Statins - - Doing More Than Lowering Your Cholesterol?

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DOCTOR'S VIEW ARCHIVE

PARIS - This is about the "statins", an important group of drugs that lower cholesterol. They may do much more, it appears, than just reduce cholesterol, as if that were not enough!

The statins are grouped together as "Antilipemic Agents" by the PDR (Physicians' Desk Reference). Lipemia is an excess of lipid (fat) in the blood, so an antilipemic agent obviously acts to reduce lipids. Among the different types of "Antilipemic Agents", the PDR has the "HMG-CoA Reductase Inhibitors", better known as the statins. The statins now on pharmacy shelves in the U.S. (putting the brand name first in capital letters followed by the generic name in parentheses) are:

More about the statins later. First for some background beginning with the prime target of the statins, cholesterol.

Cholesterol is generally thought to

be the major contributor to atherosclerosis, the process by which cholesterol is deposited in artery walls . These cholesterol deposits harden arteries and narrow their interior diameter. Atherosclerosis of the coronary arteries that supply blood and oxygen to the heart muscle leads to angina and raises the risk of heart attacks. Atherosclerosis of the carotid and vertebral arteries, the vessels that supply blood and oxygen to the brain, increases the risk of strokes.

Lowering the cholesterol, especially LDL ("bad") cholesterol, is clearly good. It helps prevent and may reverse atherosclerosis and it decreases the risk of heart attacks.

In the 1970's and 1980's, studies of diet and lipid-lowering agents (such as niacin and clofibrate) were in conclusive. They failed to prove that that lowering blood cholesterol prolonged life. Even though deaths related to heart attacks were modestly reduced, this was offset by an apparent increase in deaths related to cancer and other causes.

Only in the last 10 years has conclusive evidence surfaced showing that medications can indeed lower the "bad" LDL cholesterol. More to the point, it has been proved that reducing LDL cholesterol reduces heart attacks and lengthens life. Many of these critically important studies have used the HMO-CoA reductase inhibitors, the statins.

Now in the 90s, it is common place to be not only on a diet low in cholesterol and saturated fats but also on a drug to reduce the levels of cholesterol. And that drug is likely to be a statin.

However, there is much that is not f

ully understood about the statins. Among the questions before biomedical scientists is, do the statins prevent heart attacks purely by lowering blood levels of cholesterol? Or might some of the beneficial effects of the statins be related to other actions of the statins on blood vessels?

The statins act by inhibiting an enzyme called 3-hydroxy-3- methylglutaryl-coenzyme A reductase (blessedly abbreviated to HMG-CoA. This enzyme's normal job is to catalyze the conversion of HMG-CoA to mevalonate, an early step in the synthesis of cholesterol. In biochemical terms, it is a rate-limiting step in the body's cholesterol production by the body. Inhibit that step and you inhibit your ability to make cholesterol.

The liver is the primary site where the body makes cholesterol and the liver is the primary site of action of the statins. The statins lower the blood levels of total and LDL cholesterol by blocking the liver's production of cholesterol.

In addition to lowering LDL cholesterol, the statins lower the triglycerides (another form of fat in the blood) and increase the HDL ("good") cholesterol. While LDL cholesterol causes atherosclerosis, HDL actually removes cholesterol from artery walls and protects them from atherosclerosis. HDL cholesterol; therefore, deservedly is called the "good" cholesterol an higher levels are desirable.

Different statins have different effectiveness in lowering LDL cholesterol and triglycerides and they also differ in their effectiveness in increasing HDL cholesterol. But it is not yet known whether the differing abilities of the statins to lower LDL cholesterol and increase HDL cholesterol correlates with their effectiveness in preventing and/or reversing atherosclerosis.

One of the first statins to be scrutinized was simvastatin (Zocor). In the Scandinavian Simvastatin Survival Study, the subjects were 4444 men and women with known coronary artery heart disease (many already had previous heart attacks) and with moderately to severely elevated blood cholesterol levels. Together with advice on diet, the subjects were given simvastatin or a placebo (a dummy drug) for an average of 5 years. The study showed that those subjects who received simvastatin had significantly fewer repeat heart attacks, fewer strokes, less need for coronary artery bypass surgery, and improved overall survival. Prevention of repeat heart attacks by simvastatin is described as secondary prevention. This Scandinavian study demonstrated the value of simvastatin for the secondary prevention of heart attacks.

