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:
BAYCOL (cerivastatin sodium) made by Bayer
LESCOL (fluvastatin sodium) made by Novartis
LIPITOR (atorvastatin calcium) made by Parke-Davis and
Pfizer
MEVACOR (lovastatin) made by Merck
PRAVACHOL (pravastatin sodium) made by Bristol-Myers Squibb
ZOCOR (simvastatin) made by Merck
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 asniacin 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 fully understood about
the statins. Among the questions before biomedical scientists
is, do the statins prevent heartattacks 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 scondary 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 ofheart 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
cornary 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 alsoby 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.
