 16.7±7.4 18.1±8.8
Rosuvastatin (n)79NS79NS
Mean dose (mg/day) 12.1±5.3 10.4±3.2 12.1±4.3 10.4±2.8
Simvastatin (n)68NS68NS
Mean dose (mg/day) 26.9±7.4 25.4±6.5 26.9±8.2 25.4±6.9
Fluvastatin (n)23NS23NS
Mean dose (mg/day) 80±0 80±0 80±0 80±0
Note: BMI, body mass index; TCH, total cholesterol; LDL, LDL cholesterol; HDL, HDL cholesterol; TG, triglycerides; CK, creatin kinase;
AST, aspartate aminotransferase; ALT, alanine transaminase; GMT, glutamyl transferase; ALP, alkaline phosphatise; sBP, systolic blood
pressure; dBP, diastolic blood pressure; 1 mm Hg = 133.322 Pa.
Fedacko et al. 167
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After 3 months of treatment with the placebo, no significant
improvement in the intensity of muscle weakness was observed
(6.14 ± 1.35 vs. 5.3 ± 1.70, p= NS) (Table 6), whereas in the CoQ10
treatment group, the absolute change of intensity of muscle
weakness after 3 months was significantly higher than in placebo
group higher (–4.2 ± 2.7 vs. –0.84 ± 1.5, p< 0.01).
Muscle cramps worsened in 1 patient, remained unchanged in
3 patients, and improved in only 1 patient in the CoQ10 placebo
groups, compared to 11 improved and 2 unchanged in the CoQ10-
active form group of patients (Table 3). Changes in cramp inten-
sity are shown in Table 7, and the absolute change of intensity at
the end of the trial was statistically higher in the CoQ10-active
treatment group compared with the placebo group (–3.47 ± 2.9 vs.
–0.43 ± 1.8, p< 0.01).
Statin-associated fatigue disappeared in all patients (n= 10) in
the CoQ10-active group, while in the CoQ10 placebo group we
observed worsening in 2 patients, 6 patients remained un-
changed, and improvement was found in only 4 patients (Table 3).
In the CoQ10-active treatment group, tiredness decreased from
the initial 6.7 ± 1.34 to 1.2 ± 1.32 (p< 0.01) compared with no
significant changes in the placebo group (Table 8). Changes in the
overall intensity of tiredness in the CoQ10 active group were sta-
tistically significant compared with the placebo group (–5.5 ± 3.7
vs. –2 ± 2.8, p< 0.01).
Discussion
The most frequent adverse effects associated with statins are
asymptomatic increases in liver transaminases and myopathy
(Law and Rudnicka 2006). Statin-associated myopathy represents a
broad clinical spectrum of disorders (Thompson et al. 2003). The
mechanisms of statin-associated myopathy are still unknown, but
possibly include decreased sarcolemmal cholesterol, reduction in
small guanosine triphosphate-binding proteins, increased intra-
cellular lipid production and lipid myopathy, increased myocel-
lular phytosterols, and last but not least, possible decrease of
(intramitochondrial) CoQ10 (Corsini 2005). A hypothesis pub-
lished by Moosmann and Behl (2004a) identified a possible role of
selenium deficiency and its association with possible adverse
effects of statins, namely myopathy and polyneuropathy. They
noted that the pattern of side effects associated with statins
resembles the pathology of selenium deficiency, and postu-
lated that the mechanism lay in a well-established biochemical
pathway the isopentylation of selenocysteine-tRNA. A nega-
tive effect of statins on selenoprotein synthesis might explain
many of the enigmatic effects and side effects of statins.
