Hypercholesterolemia

Management of cholesterol and lipoproteins begins with an understanding of the normal function of these compounds and the mechanism by which disease occurs. Cholesterol is necessary to maintain body tissues and normal organ function. Seventy percent of the cholesterol utilized by the tissues of the body is fabricated within the liver. The remaining thirty percent must be consumed through daily dietary intake. 7 Daily consumption of excess cholesterol in the diet or even general poor nutritional intake can lead to one of three forms of lipid disease; hypercholesterolemia, elevated low-density lipoprotein cholesterol, and decreased high-density lipoprotein cholesterol. 2 Low-density lipoproteins (LDL) carry the cholesterol manufactured within the liver throughout the tissues of the body; high-density lipoproteins (HDL) transports cholesterol from the tissues back to the liver where the excess cholesterol is transferred out of the body. An increased level of HDL elevates the amount of LDL transported back to the liver. If LDL cholesterol intake is more than the necessary thirty percent, the excess is oxidized and macrophage uptake of LDL results in accumulation within the blood stream and blood vessels. 7 The endothelium is a preventive layer of cells that act as a barrier against platelets adhering to the walls and entering the inner layers of the arterial walls. 8 The role of the endothelium in atherosclerosis begins with a “dynamic balance between endothelial-derived vasodilating and vasoconstricting substances”. 8

The National Institutes of Health (NIH) has created a set of guidelines for cholesterol treatment for patients and doctors to standardize the management of the disease. There is a stong press for aggressive approaches to treatment and reduction of risk factors. The risk factors defined by NIH are age (=45 for men and =55 for women), smoking, hypertension (140/90mmHg), low HDL levels (<40mg/dL), family history, and elevated LDL levels. Abnormal LDL levels are the primary lipoprotein leading to atherosclerosis. NIH reports a three fold increase in abnormal cholesterol levels since 1985. 12 The National Cholesterol Education Program (NCEP) recommends fasting LDL levels of healthy individuals below 160mg/dL blood and 130mg/dL for those with two or more risk factors for coronary disease; LDL below 130mg/dL is also recommended for diabetics. NCEP advises those with known coronary disease to maintain LDL levels below 100mg/dL. HDL should be greater than 60mg/dL to decrease or eliminate one risk factor for coronary heart disease. 7

Hypercholesterolemia is a leading risk factor of coronary heart disease and atherosclerosis. “In the past three decades, numerous clinical and epidemiological studies have shown repeatedly that an elevated blood cholesterol level is one of the major modifiable risk factors associated with the development of coronary heart disease.” 12 Modifiable risk factors include smoking, hypertension, and inactivity. Diet is possibly the greatest preventable risk factor related to the development of hypercholesterolemia and coronary artery disease. 9,12 Secondary causes of increased LDL cholesterol are: diabetes mellitus, hypothyroidism, nephrotic syndrome, obstructive liver disease, anabolic steroids, progestins, Beta-blockers, and thiazides. Secondary causes of decreased levels of HDL include: cigarette smoking, diabetes mellitus, hypertriglyceridemia, menopause, obesity, uremia, anabolic steroids, and progestins. Besides diet, life style changes, weight management, smoking cessation, and exercise, are the most preventable options of this disease. 1,8 Eliminating excessive drinking of alcohol can also decrease the risk for CAD. However, drinking in moderation, one to two drinks daily, can increase HDL levels. 7

NCEP provides recommendations for dietary intake for control of cholesterol; this diet includes 50-60% carbohydrate, 25-35% fat (10% polyunsaturated fat, 7% saturated, and 15% monounsaturated fat), and 15% protein. 7 Moderate intake of monounsaturated and polyunsaturated fatty acids reduce LDL levels and total cholesterol. Excessive intake of fatty acids can lead to platelet aggregation, thrombus formation, strokes, and other coronary artery obstructions. A study by Gorbach et al. in 1990 reported that a reduction in butter, fatty meats, and products with 2% milk can reduce the intake of saturated fatty acids by 50%. 9 Most diets include a list of foods to eliminate from the diet, however, compliance to altered diets may be greater with a dietary recommendation of foods that improve lipid levels. Such suggestions may include: increased intake of fruits and vegetables for antioxidants, soy products and legumes for protein needs, monounsaturated fatty acids and n-3 or omega-3 fatty acids, garlic, and increased soluble fiber. Long-chain N-3 fatty acids decrease platelet aggregation. Soy products and legumes have been shown to decrease LDL and total cholesterol, but have no reported effect on HDL. Increased soluble fiber intake elevates the amount of fecal mater excreted and thus, an increase in cholesterol removed through the bowels. 9

