Dyslipidemias are disorders of lipoprotein metabolism, including lipoprotein overproduction or deficiency. These disorders may be manifested by elevation of the serum total cholesterol, low-density lipoprotein (LDL) cholesterol and triglyceride concentrations, and a decrease in the high-density lipoprotein (HDL) cholesterol concentration.
Epidemiologic, angiographic and postmortem studies have documented a causal relationship between elevated serum cholesterol levels and the genesis of coronary heart disease. Angiographic studies show that aggressive cholesterol reduction by a variety of methods, as opposed to dietary modifications alone, results in increased rates of plaque regression and stabilization.1 Treatment with cholesterol-lowering drugs appears to be accompanied by a reduction in the lipid content of atherosclerotic plaques, thereby making them more stable and less prone to rupture.2,3 The Scandinavian Simvastatin Survival Study4 demonstrated a 30 percent reduction in total mortality in simvastatin-treated patients with coronary heart disease as compared with patients not receiving this agent. In a primary prevention trial,5 patients treated with pravastatin showed a 26 percent reduction in LDL cholesterol levels and a 31 percent reduction in coronary events (nonfatal myocardial infarction or death from coronary heart disease) as compared with the placebo group.
Even after recognizing the controversies surrounding cholesterol screening and therapy,6,7 most experts emphasize the importance of treating hypercholesterolemia.8–10 While guidelines for treating dyslipidemias may lack uniformity, much common ground exists for the management of dyslipidemias.11 The recommendations in this article are primarily based on the guidelines from the National Cholesterol Education Program (NCEP).12
Diagnosis and Classification
Secondary causes of dyslipidemia include hypothyroidism and a genetic predisposition, such as autosomal dominant familial hypercholesterolemia (Table 1).13 Triglyceride elevation may occur in association with diabetes mellitus, alcoholism, obesity and hypothyroidism. Dyslipidemias have been traditionally classified in accordance with the elevated lipoprotein classes (Table 2).14 Currently, genetic dyslipidemias are classified as familial hypercholesterolemia, familial combined hyperlipidemia and polygenic hypercholesterolemia.
|Phenotype||Lipoprotein(s) elevated||Serum cholesterol level||Serum triglyceride level||Atherogenicity|
|I||Chylomicrons||Normal to ↑||↑↑↑↑||None seen|
|IIb||LDL and VLDL||↑↑||↑↑||+++|
|IV||VLDL||Normal to ↑||↑↑||+|
|V||VLDL and chylomicrons||Normal to ↑||↑↑↑↑||+|
The NCEP guidelines, however, are based on clinical cut points that indicate relative risk for coronary heart disease. Included in the guidelines is the general recommendation that total cholesterol and HDL cholesterol levels be measured every five years beginning at age 20 in patients who do not have coronary heart disease or other atherosclerotic disease. Both of these measurements may be obtained in the non-fasting state. The results of these measurements and the presence of other risk factors for coronary heart disease may demand a more comprehensive lipoprotein analysis (Table 3).12
|Positive risk factors|
|Male ≥45 years|
|Female ≥55 years or postmenopausal without estrogen replacement therapy|
|Family history of premature coronary heart disease (definite myocardial infarction or sudden death before age 55 in father or other male first-degree relative or before age 65 in mother or other female first-degree relative)|
|Current cigarette smoking|
|Hypertension (blood pressure ≥140/90 mm Hg or patient is receiving antihypertensive drug therapy)|
|HDL cholesterol level <35 mg per dL (<0.90 mmol per L)|
|Negative risk factor*|
|High HDL cholesterol level (≥60 mg per dL [≥1.60 mmol per L])|
The LDL cholesterol level can be measured directly or can be calculated by using the Friedwald formula (measurement is expressed in milligrams per deciliter): This formula cannot be used when the triglyceride level is greater than 400 mg per dL (4.50 mmol per L) or when patients have type III hyperlipoproteinemia.