In a systematic review of the role of CoQ10 in statin-associated
myopathy, the authors concluded that up to now there is insuffi-
cient evidence to prove the etiologic role of CoQ10 deficiency in
statin-associated myopathy and large, well-designed clinical trials
are required to address this issue. The epidemiology of statin-
associated myopathy is poorly described and mainly focused on
rhabdomyolysis. The occurence of both myopathy and rhabdomy-
olysis in clinical trials is rare; the incidence of severe myopathy is
Table 2. Plasma levels of coenzyme Q10 (CoQ10) and selenium (Se).
a. Coenzyme Q10
CoQ10 placebo
(mol/L)
CoQ10 active
(mol/L) p
Se placebo
(g/L)
Se active
(g/L) p
CoQ10 baseline 0.74±0.31 0.81±0.39 0.503 0.75±0.36 0.81±0.35 0.559
CoQ10 month 1 0.86±0.80 3.16±1.78 <0.001 1.98±1,63 2.44±2.05 0.365
CoQ10 month 3 0.68±0.31 3.31±1.72 <0.001 1.86±1.60 2.35±2.05 0.344
b. Selenium
Se placebo
(g/L)
Se active
(g/L) p
CoQ10 placebo
(mol/L)
CoQ10 active
(mol/L) p
Se baseline 68.00±9.70 70.45±12.90 0.421 70.20±9.48 68.37±12.80 0.551
Se month 1 71.08±15.79 129.84±31.81 <0.001 101.79±43.11 98.37±35.09 0.747
Se month 3 73.15±19.20 145.42±22.01 <0.001 105.24±46.98 108.62±38.06 0.778
Table 3. Symptoms in patients treated with coenzyme Q10 (CoQ10)
active compared with CoQ10 placebo.
Symptom
No. of
patients
No
change Decrease Increase p
Muscle pain
CoQ10 active 22 5 17 0 <0.001
CoQ10 placebo 18 15 1 2
Muscle weakness
CoQ10 active 13 1 12 0 0.011
CoQ10 placebo 7 4 2 1
Tiredness
CoQ10 active 10 0 10 0 0.005
CoQ10 placebo 12 6 4 2
Cramps
CoQ10 active 13 2 11 0 0.024
CoQ10 placebo 5 3 1 1
Table 4. Symptoms of statin-associated myopathy in patients treated
with coenzyme Q10 (CoQ10) active/CoQ10 placebo + selenium (Se) ac-
tive/selenium placebo.
CoQ10 Selenium
No. of
patients
No
change Decrease Increase p
Muscle pain
CoQ10 active Se active 10 1 9 0 0.194
CoQ10 active Se placebo 12 4 8 0
CoQ10 placebo Se active 7 5 1 1 0.392
CoQ10 placebo Se placebo 11 10 0 1
Muscle weakness
CoQ10 active Se active 6 0 6 0 0.335
CoQ10 active Se placebo 7 1 6 0
CoQ10 placebo Se active 2 2 0 0 0.449
CoQ10 placebo Se placebo 6 3 2 1
Tiredness
CoQ10 active Se active 4 0 4 0 0.325
CoQ10 active Se placebo 6 0 6 0
CoQ10 placebo Se active 6 4 2 0 0.263
CoQ10 placebo Se placebo 6 2 2 2
Cramps
CoQ10 active Se active 6 2 4 0 0.097
CoQ10 active Se placebo 7 0 7 0
CoQ10 placebo Se active 1 0 1 0 0.082
CoQ10 placebo Se placebo 4 3 0 1
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0.1%–0.5%, while the incidence of rhabdomyolysis is 0.02%–0.04%
(Rosenson 2004). Clinical trial protocols, however, often exclude
patients more prone to myopathy, such as those with a history of
muscle pain with another lipid-lowering therapy, history of ele-
vated creatine kinase activity, hypothyroidism, elderly patients,
and others. Moreover, mild muscular symptoms are often over-
looked by doctors (a similar situation found during screening of
the patients for our study), and their frequency is therefore prob-
ably underestimated. Muscular symptoms in the PRIMO survey
were reported by 832 of 7924 (10.5%) hyperlipidemic patients re-
ceiving high-dosage statin therapy as their usual care, with a me-
dian time of onset of 1 month following initiation of statin
therapy (the lowest rate of muscular symptoms (5.1%) was ob-
served with fluvastatin treatment, the highest rate (18.2%) with
simvastatin treatment; Bruckert et al. 2005).