Moderate excise and a proper diet can help to prevent coronary artery disease (CAD) through maintaining proper levels of lipoproteins, triglycerides, and cholesterol. The August 2003 Journal of the American Medical Association (JAMA) published a study from the University of Toronto that utilized three different diet regimens. The first was a vegetarian diet low in saturated fats, the second was the same diet with statin drug (lovastatin), and the third a fiber rich vegetarian diet that emphasized oats, barley, soy protein, almonds, and leafy greens with plant sterols – cholesterol lowering compounds. The results of this study stress the importance of diet: 31% reduction in total cholesterol for the lovastatin group and 29% reduction for the fiber and natural sterol diet group. The vegetarian diet only decreased cholesterol 8%. NCEP studied four groups for one year; diet and exercise, diet alone, exercise alone, and a control group. After one year the diet and exercise group positively affected hyperlipidemia. Diet alone and exercise alone did not improve fasting lipid values. 5 A cross-sectional study performed by Dowling favors an increase in aerobic exercise for both pre and postmenopausal women to elevate HDL cholesterol. Low HDL fasting blood levels are signals for coronary heart disease in postmenopausal women. Cross sectional studies show that women, both pre and postmenopausal, increase HDL levels by 10mg/dL when aerobic training is added into daily routine (55mg/dL sedentary, 65mg/dL active). Through aerobic training increases in lipoprotein lipase (LPL) and lecithin cholesterol acid transferease (LCAT) activity occurs. LCAT activity increases the enzyme catalysis that attaches free cholesterol to HDL for transport to the liver. Triglycerides are also decreased through increases insulin sensitivity and utilization with aerobic exercise. LPL increases the utilization of triglycerides in metabolism while preventing HDL catabolism. Dowling also researched resistance training and found no significant increases in HDL levels after resistance training. However, longitudinal studies including Goldberg et al. have shown decreases in LDL, total cholesterol, and triglycerides levels after 16 weeks of resistance training in premenopausal women. The greatest benefits of exercise on LDL, HDL, and triglycerides have been noted with training regimes of 1000 to 1200 kcal per week. Centers for Disease Control and Prevention (CDC) suggests 200kcal per day using aerobic exercise or alternative activities of daily life to complete this expenditure. 4 While ACSM does not have a recommended caloric output, it is suggested that aerobic exercise should be performed 3 to 5 days per week for 20 to 60 minutes at 55-90% maximal heart rate.

Women are usually at risk for coronary heart disease ten years later than men, however, CHD kills more women annually than men, and more than the next 14 causes of death for women combined. CHD is highly preventable, but women must approach the disease with more vigor than men. The American Heart Association has begun to encourage women to increase screenings and decrease preventable risk factors. Secondary causes of hyperlipidemia must also be treated or avoided. These include: hypothyroidism, chronic liver disease, dysglobulinemia, alcoholism, obesity, estrogen replacement therapy, and pregnancy. 10 Estrogen replacement therapy is still under research. Some studies have shown positive effects on cholesterol levels through decreased LDL and increased HDL levels. However, no reduction in myocardial infarctions or coronary disease has been observed, therefore “hormone replacement therapy for the sole purpose of secondary prevention of coronary heart disease is not recommended”. 10

Prevention is the key to eliminating CAD, yet most medical professionals and their patients over look prevention. Once treatment is provided, compliance is the next issue. Nearly half of the patients treated through drug therapy discontinue lipid-lowering medication within one year, and it is estimated that nearly seventy-five percent discontinue their medication within two years. Side effects were once a factor effecting compliance, but those that once plagued individuals have nearly been eliminated with the introduction of statin therapy. Even with new medications and reduced side effects compliance still remains very low. 13 Therapeutic lifestyle changes, diet, exercise, and weight loss are recommended by NIH Cholesterol Treatment Guidelines prior to any pharmacological treatment. 12 Even with compliance, some individuals will not benefit enough from diet and exercise to decrease their cholesterol and lipid levels to safe recommended values. For these individuals medication is necessary; nearly thirteen million people rely on drug therapy to lower LDL levels. 13

