In 2002, the 10 leading causes of death were (in rank order) diseases of the heart; malignant neoplasms; cerebrovascular diseases; chronic lower respiratory diseases; accidents (unintentional injuries); diabetes mellitus; influenza and pneumonia; alzheimer's disease; nephritis, nephrotic syndrome and nephrosis; and septicemia and accounted for about 79 percent of all deaths occurring in the United States. Notice that causes #1, #3, and #6 all derive from atherosclerosis—”hardening of the arteries”- meaning a build-up of cholesterol, fats, calcium and scar deposits on the inside of blood vessels, blocking the flow of blood to vital tissues and organs. Heart disease and cancer continued to be the primary and secondary causes of death, together accounting for over half of all deaths.

But beginning in the 1990s, we began to see significant changes in the pattern of leading causes of death. By 1998, the largest decline from the previous year--9.5 percent--in age-adjusted death rates was for atherosclerosis. This general trend has continued through the end of the century. Along with that we are seeing significant increases in the lifespan of both men and women. Why? What’s going on? I think most experts would agree that this is due largely to the extensive development and marketing of drugs specifically targeted at atherosclerosis: statins, fibrates, lipid lowering agents, anti-platelet agents, and the use of combination regimens. Are you taking advantage of these dramatic emerging trends?

Where does cholesterol come from? Cholesterol is a hydrocarbon multiple ring structure that forms a basic building block for animal cell wall construction. It is not present in plant cells. Cholesterol is also an essential backbone component of many hormones. Cholesterol is derived from the diet in the form of meat, eggs and dairy products. Although cholesterol is present in butter, it is not present in any plant oils or plant fats. In humans, most of the cholesterol in the bloodstream comes from liver production of cholesterol. The liver is the primary regulator of cholesterol metabolism, responsible for both its production and degradation. Approximately 1/5 to 1/3 of cholesterol comes from the diet. However, a diet high in cholesterol can increase that proportion.

Over the last 10 years our knowledge of cholesterol has expanded dramatically. Lipids is a term that encompasses both blood cholesterol and blood fats. Blood cholesterol can be divided into 3 broad categories: Very Low Density Cholesterol (VLDL– cholesterol mostly derived from the gut after meals), High Density Cholesterol (HDL– derived primarily from liver synthesis) and Low Density Cholesterol (LDL– derived from breakdown of VLDL particles in muscle and fat tissue and from liver synthesis). HDL is known as “good cholesterol” as it helps to transport excess cholesterol from LDL cholesterol particles (“bad cholesterol”) in the peripheral circulation back to the liver where it can be excreted into the gut. So in general the goal is to not have excess levels of total cholesterol, and to have relatively higher levels of HDL and relatively lower levels of LDL cholesterol. Blood fats (also known as triglycerides) can also predispose to hardening of the arteries (atherosclerosis—the build-up of cholesterol and fats on the insides of blood vessels, blocking blood flow). So again, here, the goal is to keep blood fat levels low.

Exactly what are those goals? For otherwise healthy adults, total cholesterol levels should be <200 mg%, HDL levels >40 mg% in men and >50 mg% in women, LDL levels <130 mg%, and triglycerides <150 mg%. For individuals who have diabetes or established vascular disease or heart disease, total cholesterol levels should be <200 mg%, HDL levels >40 mg% in men and >50 mg% in women and LDL levels <100 mg%. More aggressive guidelines recently published suggest that in individuals with established disease the LDL cholesterol goal should be < 70 mg%.

Why are the goals for people with diabetes more stringent? Studies have clearly demonstrated that people with diabetes are at higher risk of having a heart attack than people who do not have diabetes. This level of risk is in fact similar to the level of risk that a person who has had their first heart attack has for having their second (subsequent) heart attack. Because heart attack individuals HAVE ALREADY DEMONSTRATED an inclination for heart injury, they are considered at high risk for having another heart attack event, and physician expert panels have established more stringent lipid goals for such individuals. Study data shows us that that is in fact the case, and that diabetic individuals who have never had a heart attack have about the same level of risk for having their first heart attack as heart attack victims have for having a subsequent event.

There is, however, very good news about treating elevated lipid levels. Quite simply, the treatment works. What we don’t fully understand yet is how aggressive we have to be. The most recent studies which are being reported in 2006 show that in high risk individuals lowering the LDL levels to <75 will be associated with a net REVERSAL in the development of atherosclerosis. For the first time we can see evidence of improving artery obstruction when we get the lipid levels low enough. This is likely to lead to yet further revisions in the lipid goals set by national experts.

What interventions work with regard to lowering lipid levels to goal in diabetics? There are standard dietary guidelines for people who have hypercholesterolemia and hyperlipidemia. (See Dietary High Cholesterol and Low Fat Diet under the Patient Information Section of this website). If an individual has been on a typical American diet and then changes to a low cholesterol diet, you can expect to see perhaps a 15% reduction in total cholesterol and LDL cholesterol levels. If that individual were on a higher cholesterol diet than average (e.g. lots of eggs, fat, and dairy products) the drop would be more; if that individual were already on a lower cholesterol diet than average, it would be less. HDL cholesterol levels and TG levels are inversely related to each other, that is, typically lowering TG levels will increase HDL levels and typically raising TG levels will lower HDL levels. Low cholesterol diets per se will not have much of an effect on TG or HDL levels. However, a weight reduction diet DOES have a significant effect in many overweight people to markedly lower TG levels (with some subsequent rise in HDL levels). For many diabetic individuals, it makes sense to follow a low cholesterol weight loss diet, and this would be expected to improve the lipid levels across the board. It is common for people on a weight reduction diet to totally normalize their TG levels, even if they are very high. Although a weight reduction diet may help to raise HDL levels, it may still not bring them up to a desirable range. Although a low cholesterol diet can be quite helpful in lowering cholesterol levels, for many people with diabetes it will just not work to lower cholesterol levels far enough to reach desirable cholesterol and LDL goals. More is going to be required.

