Statin-induced myopathy

Abstract

Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA) or statins are important drugs used in the treatment of dyslipidemia by reducing the biosynthesis of cholesterol. In addition to the main effect of lowering blood cholesterol levels, they have pleiotropic effects of which can be highlighted: i) improvement of endothelial function through modulation of endothelial nitric oxide synthase (eNOS) activity and inhibition of endothelin; ii) anti-inflammatory effects resulting from the reduction of proinflammatory cell signaling, oxidative stress, interaction of leukocytes to endothelial cells, and platelet and tissue factor activation; iii) stabilization of atherosclerotic plaque; iv) reduction of osteoclast formation and stimulation of osteoblasts (antiosteoporotic effect); and v) immunomodulation. It is known that these effects are variable and are not common to all statins. Even so, given the potential of these drugs, statins are currently the most prescribed medicines worldwide, and generally are extremely well tolerated by patients. However, adverse effects with different magnitudes can be observed in muscles, with occurrences ranging from a mild myalgia to rhabdomyolysis, progressing to acute renal failure and even death. The statin-induced rhabdomyolysis is a rare event, and is estimated to occur in 0.3 per 100,000 patient years of exposure, with a mortality rate of 9%. Regarding muscular symptoms, myalgia is characterized by pain with or without muscle weakness, not accompanied by an increased in creatine phosphokinase (CPK) enzyme, contrasting to myositis, that leads to an increase of this enzyme associated with muscle symptoms. Conversely, rhabdomyolysis, in generally, is characterized by muscle symptoms and significant increases in CPK levels (generally greater than 10 times the normal upper limit), and elevated levels of creatinine, renal dysfunction, dark urine, and myoglobinuria. Therefore, monitoring CPK levels is recommended during treatment with statins, since it is known the occurrence of an increase in their levels with potential severe effects on muscles even in the absence of muscular symptomatology. On the other hand, the opposite also occurs with muscle manifestations even in the absence of elevated CPK. The mechanisms by which statins develops miotoxicity remains not fully understood. Among the hypotheses proposed, the blocked in cholesterol biosynthesis induced by statins can be a myotoxicity determinant since the reduction in cholesterol content of cell membranes of skeletal muscle could make them unstable. Another hypothesis considers the farnesyl pyrophosphate and geranylgeranyl pirosfofate decrease, which normally activate regulatory proteins binding to guanosine triphosphate (GTP), which promotes cell maintenance and growth while decreasing apoptosis. Lastly, the hypothesis of myopathy occurrence across the depletion of coenzyme Q10 (CoQ10) in mitochondria is also considered. In association with drug therapy in clinical practice, it is often recommended to dyslipidemic patients the practice of regular physical exercises, which are known to be the most effective and cheapest intervention in reducing morbidity and mortality from cardiovascular diseases. However, miotoxicity can negatively interfere with the exercise or, in the opposite direction, the exercises may, itself, potentiate the statin myotoxic effect..