A 58-year-old woman, who three years ago underwent stent placement in her left anterior descending for unstable angina, comes for an annual evaluation for secondary prevention. She is taking simvastatin 40 mg per day, metoprolol tartrate 25 mg twice a day, and aspirin 81 mg per day. She denies angina but does state that she has had severe thigh and low back pain. She is very physically active. Her other risk factors include hypertension, which is well controlled, and former tobacco abuse. On laboratory testing, she has total cholesterol of 160 mg/dL, triglycerides of 50 mg/dL, HDL cholesterol 75 mg/dL, and LDL cholesterol 75 mg/dL with a non-HDL cholesterol of 85 mg/dL. Her creatine kinase is normal.
Which of the following are true regarding statin-associated myalgia?
The correct answer is: C. Symptoms usually resolve within two to four weeks after stopping the statin.
Explanation of Answers:
A. The recently released ACC/AHA guidelines on cholesterol management1 expand the potential population that may benefit from cholesterol reduction. With this expanded use, it is likely that the total number of patients developing statin-associated myalgia will increase. The statins have been reported to be associated with myalgias in as low as 2% of patients studied in clinical trials.2 However, many of these randomized trials either utilized a run-in phase using statins or excluded patients with previously known statin intolerance from randomization, and the estimated risk is somewhere between 10% to 15% of the population taking statins.3 Muscle aches secondary to statins have been found to be more common in the lower extremities, especially proximal thigh and pelvic girdle.4 However, muscle aches can certainly occur in upper extremities and are usually bilateral, presenting as aches, stiffness, weakness, and/or easy fatigability. These myalgias account for a sizable portion of the low reported adherence rate to statins, reported to be as low as 25% of patients taking them after two years for primary prevention and 40% with a history of coronary artery disease.5
B. The incidence of statin intolerance has been shown to be increased when patients are taking simvastatin in conjunction with the calcium channel blockers but not the beta blockers. The FDA issued a warning in 2011 regarding the commonly used cardiovascular medications pointing out that patients should not be on more than 10 mg of simvastatin with amiodarone, verapamil, or diltiazem, or taking greater than 20 mg of simvastatin with amlodipine or ranolazine.6 Simvastatin should not be used with gemfibrozil.7
C. Myalgias due to statin intolerance commonly resolve within 2-4 weeks of discontinuation of the drug.8
D. Less than 10% of patients with statin-associated myalgias have concomitantly elevated creatine kinase levels.9
E. Vigorous exercise usually worsens symptoms.10
In general, the approach to patients with suspected statin intolerance is to stop the offending drug for two to four weeks ("statin holiday"), or until symptoms resolve. After that, one can either restart the same statin at a lower dose (if it is felt that could achieve adequate reduction in LDL) or start a different statin. There is no clear correlation between intolerance to one statin and another, and neither lipophilicity nor cytochrome P450 metabolism pathway has been shown to be predictive of intolerance. Also, recurrent statin intolerance to a new agent usually occurs less than a month after starting therapy. Treatments such as supplementation with coenzyme Q10, vitamin D, or other agents have not been shown to be consistently effective in alleviating symptoms. However, patients that have low levels of vitamin D have reported increased myalgias, and vitamin D supplementation may be a reasonable option if the patient has demonstrated low vitamin D levels, though this has not been studied in randomized trials.
In this patient with a prior coronary stent, who has excellent lipids when on a statin, it is probably worth trying at least two to three different statins before considering there to be a true permanent statin intolerance due to myalgia.
Stone NJ, Robinson J, Lichtenstein AH, Bairey Merz CN. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013; [Epub ahead of print].
Phillips PS, Haas RH, Bannykh S, Hathaway S, Gray NL, Kimura BJ, Vladutiu GD, England JD. Statin associated myopathy with normal creatine kinase levels. Ann Intern Med 2002;137:181-585.
Fernandez G, Spatz ES, Jablecki C, Phillips PS. Statin Myopathy: A Common Dilemma Not Reflected in Clinical Trials. Cleve Clin J Med 2011;78:393-403.
Buettner C, Rippberger MJ, Smith JK, Leveille SG, Davis RB, Mittleman MA. Statin use and musculoskeletal pain among adults with and without arthritis. Am J Med 2012;125:176-182.
Jackevicius CA, Mamdani M, Tu JV. Adherence with Statin Therapy in Elderly Patients with and Without Acute Coronary Syndromes. JAMA 2002;288:462-467.
FDA Drug Safety Communication: New Restrictions, Contraindications, and Dose Limitations for Zocor (simvastatin) to Reduce the Risk of Muscle Injury. December 15, 2011. US Food and Drug Administration. Drug Safety Communication. http://www.fda.gov/drugs/drugsafety/ucm256581.htm.
Graham DJ, Staffa JA, Shatin D, Andrade SE, Schech SD, La Grenade L. Incidence of Hospitalized Rhabdomyolysis in Patients Treated with Lipid Lowering Drugs. JAMA 2004;292:2585-2590.
Parker BA, Capizzi JA, Grimaldi AS, et al. Effect of Statins on Skeletal Muscle Function. Circulation 2013;127:96-103.
Mancini GBJ, Baker S, Bergeron J, Fitchett D, Frohlich J, Genest J, et al. Diagnosis, Prevention, and Management of Statin Adverse Effects and Intolerance: Proceedings of a Canadian Working Group Consensus Conference. Can J Cardiol 2011;27:635-662.
Sinzinger H, O'Grady J. Professional Athletes Suffering from Familial Hypercholesterolemia Rarely Tolerate Statin Treatment Because of Muscular Problems. Br J Clin Pharmacol 2004;57:525-528.