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The Heart Protection Study was designed to confirm how
effective statins are in reducing the risk of heart
attacks.
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Diabetes mellitus is a
chronic disease caused by an inherited and/or
acquired deficiency in production of insulin by the pancreas, or by ineffectiveness
of the insulin produced. Such a deficiency results in increased concentrations
of glucose in the blood, which in turn can damage
many of the body's systems, in particular the blood vessels and nerves.
Recent data shows that approximately
150 million people have diabetes mellitus worldwide, and that this number
may well double by the year 2025. Much of this increase will occur in developing
countries and will be due to population growth, ageing, unhealthy diets,
obesity and sedentary lifestyles.
Approximately 17 million people in the United States,
or 6.2% of the population, have diabetes. While an estimated 11.1
million have been diagnosed, unfortunately, 5.9 million people (or one-third)
are unaware that they have the disease (1).
Persons with diabetes mellitus, have early and accelerated
atherosclerosis (hardening of the blood vessels leading to hypertension,
stroke and heart disease). The most serious complications
of this are atherosclerotic heart disease, cerebrovascular disease, and
renal disease. The most common cause of death with diabetes mellitus is
myocardial infarction. They are 2- 4 times more likely to have a coronary
event than patients without diabetes (1).
Atherosclerosis is directly related to the disturbance in blood lipids
(fats).
Blood lipids and lipoproteins
In the blood the lipids are carried by lipoproteins.
Lipoproteins are conjugated proteins and lipids. They
are important cellular compounds that act as lipid transporters. The central
part of a lipoprotein molecule contains the triglyceride and cholesterol
ester while the surface is of apoprotiens, phospholipids, and cholesterol.
Lipoproteins are divided into 4 main groups:
Chylomicrons: they are the lipoproteins that
carry dietary cholesterol and triglyceride from intestine to the liver and
peripheral tissues respectively.
VLDL (very low density lipoproteins): which
transfer triglyceride from the liver to peripheral tissue.
LDL: which transfer cholesterol from the liver
to tissues, so its excess precludes high risk for atherosclerosis and ischemic
heart disease (the harmful form).
HDL: is the protective of atherosclerosis since
it transfers cholesterol from tissues back to the liver (the good form).
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Statins
A group of lipid lowering drugs known as statins (including
drugs such as simvastatin, pravastatin, fluvastatin and atorvastatin) are
known to be highly effective at lowering low-density lipoprotein, the bad
type of cholesterol in blood. Statins are HMG Co-A reductase inhibitors
the rate-limiting enzyme in cholesterol synthesis. The clinical benefit
of statin therapy is primarily attributed to its LDL-lowering effects. In
addition to reducing LDL cholesterol, statin treatment increases the levels
of the antiatherogenic HDL and its major apolipoprotein (apoA-I).
The newly completed Heart Protection Study is the
largest and most powerful trial of cholesterol lowering to date, and was
designed precisely to confirm how effective statins are
in reducing the risk of heart attacks and to answer the question 'who needs
to lower the cholesterol level?
The study involved 20,000 volunteers for 5 years showed
that one third of heart attacks and strokes can be avoided by using 40 mg
simvastatin. In addition, statin therapy also reduced the risk of hospitalization
for angina, the need for arterial surgery, angioplasty and amputations.
The benefit was seen in patients aged over 75 years and in patients with
diabetes. The benefits were shown to increase for each additional year of
statin therapy.
Diabetics do not generally receive cholesterol-lowering
therapy, although they have a particularly high risk of heart trouble.
The study included nearly 6,000 diabetics and found that a daily dose of
simvastatin 40 mg cut the risk of a first heart attack or stroke by about
a quarter, even in patients with relatively low cholesterol levels. The
drug also, significantly reduced the chances of suffering a repeat attack
to those who already have had one of these events.
The research leader of this study Dr. Rory Collins,
of the University of Oxford, England and his colleagues recommend that everyone
with diabetes who is at high risk of heart or vessel trouble be put on a
statin.
The study have sent a clear message for all doctors
that statins should be routinely prescribed for all diabetic patients at
sufficiently high risk of major vascular events, regardless their initial
cholesterol level.
Beyond
Cholesterol Lowering
Statins have been found in another study to significantly
reduce the levels of highly sensitive C-reactive protein (hsCRP) as well.
Elevated levels of hsCRP indicate inflammation and a higher-than-normal
risk for heart attack. The study showed significant reduction in the levelof
LDL and hsCRP in two weeks times, indicating a statin rapid effect.
Experimental data have shown that statins have a protective
effect for occlusive vascular disease. This is due to the fact that they
are involved in inhibition of smooth muscle proliferation and platelet aggregation,
enhancement of endothelial function, and antiinflammatory actions
(2-7).
Interstingly, experimental evidence suggests that
statins may also have oncoprotective effects by inducing certain tumor cell
types, such as acute myelogenous leukemia, to undergo apoptosis in a sensitive
and specific manner (8,9).
Although simvastatin was the only form of statin that
have been used in the clinical study, researchers believe that other forms
will efficiently work as well.
Clinical studies are going on to determine the other
possible clinical indications for routine prescription of stations in terms
beyond their cholesterol lowering effect.
References
- WHO: Fact Sheet N° 138 Revised April 2002
- Indolfi C, Cioppa A, Stabile E et al. Effects of
hydroxymethylglutaryl coenzyme A reductase inhibitor simvastatin on smooth
muscle cell proliferation in vitro and neointimal formation in vivo after
vascular injury. J Am Coll Cardiol. 2000; 35: 214–221.
- Schror K. Platelet reactivity and arachidonic acid
metabolism in type II hyperlipoproteinaemia and its modification by cholesterol-lowering
agents. Eicosanoids. 1990; 3: 67–73.
- Anderson TJ, Meredith IT, Yeung AC, et al. The
effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent
coronary vasomotion. N Engl J Med. 1995; 332: 488–493.
- Treasure CB, Klein JL, Weintraub WS, et al.
Beneficial effects of cholesterol-lowering therapy
on the coronary endothelium in patients with coronary artery disease.
N Engl J Med. 1995; 332: 481–487.
- Ridker PM, Rifai N, Clearfield M, et al. Measurement
of C-reactive protein for the targeting of statin therapy in the primary
prevention of acute coronary events. N Engl J Med. 2001; 344: 1959–1965.
- Musial J, Undas A, Gajewski P, et al. Anti-inflammatory
effects of simvastatin in subjects with hypercholesterolemia. Int J Cardiol.
2001; 103: 1191–1193.
- Eto M, Kozai T, Cosentino F, et al.
Statin prevents tissue factor expression in human endothelial
cells: role of Rho/Rho-kinase and Akt pathways.
Circulation. 2002; 105: 1756–1759.
- Kureishi Y, Luo Z, Shiojima I, et al.
The HMG-CoA reductase inhibitor simvastatin activates
the protein kinase Akt and promotes angiogenesis in normocholesterolemic
animals. Nat Med. 2000; 6: 1004–1010.
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