Adverse effects of statins - mechanisms and consequences.

Statins inhibit 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol biosynthesis, which converts HMG-CoA to mevalonate. Statins lower plasma low-density lipoprotein (LDL) cholesterol by causing intracellular cholesterol depletion and upregulating the expression of LDL receptors. Apart from cholesterol, mevalonate is also the substrate for the synthesis of nonsteroid isoprenoids including farnesylpyrophosphate, geranylgeranylpyrophosphate (both attached to small GTP-binding proteins by protein prenyltransferases), coenzyme Q, dolichol, isopentenyladenosine, etc. Depletion of these isoprenoids results in so called "pleiotropic" effects of statins which are independent of cholesterol lowering. Although statins are generally well-tolerated, adverse effects may occur in some patients. These effects result from impaired protein prenylation, deficiency of coenzyme Q involved in mitochondrial electron transport and antioxidant protection, abnormal protein glycosylation due to dolichol shortage, or deficiency of selenoproteins. Myopathy is the most frequent side effect of statins and in some cases may have a form of severe rhabdomyolysis. Less common adverse effects include hepatotoxicity, peripheral neuropathy, impaired myocardial contractility and autoimmune diseases. The risk of these unfavorable effects is largely outweighed by great reduction of cardiovascular events in statin users. However, due to increasing number of patients taking statins, monitoring for any side effects, intense research to recognize their mechanisms and to identify susceptible patients, as well as rational management of these complications are mandatory to further improve safety of these excellent drugs.