Can Statins Cause Chronic Low-Grade Myopathy? Statins (hydroxyme...

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. [PMID: 11368702] 2. Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis [Letter]. N Engl J Med. 2002;346:539-40. [PMID: 11844864] 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. [PMID: 12142128] 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