Statin induced myopathy
BMJ 2008; 337 doi: https://doi.org/10.1136/bmj.a2286 (Published 06 November 2008) Cite this as: BMJ 2008;337:a2286
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I have grave reservations about the quality and purpose of trials
attempting to show that "miracle drug" statins are blameless, and that
problems are due to something pre-existing in the damaged patient. Since
statins are recommended for virtually universal prescription, their
potential for causing permanent and distressing harm should receive
greater recognition.Trials and studies should involve more sophisticated
measurements and dosage variations than is often apparent. The most recent
MHRA listings of Yellow card reports of damage occurring from Lipitor and
simvastatin, continue to rise, deaths reported due to them are now around
60 each, and the myriad other problems similarly increase.
I understand that the WHO has noted a rise in a type of ALS in statin
users, and I know one former medical professional affected by this.
Studies are appearing showing how statins inhibit the ability of
muscles to regenerate, so wastage is prevented from reversal.
The notion that carnitine palmitoyl transferase deficiency could be a
cause flies in the face of the fact that thousands of those who suffer
muscle pain and wastage from statin use need L Carnitine supplementation,
while being without any symptoms previously. The statin has, often
permanently, reduced its production, and CPT cannot be made without the
basic substance.
Trials using Coenzyme Q10 seldom show measured levels of this
substance in the body, such a measurement is possible, and those using it
are careful to quote the levels before and with Q10 administration and the
dosage necessary to achieve them. Such trials are necessarily fairly small
due to lack of financial backing from those whose sales might be affected
by more simple treatments, but Dr Peter Langsjoen in Tyler, Texas, has
suitable apparatus and facilities and informs his patients of the actual
values in his daily cardiology practice. So often an arbitrary dose of Q10
is given, usually comparatively small, and the source of it is not given,
there are good quality sources, and indifferent ones which are not as pure
and potent.
I suggest that the reason for some folk "tolerating" statins while
others are harmed may lie in the individual's natural Q10 or carnitine
levels, those with abundant supplies being able to tolerate some
reduction, while othwrs, especially the elderly, soon feel the effects.
The trials are usually of too short a duration, problems occur sometimes
very quickly, and sometimes after years.
In any event, has not the cholesterol value recently been shown to be
less important as a predictor of CVD than such things as inflammation and
its causes, reduced by only small statim doses and avoiding the worst side
effects.
Competing interests:
Statin Damaged patient
Competing interests: No competing interests
Sathasivam and Lecky discuss the possible role coenzyme Q10 (CoQ10)
depletion as a patho-physiological mechanism of statin-induced
myopathy(1). They also indicated that one trial has shown a positive
effect of CoQ10 supplementation on statin tolerance (2), although this
trial was not placebo-controlled and patients were not on a standardised
dose or type of statin. In our study (3), 44 patients with prior statin-
induced myalgia were randomised to treatment with CoQ10 or placebo for 12
weeks in combination with upward dose titration of simvastatin at 10
mg/day, doubling every 4 weeks if tolerated to a maximum dose of 40 mg/day
simvastatin. We observed no difference between combined therapy and statin
alone in the myalgia score; in the number of patients who achieved and
tolerated 40 mg/day simvastatin or in the number remaining on any
simvastatin dose. An important explanatory variable, that may be
pertinent to responsiveness to CoQ10 in this group of patients, may be
genetic susceptibility to muscle disorders and underlying metabolic
myopathies.
Sathasivam and Lecky1 reference the study of Vladutiu et al.
who observed a 4-fold increase in mutations which cause three metabolic
myopathies: carnitine palmitoyltransferase II deficiency, McArdle’s
disease and myoadenylate deaminase deficiency, in individuals with
primarily statin-induced myopathies (4). However, they did not reference
Oh et al, who reported a 2.33 – 2.58 fold increase in the relative risk of
statin intolerance associated with polymorphisms in the CoQ2 gene (5). As
individuals with mutations for underlying metabolic myopathies may
represent a subgroup of the statin-treated population for whom CoQ10
supplementation may be more likely to confer a clinical benefit this
warrants further investigation.
