As statins are commonly prescribed and are useful in preventing strokes, heart attacks I thought this recent review published in the Lancet would be of interest. Any problems of course should be referred to your doctor as soon as possible. Other measures apart from statin use should be pursued including life style changes - more exercise, dietary changes, cutting down alcohol consumption, reducing weight are normally recommended either before considering statin treatment or as well as statin use.

However, this recent review of the safety of statins has concluded that these drugs are well tolerated, with their main adverse effects — myopathy and rhabdomyolysis — occurring very rarely at standard doses.

"With a few caveats and while awaiting good quality randomized data for the newer drugs, statins seem to be a remarkably safe group of drugs when used at their usual doses," the author, Dr Jane Armitage (University of Oxford, UK), concludes.

The review, published online in The Lancet on June 7, includes all papers published between 1985 and 2006 on the safety, efficacy, and side effects of statins. Armitage notes that since statins were first approved in 1987, their ability to reduce the risks of vascular death, non-fatal MI, stroke, and the need for arterial revascularization has been shown by several large, high-quality randomized trials. But she adds that hopes that statins might protect against fractures, dementia and macular degeneration have not been supported by evidence from randomized trials.

Myopathy

Armitage says the only well-documented, consistent adverse effects associated with statins are muscle toxicity, including myopathy and rhabdomyolysis, and effects on liver enzymes. She states that all statins occasionally cause myopathy which could progress to rhabdomyolysis but she estimates that myopathy occurs in fewer than one in 10,000 patients at standard doses of statins; and while the risk increases with higher statin doses, it remains very low with atorvastatin 80 mg. Myopathy or rhabdomyolysis are usually reported in association with concomitant use of interacting drugs (especially fibrates), the review notes, adding that this side-effect is most likely to occur within a few months of starting statin treatment, or of increasing the dose, although some cases have been reported even after some years of apparently stable statin treatment, usually as the result of starting an interacting drug.

Armitage points out that muscle pain is common in middle-aged patients (and often believed to be due to the drug because of product warnings), but is, nevertheless, unlikely to be due to statin treatment. Measurement of creatine kinase in such patients can exclude myopathy and allow safe continuation of treatment, she says. Importantly, any risks of myopathy and rhabdomyolysis can be kept to a minimum by knowledge of potential drug interactions and the vulnerability of particular groups of patients, she adds.

Transaminase Increases

The review reports that a small percentage of patients taking statins experience an increase in liver enzymes (in particular, alanine and aspartate transaminases), generally seen in the first 6 months of treatment. These are asymptomatic, are reversible on stopping the statin treatment or with dose reduction, and there is no convincing evidence from the statin trials that increases in either transaminase are associated with liver damage, Armitage writes. She adds that the effect on transaminases seems to be dose dependent, and effects on other liver enzymes and bilirubin also emerge with higher doses, but unlike with myopathy, the effects might be because of a greater fall in LDL cholesterol. But even at high doses, these liver enzyme increases have not been associated with hepatitis or liver failure.

She notes that routine monitoring of liver function after starting statin treatment is no longer recommended for simvastatin, pravastatin, or lovastatin up to 40 mg daily, but remains recommended for the other statins and higher doses. If transaminases are more than three times the upper limit of normal in an asymptomatic patient with no other liver abnormalities, the enzymes should be checked within a week and statin treatment stopped temporarily if alanine transaminase is still at this level. Increases to between two to three times the upper limit of normal in an asymptomatic patient necessitate monitoring, but will often resolve while on treatment.

The review also examines the safety of statins in several vulnerable groups. It says that no adjustment of dosage is needed for the elderly, since people aged up to 80 years were recruited in the various trials, but that the very elderly may be at increased risk of myopathy. It also reports that there is no evidence to suggest people consuming excess alcohol are at greater risk of side effects from statin use, although many such people were excluded from statin trials. Warfarin users may need to adjust the amount of the anticoagulant when statin treatment begins and again when it ends, it adds.

Lancet. Published online June 7, 2007.

The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.

Clinical Context

The statins are widely used to lower cholesterol levels via inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Several large randomized controlled trials have shown that statins reduce the risks for vascular death, nonfatal myocardial infarction, stroke, and the need for arterial revascularization procedures, all in relation to lowering of low-density lipoprotein (LDL) cholesterol levels.