Exercise by itself does not appear to have much of an effect on lipid levels except for HDL. Vigorous regular exercise while maintaining your weight at a constant level is not associated with changes in total cholesterol, LDL or TG levels. However, there is a significant rise in HDL (good cholesterol) levels. In fact, this is one of the best ways to significantly raise HDL levels.

The medications used to treat elevated lipid problems typically fall into 4 categories: statins, fibrates, cholesterol binding agents, and niacin. Statins are a large family of drugs that inhibit the liver’s production of cholesterol. These drugs work by inhibiting the rate-limiting step in the production of cholesterol, and by stimulating the degradation of LDL cholesterol. Commonly available statins, in order of their increasing potency are fluvastatin (Lescol), lovastatin (Mevacor), pravastatin (Pravachol), simvastatin (Zocor), atorvastatin (Lipitor), and rosuvastatin (Crestor). They are now in widespread use in many countries and have an established track record to significantly lower cholesterol levels. Their most common side effects are the potential to cause liver inflammation, or hepatitis (which is why your physician periodically checks a liver enzyme while you take one of these medications), a relatively rare problem of muscle inflammation, or myositis, which is manifest by diffuse muscle aches and elevated muscle enzymes, and possibly some nerve problems such as some loss of coordination or memory. People with these kinds of problems will have to stop the statin they are taking and can dry a different drug in the same family.

A second group of drugs are called fibrates. These are compounds that act by stimulating a cell nuclear receptor (PPARalpha) that results in increased activity of lipid breakdown enzymes in the blood and more rapid metabolism of TG particles, along with more rapid production of certain lipoproteins and LDL cholesterol. These drugs are not effective for lowering the LDL-cholesterol. The reductions in TGs are generally in the range of 20 to 50 percent with increases in HDL-cholesterol of 10 to 15 percent. Gastrointestinal complaints are the most common side effect and fibrates appear to increase the likelihood of developing cholesterol gallstones. Fibrates can increase the effect of medications that thin the blood. Studies with gemfibrozol (Lopid) have shown no direct effect in reducing overall mortality in patients with heart disease, in part because of slight increases in the risk of mortality from cancer and from pancreatitis. A newer fibrate, fenofibrate (Tricor), has not been as well studied.

Cholesterol binding agents and cholesterol inhibitors are compounds that block cholesterol absorption from the gut. Bile acid sequestrants are non-absorbable resins that avidly bind bile acids in the gut. Bile acids are secreted via the liver and gall bladder into the intestine to help solubilize fatty substances and allow for their absorption. Bile acids contain the majority of cholesterol that appears in the bile. Although bile acid sequestrants work well at reducing reabsorbion of bile acids, the liver partly compensates for this by increasing bile acid production. Bile acid sequestrants tend to be constipating, and have to be taken with food. Cholesterol inhibitors work by inhibiting the absorption of dietary cholesterol and the resorption of biliary cholesterol, and lower LDL cholesterol by inhibiting LDL formation. Commonly used inhibitors of cholesterol synthesis are plant sterols and stanols, which are ingested in the diet. They mimic cholesterol, binding to particles that aid cholesterol absorption, thereby displacing cholesterol, which is in turn lost in the feces. Ezetimibe is a member of a new class of drugs that blocks the assimilation of cholesterol from these particles.

Niacin is also known as nicotinic acid or vitamin B3. It is found in dairy products, poultry, fish, lean meats, nuts, and eggs. Legumes and enriched breads and cereals also supply some niacin. Niacin assists in the functioning of the digestive system, skin, and nerves. It is also important for the conversion of food to energy. Therapy with niacin (nicotinic acid) is unique in that it improves all lipoprotein abnormalities. It significantly reduces low-density lipoprotein cholesterol, triglyceride, and lipoprotein(a) levels, while increasing high-density lipoprotein cholesterol levels. This makes niacin ideal for treating a wide variety of lipid disorders, including the metabolic syndrome, diabetes mellitus, isolated low high-density lipoprotein cholesterol, and hypertriglyceridemia. Niacin-induced changes in serum lipid levels produce significant improvements in both coronary artery disease and clinical outcomes. Niacin is currently available in 3 formulations (immediate release, extended release, and long acting), which differ significantly with respect to their safety and efficacy profiles. Immediate-release niacin is generally taken 3 times a day and is associated with adverse flushing, gastrointestinal symptoms, and elevations in blood glucose levels. Long-acting niacin can be taken once daily and is associated with significantly reduced flushing, but its metabolism increases the risk of hepatotoxic (liver) effects. Extended-release niacin, also given once daily, has an absorption rate intermediate between the other formulations and is associated with fewer flushing and gastrointestinal symptoms without increasing hepatotoxic risk. Side effects from niacin include, but are not limited to flushing (redness, itching, warmth), night sweats, palpitations, cardiac fibrillations, or other arrhythmias, decreased glucose tolerance, migraines, and skin hyperpigmentation.

Revised 9/08



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