1. Sathasivam S, Lecky B. Statin induced myopathy. BMJ. 2008; 337:
1159-62.
2. Caso G, Kelly P, McNurlan MA, Lawson WE. Effect of coenzyme q10
on myopathic symptoms in patients treated with statins. Am J Cardiol.
2007;99(10):1409-12.
3. Young JM, Florkowski CM, Molyneux SL, et al. Effect of coenzyme
Q(10) supplementation on simvastatin-induced myalgia. Am J Cardiol.
2007;100(9):1400-3.
4. Vladutiu GD, Simmons Z, Isackson PJ, et al. Genetic risk factors
associated with lipid-lowering drug-induced myopathies. Muscle Nerve.
2006;34(2):153-62.
5. Oh J, Ban MR, Miskie BA, Pollex RL, Hegele RA. Genetic
determinants of statin intolerance. Lipids Health Dis. 2007;6:7.
Competing interests:
None declared
Competing interests: No competing interests
The, "Six cases ..[of].. funduscopically confirmed irreversible
anterior ischaemic optic neuropathy", reported in the BMJ a few years ago
(1) are of additional concern for patients taking statins for it is so
commonly subscribed and the mechanisms of actions appear to be similar:
i.e a fall in pH and decline in Daniel Atkinson energy charge induced by
an energy supply/demand mismatch.
Thus the graded responses to a progressive increase in reductive
stress would seem to be, 1: upregulation of oxidative phoshorylation by
an increase in protonmotive force, 2: preservation of ATP stores by down
regulation of ATP-dependent reactions, and 3: possibly the local increase
in availability of nutrients derived from autophagy, apoptosis and even
necrosis in extremis. These actions would presumably be independent of
any effect upon cytochrome P450 (2). Thus the short term gains from
statins might always come with longer term risks of cellular dysfunction,
apoptosis and even necrosis.
"Proton pump inhibitors seem not to act specifically on potassium-
hydrogen ATPases in gastric mucosa. Omeprazole inhibits the secretion of
cerebrospinal fluid in rats by decreasing ATPase activity [i.e. ATP-
dependent reactions]. Reduction in intracellular pH by omeprazole induced
blockade of potassium-hydrogen ATPase results in decreased renal function,
and renal failure as well as interstitial nephritis have been observed
with omeprazole. Potassium-hydrogen ATPase is present in vascular smooth
muscle cells, and reduction in intracellular pH causes vasoconstriction.
Chest pain or angina and raised blood pressure are mentioned as adverse
reactions in the United States data sheet on omeprazole. Anterior
ischaemic optic neuropathy may, therefore, be caused by proton pump
inhibitors blocking potassium-hydrogen ATPase, possibly inducing
vasoconstriction and ischaemia in end arteries such as the retinal
artery". The same might pathophysiological process might also cause
microscopic colitis (3).
Might, therefore, the risks of anterior ischaemic optic neuropathy,
myopathy and organ dysfunction and even damage be increased by taking
omeprazole in patients taking statins?
1. P S Schönhöfer, B Werner, and U Tröger. Drug points: Ocular damage
associated with proton pump inhibitors. BMJ 1997; 314: 1805.
2. Robert J. Herman. Drug interactions and the statins. CMAJ •
November 16, 1999; 161 (10)
3. Richard G Fiddian-Green. Re: Microscopic colitis: the tip of an
omeprazole iceberg? (26 November 2004)
www.cmaj.ca/cgi/eletters/171/11/1326
Competing interests:
None declared
Competing interests: No competing interests
"Acidosis-mediated injury to cardiac myocytes during surgery may lead
to progressive heart failure... Apoptosis was detected in atrial and
ventricular biopsy samples obtained from three porcine subjects maintained
on cardiopulmonary bypass and undergoing 110 minutes of aortic cross-clamp
and 10 minutes of reperfusion, in which the cardiac pH was 6.36, 7.14, and
7.48. The apoptosis level detected in postacidotic reperfused cardiac
tissue was pH dependent and approximately threefold greater than the
precross-clamp levels" (1).
