Elsevier

Clinical Therapeutics

Volume 36, Issue 5, 1 May 2014, Pages 770-777
Clinical Therapeutics

Low Vitamin D as a Risk Factor for the Development of Myalgia in Patients Taking High-Dose Simvastatin: A Retrospective Review

https://doi.org/10.1016/j.clinthera.2014.02.023Get rights and content

Abstract

Background

Statins are the treatment of choice for dyslipidemia, primarily lowering elevated LDL-C levels and reducing the occurrence of major cardiovascular events. In June 2011, the Food and Drug Administration issued a warning regarding the use of high-dose simvastatin 80 mg and its risk of myopathy.

Objective

The incidence of myalgia, myopathy, and rhabdomyolysis was analyzed in a veteran population prescribed simvastatin 80 mg. Risk factors for myalgia were examined and compared with the results of recently published studies.

Methods

This was a retrospective medical record review of 450 patients who were prescribed simvastatin 80 mg at the Veterans Affairs Western New York Healthcare System between August 1, 2006, and July 31, 2011. Records were examined for evidence of myalgia, myopathy (incipient or definite), and rhabdomyolysis. Variables that may have contributed to the development of myalgia were also collected and analyzed.

Results

Myalgia was reported by 50 patients (11.1%), whereas rhabdomyolysis developed in 1 patient (0.22%). No patient fit the criteria for myopathy (incipient or definite). Myalgia was statistically more likely to occur in younger patients, patients with a history of myalgia, and patients with low vitamin D levels. The mean (SD) vitamin D level in patients experiencing myalgia was 26.2 (12.9) versus 36.3 (11.8) ng/mL. The 25-hydroxyvitamin D level in those who reported myalgia was approximately 10 ng/mL lower compared with those who tolerated simvastatin 80 mg (P = 0.0003). There was no statistically significant association between length of therapy and development of myalgia.

Conclusion

A lower incidence of adverse muscle events with high-dose simvastatin 80 mg was found in patients with higher vitamin D levels, suggesting that correction of 25-hydroxyvitamin D levels before statin therapy initiation may mitigate one risk factor in the development of statin-related myalgia. Vitamin D insufficiency appears to be a risk factor for the development of myalgia.

Introduction

Statins are the treatment of choice for dyslipidemias. Statins help to reduce elevated LDL-C levels and lead to a reduction in the occurrence of major cardiovascular events. For the year 2010, simvastatin was the second most prescribed medication behind hydrocodone-acetaminophen in the United States, with 94.1 million prescriptions written.1

In June 2011, the Food and Drug Administration (FDA) issued a warning that the use of high-dose simvastatin 80 mg increases the risk of myopathy. Thus, high-dose simvastatin 80 mg is recommended only for patients whose conditions have been stable at this dose for at least 1 year without evidence of myopathy. Patients whose lipid levels are uncontrolled with the 40-mg dose can be considered for an alternative statin rather than titrated up to the 80-mg dose.2

All statins have the potential to cause myopathy, which can lead to rhabdomyolysis with or without acute kidney injury. The Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial examined the efficacy and tolerability of simvastatin 80 mg versus simvastatin 20 mg in 12,064 patients at high cardiovascular risk. In the SEARCH trial, myopathy (defined as a creatine kinase [CK] level >10 times the upper limit of normal [ULN] plus unexplained muscle symptoms) developed in 53 patients in the simvastatin 80-mg group and 2 patients in the simvastatin 20-mg group. The incidence of myopathy in the simvastatin 80-mg group was highest in the first year of treatment and decreased in subsequent years. Rhabdomyolysis was diagnosed in 7 patients in the 80-mg group and no patients in the 20-mg group.3

In this retrospective study, incidence of myalgia, myopathy, and rhabdomyolysis was analyzed in a veteran population prescribed simvastatin 80 mg. Many of the factors that were examined in the SEARCH trial were included in this study, as well as several additional factors identified by clinical pharmacists specializing in lipid management as possible risk factors (Table I) for statin-related myalgia, including vitamin D level.3 There are limited data suggesting an association between vitamin D levels and adverse muscle events in patients taking statins. A correlation between vitamin D level and myalgia was identified in this study.

Section snippets

Study Design

This was a single-center, retrospective cohort study of all patients who were prescribed simvastatin 80 mg at the Veterans Affairs Western New York Healthcare System between August 1, 2006, and July 31, 2011. This study was approved by the institution’s Research and Development Committee and was exempted by the institutional review board.

Eligible patients were 18 years or older and prescribed simvastatin 80 mg for any indication, including primary and secondary prevention of cardiovascular

Results

A total of 450 patients were included in this study. The study population consisted of primarily white male veterans (95.5%), with a mean age was 68.5 years. Myalgia was reported by 50 patients (11.1%), whereas 1 patient (0.22%) developed rhabdomyolysis. No patient fit the criteria for myopathy (incipient or definite). Myalgia led to discontinuation of simvastatin 80 mg therapy in 47 of the 50 patients. Diabetes was identified in 43.5% of patients. Twenty-two percent of patients had a history

Discussion

Because of the results of the SEARCH study,3 findings from the FDA’s Adverse Event Reporting System,7 and results of other clinical trials, the FDA released a warning regarding the use of high-dose simvastatin in June 2011.2, 8 Simvastatin 80 mg is now typically reserved for patients whose conditions have been stable with this dose for at least 1 year without evidence of myopathy.8 The FDA advises against prescribing simvastatin-naive patients the 80-mg dose. This retrospective medical record

Conclusion

This retrospective study found a lower incidence of adverse muscle events with high-dose simvastatin 80 mg compared with both the SEARCH study and the Prediction of Muscular Risk in Observational Conditions study. This study also identified an association between low vitamin D levels and myalgia in patients receiving simvastatin 80 mg. This association preliminarily suggests that monitoring and correcting for low vitamin D levels may help decrease myalgias associated with high-dose simvastatin.

Conflicts of Interest

The authors have indicated that they have no conflicts of interest regarding the content of this article.

Conflicts of Interest

The authors have indicated that they have no conflicts of interest regarding the content of this article.

Acknowledgments

This material is the result of work supported with the use of facilities at the Veterans Affairs Western New York Healthcare System. The contents of this manuscript are not intended to represent the views of the Department of Veterans Affairs or the US government.

References (16)

There are more references available in the full text version of this article.

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