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From Robarts Research Institute and Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
Grant Support: By the Jacob J. Wolfe Distinguished Medical Research Chair; the Edith Schulich Vinet Canada Research Chair (Tier I) in Human Genetics; a Career Investigator award from the Heart and Stroke Foundation of Ontario (CI-5710); and operating grants from the Canadian Institutes for Health Research (MOP-13430, MOP-39533, MOP-39833), Heart and Stroke Foundation of Ontario (PRG-5967, NA-6059, T-6018), Ontario Research Fund, and Genome Canada through the Ontario Genomics Institute.
Potential Financial Conflicts of Interest:Consultancies: R.A. Hegele (Merck-Schering, Merck Frosst, AstraZeneca, Genzyme). Honoraria: T.R. Joy (Merck Frosst, Merck-Schering), R.A. Hegele (Merck-Schering, Merck Frosst, Pfizer, AstraZeneca, Oryx, Solvay, Boehringer Ingelheim, Biovail). Grants received: R.A. Hegele (Merck-Schering, Pfizer Canada, Schering-Plough, AstraZeneca).
Requests for Single Reprints: Tisha R. Joy, MD, Division of Endocrinology, Schulich School of Medicine and Dentistry, St. Joseph's Health Care, A2-117, 268 Grosvenor Street, London, N6A 4V2 Ontario, Canada; e-mail, email@example.com.
Current Author Addresses: Dr. Joy: Division of Endocrinology, Schulich School of Medicine and Dentistry, St. Joseph's Health Care, A2-117, 268 Grosvenor Street, London, N6A 4V2 Ontario, Canada.
Dr. Hegele: Robarts Research Institute, 406-100 Perth Drive, London, N6A 5K8 Ontario, Canada.
Statin-related myopathy is a clinically important cause of statin intolerance and discontinuation. The spectrum of statin-related myopathy ranges from common but clinically benign myalgia to rare but life-threatening rhabdomyolysis. Observational studies suggest that myalgia can occur in up to 10% of persons prescribed statins, whereas rhabdomyolysis continues to be rare. The mechanisms of statin-related myopathy are unclear. Options for managing statin myopathy include statin switching, particularly to fluvastatin or low-dose rosuvastatin; nondaily dosing regimens; nonstatin alternatives, such as ezetimibe and bile acidâ€“binding resins; and coenzyme Q10 supplementation. Few of these strategies have high-quality evidence supporting them. Because statin-related myopathy will probably become more common with greater numbers of persons starting high-dose statin therapy and the increasing stringency of low-density lipoprotein cholesterol level targets, research to better identify patients at risk for statin myopathy and to evaluate management strategies for statin-related myopathy is warranted.
Acetyl-CoA = acetyl coenzyme A; GTP = guanine transfer protein; HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A; PP = pyrophosphate; tRNA = transfer ribonucleic acid. * Ubiquinone can then enter the electron transport chain.
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Joy and Hegele propose ezetimibe and bile acid-binding resins as alternatives to statins in patients with statin-related myopathy (1). In the SEAS trial (2), the combination of simvastatin and ezetimibe had a smaller effect on ischemic events than would be expected from simvastatin alone (3). No effect was seen on all-cause mortality. While larger ezetimibe trials are pending, the evidence thus far suggests that this drug may be useless.
By contrast, a randomized placebo-controlled trial in a secondary prevention population showed that niacin reduces rates of recurrent infarction (4) and all-cause mortality (5). Niacin should be the first- line lipid-modifying drug for patients who cannot tolerate a statin.
1. Joy TR, Hegele RA. Narrative review: statin-related myopathy. Ann Intern Med. 2009;150:858-68.
2. RossebÃ¸ AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008;359:1343-56.
3. Cholesterol Treatment Trialists' (CTT) Collaboration. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins. Lancet 2005;366:1267"“78.
4. The Coronary Drug Project Research Group. Clofibrate and Niacin in Coronary Heart Disease. JAMA 1975; 231:360-81.
5. Canner PL, Berge KG, Wenger NK et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol 1986; 8:1245-55
To the Editor:
In the June 16 issue of Annals of Internal Medicine, Joy and Hegele point out that there is great interest in characterizing the risk determinants underlying statin-related myopathy(1). We have previously shown that genetic variability in the cytochrome P450-mediated oxidation of atorvastatin places subjects at risk for a more severe form of myotoxicity(2). As indicated by Joy and Hegele, combinatorial information about genetic variability in the overall absorption, distribution, metabolism, and elimination (ADME) of these drugs is likely to yield a more robust predictive model than information about any single gene.
Within this context, the authors enthusiastically highlight a recent report by the SEARCH Collaborative Group, wherein simvastatin-induced muscle toxicity has been associated with a polymorphism in a membrane transporter gene called SLCO1B1(3). In SEARCH (a randomized trial of high- dose versus low dose simvastatin), the odds ratio for myopathy was 4.5 per copy of the variant allele (95% C.I. 2.6 -7.7). To assess the relevance of this finding specifically within the community, we re-tested the association between genetic variability in SLCO1B1 and statin-induced muscle toxicity in a practice-based setting.