Lovastatin-induced apoptosis in HL-60 cells is also associated with
intracellular acidification (2). The decrease in pHi is dose-dependent and
the apoptosis appears to be due to activation of the pH- dependent
endonuclease. Lovastatin-induced intracellular acidification is not due to
a complete inhibition of the Na+/H+ antiporter for is is able to respond
to stimulation of the Na+/H+ antiporter with a marked increase in pHi.
Might the fall in pH induced by lovostatin be due to an impairment of
oxidative phosphorylation, by far the largest and most dynamic buffer in
the body due to the incorporation of protons in ATP resynthesis (3).
Furthermore, given that triacylglycerols liberated from adipose tissue
generate for more ATP than either muscle or liver glycogen, might the
beta oxidation of fatty acids be the most important part of this mechanism
of buffering metabolic acids? Might, therefore, statins induce a tissue
acidosis, and apoptosis, by interfering with fatty acid metabolism?
Epidemiologic data has revealed a protective effect of a
Mediterranean diet against atherosclerosis in humans. The
atheroprotection has been attributed to the elevated consumption of olive
oil, an oil poor in saturated fatty acids (SFA) and highly enriched in
monounsaturated fatty acids (MUFA). "Based on human feeding studies, the
American Heart Association and the US Food and Drug Administration have
advocated for the consumption of MUFA as a more healthy replacement for
SFA"(4).
Lipoproteins have a hydrophobic core surrounded by a hydrophilic
coating. The core in low density lipoproteins (LDL) includes some 1500
esterified cholesterol molecules. These include the unsaturated fatty acid
linoleate, unsaturated fatty acids having a lower melting point than
saturated fatty acids and being less likely to solidify than saturated
fatty acids. LDL enter the cytoplasm by endocytosis where it releases its
amino acids and cholesteryl esters some of which liberate the cholesterol
and some of which is reesterified. The reesterified cholesterol contains
the unsaturated fatty acids oleate and palmitoleate. Fatty acids are
carried into the mitochondrial matrix by carnitine, as Raymond G Holder
observed in his rapid response, aided by the enzyme carnitine acyl
transferase. Like saturated fatty acids unsaturated fatty acids undergo
beta oxidation but require two additional enzymes, isomerase and
reductase, to deal with their double bonds. Acetyl coenzyme A, NADH and
FADH2 [and hence ATP] are the mitochondrial products (5).
Thus cholesterol contributes to the generation of ATP by aiding in
the transport of unsaturated fatty acids to mitochondria for the
generation of ATP from beta oxidation. Given the thousand fold increase
in glycolytic rate that can occur in skeletal muscles during exercise
this raises the possibility that unsaturated fatty acids might in addition
buffer tissue acids by forming saturated fatty acids and by increasing the
net yield of NADH and FADH2. Statin-induced tissue acidosis should, by
increasing the protonmotive force, upregulate oxidative phosphorylation
and enhance ATP yield be this means.
Atherosclerotic plaques might also be the product of an impairment of
the ability of mitochondria to use fatty acids to generate ATP by
oxidative phosphorylation, as previously proposed, and the impairment of
the ability of HDL to return cholesterol to the liver be a secondary
event. There is some evidence to support this possibility.
HDLs prevent atherosclerosis by removing excess cell cholesterol.
