New insights into mechanisms of statin-associated myotoxicity
Introduction
Statin drugs represent the main therapeutic class of lipid lowering molecules that lower total and low-density lipoprotein (LDL) cholesterol. Statins act by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (Figure 1). Their development over the past 20 years has represented a major medical advance [1]. The benefits of statin treatments in primary and secondary prevention are particularly well documented, and new beneficial aspects are regularly reported. In addition to the benefits of cholesterol lowering, it has been shown that statins present cholesterol-independent effects allowing for improved endothelial function, enhanced stability of atherosclerotic plaques, decreased inflammation and oxidative stress, and inhibited thrombogenic response in the vascular wall [1]. Clinical trials have demonstrated a reduction in cardiovascular-related morbidity and mortality in treated patients with or without coronary artery disease [1]. This therapeutic is the world's fastest growing class of drugs.
The currently used statins are generally well tolerated and present a good safety profile [2]. Nevertheless, adverse effects of statins have been reported such as hepato-toxicity characterized by an increased level of transaminase occurring with an incidence of 0.1–1.9% [3]. A low risk of neuropathy and other minor adverse effects such as generalized gastrointestinal discomfort are also known. The main reported adverse effects of statins are various forms of myotoxicity ranging from myalgias to rhabdomyolysis. These deleterious muscle manifestations occur in 1–7% of statin-treated patients. They do not correlate with the degree of cholesterol lowering effect of the drug used [4, 5].
Many hypotheses have been proposed to explain statin myotoxicity. This review highlights the most recent findings that can account for interpreting the pathophysiological mechanisms for statin-induced myotoxicity.
Section snippets
Clinical and pharmacological aspects
Variable incidence in the myotoxic effect of statins is reported in the literature. This could be partly due to the definition of muscle toxicity. Most clinical trials have defined the toxicity as myalgia or muscle weakness with a level of creatine kinase (CK) greater than 10 times the normal upper limit. However, this biological index is not always associated with clinical symptoms [6, 7]. The clinical symptoms are also difficult to evaluate and somehow subjective from one patient to the
Pathophysiological mechanisms
Various hypotheses have thus been proposed to explain statin-induced muscle injury. It is first important to note that this myotoxicity of statin is dose dependent [17]. Statin effect can be due to an indirect effect through the reduction of cholesterol synthesis or a direct effect on different muscle targets.
Conclusion
At first glance, statin-induced myotoxicity appears multifactorial. Nevertheless, the latest studies performed to elucidate pathophysiological mechanisms of statins on muscle function have assembled some pieces of the puzzle. Besides deleterious effect due to a reduction in cholesterol biosynthesis, statins seem to have a direct effect on the respiratory chain of the mitochondria. This effect depends nevertheless on the type of statin, as discussed earlier. Without excluding a direct effect of
References and recommended readings
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
Acknowledgements
AL is a CNRS senior scientist supported by INSERM and the ‘Leducq Fondation’.
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