We have confirmed these data, but in this double-blind, ran-
domised study, no positive effects were observed from supple-
mentation with selenium. Interestingly, there is probably some
association between selenium and CoQ10 deficiency. In our study
we observed a higher increase of CoQ10 levels when supple-
mented together with selenium. It is not easy to explain these
findings, but in a small experimental study, the effect of long-
term (18 months) selenium deficiency on the levels of liver CoQ10
was studied in rats. Levels of CoQ10 in the liver of selenium-
deficient rats were 40% and 67% of the levels in selenium-adequate
animals, respectively. The results are similar to the findings of a
study using a shorter feeding period (Vadhanavikit and Ganther
1994). Reduction of ubiquinone by thioredoxin reductase is
selenium dependent and probably connects the antioxidant
ubiquinol to the essential trace element selenium. A combined
therapeutic approach with selenium and CoQ10 could constitute
an exciting area for future research, because such a combination
could probably be useful for the treatment of statin-associated
myopathy. In contrast, selenium supplementation in atheroscle-
rosis seems to be contraindicated, owing to possible atherogenic
influences (Nordman et al 2003;Moosmann and Behl 2004b).
At the present time we may only speculate that deficiency of
CoQ10 could be worsened by coincidental deficiency of selenium.
There is not enough evidence to support the general recommen-
dation of simultaneous administration of CoQ10 and selenium to
Table 5. Muscle pain intensity changes in coenzyme Q10 (CoQ10) active (n= 22) compared with the
CoQ10 placebo group of patients (n= 18).
Placebo group muscle pain CoQ10 treatment group muscle pain
Baseline M1 M3 Baseline M1 M3 p
Baseline 5.3±1.60 6.7±1.72 <0.05
M1 NS* 5.05±1.6 NS*** <0.01* 5±1.8 <0.01*** NS
M3 NS** 5.2±1.5 <0.01** 3.2±2.1 <0.001
Note: M1, month 1 of test period; M3, month 3 (end) of test period; *, comparison between baseline and M1;
**, comparison between baseline and M3; ***, comparison between M1 and M3; NS, not statistically significant.
Table 6. Muscle weakness intensity changes in the coenzyme Q10 (CoQ10) active treatment group
(n= 13) compared with the placebo group of patients (n= 7).
Placebo group muscle weakness CoQ10 group muscle weakness
Baseline M1 M3 Baseline M1 M3 p
Baseline 6.14±1.35 7±1.63 <0.083
M1 NS* 5.42±1.51 NS*** <0.01* 5.4±2.06 <0.01*** NS
M3 NS** 5.3±1.7 <0.01** 2.8±2.34 <0.001
Note: M1, month 1 of test period; M3, month 3 (end) of test period; *, comparison between baseline and M1;
**, comparison between baseline M3; ***, comparison between M1 and M3; NS, not statistically significant.
Table 7. Muscle cramps intensity changes in the coenzyme Q10 (CoQ10) active treatment group
(n= 13) compared with the placebo group of patients (n= 5).
Placebo group muscle cramps CoQ10 group muscle cramps
Baseline M1 M3 Baseline M1 M3 p
Baseline 5.43±1.4 5.33±2.06 NS
M1 NS* 5.43±1.4 NS*** <0.01* 2.66±2.16 <0.01*** <0.01
M3 NS** 5.86±1.57 <0.01** 1.86±2.42 <0.001
Note: M1, month 1 of test period; M3, month 3 (end) of test period; *, comparison between baseline and M1;
**, comparison between baseline and M3; ***, comparison between M1 and M3; NS, not statistically significant.
Table 8. Tiredness intensity intensity changes in conenzyme Q10 (CoQ10) active group (n= 10)
compared with the placebo group of patients (n= 12).