Lipid composition affects HDL ability to remove cholesterol. To examine
the effects "thermal stability of binary complexes reconstituted from apoC
-I and diacyl PCs containing 12-18 carbons with 0-2 cis-double bonds" were
determined. "Kinetic analysis using circular dichroism show[ed].. that,
for fully saturated PCs, chain length increase by two carbons stabilizes
lipoprotein by deltaDeltaG* (37 degrees C) congruent with 1.4 kcal/mol,
suggesting that hydrophobic interactions dominate the disk stability;
distinct effects of pH and salt indicate contribution of electrostatic
interactions. Similarly, apoA-I-containing disks show increased stability
with increasing chain length. Acyl chain unsaturation reduces disk
stability". It was concluded that the "stability of discoidal HDL
correlates directly with fatty acyl chain length and saturation: the
longer and more fully saturated are the chains, the more extensive are the
stabilizing lipid-protein and lipid-lipid interactions and the higher is
the free energy barrier for protein dissociation and lipoprotein fusion"
(6).
In his rapid response Simon W Linesrenal suggested using the dipstick
test for blood as a means of detecting patients on statins that might be
at risk for rhabdomyolysis, rather than measuring renal function and
urine myoglobin as proposed by Sathasivam and Lecky (7). What of using
arterial pH, or better yet a gastric intramucosal or even sublingual pH
measured during an exercise stress test (8). Direct measurement of
intramuscular pH should be even more sensitive but possibly less reliable
because of the associated risks of tissue injury and electrode
contamination.
1. Thatte HS, Rhee JH, Zagarins SE, Treanor PR, Birjiniuk V,
Crittenden MD, Khuri SF. Acidosis-induced apoptosis in human and porcine
heart. Ann Thorac Surg. 2004 Apr;77(4):1376-83.
2. Perez-Sala D, Collado-Escobar D, Mollinedo F. Intracellular
alkalinization suppresses lovastatin-induced apoptosis in HL -60 cells
through the inactivation of a pH-dependent endonuclease. J. Biol. Chem.,
270:6235-6242, 1995.
3. Fiddian-Green RG. Gastric intramucosal pH, tissue oxygenation and
acid-base balance. British Journal of Anaesthesia 1995;74:591-606.
4. Brown JM, Shelness GS, Rudel LL. Monounsaturated fatty acids and
atherosclerosis: opposing views from epidemiology and experimental animal
models. Curr Atheroscler Rep. 2007 Dec;9(6):494-500.
5. Jeremy M. Berg, John L. Tymoczko, Lubert Stryer . Biochemistry.
Fifth Edition. 2008.
6. Guha M, Gantz DL, Gursky O. Effects of acyl chain length,
unsaturation, and pH on thermal stability of model discoidal HDLs. J
Lipid Res. 2008 Aug;49(8):1752-61.
7. Sivakumar Sathasivam and Bryan Lecky. Statin induced myopathy.
BMJ 2008; 337: a2286
8. Mensink PB, van Petersen AS, Kolkman JJ, Otte JA, Huisman AB,
Geelkerken RH Gastric exercise tonometry: the key investigation in
patients with suspected celiac artery compression syndrome. J Vasc Surg.
2006 Aug;44(2):277-81.
Competing interests:
None declared
Competing interests: No competing interests
Sathasivam and Lecky provide a comprehensive review of statin induced
myopathy but they do not emphasis sufficiently the importance of drug
transporters in the tissue distribution of statins and the effects of drug
interactions and genetic variants through these pathways.1 They state that
lipophilic statins are more likely to penetrate muscle but hydrophilic
statins will also penetrate muscle when present in high concentrations in
the systemic circulation. The dose range of all the statins is limited
because of increased risk of myopathy with higher doses.
