Comparison of Cholesterol-Lowering Regimens Hypercholesterolemia is common, affecting up to one-fourth of the general population. It is more prevalent in patients with atherosclerotic heart disease. Unlike certain other risk factors for atherosclerosis, such as age, sex and heredity, cholesterol elevation can be reversed.
The acceptable levels of cholesterol and low-density lipoprotein (LDL) have recently been revised downward.  Total cholesterol levels above 200 mg per dL (5.15 mmol per L) and LDL levels above 130 mg per dL (3.35 mmol per L) are now considered elevated. The National Cholesterol Education Project recommends use of the serum LDL level as an indicator for drug therapy.
The Framingham study showed that for every 1 percent increase in serum cholesterol above the normal level, there is a 2 percent increase in cardiovascular risk. Therefore, in the healthy individual, the lower the serum cholesterol level, the better. In addition, high-density lipoprotein (HDL) cholesterol appears to exert a protective effect against vascular disease.  Low HDL levels, particularly below 45 mg per dL (1.15 mmol per L), are associated with an increased incidence of vascular disease. Therefore, in contrast to total serum cholesterol, the higher the HDL level, the better.
Attempts to lower the serum cholesterol level have taken many forms. The most recent controversy involves the use of a diet high in soluble fiber.  Claims have been made that such a diet can lower the total cholesterol level by as much as 20 percent. However, further study using more exacting controls indicated that such a benefit was due to a reduced intake of saturated fats and calories rather than to the high dietary fiber content. 
Two large studies [5, 6] have confirmed that lowering the total cholesterol level reduces the risk of myocardial infarction. These studies and others have led to a consensus in this country that the total cholesterol level should not exceed 200 mg per dL (5.15 mmol per L). In addition, it is now believed that benefit is derived from a higher HDL level, which removes cholesterol from the tissues.  Agreement as to the approach for raising the HDL level has not been reached. Weight loss, moderate exercise, smoking cessation and limited alcohol intake tend to be associated with increased HDL levels. Although gemfibrozil (Lopid) has received publicity as an HDL-raising agent, much of the current cholesterol research is aimed at lowering total cholesterol and LDL levels rather than raising HDL cholesterol.
Seven different regimens for lowering total cholesterol are used in this country. The comparative advantages and disadvantages of drug therapies and dietary regimens are summarized in Tables 1 and 2.
General Treatment Considerations
The etiology of hypercholesterolemia is an important consideration. Patients with elevated serum cholesterol levels should be screened for diseases that may produce hypercholesterolemia, including hypothyroidism, nephrotic syndrome, biliary cirrhosis and paraproteinemias. Certain drugs may arise serum cholesterol levels, including androgens and, to a lesser degree, antihypertensive agents such as beta-adrenergic blockers and diuretics. 
About one in 500 patients with myocardial infarction have hereditary hypercholesterolemia, an enzymatic defect that is inherited as an autosomal dominant disorder. Persons heterozygous for the gene usually have serum cholesterol levels ranging from 330 to 450 mg per dL (8.55 to 11.65 mmol per L) and often develop vascular disease by the fourth decade. The rare patient with homozygous disease typically has a serum cholesterol level above 450 mg per dL (11.65 mmol per L) and usually develops vascular disease as early as the teenage years.
Inherited forms of hypercholesterolemia are strongly suggested by the degree of cholesterol elevation. A cholesterol level that exceeds 330 mg per dL (8.55 mmol per L), together with a normal triglyceride level, usually indicates genetic disease. Because of the dominant hereditary mode, one parent and half of the children would be expected to have the disease. Thus, identification of a heterozygous person on the basis of a cholesterol level above 330 mg per dL (8.55 mmol per L) or a homozygous person on the basis of a cholesterol level above 450 mg per dL (11.65 mmol per L) suggests the need for further family testing.
Diet and Soluble Fiber Therapy
No matter what the etiology of hypercholesterolemia, diet therapy should always be the first consideration. The typical American diet contains up to several grams of cholesterol per day, plus significant quantities of saturated fats. In countries where cholesterol and saturated fat intake is low, the incidence of atherosclerotic disease is much lower than in the United States.
Dietary control of hypercholesterolemia can often be achieved by modifying the intake of three different types of foodstuff: cholesterol, saturated fats and soluble fiber. First, the American Heart Association recommends that the amount of dietary cholesterol be reduced to 300 mg per day, or even lower. This goal may be achieved in several ways. The approach that is easiest for patients to understand is to simply reduce the intake of fatty cuts of beef or pork, egg yolks, cheese (except for very low cholesterol cheeses), milk (except for nonfat), butter, luncheon meats, shrimp, lobster, avocados and ice cream. Fat in convenience foods or baked goods must also be restricted.
Second, saturated fats in the form of palm oil, coconut oil or partially saturated or hydrogenated forms of vegetable oil should be avoided. Some studies show that the benefits of reducing cholesterol intake may be completely offset by a hibh intake of saturated fats. However, for the most part, saturated fats are found in-foods that also contain cholesterol.