While cholesterol levels are classified into desirable, borderline high-risk and high-risk categories (Table 4),12 decisions regarding the treatment of hypercholesterolemia are based on the LDL cholesterol level and the presence or absence of other risk factors for coronary heart disease. Two or three fasting LDL measurements must be averaged to classify the patient's risk.
|Classification||Total cholesterol level||LDL cholesterol level||HDL cholesterol level|
|Desirable||200 mg per dL (5.15 mmol per L)||<130 mg per dL (<3.35 mmol per L)||≥60 mg per dL (≥1.55 mmol per L)|
|Borderline high risk||200 to 239 mg per dL (5.15 to 6.20 mmol per L)||130 to 159 mg per dL (3.35 to 4.10 mmol per L)||35 to 59 mg per dL (0.90 to 1.55 mmol per L)|
|High risk||≥240 mg per dL (≥6.20 mmol per L)||≥160 mg per dL (≥4.15 mmol per L)||<35 mg per dL (<0.90 mmol per L)|
The target LDL cholesterol value in patients with coronary heart disease or other atherosclerotic disease is 100 mg per dL (2.60 mmol per L) or lower. If the LDL level does not exceed 100 mg per dL in a patient with coronary heart disease, the patient should begin the step I diet, regularly participate in physical activity and stop smoking. Annual lipoprotein analysis is indicated for this group. Premenopausal women and men 35 years of age or younger with dyslipidemia but without other risk factors for coronary heart disease or a genetic predisposition are generally considered at low risk.
The NCEP guidelines recommend that patients at higher risk of coronary heart disease receive more intensive interventions for dyslipidemia than patients at lower risk. Persons at highest risk for future coronary events have a history of coronary heart disease or extracoronary atherosclerotic disease. For all practical purposes, treatment of patients with multiple risk factors for coronary heart disease but without a history of coronary disease should be as aggressive as that for patients with coronary heart disease. As Oliver and colleagues stated,15 “There is probably little realistic difference between those who have had a clinical event and those who have not.” Thus, primary and secondary prevention are closely linked along this strategic continuum.
The NCEP guidelines recommend dietary modification, exercise and weight control as the foundation of treatment of dyslipidemia.12 These basic interventions may provide sufficient treatment for up to 90 percent of persons with dyslipidemia according to the NCEP cut points.16 A reduction in total cholesterol by 1 percent may decrease a person's risk of developing coronary heart disease by 2 percent.17 Cessation of cigarette smoking and reduction of other modifiable risk factors are essential aspects of prevention of coronary heart disease.
Exercise and Weight Reduction
Obesity frequently elevates cholesterol levels in both very-low-density lipoprotein (VLDL) and LDL fractions, raises triglyceride levels, lowers HDL cholesterol levels, raises blood pressure and promotes glucose intolerance. Weight loss lowers total cholesterol and its LDL and VLDL fractions, lowers triglycerides and raises HDL cholesterol.18 Weight loss also lowers blood pressure and improves glycemic control.
Patients are more likely to comply with exercise programs that are tailored to meet individual goals, interests and needs. Most patients benefit from aerobic exercise that targets large muscle groups, performed for 30 minutes four or more times a week.18 Shorter, but more frequent, aerobic exercise sessions provide similar benefits. Overweight patients should engage in low-intensity exercise more frequently and for longer durations.
Alcohol exerts several effects on lipid levels, including raising the serum triglyceride and HDL cholesterol levels. Its effect on LDL cholesterol appears to be minimal. Since excessive alcohol causes numerous adverse effects, including hepatic toxicity, cardiomyopathy, motor vehicle crashes and extensive psychosocial consequences, it is not recommended for the prevention of coronary heart disease.12
Step I and Step II Diets
Dietary therapy should be initiated in patients who have borderline-high LDL cholesterol levels (130 to 159 mg per dL [3.35 to 4.10 mmol per L]) and two or more risk factors for coronary heart disease and in patients who have LDL levels of 160 mg per dL (4.15 mmol per L) or greater. The objective of dietary therapy in primary prevention is to decrease the LDL cholesterol level to 160 mg per dL if only one risk factor for coronary heart disease is present and to less than 130 mg per dL if two or more risk factors are identified. In the presence of documented coronary heart disease, dietary therapy is indicated in patients who have LDL values exceeding 100 mg per dL (2.60 mmol per L), with the aim of lowering the LDL level to 100 mg per dL or less.