Statins are the most common and most effective pharmaceuticals currently recommended to patients with elevated cholesterol. With studies showing at least a 25% drop in risk of reoccurring coronary events, statins have become a highly marketed pharmaceutical. 14 The Adult Treatment Panel suggests that statins should be utilized as first-line therapy for high risk individuals with hypercholesterolemia, but only as a second-line therapy to diet and exercise in low risk individuals. 2 Statins, 3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase inhibitors, decrease LDL, triglycerides, and in some patients, increase HDL levels. 6,7,13 Statins help reduce cardiac event through an antiproliferative effect on smooth vessels and through anti-inflammatory and antioxidant effects. Statins also effect plaque stabilization, endothelial function, and prevent thrombus from forming. 6,10 Inhibition of cholesterol biosynthesis occurs through blocking the enzyme which initiates the conversion of HMG-CoA to mevalonate, a precursor of cholesterol. HMG-CoA reductase inhibition increases the upregulation of LDL receptors in the liver and the clearance of LDL within plasma. 2 Statin treatment may reduce all cause mortality, cardiovascular events and mortality, revascularization, stroke, and claudication. 2

Of the five statins prescribed, two are synthetic (S) and three are natural (N). The type, pharmaceutical name, and average monthly expense of the medication are atorvastating (S) (Lipitor – $56-$210), fluvastatin (S) (Lescol – $38-$75), lovastatin (N) (Mevacor – $70-$251), pravastatin (N) (Pravachol - $68-$112), and simvastatin (N) (Zocor - $114). 6,13 Studies have not proven one statin overall more effective than another. The variable bioavailability and the hydrophilic or hydrophobic nature of each statin effects the dosage and time for administering the medication. 6 Statins are the most commonly prescribed and most expensive mediations. 6,13 Simvastatin and atorvastatin are most effective in elevating HDL levels, while cerivastatin, atorvastatin, and simvastatin are most effective at lowering triglycerides levels. 13 The side effects of statins include gastrointestinal disruption, headaches, and rashes. 13

Studies performed on statins have shown decreases in coronary artery disease and events and possible decreases in coronary morbidity and mortality. Other studies, however, have shown no significant relationship between statin treatment and mortality or morbidity. One such study showing no significant difference in all cause mortality was performed in Western Scotland with 6595 male subjects (average age 55, cholesterol 272mg/dL, LDL 192mg/dL, HDL 44mg/dL, and triglycerides 163mg/dL).2,15 The results of the five-year study on pravastatin included decreased cholesterol by 20%, LDL by 26%, and triglycerides by 12%. HDL was increased on average 5% greater than the placebo group. There was no significant difference between the death rate of the treated, 1.2%, verses the placebo group, 1.7%. Overall mortality reduction due to the use of pravastatin was lowered by 22%, but was not significantly different at p=.051.15 The Scandinavian Survival Study reviewed the effects of simvastatin treatment on 4,444 men and women for 5.4 years. There were statistically significant decreases in total cholesterol, LDL cholesterol, and a statistically significant increase in HDL cholesterol. Those who were above the age of 65 benefited the greatest effect of the drug treatment. The control group had an increased rate of new coronary events; stroke increased 30%, MI increased by 34%, claudication by 38%, and angina increased 26%. This study showed significant decrease in all-cause mortality, CAD mortality, coronary events, and coronary revascularization for those treated with statin therapy. 2 The Cholesterol and Recurrent Events trial studied 4,159 men and women on pravastatin for 6.2 years. Significant changes occurred in total cholesterol, LDL cholesterol, and HDL cholesterol. Pravastatin was shown to reduce coronary events by 21% and mortality by 9%. 2 A follow up study performed on 245 patients one year after revascularization procedures, bypass grafting or angioplasty, reviewed lipid measurements and risk factors. There was little management of the patients through education, medication, or lifestyle modification. The lipid concentrations did not change in the year follow up. 55 participants who were smokers had ceased smoking immediately following the medical procedures. One year later 29 had began smoking again, increasing their risk for revascularization. Only fifty-two patients remained on a low diet. This study performed in a Swiss university shows that education, medication, and diet are important elements of treating hypercholesterolemia and decreasing modifiable risk factors. 3

