"JMDO" <
[email protected]> wrote in message news:<
[email protected]>...
> Two years after double bypass, and am now having severe leg muscle cramping at night. Could this
> be a symptom of vascular disease progression? I am presently taking aspirin and Zocor to prevent
> any future blockages.
John please read through this, and print out and take to your doctor. I do not say this is the
source of your problem, but it is something to consider. I experienced this myself, and was not
taken off statins until terrible damage had happened. I continue to struggle with statin side
effects which have not gone away, have rendered me incapable of working more than little, and
depleted my savings and pension funds to live on while disabled. I too am considered someone who
MUST take statins, but I now refuse to take any cholesteol lowering medication. The new meds out
have not been on the market long enough for me to know what they might and might not do to us. It is
truly a catch 22, and I sympathize with you. But, read the following from a summer issue of Annals
of Internal Medicine. MFG
Statin-Associated Myopathy with Normal Creatine Kinase Levels TO THE EDITOR: The article by Phillips
and colleagues (1) and the accompanying editorial by Grundy (2) highlight a clinical experience many
of us have had. Are the authors aware of any data, or in their clinical experience have they found
any other noninvasive testing, such as serum aldolase level, that might identify patients who are
experiencing creatine kinase–negative statin myopathy? Mark H. Hyman, MD University of California,
Los Angeles Los Angeles, CA 90025 References
1. Phillips PS, Haas RH, Bannykh S, Hathaway S, Gray NL, Kimura BJ, et al.
Statinassociated myopathy with normal creatine kinase levels. Ann Intern Med. 2002;137:
581-5. [PMID: 12353945]
2. Grundy SM. Can statins cause chronic low-grade myopathy? [Editorial] Ann Intern Med. 2002;137:617-
8. [PMID: 12353951] TO THE EDITOR: We read with interest the article by Phillips and
colleagues (1) and the accompanying editorial (2). One of us (Dr. Torgovnick) developed low-
grade myopathy while receiving statin therapy. Atorvastatin, 5 mg (0.5 tablet), was started
in September 1999. Nonspecific aches and pains were noticed, but no clear weakness was
evident and Dr. Torgovnick continued regular exercise. On several occasions, a burning
sensation beyond what was anticipated developed in the muscles after exercise. Low-grade
myopathy was considered in June 2000, and creatine kinase level was checked. The result,
3.14 _kat/L, was normal (reference range, 0 to 3.34 _kat/L), and atorvastatin therapy was
continued. In early May 2002, 24 hours after exercise, creatine kinase level was checked
and was found to be 4.8 _kat/L. Atorvastatin was withdrawn, and the aches, pains, and
burning sensation gradually resolved. After vigorous exercise, several weeks after
atorvastatin was discontinued, the creatine kinase level was 3.19 _kat/L. On a repeated
test, serum cholesterol level was significantly elevated and pravastatin was introduced.
Symptoms recurred but were tolerated. While Dr. Torgovnick was taking pravastatin, the
creatine kinase level was 4.98 _kat/L shortly after exercise. Phillips and colleagues'
patients ranged in age from 62 to 76 years, and no information was given on their level of
activity or their muscle mass, both of which can affect creatine kinase levels. In the
current author's case, it was clear that something was wrong, but the creatine kinase level
rose only with exercise provocation. The message of the article by Phillips and colleagues
is clear and important. As more patients with this syndrome are identified, perhaps less
invasive evaluation might include the use of exercise provocation to watch for an increase
in creatine kinase level. Alternatively, simple serial measurement of creatine kinase
levels to establish a baseline and subsequent reevaluation after a specified period (or
withdrawal of the agent and a demonstrated decrease in creatine kinase level, particularly
if associated with resolution of symptoms) would be useful. Josh Torgovnick, MD St.
Vincent's Hospital and Medical Center New York, NY 10011 Edward Arsura, MD Salem Veterans
