Low Vitamin D as a Risk Factor for the Development of Myalgia in Patients Taking High-Dose Simvastatin: A Retrospective Review
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.
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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.
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2024, Diabetes Epidemiology and ManagementEffects of vitamin D supplementation on adherence to and persistence with long-term statin therapy: Secondary analysis from the randomized, double-blind, placebo-controlled ViDA study
2018, AtherosclerosisCitation Excerpt :The most common reason for discontinuing cardiovascular medications is having adverse effects [12], which affected as many as 72% of patients in one New Zealand study [26]. Given the evidence linking vitamin D deficiency with statin myalgia [14–17], it is possible that vitamin D supplementation may increase persistence in taking statins by decreasing or preventing pain related side-effects. Previous studies aiming to increase adherence to and persistence with taking lipid lowering medication have mainly used behavioral intervention approaches, such as simplification of drug regimens, education, intensified patient care, pharmacy-led strategies and administrative improvements [27].
Myotoxicity of statins: Mechanism of action
2017, Pharmacology and TherapeuticsCitation Excerpt :Moreover, a cross-sectional study found that patients with vitamin D plasma concentrations < 15 ng/ml had two fold greater odds to present SIM (Morioka, Lee, Bertisch, & Buettner, 2015). In a retrospective medical record review of 450 patients who were prescribed simvastatin, myalgia was reported by 50 patients with serum concentrations of 25(OH) D3 of 26 ± 9 ng/ml compared with concentrations of 36 ± 12 ng/ml in patients without muscle complains (Mergenhagen, Ott, Heckman, Rubin, & Kellick, 2014). Two systematic review and meta-analysis report a strong association between 25(OH) D3 serum levels < 30 ng/ml and SIM (Michalska-Kasiczak et al., 2015; Pereda & Nishishinya, 2016).
Nutritional Modulators of Pain in the Aging Population
2017, Nutritional Modulators of Pain in the Aging PopulationLow vitamin D does not predict statin associated muscle symptoms but is associated with transient increases in muscle damage and pain
2017, AtherosclerosisCitation Excerpt :SAMS reduce medication compliance and quality of life [4,5], and 60% of adults who discontinue statins report SAMS as the reason [6]. Several studies and meta-analyses have found a higher prevalence of low vitamin D levels in patients with SAMS [7,8] and that low Vitamin D is a risk factor for SAMS [9]. In addition, vitamin D supplementation may mitigate SAMS [10], but other studies have found no relationship between low vitamin D levels and SAMS [11,12].
Impact of vitamin D status on statin-induced myopathy
2016, Journal of Clinical and Translational EndocrinologyCitation Excerpt :The improvement demonstrated in statin tolerance rates following vitamin D supplementation in patients with a baseline vitamin D ⩽20 ng/mL provides evidence that considering vitamin D ⩽20 ng/mL as a risk factor for statin-induced myopathy is reasonable. Our findings also appear consistent with previously published data in regards to statin tolerance following vitamin D supplementation [11,23]. A previous retrospective chart review performed by Kurnik and colleagues assessed the relationship between vitamin D concentrations and statin-induced myopathy in a similar fashion to our study, comparing patients who were changed from one statin to another versus patients who remained on the same statin throughout therapy [15].