Adverse Effects of Statins - Mechanisms and Consequences

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Curr Drug Saf. 2009 Sep 1. [Epub ahead of print]

Adverse Effects of Statins - Mechanisms and Consequences.

Be³towski J, Wójcicka G, Jamroz-Wiœniewska A.

Department of Pathophysiology, Medical University, Lublin, Poland.

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.