Placebo group tiredness CoQ10 group tiredness
Baseline M1 M3 Baseline M1 M3 p
Baseline 6.5±1.52 6.7±1.34 NS
M1 NS* 5±2.16 NS*** <0.01* 3.4±2.07 <0.01*** <0.01
M3 NS** 4.5±2.37 <0.01** 1.2±1.32 <0.001
Note: M1, month 1 of test period; M3, month 3 (end) of test period; *, comparison between baseline and M1;
**, comparison between baseline and M3; ***, comparison between M1 and M3; NS, not statistically significant.
Fedacko et al. 169
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every statin-treated patient with adverse effects from such ther-
apy. Although carried out in a randomized and double-blind fash-
ion, the present study involved a relatively small number of
patients, and the data must be considered in light of this.
Conclusions
Our results show that supplementation of statin-treated pa-
tients with CoQ10 diminishes the symptoms of statin-associated
myopathy. In our study, supplementation with selenium was not
associated with clinically significant benefits. In conclusion, our
double-blind randomized study showed that CoQ10 supplementa-
tion (200 mg daily) to statin-treated patients presenting with mild
to moderate statin-associated myopathy may lead not only to sta-
tistically significant increase of plasma CoQ10 levels, but is asso-
ciated with a significant reduction of statin side effects, even
without interruption of statin therapy. Thus, CoQ10 supplemen-
tation may decrease the need to withdraw these drugs if adverse
effects appear. This may be of great importance, owing to fact that
statins represent the basic treatment for secondary prevention of
atherosclerosis, and their prescription rate during recent decades
has increased dramatically. Although there is a positive outcome
from this pilot study, it is not possible to draw any definite con-
clusions, despite the study being carried out in double-blind fash-
ion, because it involved a small number of patients. Thus, further
research in this field is needed.
Conflict of interest
The authors declare that there are no conflicts of interest asso-
ciated with this study.
Acknowledgements
This investigator-initiated trial was supported by research grant
VEGA 1/2317/2005 from the Slovak Ministry of Education. The au-
thors gratefully acknowledge Pharma Nord for providing the stud-
ied medications and support for laboratory analyses, and Labor
Dr. Bayer, Postfach, Stuttgart for selenium analyses.
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... In 2 [18,19] of 5 [14,[18][19][20][21] including studies, CoQ10 supplement was statistically significant for muscle pain. In the 3 remaining studies [14,20,21], CoQ10 had no significant impact on muscle pain compared with the controls (SMD − 0.43; 95% CI, −1.21 to 0.35; P = 0.283) (shown in Fig. 4). ...
... In 2 [18,19] of 5 [14,[18][19][20][21] including studies, CoQ10 supplement was statistically significant for muscle pain. In the 3 remaining studies [14,20,21], CoQ10 had no significant impact on muscle pain compared with the controls (SMD − 0.43; 95% CI, −1.21 to 0.35; P = 0.283) (shown in Fig. 4). ...
... For plasma CK activity, 6 studies were included [11,14,19,[21][22][23]. Except for Fedacko et al. [19], they all proposed that the addition of CoQ10 could not reduce the CK concentration. ...
Article
Background: Statins can trigger a series of muscle-related adverse events, commonly referred to collectively as statin-induced myopathy. Although coenzyme Q10 (CoQ10) is widely used as a supplement in statin therapy, there is little clinical evidence for this practice. Aim: This study aims to assess the effect of adding CoQ10 on statin-induced myopathy. Methods: Searching the PubMed, EMBASE, and the Cochrane Library databases to identify randomized controlled trials investigating the effect of adding CoQ10 on creatine kinase (CK) activity and degree of muscle pain as two indicators of statin-induced myopathy. Two reviewers will independently extract data from the included articles. Results: Study screening included a randomized controlled trial of oral CoQ10 versus placebo in patients with statin-induced myopathy. We had a total of 8 studies in which 472 patients were treated with statins: 6 studies with 281 participants assessed the impact of adding CoQ10 on CK activity, and 4 studies with 220 participants were included to evaluate the impacts of CoQ10 addition on muscle pain. Compared with the controls, CK activity increased after adding CoQ10, but the change was not significant (mean difference, 3.29 U/L; 95% CI, -29.58 to 36.17 U/L; P=0.84). Similarly, the meta-analysis did not benefitCoQ10 over placebo in improving muscle pain (standardized mean difference, -0.59; 95% CI, -1.54 to 0.36; P=0.22). Conclusion: The outcomes of this meta-analysis of existing randomized controlled trials showed that supplementation with CoQ10 did not have any significant benefit in improving statin-induced myopathy.
