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Medical Forum / General / Cardiology / June 2006Statins and Low-Grade Myopathy
Statins and 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 ³background noise² of muscle symptoms in the general clinical-trial 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 study¹s 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 placebo-controlled 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 multi-center 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 patient¹s 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 low-grade 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 colleagues¹ preliminary results certainly do not provide adequate information on the spec- spectrum, 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 Inter- 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, Len-fant 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 PhysiciansAmerican Society of Internal Medicine Statins and Low-Grade Myopathy 618 1 October 2002 Annals of Internal Medicine Volume 137 € Number 7 www.annals.org > Statins and Low-Grade Myopathy > 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 eml wrote: the following is from an unbiased clinician (has not made his reputation on statins, does not research statins, nor is he funded by the statin industry): Underappreciated Statin-Induced Myopathic Weakness Causes Disability Bruce H. Dobkin University of California Los Angeles, Reed Neurologic Research Center, bdobkin@mednet.ucla.edu Introduction. Myopathic syndromes induced by 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) include muscle complaints, myalgia, myositis, and rhabdomyolysis. No prospective study of statins, however, included tests of strength, so the incidence of weakness, with or without muscle symptoms and elevated enzymes, is unknown, and perhaps overlooked. Methods. From a convenience sample of patients referred to an outpatient neurorehabilitation clinic over the course of 1 year, 8 patients with hemiparetic stroke and 10 patients with other presumed neurologic diseases presented with new difficulty walking by 3 to 12 months after starting one of 3 statins. They reported no myalgias, exercise-induced aches, or weakness. Examination revealed proximal paresis graded 4/5 on the unaffected side in the hemiparetic patients and symmetrical bilateral proximal limb and neck flexor weakness graded 4/5 in the others. They stood up with difficulty and walked with bilateral hip drop and imbalance on turns. Results. Laboratory tests did not reveal myositis or other causes for paresis. No improvement in strength or mobility was found 6 weeks after initiating resistance exercises. The statin agent was stopped. By 3 months off statin, all recovered 5/5 proximal strength. Walking improved, and they arose from a chair without pushing off with their arms. Discussion. Serial manual muscle testing after initiating a statin may detect a reversible cause of disability. A genetic predisposition to statin-induced myopathic proximal weakness with normal creatine kinase is consistent with a continuum of previously reported symptoms and signs but may be underappreciated. (in the discussion, the author notes that while single-subject, double-blinded statins vs placebo studies would make the causal relationship between disabling myopathy more apparent, he notes recurrences in his patients' symptoms when the investigator was unaware that several of the subjects had been placed back on the statin by their primary physicians. p. 261) Jason Johnson wrote: > Statins and Low-Grade Myopathy > 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 the following is from an unbiased clinician (has not made his reputation on statins, does not research statins, nor is he funded by the statin industry): Underappreciated Statin-Induced Myopathic Weakness Causes Disability Bruce H. Dobkin University of California Los Angeles, Reed Neurologic Research Center, bdobkin@mednet.ucla.edu Introduction. Myopathic syndromes induced by 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) include muscle complaints, myalgia, myositis, and rhabdomyolysis. No prospective study of statins, however, included tests of strength, so the incidence of weakness, with or without muscle symptoms and elevated enzymes, is unknown, and perhaps overlooked. Methods. From a convenience sample of patients referred to an outpatient neurorehabilitation clinic over the course of 1 year, 8 patients with hemiparetic stroke and 10 patients with other presumed neurologic diseases presented with new difficulty walking by 3 to 12 months after starting one of 3 statins. They reported no