Rhabdomyolysis associated with hydroxymethylglutaryl-coenzyme A reductase inhibitors.
BACKGROUND
The recent withdrawal of cerivastatin by the manufacturer has led to an interest in hydroxymethylglutaryl-coenzyme A (HMG-CoA) inhibitors and the incidence of myopathy. We review the epidemiology, pharmacology, and presumed mechanisms of statin-induced myopathy, with a particular focus on cerivastatin.


METHODS
A MEDLINE search of English-language articles published between 1985 and 2003 was performed. Key words included HMG-CoA inhibitors, statins, myopathy, myotoxicity, rhabdomyolysis, adverse events, drug interactions, and cerivastatin.


RESULTS
The initial trials, which assessed the efficacy of first-generation HMG-CoA inhibitors, did not show a clinically significant increase in the incidence of myopathy. However, on the basis of Food and Drug Administration post-marketing surveys, the rate of cerivastatin-induced rhabdomyolysis appeared to be 10-fold greater than that of the other statins, despite safe pre-clinical profiles. However, no clinical trials have been performed directly comparing the rates of myotoxicity of all commercially available statins. The mechanism of statin-induced myopathy remains unclear. The prevailing theory is that lipophilic statins lead to depletion of intermediates normally formed after cholesterol synthesis within myocytes. Risk factors for the development of myopathy include drug interactions (especially with fibrates) and the coexistence of conditions known to predispose patients to rhabdomyolysis.


CONCLUSIONS
The cerivastatin experience emphasizes the need for large safety trials before drug approval and for vigilant post-marketing surveillance. Further research and sound clinical judgment may lead to the identification of high-risk individuals in whom statins should be avoided.
Jamal
Shelina M
SM
Division of Cardiology, Montreal, Quebec, Canada.
Eisenberg
Mark J
MJ
Christopoulos
Stavroula
S
D016572:Cyclosporine / Q000008:administration & dosage / Q000009:adverse effects; D042926:Cytochrome P-450 CYP4A / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D015248:Gemfibrozil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects* / Q000493:pharmacokinetics; D006937:Hypercholesterolemia / Q000188:drug therapy; D006949:Hyperlipidemias / Q000188:drug therapy; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects; D015994:Incidence; D012206:Rhabdomyolysis / Q000139:chemically induced* / Q000453:epidemiology; D015996:Survival Rate
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D042926:Cytochrome P-450 CYP4A; D015248:Gemfibrozil