The medical record of a large multispecialty group practice in the Midwestern United States was screened electronically. From the records of nearly 2 million unique patients, we identified 267 potential myotoxicity cases in the context of atorvastatin, simvastatin, or pravastatin(4). Informed consent for a genetic association study of statin myotoxicity was obtained from 213 of these patients, as well as from 221 control patients, frequency-matched for age, gender, drug, and dose. All 434 subjects were genotyped retrospectively, according to our previously described methods(5).
The SLCO1B1 gene variant (rs4149056) was present in 20.2% of the case subjects, and 19.2% of the controls subjects (Fisher's Exact p = 0.868). In the subset of subjects on simvastatin only, (64 cases and 68 controls), we observed only a very weak trend toward association (odds ratio 1.31, 95% C.I. 0.75-2.46, p =0.31). Thus, in a clinical practice-based cohort, we were not able to confirm the association between genetic variability in SLCO1B1 and statin-induced muscle toxicity. A more comprehensive assessment of all biological processes contributing to variability in statin pharmacokinetics will be needed before gene-based risk prediction can be applied within the context of this class of drugs.
1. Joy TR, Hegele RA. Narrative review: statin-related myopathy. Annals of Internal Medicine. 2009;150:858-68.
2. Wilke RA, Lin DW, Roden DM, Watkins PB, Flockhart D, Zineh I, Giacomini KM, Krauss RM. Identifying genetic risk factors for serious adverse drug reactions: current progress and challenges. Nature Reviews Drug Discovery. 2007;6(11):904-16.
3. SEARCH Collaborative Group, Link E, Parish S, Armitage J, Bowman L, Heath S, Matsuda F, Gut I, Lathrop M, Collins R. SLCO1B1 variants and statin-induced myopathy-a genomewide study. New England Journal of Medicine. 2008;359(8):789-99.
4. Mareedu RK, Modhia FM, Kanin EI, Linneman JG, Kitchner T, McCarty CA, Krauss RM, and Wilke RA. Use of an electronic medical record to characterize cases of intermediate statin-induced muscle toxicity. Preventive Cardiology. 2009;12:88-94.
5. Rieder MJ, Reiner AP, Gage BF, Nickerson DA, Eby CS, McLeod HL, Blough DK, Thummel KE, Veenstra DL, Rettie AE. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. New England Journal of Medicine. 2005; 352(22):2285-93.
The article by Drs. Joy and Hegele (Ann Inter Med 2009;150:858-868) was an excellent summary of the state of the art on statin myopathy. They point out the differing recommendations of the ACC/AHA/NHLBI and the NLA on management of statin myopathy. However, even a single group such as the ACC/AHA may issue guidelines which are directly contradictory. The 2002 guideline on statin safety recommends short term discontinuation of statins in the setting of surgery (1). The 2007 ACC/AHA guideline (2) on perioperative cardiovascular evaluation and care for non cardiac surgery recommends continuation of statins in the setting of non-cardiac surgery. We agree with Joy and Hegele that further data on statin myopathy is necessary, but we also feel strongly that organizations that issue guidelines, such as the ACC/AHA, must ensure concordance in their recommendations so that clinicians can practice more effective care.
1. Pasternak RC, et al. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J Am Coll Cardiol 2002;40:567-572.
2. Fleisher LA, et al. ACC/AHA 2007 Guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2007;50:159-241.
The opinions expressed are those of the the authors and do not necessarily reflect those of the Department of Veterans Affairs.
TO THE EDITOR: The excellent review: Statin-Related Myopathy(1) noted that unusually heavy physical exertion or the intense physical activity of professional athletes can cause statin myopathy. What should be added is that other milder muscular injury, including mild sprains and strains can trigger statin myopathy. This myopathy typically starts one to two weeks after the injury at the time when one is anticipating spontaneous healing. The pain, soreness and cramping progressively worsen if the statin is continued, sometimes spilling over to adjacent muscle groups. Statin etiology is seldom suspected because of the unilateral presentation. The most striking feature of this myopathy is the abrupt alleviation of symptoms in just several days with the cessation of statin treatment. Statins can be restarted in these patients without development of myopathy after the muscle injury heals. However, there is a tendency to recurrence after a second muscle injury.
1. Joy TR and Hegele RA. Narrative Review: Statin-Related Myopathy. Ann Intern Med. 2009;150:858-868.
This is a timely and useful article. I had a question regarding the commentary on "switching the statin" with recommendations about choosing fluvastatin or rosuvastatin. My understanding is that pravastatin also does not get metabolized by CYP3A4. Is there a reason why this was not suggested as a viable alternative? How does it compare to the others in terms of incidence of myopathy?
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