Statins

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Pyramid Comment: Diabetes, Statins and NICE

Statin Withdrawal
Statin Dangers

"Statins" are a class of drugs that lowers the level of cholesterol in the blood by reducing the production of cholesterol by the liver. Statins block the enzyme in the liver that is responsible for making cholesterol. This enzyme is called hydroxy-methylglutaryl-coenzyme A reductase (HMG-CoA reductase for short). Scientifically, statins are called HMG-CoA reductase inhibitors. Cholesterol is critical to the normal function of every cell in the body. However, it also contributes to the development of atherosclerosis, a condition in which cholesterol-containing plaques form within the arteries. These plaques block the arteries and reduce the flow of blood to the tissues the arteries supply. When plaques rupture, a blood clot forms on the plaque, thereby further blocking the artery and reducing the flow of blood. When blood flow is reduced sufficiently in the arteries that supply blood to the heart, the result is angina (chest pain) or a heart attack. If the clot occurs on plaques in the brain, the result is a stroke. Clots occurring on plaques in the leg cause intermittent claudication (pain in the legs while walking). By reducing the production of cholesterol, statins are able to reduce the formation of new plaques and occasionally can reduce the size of plaques that already exist. In addition, through mechanisms that are not well understood, statins also stabilize plaques and make them less prone to rupturing and forming clots. Although the important role of cholesterol in atherosclerosis is widely accepted by scientists, research also shows that atherosclerosis is a complex process that involves more than just cholesterol. For example, scientists have discovered that inflammation in the walls of the arteries may be an important factor in atherosclerosis. New research shows that statins reduce inflammation, which could be another mechanism by which statins beneficially affect atherosclerosis. This reduction of inflammation does not depend on statins' ability to reduce cholesterol. Further, these anti-inflammatory effects can be seen as early as two weeks after starting statins.

For what conditions are statins used?

Statins are used for preventing and treating atherosclerosis that causes chest pain, heart attacks, strokes, and intermittent claudication in individuals who have or are at risk for atherosclerosis. Risk factors for atherosclerosis include abnormally elevated cholesterol levels, a family history of heart attacks (particularly at a young age), increasing age, and diabetes. Most individuals are placed on statins because of high levels of cholesterol. Though cholesterol reduction is important, heart disease is complex and, as discussed previously, other factors such as inflammation may play a role. Thirty-five percent of individuals who develop heart attacks do not have high blood cholesterol levels, yet most of them have atherosclerosis. This means that high levels of cholesterol are not always necessary for atherosclerotic plaques to form. Because it is not clear which effect of statins is responsible for their benefits, the goal of treatment with statins should not be only the reduction of cholesterol to normal levels, but rather the prevention of the complications of atherosclerosis-angina, heart attacks, stroke, intermittent claudication, and death. This concept is important because it allows for individuals who have or are at risk for atherosclerosis, but do not have high levels of cholesterol, to be considered for treatment with statins. Statins, like ACE inhibitors, are an important class of drugs because some of these drugs have been shown to reduce the incidence of heart attacks, strokes, and death.

Are there differences among statins?

Statins differ in several ways. The most obvious difference is in their ability to reduce cholesterol. Currently, atorvastatin (Lipitor) is the most potent and fluvastatin (Lescol) is the least potent. A new statin, rosuvastatin (Crestor), which is under development, may be more potent than atorvastatin. The statins also differ in how strongly they interact with other drugs. For example, pravastatin levels in the body are less likely to be elevated by other drugs because the enzymes in the liver that eliminate pravastatin (unlike the enzymes that eliminate other statins) are not blocked by most other drugs. Another difference is that only three of the statins (pravastatin, simvastatin, and lovastatin) have been shown in large studies to actually reduce heart attacks. In addition, simvastatin and pravastatin have demonstrated the ability to reduce death. Pravastatin also reduces the occurrence of strokes. Interestingly, these three statins are derived from natural sources and have similar chemical structures. The other statins are completely synthetic and have chemical structures that differ greatly from the natural statins. Statins differ in the frequency with which they cause a rare side effect called rhabdomyolysis, in which muscles are damaged. Cerivastatin (Baycol) was withdrawn from pharmacies worldwide because it causes rhabdomyolysis more often than other statins. In contrast, the results from three large studies of pravastatin and over ten years of experience with pravastatin have proven that pravastatin is safe. Finally, statins also differ in how they affect fibrinogen, a protein that is important in the clotting of blood and the growth of smooth muscle cells (which, like inflammation, also may be involved in atherosclerosis). The importance of this difference is unclear. However, in view of the complexity of the process of atherosclerosis and the possibility that the beneficial effects of statins are due to effects other than their lowering of cholesterol, these differences could be quite important. Moreover, since it is not yet clear exactly how statins bring about their beneficial effects, it is important to demonstrate that each statin reduces heart attacks, strokes, and deaths in addition to comparing their effects. One such study now underway is comparing the effects of pravastatin and atorvastatin in reducing heart attacks, strokes, and death.

What are the side effects of statins?

Statins have few important side effects. The most common side effects are headache, nausea, vomiting, constipation, diarrhea, headache, rash, weakness, and muscle pain. The most serious (but fortunately rare) side effects are liver failure and rhabdomyolysis. Rhabdomyolysis is a serious side effect in which there is damage to muscles. Rhabdomyolysis often begins as muscle pain and can progress to loss of muscle cells, kidney failure, and death. It occurs more often when statins are used in combination with other drugs that themselves cause rhabdomyolysis or with drugs that prevent the elimination of statins and raise the levels of statins in the blood. Since rhabdomyolysis may be fatal, unexplained joint or muscle pain that occurs while taking statins should be brought to the attention of a healthcare provider for evaluation.

With which drugs do statins interact?

Statins have some important drug interactions. The first type of interaction involves the elimination of statins by the liver. Liver enzymes (specifically the cytochrome P-450 liver enzymes) are responsible for eliminating all statins from the body with the exception of pravastatin. Therefore, drugs that block the action of these liver enzymes increase the levels of simvastatin, lovastatin, fluvastatin, and atorvastatin (but not pravastatin) in the blood and can lead to the development of rhabdomyolysis. Drugs or agents that block these enzymes include protease inhibitors (used in treating AIDS), erythromycin, itraconazole, clarithromycin, diltiazem, verapamil, and grapefruit juice. Another important drug interaction occurs between statins and niacin or fibric acids, e.g., gemfibrozil (Lopid), clofibrate (Atromid-S), and fenofibrate (Tricor). Fibric acids and niacin can cause rhabdomyolysis or liver failure when used alone and combining them with statins increases the likelihood of rhabdomyolysis or liver failure. Nevertheless, fibric acids and niacin are often used with caution in combination with most statins. Cholestyramine (Questran) as well as colestipol (Colestid) bind statins in the intestine and reduce their absorption into the body. To prevent this binding within the intestine, statins should be taken one hour before or four hours after cholestyramine or colestipol.

Which statins are available?

Statins that are approved for use in the United States include:

• atorvastatin (Lipitor) 
• fluvastatin (Lescol) 
• lovastatin (Mevacor) 
• pravastatin (Pravachol) 
• rosuvastatin (Crestor) 
• simvastatin (Zocor)
• pitavastatin (Livalo)