Mechanisms of Statin-Induced Myopathy

Abstract

The advent of the HMG-CoA reductase inhibitors, or statins, in the 1980’s as highly efficacious agents for the lowering of low-density lipoprotein-cholesterol (LDL-C) revolutionized treatment of hypercholesterolemia, a long established risk factor for premature coronary heart disease. Indeed, a recent prospective meta-analysis of data from more than 90 000 participants in 14 randomized clinical trials revealed that a statin-mediated reduction of 1 mmol/L (40 mg/dL) in LDL-C that is sustained for 5 years may produce a proportional reduction in major vascular events of some 23%.1 Greater reductions in LDL-C, which may be attained with intensive statin therapy as exemplified in the recent Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22), Treating to New Targets (TNT), and Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trials involving use of atorvastatin (80 mg/d), produce larger reductions in vascular disease risk.2–4 Importantly, risk reductions are proportional to the absolute reduction in LDL-C1, and moreover clinical benefit may be apparent with intensive statin treatment as early as 30 days after initiation in acute coronary syndrome patients, with significant decrement in cardiovascular morbi-mortality.5 See page 2560 Statins not only exhibit a remarkably high benefit to risk ratio, but are equally characterized by a safety profile with excellent tolerance.6,7 Nonetheless, statins may exert toxic effects on skeletal muscle which are generally referred to as myopathy, and whose overall incidence is typically <0.1% of patients receiving statin monotherapy.6 Although myopathy can refer to any muscular disease, the recent clinical advisory on the use and safety of statins differentiated myalgia as muscle ache or weakness in the absence of elevation in creatine kinase (CK), and myositis as adverse muscular symptoms associated with increased CK levels.7 Rhabdomyolysis is a severe form of myositis involving myoglobulinuria, …