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Combined hyperlipidemia, familial

In medicine, combined hyperlipidemia (or -aemia) is a commonly occurring form of hypercholesterolemia (elevated cholesterol levels) characterised by increased LDL and triglyceride concentrations, often accompanied by decreased HDL. On lipoprotein electrophoresis (a test now rarely performed) is shows as a hyperlipoproteinemia type IIB. more...

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The elevated triglyceride levels (>5 mmol/l) are generally due to an increase in VLDL (very low density lipoprotein), a class of lipoprotein that is prone to cause atherosclerosis.

There are roughly two forms of this lipid disorder:

  • Familiar combined hyperlipidemia (FCH) is the familiar occurrence of this disorder, probably caused by polymorphisms in molecules and enzymes that participate in lipoprotein metabolism, such as ApoCII and ApoCIII and CETP (cholesterylester transferring protein).
  • Acquired combined hyperlipidemia is extremely common in patients who suffer from other diseases from the metabolic syndrome ("syndrome X", incorporating diabetes mellitus type II, hypertension, central obesity and CH). Excessive free fatty acid production by various tissues leads to increased VLDL synthesis by the liver. Initially, most VLDL is converted into LDL until this mechanism is saturated, after which VLDL levels elevate.

Both conditions are treated with fibrate drugs, which act on the peroxisome proliferator-activated receptors (PPARs), specifically PPARα, to decrease free fatty acid production. Statin drugs, especially the synthetic statins (atorvastatin and rosuvastatin) can decrease LDL levels by increasing hepatic reuptake of LDL due to increased LDL-receptor expression.


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Management of dyslipidemia in adults - includes patient information
From American Family Physician, 5/1/98 by Syed M. Ahmed

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 post-mortem 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 Study[4] 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.

LDL = low-density lipoprotein; HDL = high-density lipoprotein.

Adapted with permission from Schaefer EJ. Diagnosis and management of lipoprotein disorders. In: Rifkind BM, ed. Drug treatment of hyperlipidemia. New York: Dekker 1991:17-52.

LDL low-density lipoprotein; IDL intermediate-density lipoprotein; VLDL = very-low-density lipoprotein; HDL high-density lipoprotein; [arrow up] mildly increased; 2 arrow up = moderately increased; 3 arrow up = severely increased; 4 arrow up = very severely increased; + mild to moderate atherogenicity; +++ = severe atherogenicity.

(*)--HDL cholesterol levels are not considered in the Fredrickson classification.

Adapted from Fredrickson DS, Levy RI, Lees RS. Fat transport in lipoproteins--an integrated approach to mechanisms and disorders. N Engl J Med 1967;276:34-42, 94-103, 148-56, 215-25,273-81.

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 nonfasting 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]

TABLE 3 Coronary Heart Disease Risk Based on Risk Factors Other Than the LDL Level

LDL = low-density lipoprotein; HDL = high-density lipoprotein.

(*)--Subtract one positive risk factor if negative risk factor is present

Adapted from National Cholesterol Education Program. Second report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (adult treatment panel II). Bethesda, Md.: National Cholesterol Education Program, National Institutes of Health, National Heart, Lung, and Blood Institute, 1993; DHSS publication no. (NIH) 93-3095:5.

The LDL cholesterol level can be measured directly or can be calculated by using the Friedwald formula (measurement is expressed in milligrams per deciliter):

LDL = total cholesterol - HDL - (triglyceride/5)

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.

TABLE 4 Risk classification of Hypercholesterolemia in Patients Without Coronary Heart Disease

LDL = low-density lipoprotein; HDL = high-density lipoprotein.

Reprinted from National Cholesterol Education Program. Second report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (adult treatment panel W. Bethesda, Md.: National Cholesterol Education Program, National Institutes of Health, National Heart, Lung, and Blood Institute, 1993; DHSS publication no. (NIH) 93-3095:5.


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.

Lifestyle Modifications

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 Intake

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 A [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]

Step I and step Il diets are designed to progressively reduce intake of saturated fats, cholesterol and total calories to decrease lipoprotein values and promote weight loss in overweight persons (Table 5).[12] Complex carbohydrates, rather than simple sugars, should be emphasized.

TABLE 5 Examples of Foods to Eat and Foods to Avoid in the Step I and Step II Diets

Reprinted from National Cholesterol Education Program. Second report for the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (adult treatment panel II). Bethesda, Md.: National Cholesterol Education Program, National Institutes of Health, National Heart, Lung, and Blood Institute, 1993; DHHS publication no. (NIH) 93-3095:5.

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 11 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 11 diet requires dose 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.

Dietary Fiber

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.

Drug Therapy

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 Q 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 dear 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.

