Creatine kinase levels symptoms and conditions

Can Statins Cause Chronic Low-Grade Myopathy?
Statins (hydroxymethyl glutaryl coenzyme A reductase
inhibitors) are highly effective drugs for reducing serum
cholesterol and low-density lipoprotein cholesterol levels.
Clinical trials have shown that they also reduce risk for
coronary heart disease events, coronary procedures, and
stroke by about one third (1). Millions of people in the
United States and worldwide are being treated with statins.
In clinical trials and in clinical practice, statins have proved
to be remarkably safe.
The one notable side effect of statin therapy is myopathy.
A small fraction of patients who are treated with
statins will develop severe myopathy (2). In the worst cases,
severe myoglobinuria, acute renal failure, and even death
can occur. The incidence of severe myopathy is low, perhaps
1 in 1000 patients (2). Predisposing factors for severe
myopathy appear to include advanced age, relatively low
body weight, female sex, certain medications, use of multiple
medications, multisystem disease, and acute illnesses
or major surgery (3). If statins were avoided or used in low
doses in these circumstances, it is likely that the incidence
of severe myopathy could be greatly reduced.
Less severe forms of myopathy undoubtedly occur. In
some patients, fatigue and muscle pain and weakness develop
with moderately high serum creatine kinase levels
but not acute renal failure. In these cases, the myopathy
resolves when statin therapy is discontinued.
Still more patients report various muscle symptoms—
fatigue, pain, and muscle weakness—but have normal creatine
kinase levels. These symptoms probably are unrelated
to statin therapy in many patients. In middle-aged and
older people, muscle, joint, and tendon symptoms are very
common. Naturally, if a patient takes a medication that is
believed to produce muscle problems, symptoms are often
attributed to the medication. On the other hand, the major
controlled clinical trials have not detected a higher prevalence
of muscle symptoms during statin therapy versus placebo
(1). This failure of detection has generally led clinical
trialists to conclude that statin-associated myopathy with
normal creatine kinase levels essentially does not exist or
that, if it does exist, it cannot be detected above the “background
noise” of muscle symptoms in the general clinicaltrial
population.
Many physicians in clinical practice nonetheless believe
that they can identify a subset of statin-treated patients
who have a unique set of statin-related muscle symptoms.
Some patients clearly relate the onset of muscle
symptoms to initiation of statin therapy. These symptoms
may abate after discontinuation of therapy, only to reappear
when statin therapy is restarted. The number of such
patients is not large, and thus it may have been impossible
to identify them in large clinical trials.
In this issue, Phillips and colleagues (4) report on a set
of studies in four patients who had muscle symptoms during
statin therapy that resolved during placebo use. Quantitatively
measured muscle weakness also resolved during
placebo use. Muscle biopsies were performed in three patients
during statin therapy and then during placebo use.
Several pathologic changes were seen on biopsy specimens
obtained during statin therapy: increased lipid content of
mitochondria, fibers that did not stain for cytochrome oxidase
activity, and ragged red fibers. The authors suggest
that these patients had statin-associated myopathy with
normal serum creatine kinase levels.
Despite the study’s small size, we cannot dismiss these
observations as random variation in muscle structure.
However, these highly suggestive results are clearly preliminary.
The number of patients was small, and all appropriate
controls were not used. Nonetheless, this study is novel
because it used quantitative measures of muscle strength
and muscle biopsy to address the question of myopathy
with normal creatine kinase levels during statin therapy.
To be confirmed, the current data would have to be
extended to many more patients in whom muscle symptoms
are closely correlated with statin use. Reproducibility
of symptoms during therapy and symptom resolution after
discontinuation of statin therapy would be necessary. A
definitive study would have to be carefully designed and
executed. It would need to be double-blinded and placebocontrolled
and include sufficient numbers of patients to
provide a valid statistical comparison. In addition, investigators
would have to carefully consider the appropriate
selection of patients. The development of a registry of candidate
patients at multiple sites could facilitate a multicenter
study.
Is a carefully controlled, sizable study of this type
worth the investment of time and effort? To date, no evidence
indicates that prolonged statin therapy leads to permanent
muscle damage or progressive myopathy in patients
with normal creatine kinase levels. Controlled
clinical trials attest to the general safety of statins, and
symptomatic side effects appear to be limited to a relatively
small proportion of treated patients. In addition, no therapy
prevents or treats statin-induced myopathy, short of
withholding the drug. On the other hand, statins are being
prescribed to millions of people, and are usually continued
throughout the patient’s lifetime. It is certain that statins
cause myopathy in some patients. For these reasons, a valid
argument can be made for a more extensive study of lowgrade
myopathy in patients treated with statins.
In the meantime, physicians should recognize the great
benefit of statin therapy in high-risk patients and their
documented safety for most patients. For high-risk persons,
the proven efficacy for preventing cardiovascular disease
outweighs the unlikely possibility of permanent muscle
damage. Phillips and colleagues’ preliminary results
certainly do not provide adequate information on the spec-
Editorial
www.annals.org 1 October 2002 Annals of Internal Medicine Volume 137 • Number 7 617
trum, scope, or prognosis of myopathy with normal creatine
kinase levels during statin therapy. For these reasons,
prescription of statins for eligible patients should continue
despite the current results. Moreover, before discontinuing
therapy, physicians should carefully evaluate any patient
receiving statins who reports muscle symptoms. In most
cases, the symptoms will be found not to be consistent
with chronic myopathy, and often they will not be related
temporally to statin treatment. High-risk patients in particular
should not be deprived of major cardiovascular risk
reduction just because they display symptoms not clearly
documented to be closely related to statin therapy.
Despite these comments, the actions of statin on muscle
metabolism and structure deserve further investigation
to clarify the confusing area of low-grade myopathy apparently
associated with statin use in a few patients.
Scott M. Grundy, MD, PhD
University of Texas Southwestern Medical Center at Dallas
Dallas, TX 75390-9052
Current Author Address: Scott M. Grundy, MD, PhD, Center for
Human Nutrition and the Departments of Clinical Nutrition and Internal
Medicine, University of Texas Southwestern Medical Center at Dallas,
5323 Harry Hines Boulevard, Y3.206, Dallas, TX 75390-9052.
Potential Financial Conflicts of Interest: Honoraria (from Merck &
Co.; Pfizer, Inc.; Bristol-Myers Squibb; and Bayer); Grants (from Merck
& Co. and Pfizer, Inc.)
Ann Intern Med. 2002;137:617-618.
References
1. Executive Summary of The Third Report of The National Cholesterol Education
Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment
of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001;
285:2486-97.
2. Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis
. N Engl J Med. 2002;346:539-40.
3. Pasternak RC, Smith SC, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant
C. ACC/AHA/NHLBI clinical advisory on the use and safety of statins (1)
(2). J Am Coll Cardiol. 2002;40:567-72.
4. Phillips PS, Haas RH, Bannykh S, Hathaway S, Gray NL, Kimura BJ, et al.
Statin-associated myopathy with normal creatine kinase levels. The Scripps Mercy
Clinical Research Center. Ann Intern Med. 2002;137:581-5.
© 2002 American College of Physicians–American Society of Internal
Medicine
Editorial Statins and Low-Grade Myopathy
618 1 October 2002 Annals of Internal Medicine Volume 137 • Number 7 www.annals.org