Third, the amount of dietary fiber may affect the serum cholesterol level. There are two types of fiber: insoluble and soluble. Insoluble fiber is found in vegetables, grains and fruits. Although insoluble fiber promotes bowel regularity, this type of fiber does not directly affect the serum cholesterol level. Soluble fiber is found in legumes, pectin, psyllium and oat bran. In one study,  a daily intake of 50 g of oat bran lowered the serum cholesterol by nearly 20 percent. Commercial forms of the soluble fiber psyllium are available. Patients can ingest large quantities of the substance with almost no caloric intake.
Recently, the effect of soluble fiber on serum cholesterol has been disputed by some investigators,  who postulated that the decrease in serum cholesterol attributed to bran may have been a result of the decreased dietary fat that occurred from the satiation effect of the bran products. While some doubt remains concerning the role of soluble fiber in cholesterol reduction, this approach should not be abandoned. High-fiber diets are low in cholesterol and saturated fats, and generally are well understood by the public.
The recommended low-fat diet consists of fruits, grains, salads, fish, and skinless turkey and chicken. Dietary therapy alone is usually sufficient in patients with LDL cholesterol levels below 160 mg per dL (4.15 mmol per L; cholesterol level of approximately 240 mg per dL [6.20 mmol per L]). for most patients, dietary restrictions succeed in reducing the serum cholesterol level by about 10 to 20 percent. Some patients who adhere to a strict vegetarian diet may achieve up to a 50 percent reduction in serum cholesterol. A reduction of 15 percent or less probably suggests dieatary noncompliance. The treatment goal is to reduce the serum cholesterol level to under 200 mg per dL (5.15 mmol per L), but even further reduction will reduce cardiac risk.
Generally, dietary therapy should be continued for six to 12 months before drug therapy is considered. Drug therapy should be initiated in patients with coronary artery disease or two or more risk factors and an LDL cholesterol level of 160 mg per dL (4.15 mmol per L; cholesterol level of approximately 240 mg per dL [6.20mmol per L]) or more. Cholesterol-lowering agents should also be given if the LDL is 190 mg per dL (4.90 mmol per L; cholesterol level of approximately 280 mg per dL [7.25 mmol per L]) or greater, whether or not the patient has heart disease or only one risk factor.
Bile Acid Sequestrants
Cholestyramine (Cholybar, Questran) and colestipol (Colestid) are resins that bind bile acids in the intestine, forming an insoluble complex that prevents reabsorption. Increased fecal loss of bile acids induces the liver to increase the oxidation of cholesterol to bile acide, leading to lower LDL and total cholesterol levels. However, bile acid sequestrants tend to raise triglyceride levels.
While these agents are effective in modestly raising the HLD level, their side effects, including bloating, cramps, nausea and constipation, are roublesome for many patients: Moreover, bile acid sequestrants reduce the absorption of a variety of commonly used medications, including digitalis, acetaminophen, propranolol (Inderal), warfarin (Coumadin, Panwarfin, etc.), nonsteroidal anti-inflammatory drugs and thiazide diuretics. For this resons, medications should be taken at least one hour before or four to six hours after bile acid sequestrants are taken. Unfortunately, this is not always convenient or feasible. In addition, most bile acide sequestrants have a gritty taste. For all these reasons, compliance is often poor.
Nevertheless, bile acid sequestrants are valuable because they are the least toxic drug regimen available. They are especially valuable in conjunction with dietary therapy and other cholesterol-lowering agents, since the combined effects are additive. Combination therapy is useful for severe or refractory cases. Since bile acid sequestrants increase serum triglyceride levels, they are contraindicated in patients with hypertriglyceridemia. 
The acid form of the essential vitamin niacin, nicotinic acid (Nicolar, Span-Niacin-150, etc.), has been used for over 40 years as a cholesterol-lowering agent. Use as a cholesterol-lowering agent is entirely separate from nicotinic acid's function as a vitamin, which requires an intake of only 25 mg per day.  To achieve a cholesterol-lowering effect, a daily dosage of 2 to 6 g is required. In this dosage range, nicotinic acid lowers serum LDL and very-low-density lipoprotein (VLDL) cholesterol levels and modestly raises serum HDL levels. The decrease in the total cholesterol level is usually 10 to 15 percent.
The most common side effect of nicotinic acid is a flushing or pruritic sensation, caused by marked cutaneous vasodilatation. While this reaction is usually not serious, it may be intolerable to many patients. Occasionally, systemic hypotension may also occur. This side effect can be averted by slowly increasing the dosage so that tachyphylaxis develops. Taking one aspirin tablet one hour before each dose may also be helpful.
Occasionally, nicotinic acid may have more serious side effects, including activation of peptic ulcer disease, hypotension, aggravation of diabetes mellitus, hyperuricemia and hepatitis. Although rare, cases of fulminant hepatic destruction from long-acting nicotinic acid have been reported. Because of por compliance and modest cholesterol-lowering effects, nicotinic acid has often been combined with other regimens, such as bile acid sequestrants.