The goal of dietary therapy is to reduce elevated total cholesterol and LDL cholesterol levels to the target values while maintaining a nutritious diet. In the average American diet, fat comprises about 35 percent of total calories, with saturated fat accounting for 13 to 14 percent.12,18 Cholesterol intake averages about 360 mg per day in American men; daily cholesterol intake is less in American women.12 In a patient with coronary heart disease who eats an average American diet and then switches to the step II diet, LDL cholesterol levels can be reduced by 10 to 20 percent.19 However, some patients who strictly adhere to dietary therapy have only slight reductions in total cholesterol levels. Clinical trials consistently report that the lipid-lowering effects of dietary measures are greatest in persons with higher initial values of total cholesterol, LDL cholesterol and triglycerides.12,16,18
|Food group||Foods to eat||Foods to avoid|
|Lean meat, poultry and fish (≤6 oz a day)||Beef, pork, lamb—lean cuts, well-trimmed before cooking||Beef, pork, lamb—regular, ground beef, fatty cuts, spare ribs, organ meats|
|Poultry, without skin||Poultry with skin, fried chicken|
|Fish, shellfish||Fried fish, fried shellfish|
|Processed meat prepared from lean meat||Regular luncheon meat|
|Eggs (step I: ≤4 yolks per week; step II: ≤2 yolks per week)||Egg whites, cholesterol-free egg substitute||Egg yolks (including eggs used in cooking and baking)|
|Low-fat dairy products (2 to 3 servings a day)||Milk—skim, ½% or 1% low-fat milk, buttermilk||Whole milk, 2% low-fat milk, imitation milk|
|Nonfat or low-fat yogurt||Whole-milk yogurt|
|Low-fat or processed cheese||Regular cheese|
|Nonfat or low-fat cottage cheese||Regular cottage cheese (4% fat)|
|Frozen yogurt, ice milk||Ice cream|
|Low-fat coffee creamer, nonfat or low-fat sour cream||Cream, half & half, whipping cream, regular sour cream|
|Fats and oils (≤6 to 8 teaspoons a day)||Unsaturated oils—safflower, sunflower, corn, soybean, canola, olive, peanut||Coconut oil, palm oil|
|Margarine—made from unsaturated oils listed above, soft margarine||Butter, lard, shortening, bacon fat, hard margarine|
|Salad dressings—made from unsaturated oils listed above, fat-free or low-fat dressing||Salad dressings—made with egg yolk, cheese, whole milk, sour cream|
|Seeds and nuts, peanut butter||Coconut|
|Cocoa powder||Milk chocolate|
|Breads and cereals (≥6 servings a day)||Whole grain breads, English muffins, bagels, corn and flour tortillas||Croissants, breads in which eggs, fat or butter are major ingredients|
|Oat, wheat, corn and multigrain cereals, pasta, rice, dry beans and peas||Most granolas|
|Low-fat crackers (graham, animal-type, soda, melba toast, breadsticks)||High-fat crackers|
|Homemade baked goods containing unsaturated oils, skim or 1% milk, egg substitute||Commercially baked biscuits, pastries, muffins containing whole milk, egg yolks, saturated oils|
|Soups||Low-fat and reduced-sodium varieties||Soups containing whole milk, cream, meat fat, poultry fat, poultry skin|
|Vegetables (3 to 5 servings a day)||Fresh, frozen or canned vegetables without added fat or sauce||Fried vegetables or those prepared with butter, cheese or cream sauce|
|Fruits (2 to 4 servings a day)||Fresh, frozen, canned or dried fruits||Fried fruit or fruit served with butter or cream sauce|
|Sweets and modified-fat desserts||Beverages, candy made without fat, gelatin||Candy made with whole milk, chocolate, coconut oil, palm kernel oil, palm oil|
|Frozen yogurt, sherbet, sorbet, ice milk, popsicles||Ice cream|
|Cookies, cake, pie, pudding prepared with egg substitute, skim or 1% milk, unsaturated oils||Commercially baked pies, cakes, doughnuts, high-fat cookies prepared with egg yolks, whole milk, saturated oils|
The step I diet limits calories derived from saturated fats to 8 to 10 percent of total calories and cholesterol to less than 300 mg per day. The step II diet further restricts calories from saturated fats to less than 7 percent of total calories and restricts cholesterol intake to less than 200 mg per day. For both diets, it is recommended that monounsaturated fats constitute no more than 15 percent of total calories and polyunsaturated fats no more than 10 percent of total calories. Monounsaturated fats, such as those found in peanuts, almonds and canola oil, appear to have less of an adverse effect on the HDL cholesterol level than polyunsaturated fats. Omega-3 fatty acids, which are polyunsaturated fatty acids found in many fish, have been shown to reduce serum triglyceride concentrations. They have only a minor effect on LDL cholesterol in patients with normal triglyceride levels. The benefits of fish oils and other omega-3 fatty acid supplements are presently under investigation. The NCEP guidelines do not routinely recommend use of fish oils, although the consumption of fish is recommended in both step I and step II diets.