Pravastatin (Pravachol) is the most

extensively studied of all the statins. In the West of Scotland Coronary Prevention Study, 6595 men with moderately elevated blood cholesterol were put on a lipid- lowering diet and given pravastatin or a placebo for an average of 5 years. This study differed from the Scandinavian study in that none of the subjects in the West of Scotland had had heart attacks and most of them had no known coronary artery heart disease. Pravastatin was found to decrease the risk of heart attack and death from coronary heart disease by 30% and to improve overall survival. Prevention of heart attacks in patients with no prior heart attacks is called primary prevention. Thus, pravastatin proved of value in the primary prevention of heart attacks.

Four additional trials in Europe and the United States using pravastatin (Pravachol) for 2-3 years involved a total of 1891 men and women with only mildly to moderately elevated total and LDL cholesterol. (The levels were lower than in the Scandinavian and West of Scotland studies). Most participants had had documented evidence of atherosclerosis of the coronary arteries and some had had heart attacks. When the results from these 4 trials were analyzed (they were so similar they could be pooled) there was an impressive reduction in heart attack (by 62%) and stroke, along with improved overall survival in the pravastatin-treated patients. The results further showed that pravastatin benefited both men and women, older and younger patients, and patients with or without a prior history of heart attacks and high blood pressure. There were thus significant benefits of pravastatin even for people with only modestly elevated cholesterol. X-ray studies of the coronary arteries (coronary angiograms) confirm a decrease in the progression of atherosclerosis (or even a regression of established atherosclerosis) inpatients treated with pravastatin.

However, the reduction of heart attacks and deaths from coronary heart disease appears out of proportion to the degree of improvement observed in an giograms and the survival benefits of pravastatin seem out of proportion to the modest degree of reduction (20-30%) in LDL cholesterol attained with pravastatin.

Scientists are therefore starting to

wonder if there is more to pravastatin than just lowering the LDL cholesterol. Heart attacks cause the death of heart muscle by obstructing a coronary artery and thereby interrupting the supply of oxygen to the heart muscle . The obstruction is caused by the formation of a blood clot usually next to a ruptured cholesterol plaque on the inner wall of the artery. The rupture of the plaque initiates the aggregation of platelets (blood elements that form blood clots) and leads to clot formation. Factors that increase plaque instability increase the chances of rupture and risks of heart attacks. These factors include high levels of LDL cholesterol in the blood, infection and inflammation of the artery. Measures that prevent plaque rupture and agents (such as aspirin) that prevent clotting of platelets should and do decrease heart attacks.

Pravastatin, it is thought, serves to stabilize cholesterol plaques. This it may do by decreasing the total amount of cholesterol in the plaque and also by decreasing the LDL cholesterol in the plaque.

Pravastatin may additionally decrease the degree of inflammation in the artery walls. And inflammation may be a key contributor to heart disease. (There are recent reports of chronic infection with the bacteria Chlamydia pneumoniae leading to increased atherosclerosis and heart attacks. These risks were lowered with antibiotics).

Like aspirin, pravastatin may decrease the tendency of platelets to clot, as well as decrease the viscosity (the thickness) of blood.

Decreasing the level of LDL cholesterol is, it seems, only part of the statin story.

The ability of the statins to lower LDL cholesterol has been under intensive study in the 90s and much remains to be investigated.

What is the comparative effectiveness of the different statins in stabilizing plaques? In decreasing inflammation in the coronary artery walls? In decreasing the aggregation of platelets? In decreasing the viscosity of the blood, in "thinning" it? And what else do the statins do?

To paraphrase Pascal, the great 17th-century French scientist- philosopher, the statins are a sphere. The more that sphere expands, the more the statins come in contact with the unknown.


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Reviewed on 2/1/2005

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