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Tuesday, 1st July 2003
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).
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.
- 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.
|Article reviewed by:||
Dr. Safaa Mahmoud, M.D.
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