Many patients with hyperlipidemia may already have adopted eating patterns similar to those of the step I diet. The cholesterol-lowering effects of the step I diet in such patients will likely be modest. The more stringent step II diet requires close inspection to ensure that the patient maintains a nutritious diet. The NCEP guidelines recommend consultation with a registered dietitian for patients following the step II diet.
The step I diet has been shown to lower the total serum cholesterol level by 3 to 14 percent, while the step II diet may lower the total cholesterol level an additional 3 to 7 percent.12 Not all studies, however, have reported similar reductions. Hence, patients should be informed that even with strict adherence to the step I diet, a step II diet may be needed to effect significant improvement in the lipid profile. Obese patients who lose weight may have greater reductions in the total cholesterol level. The NCEP recommends evaluating the patient's response to dietary therapy by monitoring the total cholesterol level after six weeks and 12 weeks of the step I diet.
In primary prevention of coronary heart disease (that is, in patients without evidence of coronary heart disease), dietary therapy should be maintained for six months before drug therapy is initiated. Referral to a registered dietitian is indicated in patients who are already adhering to the step I diet at the time of the diagnosis of dyslipidemia or who are unable to achieve the goals of dietary therapy while adhering to the step I diet. In patients at high risk of coronary heart disease or with a high total cholesterol or LDL value, drug therapy should be initiated at an earlier stage. In patients with coronary heart disease and an LDL cholesterol value above 100 mg per dL (2.60 mmol per L), therapy should begin with the step II diet.
Soluble fiber has been shown to modestly reduce total cholesterol and LDL cholesterol levels.12 Current dietary guidelines recommend a total daily fiber intake of at least 20 to 30 g for adults, with 25 percent of the fiber being soluble fiber.12 These levels can be attained with the proposed six or more daily servings of grain products and five or more daily servings of fruits and vegetables. Adding 3 g per day of soluble fiber from oat bran can reduce total cholesterol by 5 to 6 mg per dL.18 Higher daily intake of soluble fiber promotes a further modest reduction of cholesterol values.
The American Heart Association diet may lower total cholesterol by 5 to 7 percent, whereas similar diets that emphasize dietary fiber may reduce total cholesterol by 11 to 32 percent and may exert beneficial effects on LDL and HDL cholesterol levels as well.20 Moreover, a high-carbohydrate, low-fiber diet typically raises serum triglyceride levels and lowers HDL cholesterol levels. Conversely, a high-carbohydrate, high-fiber diet may lower the serum triglyceride level and raise the HDL cholesterol level.20 A high-fiber, low-fat diet also provides other beneficial effects, including improved glycemic control, weight reduction and earlier satiety, prevention of diverticular disease and, possibly, prevention of colorectal cancer.20
High intake of soluble fiber contributes to gastrointestinal side effects such as bloating and flatulence. Excessive intake of fiber may be associated with impaired absorption of important nutrients such as calcium. Supplementation with a daily multivitamin is therefore recommended for patients consuming a high-fiber diet and high-fiber supplements.20
Atherogenicity is promoted by oxidation and glycosylation of LDL cholesterol.12 Several vitamins, including vitamin C, vitamin E and beta carotene, have antioxidant properties, which may provide protection against atherogenesis. Fruits, and dark-green and deep-yellow vegetables are rich sources of antioxidant vitamins.
Because dietary modification rarely reduces LDL cholesterol levels by more than 10 to 20 percent, the NCEP guidelines recommend that consideration be given to the use of cholesterol-lowering agents if lipid levels remain elevated after six months of intensive dietary therapy or sooner under certain circumstances.