myalgias, exercise-induced aches, or weakness. Examination revealed proximal paresis graded 4/5 on the unaffected side in the hemiparetic patients and symmetrical bilateral proximal limb and neck flexor weakness graded 4/5 in the others. They stood up with difficulty and walked with bilateral hip drop and imbalance on turns. Results. Laboratory tests did not reveal myositis or other causes for paresis. No improvement in strength or mobility was found 6 weeks after initiating resistance exercises. The statin agent was stopped. By 3 months off statin, all recovered 5/5 proximal strength. Walking improved, and they arose from a chair without pushing off with their arms. Discussion. Serial manual muscle testing after initiating a statin may detect a reversible cause of disability. A genetic predisposition to statin-induced myopathic proximal weakness with normal creatine kinase is consistent with a continuum of previously reported symptoms and signs but may be underappreciated. (in the discussion, the author notes that while single-subject, double-blinded statins vs placebo studies would make the causal relationship between disabling myopathy more apparent, he notes recurrences in his patients' symptoms when the investigator was unaware that several of the subjects had been placed back on the statin by their primary physicians. p. 261) Thanks for your post. If possible, try to find a research report related to Rhabdomyolyis. I found several research reports related to Statin-Induced Myopathic but could not find any research reports related to Statin-Induced Rhabdomyolysis. I found this information in a research report I found in the Journal of the American College of Cardiology (Vol. 40, No. 3,2002) "...It is rare that patients treated with a statin exhibit severe myositis.... In this setting, failure to discontinue drug therapy can lead to rhabdomyoysis and acute renal necrosis..." JAMA 1990 264:71-95 In other words, if any statin patients develop severe myositis (severe muscle pain), they should see their doctors ASAP. Jason In article <jason-0106060959230001@66-52-22-15.lsan.pw-dia.impulse.net>, > Jason Johnson wrote: > > Statins and Low-Grade Myopathy [quoted text clipped - 62 lines] > muscle pain), they should see their doctors ASAP. > Jason I did and my Cardio guy made a note of as did my PCP. A few times. This for two years after being on lesser statins for about three. Cardio guy increased my lipitor from 20 to 80 and it was not good for me. Down hill real quick . Like I mention often measure your calfs!! Bill who is off all Doc's and trying to get BP happy. LDL 160 HDL 70 and throw in CABG.  SignatureS Jersey USA Zone 5 Shade This article is posted under fair use rules in accordance with Title 17 U.S.C. Section 107, and is strictly for the educational and informative purposes. This material is distributed without profit. In article <not-to-here-williamwag-745925.13092901062006@sn-indi.vsrv-sjc.supernews.net>, In article <jason-0106060959230001@66-52-22-15.lsan.pw-dia.impulse.net>, jason@nospam.com (Jason Johnson) wrote: > In article <1149175772.834853.94160@i39g2000cwa.googlegroups.com>, "eml" > <mmlevy46@hotmail.com> wrote: [quoted text clipped - 65 lines] > muscle pain), they should see their doctors ASAP. > Jason I did and my Cardio guy made a note of as did my PCP. A few times. This for two years after being on lesser statins for about three. Cardio guy increased my lipitor from 20 to 80 and it was not good for me. Down hill real quick . Like I mention often measure your calfs!! Bill who is off all Doc's and trying to get BP happy. LDL 160 HDL 70 and throw in CABG. I hate to say bad things about doctors since I have a lot of respect for the doctors that I have met in my life. However, I will make an exception in this case--the doctor that increased your lipitor from 20 mg to 80 mg was a fool. I read WHAT YOU MUST KOW ABOUT STATIN DRUGS AND THEIR NATURAL ALTERNATIVES by Jay S. Cohen, M.D. and he made it very clear in that book that it is a risk any time a dose that high is prescribed. He said that low dose statins are much safer. Believe it or not, some people can not even handle a low dose (20 mg or below). > Thanks for your post. If possible, try to find a research report related > to Rhabdomyolyis. I found several research reports related to [quoted text clipped - 11 lines] > muscle pain), they should see their doctors ASAP. > Jason Jason, Pub Med pulls about 26 pages of articles on the search "rhabdomyolysis statin" I've included links and abstracts to the ones that seemed most relevent to your concerns. If you have access to journal databases through your college or community library, you might want to search there, also. They often have full-text articles available at no cost to the consumer. