Hydroxy-methyl-glutaryl (HMG) CoA reductase inhibitors or statins are the most effective medications for reducing low-density lipoprotein cholesterol (LDL-C) and cardiac events in both coronary artery disease (CAD) patients and in previously healthy subjects. Statins are so effective that they are presently the most prescribed drugs in the United States and the world. Statins are well tolerated by the majority of patients, but can produce a variety of muscle problems ranging from myalgia, cramps and weakness to rhabdomyolysis with acute renal failure and even death. Muscle symptoms are reported in 3-5% of patients enrolled in industry-sponsored clinical trials 5, but have been reported in approximately 10% of patients treated with high doses statins in clinical practice 6. How statins produce myalgia and muscle injury is unknown. One theory maintains that blocking cholesterol synthesis reduces the cholesterol content of skeletal muscle cell membranes, making the membranes unstable, but muscle injury has not correlated with cholesterol reduction, however, and blocking cholesterol synthesis with other drugs does not produce myotoxicity making cholesterol reduction alone an unlikely culprit. Alternatively, statins reduce the production of isoprenoids, such as ubiquinone. Ubiquinone, or Co-enzyme Q10, participates in electron transport during oxidative phosphorylation in mammalian mitochondria. Serum ubiquinone levels decrease with statin treatment probably because ubiquinone is transported in the LDL particle. Intramuscular ubiquinone levels do not decrease, however, making ubiquinone an unlikely cause of the myopathy, although only one study no studies to our knowledge have examined ubiquinone levels in statin myopathic patients. More recent work suggests that a reduction in small GTP proteins may contribute to the myotoxicity of statins. Farnesyl and geranylgerranyl pyrophosphate production is reduced by statin therapy. Farnesyl pyrophosphate (FPP) is required for the activation of small guanosine triphosphate (GTP) binding regulatory proteins. These GTP binding proteins such as Ras, Rac and Rho promote cell maintenance and growth and attenuate apoptosis. 10, 11, 12 11;12 Apoptosis, or programmed cell death, is designed to assist in the remodeling and maintenance of tissue structure, but when inappropriately activated, apoptosis can produce pathological conditions. Statins produce a dose-dependent increase in apoptosis in vascular smooth muscle cells (VSMCs). Apoptosis in skeletal muscle, produced by reduced levels of small GTP binding proteins, could produce the skeletal muscle myopathy. We have documented that statins increase the muscle injury produced by exercise 14-16 suggesting that exercise may provide insight into the pathologic mechanisms. Management of the myalgias associated with statin therapy include using the lowest dose of statin possible, trying alternative statins, using lower doses with ezetimibe, trying other classes of lipid-lowering drugs, using Chinese red rice yeast, using long acting statins in QOD or BIW treatment schedules, using quinine for muscle cramps, doing “pulse therapy”, or even trying Co Q10. These treatments will be described.
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