statins trigger neuromuscular disorders--there are many many neuromuscular disorders thought to be due to mitochondrial dysfunction (which underlies all the disorders mentioned here--including ALS, Parkinson's, Alzheimer's, as well as all the mitochondrial cytopathy disorders:

NEW YORK (Reuters Health) Jul 26 - Patients with asymptomatic neuromuscular disorders may have their condition precipitated by statin use, according to investigators from the University of Athens Medical School.

Dr. Panagiota Manta and colleagues describe four such cases in the July 24th issue of the Archives of Internal Medicine.

Case 1 was a 46-year-old man with a history of hypertension and diabetes mellitus who was prescribed pravastatin for hypercholesterolemia. Three months later, he complained of fatigue, muscle pain and stiffness. Serum creatine kinase levels were persistently elevated. After stopping the drug, creatine kinase levels fell somewhat and there was mild symptom improvement. Mild myopathy was seen on needle electromyography and muscle biopsy showed numerous internal nuclei, nuclear clumps and variations in fiber size. Genetic testing revealed myotonic dystrophy.

Case 2 was a 62-year-old man with a history of MI and diabetes. Hypercholesterolemia was treated with simvastatin. Creatine kinase levels became persistently elevated and did not return to normal after drug discontinuation. Biopsy was positive for muscle enzyme activity. He was eventually diagnosed with McArdle disease.

Case 3 was a 51-year-old man with hypertension and hypercholesterolemia who was hospitalized with acute rhabdomyolytis after taking atorvastatin for 18 months. Exercise intolerance and muscle pain persisted for months after discontinuation of statin therapy. Some time later, he was diagnosed with mitochondrial myopathy.

The last case was a 58-year-old man with a history of hypertension, hyperuricemia and coronary artery disease. He began treatment with pravastatin. Shortly after a dose increase, he developed muscle twitching, muscle cramps and difficulty walking. Like the other cases, there was only mild symptom improvement and a modest decline in creatine kinase levels after the statin was discontinued. He was eventually diagnosed with Kennedy disease.

Statin-induced neuropathy is well recognized and reported more and more often, Dr. Manta's group notes. These four cases show that statins can also trigger underlying neuromuscular conditions.

The investigators suggest that if neuromuscular symptoms persist after discontinuation of statin therapy, clinicians should "pursue further diagnostic evaluations for the detection of underlying neuromuscular disease."

Arch Intern Med 2006;166:1519-1524.

Those of you who are suffering from muscle achiness should tell your doctors that this is now a recognized side-effect of statins. An article published in the October 1, 2002 issue of the Annals of Internal Medicine concluded "Some patients who develop muscle symptoms while receiving statin therapy have demonstrable weakness and histopathologic findings of myopathy despite normal serum creatine kinase levels." Similar problems are recognized by the American College of Cardiology, the American Heart Association adn the National Heart, Lung and Blood Institute. Their findings are cited in Jane Brody's column in the New York Times (December 10, 2002).
I experienced intense muscle achiness in my legs while on generic lovastatin. Interestingly, for me, this disappeared when I switched to Lipitor.