Because cholesterol lowering is now recommended for a wide range of people at cardiovascular risk, including those with average and below-average lipid levels, statin safety is of paramount importance. Six statins are available worldwide: lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and rosuvastatin; pitavastatin is available only in Japan and India. This review highlights the safety of achieving and maintaining low levels of total and LDL cholesterol as well as the specific safety of the available statins at different doses.

Study Highlights

The authors reviewed safety information from randomized trials of specific statins, including reports of spontaneous adverse effects and other sources of safety data.

"Standard doses," or the commonly prescribed daily doses that typically reduce LDL cholesterol levels by 30% to 45%, are 10 to 20 mg for atorvastatin, 40 to 80 mg for fluvastatin, 40 mg for lovastatin, 40 mg for pravastatin, 10 mg for rosuvastatin, and 20 to 40 mg for simvastatin. Statins have qualitatively similar effects on lipid levels but varying efficacy in lowering LDL cholesterol levels.

Statins are safe and well tolerated by most people, and they have been extensively studied. Their widespread use may globally affect the burden of cardiovascular disease.

Statins are metabolized in the liver. Those that are metabolized primarily by the cytochrome P-450 system can interact with other commonly prescribed drugs (itraconazole, ketoconazole, miconazole, gemfibrozil, bezafibrate, fenofibrate, ciprofibrate, erythromycin, clarithromycin, telithromycin, nefazodone, verapamil, amiodarone, and HIV protease inhibitors) and regular ingestion of grapefruit juice.

Although the adverse effects on muscle and on liver enzymes generally apply to all statins, other aspects of safety should not automatically be extrapolated from 1 statin to another, because each statin has a different risk for adverse effects and for drug interactions.

Muscle pain is common in middle-aged patients using statins and is often thought to be related to statin use because of product warnings. However, muscle pain is actually unlikely to be caused by statin treatment, and adverse effects on muscle are rare at standard doses.

Myopathy, or muscle pain or weakness with blood creatine kinase (CK) levels more than 10 times the upper limit of normal, typically occurs in fewer than 1 in 10,000 patients receiving standard statin doses, but this risk varies between statins and increases with use of higher doses and interacting drugs. Measurement of CK levels in patients with muscle pain can rule out myopathy and allow safe continuation of treatment.

Rhabdomyolysis is a rarer and more severe form of myopathy with myoglobin release into the circulation, CK levels more than 40 times the upper limit of normal, and risk for renal failure. Both of these adverse effects on muscle occur more often with higher statin doses and are reversed by stopping statin use, usually leading to full recovery.

All statins can cause myopathy and rhabdomyolysis, with varying risk for different statins that is not clearly related to the LDL cholesterol–lowering efficacy. For example, cerivastatin is not particularly effective but is much more likely to cause rhabdomyolysis vs other statins.

Other cholesterol-lowering agents, especially fibrates, can also rarely cause myopathy, but combining statins with some fibrates, particularly gemfibrozil, increases the risk. Gemfibrozil also increases plasma concentrations of some statins by inhibiting their glucuronidation.

The risk for myopathy with all statins is affected by drug interactions that are sometimes related to the metabolism of particular statins via the cytochrome P-450 system. However, other mechanisms may also be involved.

Patients with renal impairment, hypothyroidism, or a seriously debilitated state or who are older than 80 years are more susceptible than others to myopathy.

Adverse effects on the liver are rare at standard statin doses. All statins are associated with asymptomatic increases in concentrations of liver transaminases but not clearly associated with increased risk for liver disease.

Pearls for Practice

Statins are typically safe and well tolerated at standard doses and are metabolized in the liver. Those that are metabolized primarily by the cytochrome P-450 system can interact with other commonly prescribed drugs (itraconazole, ketoconazole, miconazole, gemfibrozil, bezafibrate, fenofibrate, ciprofibrate, erythromycin, clarithromycin, telithromycin, nefazodone, verapamil, amiodarone, and HIV protease inhibitors) and regular ingestion of grapefruit juice.

Myopathy typically occurs in fewer than 1 in 10,000 patients receiving standard statin doses, but this risk varies between statins and increases with use of higher doses and interacting drugs. Measurement of CK levels in patients with muscle pain can rule out myopathy and allow safe continuation of treatment. Both myopathy and rhabdomyolysis occur more often with higher statin doses and are reversed by stopping statin use, usually leading to full recovery.

Medscape Medical News 2007. ©2007 Medscape