... 68,69 In addition, secondary CoQ10 deficiency may occur. In this regard, the inhibitory effect of statins on the mevalonate pathway ( Figure 1) may reduce CoQ10 levels by 16-54% 64 and cause mitochondrial dysfunction, revealed by inhibition of mitochondrial ETC complexes, 70,71 disruption of mitochondrial membrane potential, decrease in mitochondrial DNA (mtDNA) copy number, interference with oxidative phosphorylation, mitochondrial swelling, and release of cytochrome c. 71,72 However, decrease in plasma CoQ10 level is mostly due to the reduction of circulating lipoproteins, because around 74% of CoQ10 is carried in the blood by apo B-containing lipoproteins. 64 Accordingly, no significant difference in CoQ10 to total cholesterol ratio was found before and after statin treatment. ...
... In this regard, the inhibitory effect of statins on the mevalonate pathway ( Figure 1) may reduce CoQ10 levels by 16-54% 64 and cause mitochondrial dysfunction, revealed by inhibition of mitochondrial ETC complexes, 70,71 disruption of mitochondrial membrane potential, decrease in mitochondrial DNA (mtDNA) copy number, interference with oxidative phosphorylation, mitochondrial swelling, and release of cytochrome c. 71,72 However, decrease in plasma CoQ10 level is mostly due to the reduction of circulating lipoproteins, because around 74% of CoQ10 is carried in the blood by apo B-containing lipoproteins. 64 Accordingly, no significant difference in CoQ10 to total cholesterol ratio was found before and after statin treatment. Scarce and contradictory data are available about the impact of statin treatment on skeletal muscle CoQ10 concentration. ...
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Statins are a family of drugs that are used for treating hyperlipidaemia with a recognized capacity to prevent cardiovascular disease events. They inhibit β‐hydroxy β‐methylglutaryl‐coenzyme A reductase, i.e. the rate‐limiting enzyme in mevalonate pathway, reduce endogenous cholesterol synthesis, and increase low‐density lipoprotein clearance by promoting low‐density lipoprotein receptor expression mainly in the hepatocytes. Statins have pleiotropic effects including stabilization of atherosclerotic plaques, immunomodulation, anti‐inflammatory properties, improvement of endothelial function, antioxidant, and anti‐thrombotic action. Despite all beneficial effects, statins may elicit adverse reactions such as myopathy. Studies have shown that mitochondria play an important role in statin‐induced myopathies. In this review, we aim to report the mechanisms of action of statins on mitochondrial function. Results have shown that statins have several effects on mitochondria including reduction of coenzyme Q10 level, inhibition of respiratory chain complexes, induction of mitochondrial apoptosis, dysregulation of Ca²⁺ metabolism, and carnitine palmitoyltransferase‐2 expression. The use of statins has been associated with the onset of additional pathological conditions like diabetes and dementia as a result of interference with mitochondrial pathways by various mechanisms, such as reduction in mitochondrial oxidative phosphorylation, increase in oxidative stress, decrease in uncoupling protein 3 concentration, and interference in amyloid‐β metabolism. Overall, data reported in this review suggest that statins may have major effects on mitochondrial function, and some of their adverse effects might be mediated through mitochondrial pathways.
... Considering that CoQ and cholesterol share part of their biosynthetic pathway, we asked whether inhibition of the mitochondrial prenyltransferase coq2 could affect the cellular cholesterol content [28,29]. By using both gas chromatography mass spectrometry (GC-MS) (Fig. 3A) and high performance liquid chromatography (HPLC) analysis (Fig. 3B), we detected a significant increase in cholesterol content in cells treated with 4-NB, which was reduced by a short treatment with cyclodextrins (CDs) [30]. ...