Affairs Medical Center Salem, VA 24153 References
3. Phillips PS, Haas RH, Bannykh S, Hathaway S, Gray NL, Kimura BJ, et al.
Statinassociated myopathy with normal creatine kinase levels. Ann Intern Med. 2002;137:
581-5. [PMID: 12353945]
4. Grundy SM. Can statins cause chronic low-grade myopathy? [Editorial] Ann Intern Med. 2002;137:617-
8. [PMID: 12353951] TO THE EDITOR: Phillips and colleagues (1) nicely documented biopsy-
confirmed myopathy in patients with normal creatine kinase levels in association with
statin therapy. As they mentioned in their discussion, similar features are reported for
coenzyme Q10 deficiency. It is known that 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA)
reductase inhibition by statins influences not only the cholesterol synthesis but also that
of proteins such as farnesylated and geranylgeranylated proteins and ubiquinones such as
coenzyme Q10. Similar to cholesterol synthesis, the primary regulation of coenzyme Q10
biosynthesis is the HMG-CoA reductase reaction, providing its www.annals.org 17 June 2003
Annals of Internal Medicine Volume 138 • Number 12 1007 isoprenyl side chain deriving from
mevalonate. Decreased plasma levels of coenzyme Q10 have been reported in statin-treated
patients (2, 3), and in one of them this decrease was dose related (3). Furthermore, in one
study (4), statin-induced coenzyme Q10 reduction was prevented by exogenous coenzyme Q10
supplementation. On the other hand, similar histopathologic findings of myopathy are well
documented in patients with carnitine deficiency. A 16-week trial of treatment with
lovastatin significantly altered carnitine status in rabbits with decreased tissue levels
of carnitine and increased serum levels of acylcarnitine (5). Use of HMG-CoA reductase
inhibitors leads to increased levels of acyl-CoA and, therefore, to higher requirements of
carnitine for the buffering of acyl-CoA moieties. Assessing the acylcarnitine–free
carnitine ratio before and during therapy with statins might identify the patients who are
most vulnerable to this possible myopathic complication. Although the incidence of statin-
associated myopathy (with abnormal or normal creatine kinase levels) is low, studies on
pathogenic roles of coenzyme Q10 and carnitine are imperative. Finally, well-done clinical
trials addressing the preventive or therapeutic effects of coenzyme Q10 and L-carnitine are
worthy, since millions of people are receiving statins. Emil Toma, MD, DSc, FRCP(C) Maude
Loignon, BSc Hoˆtel-Dieu Hospital Montreal, Quebec H2W 1T8, Canada References
5. Phillips PS, Haas RH, Bannykh S, Hathaway S, Gray NL, Kimura BJ, et al.
Statinassociated myopathy with normal creatine kinase levels. Ann Intern Med. 2002;137:
581-5. [PMID: 12353945]
6. Watts GF, Castelluccio C, Rice-Evans C, Taub NA, Baum H, Quinn PJ. Plasma coenzyme Q
(ubiquinone) concentrations in patients treated with simvastatin. J Clin Pathol. 1993;46:1055-
7. [PMID: 8254097]
7. Mortensen SA, Leth A, Agner E, Rohde M. Dose-related decrease of serum coenzyme Q10 during
treatment with HMG-CoA reductase inhibitors. Mol Aspects Med. 1997;18 Suppl:S137-44.
[PMID: 9266515]
8. Bargossi AM, Grossi G, Fiorella PL, Gaddi A, Di Giulio R, Battino
M. Exogenous CoQ10 supplementation prevents plasma ubiquinone reduction induced by HMGCoA reductase
inhibitors. Mol Aspects Med. 1994;15 Suppl:s187-93. [PMID:
7752830]
7752831. Bhuiyan J, Seccombe DW. The effects of 3-hydroxy-3-methylglutaryl-CoA reductase inhibition
on tissue levels of carnitine and carnitine acyltransferase activity in the rabbit. Lipids.
1996;31:867-70. [PMID: 8869889] TO THE EDITOR: Phillips and colleagues (1) posited that
myopathy with normal creatine kinase levels may occur in patients receiving statin therapy.
Patients with muscular pain or weakness but without elevated enzyme levels pose an
important clinical problem, although the exact incidence of this disorder is not known.
Phillips and colleagues did not discuss a potential mechanism or mechanisms. However, they
reported 3-methylglutaconic aciduria consistent with respiratory chain dysfunction and
pathologic findings similar to those found in coenzyme Q10 deficiency (2). The American
College of Cardiology/American Heart Association/National Heart, Lung, and Blood Institute
clinical advisory states that ubiquinone (coenzyme
Q10) deficiency could be a possible mechanism, although no conclusive data support this hypothesis
(3). The synthesis of coenzyme Q10 in cells involves pathways that are blocked by the statins.
