title: Statin-associated neuromyotoxicity.
abstract: The sequelae of cardiovascular disease contribute significantly to morbidity and mortality in developed nations. As a class, the statins have been shown to measurably reduce the burden of atherosclerotic illness. However, muscle- and, more recently, nerve-related toxicity have emerged as potential complications leading to treatment withdrawal. Generally, the myopathic signs and symptoms of tenderness, myalgias, cramping and elevated serum creatine kinase (CK) activity are fully reversible after drug discontinuation. Growing evidence suggests that latent or previously minimal symptomatic muscle disease may predispose to the development of myopathy. Less information is available regarding the natural history of the sensorimotor neuropathy, but it appears to be less reversible if large fiber function is clinically manifest. Pathophysiologic clues regarding the potential causes of statin myopathy with or without neuropathy are discussed with particular attention paid to the implications of disrupted mevalonate metabolism. For example, secondary defects in isoprenoid biosynthesis are expected to impair the production of a variety of intermediaries such as dolichols, which are crucial for N-linked glycosylation; geranylgeranyl pyrophosphate, which is necessary for coenzyme Q10 and G-protein synthesis; farnesyl-pyrophosphate, which facilitates the endoproteolytic cleavage and maturation of prelamin A and modifies B-type lamins and G-proteins; and isopentenylpyrophosphate, which is involved in a nucleoside modification of selenocysteinyl-tRNA and thus indirectly related to the synthesis of all selenoproteins (estimated at 35). The nature of statin neuromyotoxicity remains unresolved; however, investigating the cellular corollaries of deranged isoprenoid metabolism may uncover clues that lead to a more complete understanding of the elusive pathophysiology.
authors.affiliation: Department of Pediatrics, McMaster University Medical Center, Hamilton, Ontario, Canada.
authors.forename: Steven K
authors.initials: SK
authors.lastname: Baker
authors.forename: Mark A
authors.initials: MA
authors.lastname: Tarnopolsky
mesh_terms: D003402:Creatine Kinase / Q000097:blood; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D008798:Mevalonic Acid / Q000378:metabolism; D009120:Muscle Cramp / Q000188:drug therapy; D009135:Muscular Diseases / Q000097:blood; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D003402:Creatine Kinase; D008798:Mevalonic Acid