A patient with a very high LDL cholesterol level may need to start drug therapy sooner,21 because it is unlikely that a patient with an LDL level of 130 mg per dL (3.35 mmol per L) or greater will be able to achieve the goal of 100 mg per dL (2.60 mmol per L) with diet alone.19 Patients should be given the clear message that drug therapy is not a substitute for appropriate diet and exercise. Addressing other modifiable risk factors is vital to the overall success of any treatment plan.
|Bile acid–binding resins|
|Cholestyramine (Questran, Questran Lite)||4 g, 8 g, 12 g or 16 g twice daily||$ 89.00 (packets)|
|Colestipol (Colestid)||5 g twice daily or 30 g per day, in divided doses||81.00 (packets)|
|HMG-CoA reductase inhibitors (statins)|
|Atorvastatin (Lipitor)||10 to 80 mg per day anytime||55.00|
|Cerivastatin (Baycol)||0.3 mg in the evening||40.00|
|Fluvastatin (Lescol)||20 mg or 40 mg at bedtime, or 20 mg twice daily||41.00|
|Lovastatin (Mevacor)||20 mg, 40 mg or 80 mg with evening meal||67.00|
|Pravastatin (Pravachol)||10 mg, 20 mg or 40 mg at bedtime||55.00|
|Simvastatin (Zocor)||5 mg, 10 mg, 20 mg or 40 mg at bedtime||53.00|
|Fibric acid analogs|
|Clofibrate (Atromid-5)||500 mg four times daily||115.00|
|Gemfibrozil (Lopid)||600 mg twice daily||75.00|
|Nicotinic acid||1.5 to 6 g daily in divided doses||4.00 to 7.00 (generic)|
HMG-CoA Reductase Inhibitors
Lovastatin (Mevacor), pravastatin (Pravachol), simvastatin (Zocor), fluvastatin (Lescol), atorvastatin (Lipitor) and cerivastatin (Baycol) are HMG-CoA reductase inhibitors, or statins, that inhibit cholesterol synthesis. To varying degrees, all of these agents lower total, LDL and triglyceride cholesterol components and slightly raise the HDL fraction. While these agents are generally well tolerated, a small percentage of patients (fewer than 1 percent) may develop elevated hepatic transaminase levels, which may necessitate discontinuation of the drug.21 Other adverse effects include myopathy (fewer than 0.1 percent of cases) and gastrointestinal complaints. The gastrointestinal effects often subside with continued therapy.
Evidence suggests that these agents reduce untoward cardiovascular events4,5 and work by mechanisms beyond the simple reduction in the LDL cholesterol level.23 The results of the Primary Prevention of Coronary Heart Disease with Pravastatin trial demonstrated reductions of 31 percent in first myocardial infarctions, 32 percent in cardiovascular mortality, 22 percent in total mortality and 37 percent in the need for revascularization procedures.5
There are differences among the statins. For example, atorvastatin has a slightly different side effect profile than the other statins. It may exert a greater effect on lowering LDL cholesterol, total cholesterol and triglycerides, but higher doses of other statins may produce the same response. However, atorvastatin as a single agent may obviate the need for multiple drug therapy in high-risk patients.24 In view of the numerous other mechanisms being investigated, such as plaque stabilization, antiplatelet aggregation activity and anti-arterial spasmodic effects, this particular difference may be less important than other factors. To date, no comparative studies of the statins have been performed to delineate all of the clinically important differences. However, analysis of the Scandanavian Simvastatin Survival Study showed that hospitalization costs for patients hospitalized because of cardiovascular disease were reduced by approximately 31 percent, making statins quite cost-effective.25
Statins should generally be taken in a single dose with the evening meal or at bedtime to maximize the LDL lowering effect.
Bile Acid–Binding Resins
The anion exchange resins cholestyramine (Questran) and colestipol (Colestid) bind cholesterol-containing bile acids in the intestines, producing an insoluble complex that prevents reabsorption. This results in increased hepatic oxidation of cholesterol to bile acids, fecal cholesterol excretion and LDL receptor activity.26 These agents decrease LDL cholesterol levels by up to 20 percent. They may be a good choice in patients with hepatic disease because they do not affect hepatic metabolism. They are also a good choice in very young patients and women of childbearing age.11
Bile acid–binding resins may cause an increase in triglyceride levels. Because of their gritty texture and side effects, compliance may be a problem. Side effects include constipation, abdominal discomfort, flatulence, nausea, bloating and heartburn. A dosage reduction, increased dietary fiber, taking bile acid sequestrants with meals and letting the resin stand in liquid for 10 minutes before taking it are strategies that minimize the side effects.
