SOMETIMES, a patient's high cholesterol numbers won't budge despite his efforts to eat healthier and exercise regularly. For these patients, statins may be the best option.
Statins are cholesterol-lowering drugs that inhibit beta-hydroxy-beta-methylglutaryl coenzyme A (HMG-CoA) reductase. HMG-CoA reductase is an enzyme that helps regulate cholesterol production. Commonly prescribed statins include lovastatin (Mevacor), simvastatin (Zocor), atorvastatin (Lipitor), pravastatin (Pravachol), and rosuvastatin (Crestor).
Statins lower low-density lipoprotein cholesterol (LDL-C)-the so-called bad cholesterol-by slowing its production and boosting the liver's ability to remove it from the blood. To a lesser extent, they also reduce absorption of cholesterol by the intestines.
How do patients benefit from a lower LDL-C level? An elevated LDL-C level in the blood can lead to buildup of plaque inside artery walls, called atherosclerosis. This can cause cardiovascular disease (CVD) and increase the risk of stroke or heart attack. Statins have been shown to decrease serum LDL-C levels by as much as 55%.
A bright future?
Statins may have other benefits for patients with CVD, including decreasing vascular inflammation and slowing the process of atherosclerosis. Researchers are also investigating other potential uses for statins, including reducing diabetes complications, slowing osteoporosis progression, lessening the effects of dementia, lowering blood pressure, and improving ventricular function in patients with heart failure.
How can all of these benefits be possible with one type of drug? It's theorized that the possible wide-ranging benefits of statins result from a variety of mechanisms, from direct effects on regenerating tissue to stabilizing the endothelium of blood vessels. The result of these actions is that the vasculature is stabilized, blood flow is improved, and tissue health is maintained.
Caution signs
Statins boast a high margin of safety, but you need to watch for two rare but potentially serious adverse effects: liver toxicity and myopathy.
Liver toxicity can develop if a patient's taking a high dose of a statin or if he combines a statin with another potentially hepatotoxic drug, such as acetaminophen or alcohol.
Myopathy can occur even when a statin is used alone, but the risk increases when a statin is combined with niacin (also known as vitamin B3 or nicotinic acid) or a fibrate, like gemfibrozil (Lopid) or fenofibrate (Tricor). It's also more common in patients who have diabetes or renal disease and are taking a statin. If left unchecked, myopathy can progress to life-threatening rhabdomyolysis and kidney failure (see Statin-induced rhabdomyolysis).
Stop signs
Statins are metabolized by the liver and excreted by the kidneys. The primary mechanism of statin metabolism is the cytochrome P450 pathway (CYP3A4 or CYP2C9 isoenzyme) in the liver. (Pravastatin is metabolized via a different CYP system.) Most drug-drug interactions with statins come from interference with this pathway. Statins interfere with the metabolism of other drugs and cause toxicity by blocking the P450 pathway. For example, statins decrease digoxin metabolism by this mechanism and can result in digoxin toxicity.
Concomitant drug therapy can also interfere with statin metabolism, leading to adverse effects from a very high statin level. When other drugs block the cytochrome P450 pathway, the statin can't be metabolized and a high level results. Combining a statin with any of the following drugs should be avoided or done with extreme caution:
* cyclosporine (Neoral, Sandimmune)
* itraconazole (Sporanox)
* ketoconazole (Nizoral)
* erythromycin (Ilotycin)
* clarithromycin (Biaxin)
* telithromycin (Ketek)
* HIV protease inhibitors
* nefazodone (Serzone).
Refer to the drug's prescribing information for specific recommendations.
The herbal supplement St. John's wort may decrease statin blood levels and reduce the drug's effectiveness in lowering blood lipid levels. And here's one more contraindication to keep in mind: Grapefruit products interfere with the metabolism of most statins (except pravastatin) and can significantly increase blood levels of the drug. Strongly advise patients to avoid grapefruit products while on statin therapy. However, you can give them the green light on other citrus products, like orange juice and lemonade.
Proceed with care
Statins are safe drugs for many patients, but taking them in high doses or combining them with other medications can lead to treatment complications and adverse drug effects. To reduce the risk of harmful drug-drug interactions, always question patients carefully about all prescription and over-the-counter medications and herbal supplements they're taking when a statin is prescribed.
Patients who take other medications metabolized by the liver's cytochrome P450 pathway or who take multiple daily medications should be encouraged to eat a healthy diet, lose weight, quit smoking, and exercise regularly to decrease or eliminate their need for statins, thereby reducing the risk of harmful interactions.
Because statins have possible toxic effects, patients should have their liver and kidney functions tested regularly, with especially close monitoring during severe physiologic stress, including major surgery, trauma, and sepsis.
If a patient shows signs of toxicity (muscle pain, weakness, or tenderness), temporarily discontinuing the statin will usually allow liver and renal function to normalize. The drug may be resumed at a lower dose or a different statin may be ordered once the cause of the reaction is discovered and treated.
Finally, advise your patients who take statins to be careful in the sun; photosensitivity is sometimes an effect of statin therapy.
Statin-induced rhabdomyolysis
The growing use of statins for controlling hyperlipidemia has produced a rise in cases of statin-induced rhabdomyolysis, a serious and potentially fatal condition in which muscle fibers break down and their components-including creatine kinase, myoglobin, and potassium-are released into the bloodstream. The breakdown may be manifested by severe muscle pain or, in extreme cases, dark or cola-colored urine.
Patients taking statins should have their creatine kinase levels carefully monitored along with their blood lipids and liver enzymes. The following factors increase the risk of statin-induced rhabdomyolysis:
* renal impairment
* hypothyroidism
* personal or family history of hereditary muscular disorders
* history of muscular toxicity with another statin or a fibrate
* alcohol abuse
* increase in plasma levels
* Japanese/Chinese ethnicity
* concomitant use of a fibrate.
Selected references