A recent review of statin myopathy (4) discusses this and other topics. Members of the
complementary and alternative medicine community have been advocating the concomitant use of
coenzyme Q10 with statins, although this practice has not been accepted by most mainstream
physicians. Data on whether statins lower coenzyme Q10 levels are contradictory. However,
certain persons with a genetic, biochemical, or other cause of decreased levels of coenzyme Q10
levels in tissue, such as increasing age (5), may experience statininduced decreases in muscle
coenzyme Q10 levels as a cause of the myopathy. Of note, the patients in Phillips and
colleagues' study were 62 to 76 years of age. Do the authors have any information on serum or
muscle coenzyme Q10 levels or coenzyme Q10 use in these patients? I believe the clinical and
pathologic data in Phillips and colleagues' study, coupled with other reports in the peer-
reviewed literature, suggest an etiologic role of coenzyme Q10 deficiency in some patients with
statin-induced myopathy. Although isolated case reports have supported this hypothesis, we need
large randomized, controlled studies studying the concomitant administration of coenzyme Q10
and statins to prevent or treat muscle symptoms, with or without muscle enzyme elevations. Only
then will we be able to address this important controversy. Louis Evan Teichholz, MD Hackensack
University Medical Center Hackensack, NJ 07601 References
1. Phillips PS, Haas RH, Bannykh S, Hathaway S, Gray NL, Kimura BJ, et al.
Statinassociated myopathy with normal creatine kinase levels. Ann Intern Med. 2002;137:
581-5. [PMID: 12353945]
2. Ogasahara S, Engel AG, Frens D, Mack D. Muscle coenzyme Q deficiency in familial
mitochondrial encephalomyopathy. Proc Natl Acad Sci U S A. 1989;86:2379-
3. [PMID: 2928337]
4. Pasternak RC, Smith SC Jr, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C, et al.
ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J Am Coll Cardiol. 2002;40:567-
72. [PMID: 12142128]
5. Baker SK, Tarnopolsky MA. Statin myopathies: pathophysiologic and clinical perspectives.
Clin Invest Med. 2001;24:258-72. [PMID: 11603510]
6. Rosenfeldt FL, Pepe S, Ou R, Mariani JA, Rowland MA, Nagley P, et al. Coenzyme Q10 improves
the tolerance of the senescent myocardium to aerobic and ischemic stress: studies in rats
and in human atrial tissue. Biofactors. 1999;9:291-9. [PMID:
7]IN RESPONSE: Dr. Hyman asks whether other biochemical markers might identify patients with
statin-induced myopathy. Levels of aldolase and myoglobin, which would be released by
disrupted myocyte membranes, have been normal whenever we have tested them in our patients.
We are currently testing other indicators of the metabolic defect associated with this
muscle toxicity (1). Drs. Torgovnick and Arsura inquire about the relation of this toxicity
to exercise. Postexercise creatine kinase level is more sensitive than resting creatine
kinase level in assessing muscle toxicity. The latter is related to membrane disruption but
has not met with much success in assessing statin toxicity (2, 3). We required that all
study patients maintain a consistent exercise and dietary regimen during the 5-month
evaluation. Although all of the creatine kinase evaluations were performed after exercise,
they were not performed late enough (6 to 12 hours later) to make this a sensitive test. We
believe that the preoccupation with muscle membrane abnormalities and Letters 1008 17 June
2003 Annals of Internal Medicine Volume 138 • Number 12 www.annals.org elevation of creatine
kinase levels as indicators of toxicity has delayed the detection of the metabolic toxicity
we described. Other afflictions with similar pathologic characteristics—mitochondrial
myopathies, for example—cause significant abnormalities in muscle function without
disrupting membranes sufficiently to elevate creatine kinase levels. We suspect that further
evaluation of metabolic defects in patients with statin myotoxicity will prove more fruitful
than repeated attempts to evaluate this abnormality from the perspective of muscle membrane
toxicities or rhabdomyolysis. The comments of Dr. Toma and Ms. Loignon and Dr. Teichholz
regarding the possible relationships of carnitine and coenzyme Q10 to statin myotoxicity are
correct. While we found no depression in either serum or muscle carnitine levels in our
patients, measurement of coenzyme Q10 may be more productive. Muscle coenzyme Q10 levels
correlated with toxicity in one of the three patients in our study who underwent muscle
biopsy, both while myopathic and again when toxicity had resolved. We have a report in
preparation that discusses measurement of coenzyme Q10 level in a series of 50 muscle biopsy
specimens from patients under evaluation for statin myotoxicity. The results of that study
should provide further impetus for future trials assessing coenzyme Q10 and carnitine.