Hydrophilic statins are highly dependent on drug transporters to
access their hepatic site of action but the tissue distribution and
toxicity of lipophilic statins is also considerably influenced by
transporters. In SEARCH (study of the effectiveness of additional
reductions in cholesterol and homocysteine), the only polymorphism related
to myopathy with simvastatin identified from a genomewide scan was not in
the cytochrome P450 (CYP) enzymes but in the hepatic uptake transporter
organic anion-transporting polypeptide (OATP1B1, encoded by SLCO1B1).2
This might have been predicted as it had already been shown in
pharmacokinetic interaction studies that the 521T>C polymorphism in
SLCO1B1 with reduced function had a marked effect on the slightly more
hydrophilic active metabolite simvastatin acid.3 All the statins appear to
be substrates for this transporter and a number of the more important drug
interactions such as those with ciclosporin and gemfibrozil are
predominantly mediated through inhibition of OATP1B1 with additional
effects though other transporters and CYP enzymes.3 4 Less active genetic
variants of OATP1B1 or inhibition with drugs are likely to lead to
increased systemic exposure and toxicity without increased efficacy with
all statins, except possibly fluvastatin.
Strong inhibitors of CYP3A4, such as some azole antifungals and
protease inhibitors, clearly increase the risk of myopathy with statins
metabolized through this pathway, but many of these drugs also inhibit the
efflux transporter P-glycoprotein or multidrug resistance protein 1 (MDR1,
encoded by ABCB1). One noteworthy example is clarithromycin, widely used
in triple therapy for Helicobacter pylori and for community acquired
pneumonia. This interacts strongly with simvastatin and atrovastatin and
to a lesser extent pravastatin, probably through P-glycoprotein
inhibition.5 It has been suggested that the use of weak inhibitors of
CYP3A4 and/or efflux transporters, such as diltiazem, along with
lipophilic statins may increase the lipid lowering efficacy but beneficial
effects appear to vary greatly between patients and the combination
certainly increases the risk of myopathy with higher statin doses.
References:
1. Sathasivam S, Lecky B. Statin induced myopathy. BMJ
2008;337:a2286.
2. The SEARCH Collaborative Group. SLCO1B1 variants and statin-induced
myopathy--a genomewide study. N Engl J Med 2008;359(8):789-99.
3. Neuvonen PJ, Niemi M, Backman JT. Drug interactions with lipid-lowering
drugs: mechanisms and clinical relevance. Clin Pharmacol Ther
2006;80(6):565-81.
4. Shitara Y, Sugiyama Y. Pharmacokinetic and pharmacodynamic alterations
of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors:
drug-drug interactions and interindividual differences in transporter and
metabolic enzyme functions. Pharmacol Ther 2006;112(1):71-105.
5. Jacobson TA. Comparative pharmacokinetic interaction profiles of
pravastatin, simvastatin, and atorvastatin when coadministered with
cytochrome P450 inhibitors. Am J Cardiol 2004;94(9):1140-6.
Competing interests:
Prof Brian Tomlinson has received research funding from or acted as a consultant or speaker on occasions for AstraZeneca, Bristol-Myers Squibb, Merck Sharp and Dohme, Novartis and Pfizer.
Competing interests: No competing interests
Statin induced myopathy is commonly seen during the first years of
treatment and develops in those people who are taking 40 mg to 80 mg of
symvastatin or atorvasstatin daily. However evidence from large scale
randomized studies shows that statin therapy reduces the incidence of
heart diseases (AMI), strokes and reduces also the need for
revascularization procedures as it reduces serum cholesterol and LDL. In
very rare cases statin when prescribed in very high doses (40-80 mg daily)
causes myopathy, elevates creatine kinase level, muscle breakdown and
release of myoglobin and there remains high risk for renal failure &
death. The incidence of such a myopathy is rarest when statins are taken in
low doses like 10mg or 20 mg daily
High doses of statin therapy (80mg daily) results in myopathy in people
having candidate genes CYP3A4 which is involved in metabolism of statin,
organic anion transporting metabolism and statin elimination from the body
However those taking statin 10-20mg daily must be very cautious about
unexplained muscle pain and weakness and blood must be tested for creatine
kinases and ALT and when creatine kinase level is elevated 10 times the
upper level of normal value statin should be stopped immediately. Those
who are taking statin even at low doses 10-20mg daily must not take other
drugs like cyclosporine and amodarone as combination of these drugs
increases chance of myopathy
Reference
Bhattacharya Pranab Kumar, Bhattacharya Rupak, Islam Sahidul, Chatterjee
Bhabani Prasad’ Low dose Statins are effective in Post menopausal women
for primary prevention of coronary heart disease(CHD) rapid response
published to Grundy” Should women be offered cholesterol lowering drugs to
prevent cardiovascular disease?”
