The Spectrum of Statin Myopathy
Muscle biopsy from patients with statin myopathy may show a variety of nonspecific findings. Cytochrome oxidase negative fibres (characteristic of mitochondrial dysfunction), increased lipid stores and cytoplasmic vacuolization with intact sarcolemma are routinely seen.
The underlying cellular mechanism of toxic statin myopathy or statin intolerance has not been elucidated. One major hypothesis suggests that coenzyme Q10 (coQ10) depletion as a result of statin therapy may result in mitochondrial dysfunction and muscle fibre injury. Although low levels of coQ10 have been associated with statin use and statin myopathy, a few trials of coQ10 supplementation have had conflicting results. A recent study of coQ10 and selenium supplementation in patients with self-limited statin myopathy failed to improve any muscle-related symptoms compared with placebo.
Other mechanisms relating to calcium metabolism or structural effects of low cholesterol on myocyte membrane integrity are suggested, but none has been clearly shown to account for the muscle-related symptoms of statin use. Several investigations are ongoing and their discussion is beyond the scope of this review.
Self-limited toxic statin myopathy is dose-dependent. High-dose statins are more likely to cause myotoxicity. Indirect evidence for dose dependence is also suggested by genetic risk factors or drug interactions associated with statin intolerance; most interfere with statin clearance and increase its serum levels. In addition, muscle symptoms tend to resolve in some patients with an adjustment of the dose, change to a lower potency statin or discontinuation. Most symptoms and elevated creatine kinase levels associated with statin use usually resolve after statin withdrawal. However, the resolution of symptoms usually takes 2–3 months and, in some instances, may take longer than14 months.
Histopathology and Pathophysiology
Muscle biopsy from patients with statin myopathy may show a variety of nonspecific findings. Cytochrome oxidase negative fibres (characteristic of mitochondrial dysfunction), increased lipid stores and cytoplasmic vacuolization with intact sarcolemma are routinely seen.
The underlying cellular mechanism of toxic statin myopathy or statin intolerance has not been elucidated. One major hypothesis suggests that coenzyme Q10 (coQ10) depletion as a result of statin therapy may result in mitochondrial dysfunction and muscle fibre injury. Although low levels of coQ10 have been associated with statin use and statin myopathy, a few trials of coQ10 supplementation have had conflicting results. A recent study of coQ10 and selenium supplementation in patients with self-limited statin myopathy failed to improve any muscle-related symptoms compared with placebo.
Other mechanisms relating to calcium metabolism or structural effects of low cholesterol on myocyte membrane integrity are suggested, but none has been clearly shown to account for the muscle-related symptoms of statin use. Several investigations are ongoing and their discussion is beyond the scope of this review.
Self-limited toxic statin myopathy is dose-dependent. High-dose statins are more likely to cause myotoxicity. Indirect evidence for dose dependence is also suggested by genetic risk factors or drug interactions associated with statin intolerance; most interfere with statin clearance and increase its serum levels. In addition, muscle symptoms tend to resolve in some patients with an adjustment of the dose, change to a lower potency statin or discontinuation. Most symptoms and elevated creatine kinase levels associated with statin use usually resolve after statin withdrawal. However, the resolution of symptoms usually takes 2–3 months and, in some instances, may take longer than14 months.