Statins are the best therapy available to reduce cardiovascular end points in patients with
atherosclerotic risks. The optimal use of these agents requires a thorough understanding of
their toxicities as well as of their efficacy. We agree that we know too little about the
mechanism and pathophysiology of statin myotoxicity and that further clinical evaluations
and biochemical description are essential. Paul S. Phillips, MD Scripps Mercy Hospital San
Diego, CA 92103 Richard H. Haas, MD University of California, San Diego La Jolla, CA 92093-
0935 References
8. Phillips P, Haas R, Barshop B, Bannykh S, Amjadi D. Utility of abnormal 3-methylglutaconic
aciduria (3MGA) in diagnosing statin associated myopathy. Atheroscler Thromb Vasc Biol
Online Journal. 2002;22:878. Accessed at
http://aha.agora.com/ abstractviewer/av_view.asp.
9. Reust CS, Curry SC, Guidry JR. Lovastatin use and muscle damage in healthy volunteers
undergoing eccentric muscle exercise. West J Med. 1991;154:198-200. [PMID: 2006566]
10. Smit JW, Bar PR, Geerdink RA, Erkelens DW. Heterozygous familial hypercholesterolaemia is
associated with pathological exercise-induced leakage of muscle proteins, which is not
aggravated by simvastatin therapy. Eur J Clin Invest. 1995;25:79-84. [PMID: 7737266]
And in the same issue of Annals of Internal Medicine:
Simvastatin TO THE EDITOR: Simvastatin is an antilipemic agent that decreases low-density
lipoprotein cholesterol levels by inhibiting hydroxymethylglutaryl coenzyme A reductase. Statins
have an excellent safety profile (1). However, reports have described a lupus-like hypersensitivity
reaction with late, insidious onset (2– 4). Symptoms include polymyalgia, elevated erythrocyte
sedimentation rate (ESR), positivity for antinuclear antibodies, and potentially life-threatening
pneumonitis. To highlight the diversity of this drug-induced hypersensitivity, we report a case in
which the patient presented with dysphasia. A 74-year-old man with coronary artery disease and
hypertension presented with sudden onset of dysphasia. He was initially thought to have a viral
illness, but symptoms progressed over weeks to the point where he was able to swallow only liquids.
His hematocrit decreased from an initial value of 0.44 to 0.28 with no reticulocyte response or
evidence of hemolysis. Eosinophilia (eosinophils, 38%), ESR of 100 mm/h, and lactate dehydrogenase
level of 320
U/L were noted. Results of endoscopy and esophageal peristalsis studies were normal. Computed
tomography showed borderline splenomegaly with mediastinal and retroperitoneal adenopathy. Bone
marrow biopsy revealed only increased eosinophils. The rheumatoid factor level was normal, and the
patient was strongly positive for antinuclear antibodies. Medications included simvastatin,
fosinopril, aspirin, colchicine, ranitidine, gemfibrozil, digoxin, and atenolol. The patient had
the only drug discontinued, and afterward, the patient's dysphasia resolved in a few days. Lactase
dehydrogenase level and ESR normalized, and hematocrit subsequently improved. Statins are commonly
used, well-tolerated drugs. A few cases of lupus-like hypersensitivity to statins have been
described. Although these reactions are rare, they are difficult to diagnose because they can
occur after several years of treatment. This report highlights the diverse symptoms of this
reaction. For prescribing clinicians, it is very important to bear these unusual, potentially life-
threatening adverse effects in mind. Katarina LeBlanc, MD, PhD Mary T. Brophy, MD, MPH Boston
Veterans Affairs Healthcare System Boston, MA 02130 References
1. Grundy SM. HMG-CoA reductase inhibitors for treatment of hypercholesterolemia. N Engl J
Med. 1988;319:24-33. [PMID: 3288867]
2. Hill C, Zeitz C, Kirkham B. Dermatomyositis with lung involvement in a patient treated with
simvastatin [Letter]. Aust N Z J Med. 1995;25:745-6. [PMID: 8770347]
3. De Groot RE, Willems LN, Dijkman JH. Interstitial lung disease with pleural effusion caused
by simvastin. J Intern Med. 1996;239:361-3. [PMID:
4]
5. Liebhaber MI, Wright RS, Gelberg HJ, Dyer Z, Kupperman JL. Polymyalgia, hypersensitivity
pneumonitis and other reactions in patients receiving HMG-CoA reductase inhibitors: a
report of ten cases. Chest. 1999;115:886-9. [PMID:
6]