Bile acid sequestrants can bind with warfarin, digitalis, thyroxine, thiazides, furosemide, tetracycline, penicillin G, phenobarbital, iron, propranolol (Inderal), acetaminophen and nonsteroidal anti-inflammatory agents, as well as oral phosphate supplements and hydrocortisone. Ingesting such agents at least an hour before or four to six hours after a resin dose reduces the potential for drug interactions.27
Nicotinic acid, or niacin, decreases the synthesis of LDL cholesterol by reducing the hepatic synthesis of VLDL cholesterol, by increasing the synthesis of HDL cholesterol, by inhibiting lipolysis in adipose tissue and by increasing lipase activity. This agent increases the HDL level by 15 to 35 percent, reduces total and LDL cholesterol levels by 10 to 25 percent, and decreases the triglyceride level by 20 to 50 percent.21
Side effects of nicotinic acid include flushing, pruritus, gastrointestinal discomfort, hyperuricemia, gout, elevated liver function tests and glucose intolerance. Taking 325 mg of aspirin 30 minutes before the drug is ingested may minimize flushing.28 Frequently, however, flushing and pruritus resolve spontaneously with continued use. Nicotinic acid should be taken with meals to reduce the occurrence of gastrointestinal upset. Hepatotoxic side effects are more common with sustained-release nicotinic acid preparations than with regular formulations. A hepatitis-like syndrome, manifested by weakness and a lack of appetite, may develop in patients receiving sustained-release preparations.16 Other side effects of nicotinic acid include atrial fibrillation, hypotension, transient headaches and activation of peptic ulcer disease. Nicotinic acid therapy should be avoided in patients with diabetes mellitus because it tends to worsen glycemic control.27
Fibric Acid Derivatives
Fibric acid derivatives, or fibrates, increase the clearance of VLDL cholesterol by enhancing lipolysis and reducing hepatic cholesterol synthesis. These agents have been reported to lower triglyceride levels by 20 to 50 percent, raise HDL levels by up to 20 percent and reduce LDL levels by approximately 5 to 15 percent.29–31 Some patients with hypertriglyceridemia may have an increase in LDL levels, so such patients should be very closely monitored if fibrates are used. Gemfibrozil (Lopid) is particularly useful in patients with diabetes and familial dysbetalipoproteinemia.
Side effects of gemfibrozil include nausea, bloating, flatulence, abdominal distress and mild liver-function abnormalities. Myositis, gallstones and elevation of the LDL cholesterol level have also been reported.21,31 Clofibrate (Atromid-S) has been associated with formation of gallstones and serious gastrointestinal disease, including hepatic malignancy,21 and therefore should only be used in certain select patients with types II, IV or V hyperlipidemia. In addition, clofibrate has not been shown to prevent coronary heart disease. Fibrates should generally not be used with HMG-CoA reductase inhibitors because the risk of severe myopathy is greatly increased.19
Multiple Drug Therapy
As mentioned previously, the NCEP guidelines define a target LDL cholesterol level of 100 mg per dL (2.60 mmol per L) as a goal for high-risk patients with established coronary heart disease. But this population, even with a step II diet, often cannot achieve such a low LDL level. An LDL level greater than 130 mg per dL (3.35 mmol per L) requires further reduction in patients with coronary heart disease, and combination drug regimens are sometimes required (Table 8). 19 An additional cholesterol-lowering drug is probably required if the LDL cholesterol level remains above the target level after three months of single-drug therapy. In patients with coronary heart disease and LDL levels between 100 and 130 mg per dL (2.60 and 3.35 mmol per L), clinical judgment is needed to decide whether to initiate cholesterol-lowering medication (or add a second medication) in conjunction with dietary therapy. Although drug therapy is not usually started until patients have undergone a three- to six-month trial of dietary therapy, in some patients with marked hypercholesterolemia or coronary heart disease, it is reasonable to initiate drug therapy earlier.11
|Lipid levels||First drug → drug to add|
|Elevated LDL level and triglyceride level <200 mg per dL||Statin → bile acid–binding resin|
|Nicotinic acid* → statin*|
|Bile acid–binding resin → nicotinic acid|
|Elevated LDL level and triglyceride level 200 to 400 mg per dL||Statin* → nicotinic acid*|
|Statin * → gemfibrozil (Lopid)†|
|Nicotinic acid‡→ statin‡|
|Nicotinic acid → gemfibrozil|
Follow-Up of Drug Therapy
Because of biologic and analytic variability of lipoprotein levels, it is advisable to obtain at least two lipoprotein levels during one to two months of maximum dietary therapy before beginning drug therapy.11 If it seems likely that pharmacotherapy will be needed, baseline liver function tests should also be performed.
