Statin-induced Myopathy: Hypothesis About Randomized Evidence and Clinical Impressions
Article Outline
Myopathy refers to any muscle disease, myalgia to muscle aches or weakness without creatine kinase elevation, and myositis includes increased creatine kinase. Rhabdomyolysis includes marked creatine kinase elevations usually with brown urine and urinary myoglobin.1
Statins confer statistically significant and clinically important reductions in myocardial infarction, stroke, and cardiovascular death.2 The class is well tolerated, but statins are associated with myopathy, most commonly myalgia. In randomized, double-blind, placebo-controlled trials, these conditions are similar between the statin and placebo groups. Nonetheless, in some instances the findings are sufficient for clinicians to implicate statins as a cause of these symptoms.1
The absolute rates of myalgia (∼5%)1 are increasing. For example, the Measuring Effects on Intima-Media Thickness: an Evaluation of Rosuvastatin trial,3 published in 2007, was a randomized, double-blind, placebo-controlled trial among 984 patients treated for 2 years with 40 mg of rosuvastatin on progression of carotid artery intima-medial thickness. This is the highest marketed dose of the most potent statin as measured by beneficial effects on low- and high-density lipoprotein cholesterol. This dose demonstrated inhibition of progression of carotid artery intima-medial thickness. Myalgia rates were 12.7% and 12.1% in the statin and placebo groups, respectively, providing reassuring data from a randomized, double-blind, placebo-controlled trial concerning statin-induced myalgia. Nonetheless, 1 in 8 patients in the placebo group reported myalgia.
In a comprehensive individual patient data meta-analysis of 90,014 subjects randomized to statins or placebo or open control, 15 cases of rhabdomyolysis occurred in 5 years, 9 in the statin group and 6 in the control group. The excess of 3 attributable to statins was half as large as the 6 resulting from the standard use of cardiovascular drugs.
It is tempting to speculate that the perceptions by clinicians of high rates of myopathy among patients treated with statins may be due, at least in part, to direct to consumer advertising by the various drug manufacturers. To comply with US federal regulations,4 such advertisements may state benefits but also must clearly articulate potential risks. Presumably, such direct to consumer advertising must increase sales, at least in the short run, but in the long run may contribute to increasing difficulties for clinicians trying to implement the US federal guidelines for more widespread and intensive statin therapy.5 It also is tempting to speculate that nonbranded public service announcements could emphasize that cardiovascular disease is the leading killer in the United States and is becoming so worldwide.6 Further, it could be emphasized that therapeutic lifestyle changes and adjunctive drug therapies, particularly statins, may reduce premature morbidity and mortality from cardiovascular disease.
A final suggestion to fellow academicians is to emphasize to the media that the current life expectancy in the United States is the result of not only improvements by patients in their risk factors for cardiovascular disease, but also the substantial contributions by clinicians, including earlier diagnosis and more aggressive treatment. Despite increasingly formidable challenges in the US health care system, clinicians are perhaps doing more good for more patients than ever before.
References
- ACC/AHA/NHLBI Clinical advisory on the use and safety of statins. Circulation. 2002;106:1024–1028
- Cholesterol Treatment Trialists' (CTT) Collaborators (Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomized trials of statins). Lancet. 2005;366:1267–1278
- Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis; The METEOR Trial. JAMA. 2007;297:1344–1353
- . November PhRMA Guiding Principles Direct to Consumer Advertisements about Prescription Medicines. 2005;http://www.phrma.org/files/DTCGuidingprinciples.pdfAccessed September 23, 2008
- . The need for wider and appropriate utilization of aspirin and statins in the treatment and prevention of cardiovascular disease. Expert Rev Cardiovasc Ther. 2008;6:95–107
- . Increasing burden of cardiovascular disease: current knowledge and future directions for research on risk factors. Circulation. 1998;97:1095–1102
Conflict of Interest: This article poses no conflicts of interest for the author. The work is original and the author meets the criteria for authorship, including acceptance of responsibility for the scientific content and writing of the article. The author's financial affiliations with all organizations, including any with a financial interest, direct or indirect, in the subject matter or materials discussed in the article that may affect the conduct or reporting of the work submitted are listed below:
The author serves as an independent scientist in an advisory role to investigators and sponsors, including as Chair or Member on Data and Safety Monitoring Boards, for AstraZeneca, Bristol-Myers Squibb, Food and Drug Administration, Merck, National Association for Continuing Education, National Institutes of Health, Pfizer, PriMed and UpToDate. The author serves on speakers' bureaus for the International Atherosclerosis Society and AstraZeneca, concerning lipids and heart failure, as well as Pfizer, concerning lipids.
The author receives royalties for authorship or editorship of 3 textbooks.
The author receives royalties as co-inventor on patents concerning inflammatory markers and cardiovascular disease, which are held by Brigham and Women's Hospital.
The author has an investment management relationship with SunTrust Bank, who has sole discretionary investment authority.
PII: S0002-9343(08)00896-6
doi:10.1016/j.amjmed.2008.06.043
© 2009 Published by Elsevier Inc.