http://bmj.com/cgi/eletters/334/7601/982#166023
Competing interests:
None declared
Competing interests: No competing interests
An interesting abstract by Duell and Connor (Vitamin D deficiency is
associated with myalgias in hyperlipidemic subjects taking statins) at the
recent American Heart Association Scientific Sessions 2008 in New Orleans
suggested that vitamin D may indeed be involved with myalgias during
statin treatment. Their data on 99 patients showed a strong correlation
between myalgias and vitamin D deficiency. Sixty two percent of those with
vitamin D level below 20 ng/mL had symptoms during statin treatment as
compared to only 18 % among those with their level over 30 (P<0.01).
Vitamin D deficiency is common and adequate supplementation carries
several benefits, not only related to statin treatment. These findings and
the discovery of the SLCO1B1-gene (The SEARCH Collaborative Group, NEJM,
2008;359) give hope that doctors will both identify and better treat those
patients who genuinely get muscle symptoms from statins.
Competing interests:
None declared
Competing interests: No competing interests
I have had RRs published on this subject many times, for which I am
grateful, but all discussion seems to centre on trials which only take
arbitrary happenings into statistical account, and studiously ignore the
fundamental biological principles involved.
It is as if the Krebs cycle for energy production was a subject to be
understood just sufficiently to pass A-level Biology, but no longer
relevant on the world of medicine. The equivalent in electronic
engineering would be to assume Ohm's Law no longer applies,disaster waits
for those who might believe this!!
The production of ATP (adenosine triphosphate)in the mitochondria is
virtually the only source of bodily energy to perform every action needing
it, whether muscular (including most of all cardiac muscle),or chemical
processing as in liver and kidneys. Let me remind you that this all takes
place in microscopic mitochondria, each only one thousandth of a
millimetre in length, but inhabiting virtually every cell in the body. A
single muscle fibre contains 1,000 mitochondria. Glucose is one of their
basic fuels, but Coenzyme Q10 is necessary as electron transport between
Complex 1 and 2, and then on into the next stage, which needs heme A to
function. Fat is also used as a fuel, but needs Carnitine in order to
penetrate the membrane into the mitochondra.
We then have five essential ingredients (at least), glucose, fat
CoQ10. Carnitine and heme A, and the last three of these are all reduced
by statins in the mevalonate pathway. Who can imagine that modification on
this scale to a core necessity of life is without danger??
CoQ10 shortage can show its effects almost anywhere in the body, but
the consequent loss of carnitine may lead to myopathy by denying access of
fat to the mitochondria for metabolism. A kind of starvation can then
occur when the muscle protein becomes the fuel to maintain action. This
can occur without elevating CK, and this has been documented, I had bad
leg muscle wastage with a CK figure of only 500, my normal is now 200 with
carnitine supplementation. I believe elevated CK from other causes to be
irrelevent to statin damage, fully fit individuals suffer frequently.
Muscle pain is a much more common problem from statin use, the
figures recognised officially are very much out of touch with reality,
many thousands suffer this in most disabling ways.
The use of CoQ10 is recommended to take prevent statin damage, and is
in very wide use by statin damage forum members, but carnitine has been
found essential for myopathy and muscle pain, in the latter case it is
needed to carry the "combustion products" out from the muscle, otherwise
lactic acidosis occurs.
This is in no way alternative medicine but real science which does
not attract large financial rewards, but can give much needed relief to
those for whom mainstream medicine has no answers, and it deserves much
greater attention.