Another form of treatment is Nicotinic Acid or Niacin decreases lipid levels, triglycerides, cardiovascular disease, and mortality. Although less effective than statins for decreasing LDL levels, Niacin is more effective in increasing HDL. 13 Niacin effects the hepatic synthesis of VLDL cholesterol , increases the synthesis of HDL cholesterol, and through inhibiting lipolysis of fatty tissue. 1 Niacin is a third less expensive than statins, however the side effects are more severe for many patients. Recent extended release niacin has decreased the difficulty of flushing and nausea in most patients. 13

Bile acid-binding resins (Questran, Colestid) actually attach to cholesterol-containing bile acids within the intestinal tract and prevent absorption through the gut. HDL levels are increased by 5%, while LDL levels are decreased up to 20% through fecal excretion with bile acid-binding resins. 1,7 The side effects of bile acid sequestrants are gastrointestinal disturbance and diarrhea in patients. 7,13 Nutritional concerns are also a concern of bile acid sequestrants due to reduced absorption of vitamin A, D, E, and K and the following minerals: folic acid, magnesium, iron, and zinc. 13 Nicotinic Acid or Niacin has a similar effect on LDL levels and is the oldest prescription for positively effecting HDL,LDL, triglycerides, and cardiovascular morbidity. 7,13 The prescription for niacin has been avoided due to severe flushing, especially in the face, and abdominal and gastrointestinal discomfort in patients. Gout and increased uric acid are also concerns of the patient medicated with niacin. The poor physical tolerability coupled with possible decreased glucose intolerance has caused a push for changes within the Niacin pharmaceuticals. 10,13 Niaspan is an extended-release niacin medication administered at night that has the same positive effects without the extreme side effects. HDL levels have been increased as much as 20 percent, while triglycerides have been decreased by 25 percent. 13

Fibric Acid Derivatives or Fibrates (Lopid, Lipidil) increase VLDL clearance, enhance lipolysis, treat hypertriglyceridemia, and reduce hepatic cholesterol synthesis. 1 Fibrates are HDL raising, triglyceride lowering agents, that reduce mortality as much as 22 percent; however, they are rarely recommended unless fasting triglycerides are above 400mg/dL due to adverse effect of the hepatic and renal systems. 10,13 Other side effects include gastrointestinal disturbance, and intolerance, neuromuscular dysfunction, and dermatological reactions. 13

Studies performed on children through NCEP have shown that screening in children may aid in prevention of adult hyperlipidemia or hypercholesterolemia, especially those who have family history cardiovascular disease. Sheldon et al. studied 182 children, ages 18 months to 20 years old, with lipid abnormalities for two years. Through education and dietary treatment, the classification of children with elevated LDL and triglycerides had significant decreases in LDL cholesterol and total cholesterol, while triglycerides and HDL cholesterol did not have a significant change. The second classification of children with elevated triglycerides/HDL ratios had a significant decrease in triglycerides and a significant increase in HDL cholesterol. Total cholesterol and LDL levels were decreased but not significantly. 11 Sothern et al. studied behavior modification, as well as, diet and exercise on 50 obese girls and boys (aged 12.27 +/- 2.67 years). Total cholesterol and triglycerides were significantly decreased, while LDL levels were only significantly decreased in the female subjects. HDL levels were not affected in either group. A combination of the three methods, diet, education, and exercise, seems to be the most effective for lowering total cholesterol and triglycerides for young males and females. 16 The results of these studies represent the need to evaluate and educate children on proper diet and exercise. Screening can play a role in those under the age of twenty. Benefits from treatment at an early age include avoidance of pharmacological treatment later in life, but more importantly avert the possibilities of cardiovascular disease and coronary artery disease. NIH recommends blood tests performed at least every five years for all individuals over the age of twenty. 12

[When a test is administered, all subjects are aware that a change may occur through treatment. This awareness can cause changes within daily activity and diet, even when the participants are instructed to maintain normal activity and life style. Even when a placebo is utilized, behaviors may change. “Any study of a social process, by involving the participants in the process, can influence its own results,” this effect is termed the Hawthorne Effect. 15 It is possible that each of these studies are not a true illustration of the effect of these medications, diet, exercise, and/or education, however, including a control group makes these methods the most valid testing to determine the effect of the treatment.]

REFERENCE

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