After starting drug therapy, the LDL cholesterol level should be measured in about six weeks and again in 12 weeks.11 Liver function and other tests for drug toxicity can be done at these times. If the LDL goal is reached, lipid levels should be checked every six to 12 months.32 Follow-up analysis should occur six to eight weeks after a change in drug therapy. In patients receiving nicotinic acid, follow-up measurements should be obtained four to six weeks after a stable dose has been reached.19
Role of Lipoprotein(a)
Lipoprotein(a), or Lp(a), is a specialized form of glycoprotein-LDL-cholesterol complex. Elevated Lp(a) (over 30 mg per dL [300 mg per L]) can be an independent risk factor for the development of early coronary disease in men.33,34 Controversy exists over whether elevated Lp(a) is the cause or the effect of coronary artery damage.35 Nicotinic acid (given at dosages of at least 3 g per day) and estrogen have been found to reduce elevated Lp(a) levels.36 A recent trial suggests that postmenopausal hormone replacement therapy lowers the Lp(a) level,37 and preliminary clinical trials have shown that the experimental drug lifibrol also lowers Lp(a) levels.33
Estrogen Replacement Therapy
Although estrogens have not yet received an indication for the treatment of dyslipidemia, the NCEP recommends that consideration be given to estrogen replacement therapy as a means of decreasing (by about 15 percent) LDL cholesterol levels and increasing (by about 22 percent) HDL cholesterol levels in postmenopausal women. A recent study showed a reduction in mortality among women who received postmenopausal hormone replacement therapy, although the survival benefits were noted to diminish with a longer duration of use.38 Hormone replacement therapy may be combined with other cholesterol-lowering interventions to achieve an even more favorable alteration of the lipid profile. It has been reported that pravastatin plus conjugated estrogen improves LDL cholesterol levels more than either agent used alone.39
Other Therapeutic Modalities
Lifibrol is a lipid-lowering agent presently under investigation. Clinical trials have shown that lifibrol lowers total cholesterol and LDL cholesterol levels with a potency similar to that of high-dose statins.33 Lifibrol has also been shown to reduce Lp(a), fibrinogen and uric acid levels.33 Its effects on HDL cholesterol and triglyceride levels are less consistent.
The mechanism of action of this agent is complex and probably multimodal. It appears to act at an earlier level of the cholesterol synthesis pathway than do the statins. Side effects are primarily gastrointestinal.
Gene therapy is several years from clinical use. It may prove ideal for use in patients with genetic disorders such as familial hypercholesterolemia. Gene therapy will probably not be appropriate in dyslipidemic patients whose predominant risks for coronary heart disease are exogenous.10
Plasmapheresis has become the most common nonpharmacologic, nondietary treatment of severe hypercholesterolemia.40 In nonselective plasmapheresis, the patient's plasma is replaced with salt-free human albumin. This action reduces triglyceride levels dramatically and decreases the risk of pancreatitis. In patients with severe, refractory forms of familial hypercholesterolemia, a highly specific LDL cholesterol absorption system is utilized for extended use.40
Partial ileal bypass that eliminates the reabsorption of bile acids at the distal portion of the ileum has been shown to be a viable treatment in some cases of severe dyslipidemia.41 Portacaval shunt and liver transplantation have been shown to be effective in treating severe hypercholesterolemia. These proceures, of course, are not first-line treatments.