Related chemically to clofibrate (Atromid-S), gemfibrozil (Lopid) is an antihyperlipidemic agent that has been available for almost a decade. It lowers serum cholesterol, LDL cholesterol and triglyceride levels and raises serum HDL cholesterol levels. Until the results of the Helsinki study  were released, widespread use of gemfibrozil was not advocated. However, this study showed a one-third reduction in cardiovascular events in patients receiving this drug. While gemfibrozil has its most potent effect on the serum triglycerides, the results observed in the Helsinki study were thought to be due to reductions in LDL levels and increases in HDL levels rather than to marked reductions in serum triglycerides. 
Which patients should receive gemfibrozil has not been established, but generally it is recommended for patients with marked hypertriglyceridemia (over 250 mg per dL [2.82 mmol per L]). It is particularly useful in patients who have low HDL levels or either total cholesterol or LDL elevation.
Gemfibrozil appears to be quite safe. The most common side effects are nausea, flatulence, abdominal distress and bloating. Gallstones may form in about 1 percent of patients receiving this agent. In addition, myositis, with rare cases of extensive rhabdomyolysis, has been reported. The prescribing physician needs to be alert for flu-like symptoms, with diffuse muscle aching, in patients receiving gemfibrozil, since their occurrence may herald this syndrome. Diagnosis is usually made by obtaining a measurement of the creatine kinase level.
The newest group of agents for the treatment of hypercholesterolemia is the 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitors. The first of these, lovastatin (Mevacor), has been available for prescription for almost three years. Lovastatin is more potent than any other antihyperlipedemic agent; a 40 percent reduction in the serum cholesterol level is not unusual. While lovastatin inhibits cholesterol metabolism at a very early stage, studies have not shown that the drug interferes with the formation of any other sterols, such as androgens, estrogens or adrenal steroids. Lovastatin lowers serum LDL and VLDL level while modestly raising HDL levels.
Lovastatin has a low incidence of side effects. (11) However, it may produce a rise in transaminase levels. When this occurs in the first three months of therapy, the rise is often less than chreefold and is often transient. After three months of therapy, transaminase elevation of three times the baseline may develop in a small number of patients (less than 1 percent). The elevation may persist. This reaction is an indication for cessation of therapy. Rarely, jaundice has beeb reported, but it usually resolves after the drug is discontinued.
Like gemfibrozil, lovastatin can produce rhabdomyolysis. The incidence is quite low, except in patients who are aso receiving gemfibrozil, nicotinic acid, erythromycin or cyclosporine (Sandimmune). Therefore, lovastatin should ordinarily not be used in combination with these agents, and it should be used with great caution in recipients of heart or kidney transplants. 
Whether lovastatin therapy leads to cataracts has caused some concern. In preclinical studies, the drug was found to produce cataracts in Dalmatian dogs, but these changes were not seen in any other species. Many of the side effects that developed in experimental animals are species specific and not a problem for humans. Yet, because of the cataract formation in Dalmatian dogs, the manufacturer recommends twice yearly eye examinations in patients who receive lovastatin for prolonged periods. However, no evidene to date suggests that the drug causes cataracts in humans. 
Of all the cholesterol-lowering agents available, lovastatin has received the widest acceptance by patinets because troublesome side effects are comparatively few. Response to therapy is satisfactory in most patients when lovastatin is combined with a low cholesterol diet. In refractory cases, an even greater lowering of serum cholesterol can be achieved by adding a bile acid sequestrant to the regime. The combination of lovastatin and colestipol seems to be particularly effective.  Possible regression of coronary atherosclerosis has been reported with the combination of colestipol and nicotinic acid.  However, the combination of lovastatin and gemfibrozil or nicotinic acid is discouraged due to increased incidence of rhabdomyolysis.
The main disadvantage of lovastatin is the lack of information about long-term toxicity. It sometimes takes many years (ten to 20) of surveillance to confirm suspicions of serious adverse reactions. Another disadvantage is the higher cost of this drug. Cost of therapy may amount to $1,500 per year when the costs of twice-yearly liver function tests and slit-lamp ophthalmic examinations are added to the cost of the drug.
A less frequently used antihyperlipidemic agent is probucol (Lorelco). While this drug lowers serum LDL levels, it also modestly lowers HDL levels. However, recent studies showing that this drug may interfere with the oxidation and tissue deposition of LDL have created renewed interest.  Probucol has a tendency to cause prolongation of the QT interval and may possibly have a tendency to cause arrhythmias. Because of these actions, widespread use of this drug has been discouraged.
Other new cholesterol-lowering drugs are undergoing clinical investigation,  including other HMG-CoA reductase inhibitors, such as pravastatin and semvastatin. Fenofibrate, a drug with properties similar to those of gemfibrozil, also seems to hold considerable promise.
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JOSEPH R. DIPALMA, M.D., coordinator of this series, is emeritus professor of pharmacology and medicine at Hahnemann University School of Medicine, Philadelphia.
COPYRIGHT 1990 American Academy of Family Physicians
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