... Considering that CoQ and cholesterol share part of their biosynthetic pathway, it is reasonable that inhibition of the mitochondrial prenyltransferase coq2 could also affect the cellular cholesterol content [28,29]. We demonstrate here that the inhibition of coq2 significantly increased the cholesterol level in comparison with controls (Fig. 4B). ...
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... Fedacko et al found that the symptoms of SAM improved significantly in the active group, with the intensity of muscle pain decreasing (-53.4± 28.2 percent), muscle weakness decreasing (-60± 24.0 percent), muscle cramps decreasing (-65 ±28 percent) and tiredness decreasing from the initial (-82± 22 percent) and plasma levels of CoQ10 increasing in the active group (Fedacko et al, 2013). Moreover, a strong negative correlation between muscle pain, weakness and fatigue, and serum CoQ10 level among patients, who received CoQ10 supplements after 3 months (P-value ≤ 0.01). ...
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... Importantly, ubiquinone supplementation rescues lost mitochondrial volume induced by statins during treatment of cardiovascular disease (Vaughan et al., 2013). Several placebo-controlled trials of coenzyme Q10 supplementation reported a significant reduction in the myalgia on long term statin therapy (Fedacko et al., 2013;Pourmoghaddas et al., 2014), which may be due to the differences in supplement composition and methods of pain assessment (Bogsrud et al., 2013). ...
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... Only two clinical trials have examined the impact of CoQ10 supplementation against fatigue in statin-associated myopathy patients. Fedacko et al. highlighted a marked improvement of VAS in patients with statin-associated myopathy treated with 200 mg/day CoQ10 for 3 months compared to the control [50]. Another study conducted on 50 patients who followed a discontinuous therapy with statin and supplemented with 240 mg/day CoQ10 for 22 months, showed that the incidence of fatigue decreased from 84%, observed at the beginning of the treatment, to 16% at the end of the study [45]. ...
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... Well-designed RCTs demonstrate CoQ to be safe and effective in treating a number of human diseases such as primary CoQ deficiency syndrome, a rare mitochondrial disease, with a highest possible dose of 1200 mg/d [92,104]. Small clinical trials of statin and CoQ coadministration provided some early evidence of reducing statin-associated myopathy [105,106]. A 2018 meta-analysis has since identified 12 RCTs involving 575 patients [107]. ...
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Aim: To determine the association of coenzyme Q10 (CoQ10) use with the resolution of statin-associated muscle symptoms (SAMS). Patients & methods: Retrospective analysis of a large, multi-center survey study of SAMS (total n = 511; n = 64 CoQ10 users). Univariate and multivariate logistic regression models assessed the association between CoQ10 use and the resolution of SAMS. Results: The frequency of SAMS resolution was similar between CoQ10 users and non-users (25% vs 31%, respectively; unadjusted odds ratio [OR]: 0.75 [95% CI: 0.41–1.38]; p = 0.357). Similarly, CoQ10 use was not significantly associated with the resolution of SAMS in multivariable models adjusted for SAMS risk factors (OR: 0.84 [95% CI: 0.45–1.55]; p = 0.568) or adjusted for significant differences among CoQ10 users and non-users (OR: 0.82 [95% CI: 0.45–1.51]; p = 0.522). Conclusion: CoQ10 was not significantly associated with the resolution of SAMS.
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Coenzyme Q is well defined as a crucial component of the oxidative phosphorylation process in mitochondria which converts the energy in carbohydrates and fatty acids into ATP to drive cellular machinery and synthesis. New roles for coenzyme Q in other cellular functions are only becoming recognized. The new aspects have developed from the recognition that coenzyme Q can undergo oxidation/reduction reactions in other cell membranes such as lysosomes. Golgi or plasma membranes. In mitochondria and lysosomes, coenzyme Q undergoes reduction/oxidation cycles during which it transfers protons across the membrane to form a proton gradient. The presence of high concentrations of quinol in all membranes provides a basis for antioxidant action either by direct reaction with radicals or by regeneration of tocopherol and ascorbate. Evidence for a function in redox control of cell signaling and gene expression is developing from studies on coenzyme Q stimulation of cell growth, inhibition of apoptosis, control of thiol groups, formation of hydrogen peroxide and control of membrane channels. Deficiency of coenzyme Q has been described based on failure of biosynthesis caused by gene mutation, inhibition of biosynthesis by HMG coA reductase inhibitors (statins) or for unknown reasons in ageing and cancer. Correction of deficiency requires supplementation with higher levels of coenzyme Q than are available in the diet.
