Analysis of vitamin D levels in patients with and without statin-associated myalgia — A systematic review and meta-analysis of 7 studies with 2420 patients☆
Introduction
Statins are very effective agents in both primary and secondary prevention of cardiovascular (CV) events in high-risk patients [1], [2], [3], [4]. According to the available studies in patients with CV disease (CVD), statin therapy significantly reduces all-cause mortality, CV mortality, morbidity, recurrent CV events and ischemic stroke [5], [6], [7], [8]. Therefore, the number of people treated with statins has been increasing during the past several years, and it is predicted that it will increase further due to an increase of high risk patients, population aging and expanded indications [9], [10], [11].
However, side effects, most frequently muscle aches (i.e., myalgia), are commonly observed in patients treated with statins, and these side effects greatly affect statin therapy adherence [12], [13], [14], [15], [16], [17]. It is therefore important to increase our understanding of the pathology underlying statin adverse effects and how to manage or prevent them in statin-intolerant patients [12], [13]. Observational studies show that myalgia can occur even in 15–20% of patients on statin therapy [12], [13], [14]. Its occurrence is much more prevalent in daily clinical practice than reported in randomized controlled trials (RCTs; 3–5%), since patients prone to these adverse events may have been excluded from participation during the run-in phase prior to randomization, and due to selection of patients in trials with lesser complexity of illness and comorbidities [12], [13]. Muscle-related adverse effects often lead to cessation of statin use, with consequent failure to lower low-density lipoprotein cholesterol (LDL-C) to target levels for primary and secondary prevention of CVD [12], [13], [14], [15]. Genetic predisposition, high drug dose, low body mass index (BMI), female gender, hypothyroidism, parathyroid dysfunction, underlying fibromyalgia or polymyalgia rheumatica, autoimmune phenomena, disturbances in muscle metabolism, alcohol abuse, low plasma vitamin D (vit D) level, drug interaction, as well as renal and hepatic dysfunction have been suggested as etiological factors [18], [19].
Vitamin D receptors are present on muscle cells [19], and low plasma levels of vit D are associated with hypotonia, proximal muscle weakness, prolonged time to peak muscle contraction and relaxation, as well as non-specific musculoskeletal pain [20]. In recent studies, it has been shown that vit D deficiency may be associated with an increased risk of statin-related muscle complaints [12], [18], [21] and some hypothetical mechanisms underlying statin-associated myalgia have been proposed. One of them concerns a reduction in muscle mitochondrial levels of coenzyme Q10 (CoQ10) that has a role in muscle energy production, subsequent to inhibition of the mevalonate pathway by statins [22]. However, according to a recent meta-analysis, CoQ10 supplementation does not prevent statin-related myopathy [23]. A second concern is increased beta-oxidation. In patients on high doses of statins, skeletal muscle levels of plant sterols might be increased by nearly 50%, which by inhibiting acetyl coenzyme A carboxylase, reduces fat synthesis, increases beta-oxidation, and results in muscle injury [24]. Others have suggested that individual genetic susceptibility plays an important role in statin-associated myalgia [25]. Finally, a potential mechanistic link for vit D is that the metabolism of some statins depends on cytochrome P450 3A4 (CYP3A4), which displays 25-hydroxylase activity in vitro [26]. Therefore, vit D deficiency may lead to ‘preferential shunting’ of CYP3A4 for vit D hydroxylation, in an effort to maintain levels of vit D (25[OH]D) within a physiological range, thereby reducing the availability of CYP3A4 for statin metabolism, which ultimately results in increased serum statin levels [26]. However, not all studies show consistent results with regard to vit D levels and statin-associated myalgia [12], [13], [18].
Taking into account the divergent data, we performed a meta-analysis to investigate whether there are differences of vitamin D (25[OH]D) levels between statin-treated subjects with and without myalgia.
Section snippets
Data sources
This study was designed in conformity to the guidelines of the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement [27]. We searched PubMed, Web of Science and Scopus, using keywords such as: statin, vitamin D level, statin-induced myalgia, statin-associated myalgia, myopathy, muscle pain, muscle function, side effect, adverse effect, adverse events, statin intolerance and supplementation. Data were collected from January 1, 1987 to April 1, 2014.
Study characteristics
The electronic search provided 437 articles: 141 from PubMed, 136 from Web of Science and 160 from Scopus. Of those, 20 were scrutinized as full texts; 13 studies were considered unsuitable, while 7 [21], [33], [34], [35], [36], [37], [38] met the inclusion criteria and were included in the analysis (Fig. 1). The final meta-analysis included 2420 statin-treated patients divided into subgroups of patients with myalgia (n = 666 [27.5%]) or asymptomatic (n = 1754). Table 1 shows the baseline
Discussion
This analysis involving 2420 statin-treated patients from 7 studies provides suggestive evidence that there is an association between plasma vit D levels and statin-associated myalgia. Patients with statin-associated myalgia had significantly lower levels of vit D compared to asymptomatic patients. To our knowledge, the present meta-analysis is the first to assess the association of vit D levels and statin-associated myalgia. This meta-analysis is hypothesis generating, and RCTs investigating
Acknowledgment
The meta-analysis has been prepared within the Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group (http://lbpmcgroup.umed.pl). This meta-analysis was written independently; no company or institution supported it financially. No professional writer was involved in the preparation of this meta-analysis.
Some of the authors have given talks, attended conferences and participated in trials and advisory boards sponsored by various pharmaceutical companies.
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Conflict of interest disclosures: None.