Competing interests:
Statin damaged patient
Competing interests: No competing interests
"Skeletal muscle is a major mass peripheral tissue that accounts for
40% of the total body mass and a major player in energy balance. It
accounts for >30% of energy expenditure, is the primary tissue of
insulin stimulated glucose uptake, disposal, and storage. Furthermore, it
influences metabolism via modulation of circulating and stored lipid (and
cholesterol) flux. Lipid catabolism supplies up to 70% of the energy
requirements for resting muscle. However, initial aerobic exercise
utilizes stored muscle glycogen but as exercise continues, glucose and
stored muscle triglycerides become important energy substrates. Endurance
exercise increasingly depends on fatty acid oxidation (and lipid
mobilization from other tissues)"(1).
In a study of patients over 60 those who exhibited the greatest
hypertrophy of their muscles after 12 weeks of high intensity resistance
exercise training were those on a high cholesterol diet, those with high
blood cholesterol levels and those on statins, the latter being an
independent variable (2).
Why then are statins associated with the development of myalgia,
myopathy and rhabdomyolysis? Because resistance exercise training causes
an energy supply/demand mismatch and statins prevent cholesterol from
providing the nutrient substrate that would normally have satisfied the
increased demand for ATP resynthesis by oxidative phosphorylation? If so
the myalgia, myopathy and rhabdomyolysis might be the graded products of
a shift in substrate utilization to amino acids derived from autophagy,
apoptosis and/or necrosis of muscle cells.
Amino acids are known to serve as substrate for oxidative
phosphorylation in the citric acid cycle but glucose and fatty acids are
the preferred substrates, a shift from glucose to fatty acids in exercise
being induced by the down regulation of phosphofructokinase by the
accompanying fall in muscle pH. The metabolism of amino acids derived
from autophagy, apoptosis and/or myocyte necrosis would be expected to
elude detection in plasma. Those derived from autophagy would be consumed
by the cells from which they were derived, and those derived from
apoptosis and/or necrosis by contiguous but still healthy cells [the buddy
cell hypothesis]. Using amino acids in preference to glucose or lipids
might confer metabolic advantages, such as reversing a regional tissue
acidosis by releasing ammonia, associated with the specific dynamic action
unique to proteins.
Such a mechanism would protect muscle from being catabolized under
normal circumstances and enable ATP resynthesis to continue when regional
blood flow failed to meet demands for nutrient delivery under abnormal
circumstances. The inflammatory response associated with cellular necrosis
might even be the primary cause of the stiffness and pain experienced
after the first sessions of a vigorous training programme. Why then the
inhibition of myocardial hypertrophy by statins(3)? Because the
myocardium behaves as a trained muscle and has acquired metabolic
advantages not normally present in skeletal muscle?
Statins are known to impair the synthesis of coenzyme Q(10), an
essential cofactor for mitochondrial electron transport and energy supply
(4). "Patients with CHF have low plasma concentrations of
CoQ(10)....Plasma CoQ(10) is closely associated with low-density
lipoprotein cholesterol (LDL-C)". Furthermore [low] CoQ(10) and low
cholesterol are independent predictors of survival from CHF. (5). The
inference is that statins might also deplete CoQ(10) in skeletal muscle
but CoQ(10) supplementation had no beneficial effect upon simvastatin-
induced myalgia (6) even though supplementation was of some benefit in
patients with heart failure (7). Statins might indeed behave differently
in skeletal and myocardial muscle and autophagy, apoptosis and necrosis in
myocytes might not occur except in pathological circumstances. A
disturbance in energy supply/demand balance [or products released by
autophagy or apoptosis] might, nevertheless, still be the common stimulus
for hypertrophy.
If autophagy, apoptosis and even necrosis are the graded products of
a dosr-related anti-anapleuretic action of statins, as considered in
eLetters addressing the reduction in in-hospital mortality after major
noncardiac surgery achieved by lipid-lowering therapy (8), then some of
the benefits ascribed to statins might have been achieved at the expense
of regional cellular function and even viability. Harmful effects might
not be confined to skeletal muscle for "experimental data suggest that
manipulation of cholesterol levels may lead to changes in tau
phosphorylation [in the brain]. .. Effects seem to be either mild and
transient, or drastic and related to neurodegeneration, or independent of
the mevalonate pathway" (9).