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A batch of 77Se-labelled and enriched yeast was characterised with regard to isotopic composition and content of selenium species for later use in a human absorption study based on the method of enriched stable isotopes. The abundance of the six stable selenium isotopes was determined by ICP-MS equipped with a dynamic reaction cell (DRC). The results showed that the 77Se isotope was enriched to 98.5 atom-%, whereas the remaining selenium was present as the other five isotopes at low abundance. The low-molecular 77Se containing species, which were biosynthesised by the yeast during fermentation using the enriched 77Se-selenite as substrate, were released by enzymatic hydrolysis using (I), a β-glucosidase followed by a protease mixture, and (II), a commercial protease preparation. For selenium speciation the chromatographic selectivity of the cation exchange HPLC system was adjusted to the separation of over 30 selenium species occurring in the hydrolysates by applying gradient elution using pyridinium formate as mobile phase. The quantitative results obtained by detection with ICP-DRC-MS of 77Se and 80Se showed that both enzymatic sample preparation systems released 90–95% of the yeast's selenium content. The total area of the cation exchange chromatograms, however, amounted to 64% of the total selenium content in the yeast, which was 1390 µg g−1. In the enzymatic extracts selenomethionine (SeMet) constituted 82% of all separated and quantified selenium species, which was equivalent to 53% of the total selenium content in the yeast. Oxidation of SeMet to selenomethionine-Se-oxide (SeOMet) occurred during sample preparation. The degree of formation of SeOMet was large and variable when using enzyme system I, but low when using enzyme II.
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Cited By (since 1996): 40, Export Date: 21 September 2011, Source: Scopus
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Twenty-one healthy subjects received oral Coenzyme Q10 supplementation in soft capsules of 30 mg t.i.d. for 9 months, followed by a withdrawal period of 3 months. Blood samples were taken before start of supplementation, after 3 and 9 months of supplementation, and finally 3 months after withdrawal. Average blood coenzyme Q10 concentration increased from about 1 mg/l before supplementation to about 2 mg/l after 3 and 9 months of supplementation, and returned to the pretreatment level after withdrawal. The rise of coenzyme Q10 concentration was statistically significant (P < 0.001, t-test).
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Inhibitors of HMG-CoA reductase are new safe and effective cholesterol-lowering agents. Elevation of alanine-amino transferase (ALT) and aspartate-amino transferase (AST) has been described in a few cases and a myopathy with elevation of creatinine kinase (CK) has been reported rarely. The inhibition of HMG-CoA reductase affects also the biosynthesis of ubiquinone (CoQ10). We studied two groups of five healthy volunteers treated with 20 mg/day of pravastatin (Squibb, Italy) or simvastatin (MSD) for a month. Then we treated 30 hypercholesterolemic patients in a double-blind controlled study with pravastatin, simvastatin (20 mg/day), or placebo for 3 months. At the beginning, and 3 months thereafter we measured plasma total cholesterol, CoQ10, ALT, AST, CK, and other parameters (urea, creatinine, uric acid, total bilirubin, gamma GT, total protein). Significant changes in the healthy volunteer group were detected for total cholesterol and CoQ10 levels, which underwent about a 40% reduction after the treatment. The same extent of reduction, compared with placebo was measured in hypercholesterolemic patients treated with pravastatin or simvastatin. Our data show that the treatment with HMG-CoA reductase inhibitors lowers both total cholesterol and CoQ10 plasma levels in normal volunteers and in hypercholesterolemic patients. CoQ10 is essential for the production of energy and also has antioxidative properties. A diminution of CoQ10 availability may be the cause of membrane alteration with consequent cellular damage.