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra ct&list_uids=16716459&query_hl=2&itool=pubmed_docsum Rev Med Interne. 2006 May 3; [Epub ahead of print] Related Articles, Links [Rhabdomyolysis induced by fenofibrate monotherapy.] [Article in French] Archambeaud-Mouveroux F, Lopez S, Combes C, Lassandre S, Amaniou M, Teissier MP, Galinat S. Service de medecine interne B-d'endocrinologie, hopital du Cluzeau, 23, avenue Dominique-Larrey, 87042 Limoges, France. INTRODUCTION: Rhabdomyolysis with fibrate have been reported when fibrate are associated with statin or during renal insufficiency or hypothyroidism. CASE RECORD: We describe one patient with diabetes mellitus treated by fenofibrate monotherapy since several years; 48 h after gliclazide therapy was introduced, rhabdomyolysis occurred. DISCUSSION: Responsibilities of deshydratation and / or drug interaction with gliclazide. are discussed. PMID: 16716459 [PubMed - as supplied by publisher] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra ct&list_uids=16671104&query_hl=2&itool=pubmed_docsum 1: Muscle Nerve. 2006 May 2; [Epub ahead of print] Related Articles, Links Genetic risk factors associated with lipid-lowering drug-induced myopathies. Vladutiu GD, Simmons Z, Isackson PJ, Tarnopolsky M, Peltier WL, Barboi AC, Sripathi N, Wortmann RL, Phillips PS. Department of Pediatrics, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, 936 Delaware Avenue, Buffalo, New York 14209, USA. Lipid-lowering drugs produce myopathic side effects in up to 7% of treated patients, with severe rhabdomyolysis occurring in as many as 0.5%. Underlying metabolic muscle diseases have not been evaluated extensively. In a cross-sectional study of 136 patients with drug-induced myopathies, we report a higher prevalence of underlying metabolic muscle diseases than expected in the general population. Control groups included 116 patients on therapy with no myopathic symptoms, 100 asymptomatic individuals from the general population never exposed to statins, and 106 patients with non-statin-induced myopathies. Of 110 patients who underwent mutation testing, 10% were heterozygous or homozygous for mutations causing three metabolic myopathies, compared to 3% testing positive among asymptomatic patients on therapy (P = 0.04). The actual number of mutant alleles found in the test group patients was increased fourfold over the control group (P < 0.0001) due to an increased presence of mutation homozygotes. The number of carriers for carnitine palmitoyltransferase II deficiency and for McArdle disease was increased 13- and 20-fold, respectively, over expected general population frequencies. Homozygotes for myoadenylate deaminase deficiency were increased 3.25-fold with no increase in carrier status. In 52% of muscle biopsies from patients, significant biochemical abnormalities were found in mitochondrial or fatty acid metabolism, with 31% having multiple defects. Variable persistent symptoms occurred in 68% of patients despite cessation of therapy. The effect of statins on energy metabolism combined with a genetic susceptibility to triggering of muscle symptoms may account for myopathic outcomes in certain high-risk groups. Muscle Nerve, 2006. PMID: 16671104 [PubMed - as supplied by publisher] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra ct&list_uids=16651050&query_hl=2&itool=pubmed_docsum 1: Am J Med. 2006 May;119(5):400-9. Related Articles, Links Clinical perspectives of statin-induced rhabdomyolysis. Antons KA, Williams CD, Baker SK, Phillips PS. Scripps Mercy Clinical Research Center, Scripps Mercy Hospital, San Diego, Calif 92103, USA. Fear of muscle toxicity remains a major reason that patients with hyperlipidemia are undertreated. Recent evaluations of statin-induced rhabdomyolysis offer new insights on the clinical management of both muscle symptoms and hyperlipidemia after rhabdomyolysis. The incidence of statin-induced rhabdomyolysis is higher in practice than in controlled trials in which high-risk subjects are excluded. Accepted risks include age; renal, hepatic, and thyroid dysfunction; and hypertriglyceridemia. New findings suggest that exercise, Asian race, and perioperative status also may increase the risk of statin muscle toxicity. The proposed causes and the relationship of drug levels to statin rhabdomyolysis are briefly reviewed along with the problems with the pharmacokinetic theory. Data suggesting that patients with certain metabolic abnormalities are predisposed to statin rhabdomyolysis are presented. The evaluation and treatment of patients' muscle symptoms and