It will be a brave physician who starts statin therapy from a very
early age (10) and/or continues it through reproductive cycles for
harmful effects might appear years later and even be transmitted to future
generations.
1. Aaron G. Smith and George E.O. Muscat. Skeletal muscle and nuclear
hormone receptors: Implications for cardiovascular and metabolic disease.
The International Journal of Biochemistry & Cell Biology
Volume 37, Issue 10, October 2005, Pages 2047-2063
2. Steven E. Riechman, Ryan D. Andrews, David A. MacLean and Simon
Sheather. Statins and Dietary and Serum Cholesterol Are Associated With
Increased Lean Mass Following Resistance Training. The Journals of
Gerontology Series A: Biological Sciences and Medical Sciences 62:1164-
1171 (2007)
3. Nakagami, Hironori; Liao, James K. Statins and myocardial
hypertrophy. Coronary Artery Disease. 15(5):247-250, August 2004.
4. Chatzizisis YS, Vaklavas C, Giannoglou GD. Coenzyme Q10
depletion: etiopathogenic or predisposing factor in statin associated
myopathy?
Am J Cardiol. 2008 Apr 1;101(7):1071.
5. Molyneux SL, Florkowski CM, George PM, Pilbrow AP, Frampton CM,
Lever M, Richards AM. Coenzyme Q(10) An Independent Predictor of
Mortality in Chronic Heart Failure. J Am Coll Cardiol. 2008 Oct
28;52(18):1435-1441.
6. Young JM, Florkowski CM, Molyneux SL, McEwanRG, Framton CM, George
PM, Scott RS. Effect of coenzyme Q(10) supplementation on simvastatin-
induced myalgia. Am J Cardiol. 2007 Nov 1;100(9):1400-3.
7. Keogh A, Fenton S, Leslie C, Aboyoun C, Macdonald P, Zhao YC,
Bailey M, Rosenfeldt F. Randomised double-blind, placebo-controlled trial
of coenzyme Q, therapy in class II and III systolic heart failure. Heart
Lung Circ. 2003;12(3):135-41
8. Rodrigo B. Cavalcanti . Does perioperative lipid-lowering therapy
reduce in-hospital mortality after major noncardiac surgery?
CMAJ 2004; 171: 328
9. OHM T. G., MESKE V. Cholesterol, statins and tau. Symposium on
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2006;114:93-101.
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Competing interests:
None declared
Competing interests: No competing interests
Re: Statin induced myopathy
There is nothing like a real life experience.
My cholesterol is 9.8 which in Australia is considered very high.
I took the doctors advice and took Statin tabs but after 3 weeks I noticed my legs would seize when out and about which was very embarrassing when shopping as it eventually took me 30 to 40 minutes to get back to my car - I pretended to be window shopping. Sometimes it just left me and I was able to walk again - very odd experience let me say.
Then I noticed I could no longer make a fist. My loving wife began researching Statin user forums and found my problems were common and then I met with fellow sufferers and realized I was being harmed by the medical system.
Remember please, I only used Statins for 3 weeks - but it took me 2 years to fully recover and I was astonished at how many never recover.
I began taking whey, eating greens, nuts, herbs, veges, coconut oil, hemp seeds and hemp seed oil - and because I have an infra red sauna I was able to detox and now at 65 I'm back to being fit and strong again.
When I discovered that cholesterol is brain food & that no one has ever died from high cholesterol I approached the doctor regarding food and diet only to discover he knew nothing about natural cures or diet.
So, thanks to a friend who is a Chinese Doctor, I found the truth about cholesterol. This wonderful lady cured her father in law of cancer and she I trust. Statins are poison - unnecessary! Cholesterol represents longevity - may yours be high.
Competing interests: No competing interests