hyperlipidemia after statin rhabdomyolysis are presented. Patients whose symptoms are related to other disorders need to be identified. Lipid management of those whose symptoms are statin-related is reviewed including treatment suggestions. Publication Types: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra ct&list_uids=16623120&query_hl=2&itool=pubmed_docsum 1: Przegl Lek. 2005;62 Suppl 2:51-4. Related Articles, Links [Statins in patients with renal failure--the current therapeutic status] [Article in Polish] Filipiak KJ, Zawadzka-Bysko M. I Katedra i Klinika Kardiologii Akademii Medycznej w Warszawie. krzysztof.filipiak@amwaw.edu.pl Statins are the most frequently used lipid-lowering drugs in all cardiovascular disease. It has been postulated that also patients with renal failure and end-stage renal disease (ESRD) may benefit from statin therapy. Moreover, statins may exhibit additional inhibitory effects on the atherogenesis, such as a modulation of the immune system as triggered by oxidatively modified LDL and a reduction of the inflammatory marker C-reactive protein (CRP). Statins reduce inflammation, cell proliferation, which leads to a reduction in cellular damage. Those effects are probably independent of cholesterol levels. Limited data suggest that HMG-CoA reductase inhibitors (statins) may slow loss of renal function in individuals with chronic renal insufficiency. It is concluded on the basis of the CARE trial that pravastatin may slow renal function loss in individuals with moderate to severe kidney disease, especially those with proteinuria. Similar data were obtained from recently published HPS trial with simvastatin. These findings require confirmation by a large randomized trial conducted specifically in people with chronic renal insufficiency. Statins vary in their pharmacological profiles, leading to distinct levels of systemic exposure and capacities to penetrate skeletal myocytes. Pharmacokinetic interactions with certain agents increase the likelihood of statin-induced myopathy and, in exceedingly rare instances, potentially fatal rhabdomyolysis with myoglobinuria and renal failure, therefore two statins have been suggested for renal failure patients. These are the ones that are not metabolised by the cytochrome P450 3A4 system--fluvastatin and pravastatin. The article summarizes the current therapeutic status of statin use in renal failure patients. PMID: 16623120 [PubMed - in process] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra ct&list_uids=16581337&query_hl=2&itool=pubmed_docsum 1: Am J Cardiol. 2006 Apr 17;97(8A):95C-97C. Epub 2006 Jan 30. Related Articles, Links Benefit versus risk in statin treatment. Guyton JR. Duke University Medical Center, Durham, North Carolina 27710, USA. john.guyton@duke.edu The Statin Safety Assessment Conference of the National Lipid Association (NLA), reported in this supplement to The American Journal of Cardiology, provides a comprehensive evaluation of old and new experience on adverse events associated with the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins. To place these in context, one can express both the risk of side effects and the benefits for cardiovascular disease in terms of events per person-year of statin treatment. The mortality risk from fatal rhabdomyolysis is approximately 0.3 per 100,000 person-years, and the risks of nonfatal rhabdomyolysis and of putative statin-attributable peripheral neuropathy are approximately 3 and 12 events, respectively, per 100,000 person-years. Reports of acute liver failure and acute or chronic kidney disease give lower rate estimates that, even when corrected for underreporting, are approximately equal to the background rates of these conditions in the general population, lending scant support for statin-attributable etiology. In contrast, the benefit of statin use is to avert several hundred deaths and several hundred cases each of heart and brain infarction per 100,000 person-years in appropriately treated high-risk patients. Although population estimates such as these are useful, they must be translated repeatedly to individual patient-provider encounters, where clinical skill and art must combine with scientific evidence. The continued publication of individual case reports and small randomized trials among groups of patients with potential side effects should be encouraged. Statins should not be used in situations where minimal benefit is expected, as safety data and risk-benefit analysis must be meshed with guidelines that help the clinician decide whom to treat and how aggressively to treat. PMID: 16581337 [PubMed - in process] |
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