In most patients with hypercholesterolemia, HMG-CoA reductase inhibitors are the drugs of choice because they reduce LDL cholesterol most effectively (Tables 6 and 7).[18,22] Gemfibrozil (Lopid) or nicotinic acid may be better choices in patients with significant hypertriglyceridemia.

TABLE 6 Cholesterol-Lowering Agents, Their Dosages and Cost

NOTE: Lowest maintenance dosages are not necessarily equivalent when switching from one brand to another.

(*) -- Estimated cost to the pharmacist based on average wholesale prices for lowest-dosage maintenance therapy rounded to the nearest dollar in Red book. Montvale, N.J.: Medical Economics Data, 1998. Cost to the patient will be higher depending on prescription filling fee.

Adapted from Blake GH, Triplett LC Management of hypercholesterolemia. Am Fam Physician 1995; 51:1157-66.

TABLE 7 Changes in Serum-Lipid Values with Different Classes of Cholesterol-Lowering Drugs and Some of Their Side Effects

LDL = low-density lipoprotein; HDL = high-density lipoprotein.

Adapted with permission from Gotto AM Jr. Management of lipid and lipoprotein disorders. In: Gotto AM Jr Pownall HJ, eds. Manual of lipid disorders. Baltimore: Williams & Wilkins, 1992.

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 events[4,5] 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 antiarterial 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 add 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

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, dofibrate 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]

TABLE 8 Possible Combination Therapies if Single-Agent Therapy Is Not Effective in Reducing Lipid Levels

LDL = low-density lipoprotein.

(*) -- Possible increased risk of myopathy and hepatitis.

([dagger]) -- Increased risk of severe myopathy.

([double dagger]) -- The combination of nicotinic acid and lovastatin (Mevacor) may induce rhabdomyolysis, a rare adverse drug interaction.

Adapted from National Cholesterol Education Program. Cholesterol lowering in the patient with coronary heart disease. Bethesda, Md.: National institutes of Health, National Heart, Lung, and Blood Institute, 1997; DHHS publication no. (NIH) 97-3794.

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]

Special Considerations

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 slating.[33] Lifibrol has also been shown to reduce Lp(a), fibrinogen and uric acid levels." 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

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]

Surgical Modalities

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 procedures, of course, are not first-line treatments.

The authors gratefully thank Lawrence E. Mieczkowski, M.D., Center for Cholesterol Treatment & Education, Inc., Dayton, Ohio, for review of the manuscript, and Dorothy Leibold for assistance in preparation of the manuscript.


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[3.] Levine GN, Keaney JF Jr, Vita JA. Cholesterol reduction in cardiovascular disease. Clinical benefits and possible mechanisms. N Engl J Med 1995;332:512-21.

[4.] Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344:1383-9.

[5.] Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, et al. Prevention of coronary heart disease in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995;333:1301-7.

[6.] Gibaldi M, Kradjan W. Treating elevated cholesterol levels: the great Satan in perspective. J Clin Pharmacol 1996;36:189-97.

[7.] Geurian KL. The cholesterol controversy. Ann Pharmacother 1996;30:495-500.

[8.] Jungnickel PW. Cholesterol-lowering therapy: is there really a controversy? Ann Pharmacother 1996;30:539-42.

[9.] LaRosa JC. Cholesterol lowering and morbidity and mortality. Curr Opin Lipidol 1995;6:62-5.

[10.] Gotto AM Jr. Lipid-regulating and antiatherosclerotic therapy: current options and future approaches. Cleve Clin J Med 1996;63:31-41.

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Each year members of a different medical faculty prepare articles for "Practical Therapeutics." This series is coordinated by the Department of Family Medicine at Wright State University School of Medicine, Dayton, Ohio. Guest editors of the series are Cynthia G. Olsen, M.D., and Gordon S. Walbroehl, M.D.

SYED M. AHMED, M.D., M.P.H., DR.P.H., is an assistant professor of family medicine at Wright State University School of Medicine and the Miami Valley Hospital family medicine residency program, both in Dayton, Ohio. He is a graduate of Sir. Salimullah Medical College, Dhaka University, Dhaka. He completed a residency and fellowship in family medicine at Baylor College of Medicine, Houston. He obtained both a masters degree and a doctorate in public health from the University of Texas School of Public Health, Houston.

MARK E. CLASEN, M.D., PH.D., is chairman of the Department of Family Medicine at Wright State University School of Medicine. He completed a residency in family medicine at the University of Mississippi Medical Center, Jackson. He has a certificate of added qualification in geriatrics. He is also president of University Medical Services Association, Dayton, Ohio.

JOHN F. DONNELLY, M.D., is associate professor in the Department of Family Medicine at Wright State University School of Medicine. He received a medical degree from the University of Texas-Houston Medical School and completed a residency in family medicine at Memorial Hospital Family Practice Residency Program in Houston.

Address correspondence to Syed M. Ahmed, M.D., M.P.H., Dr.P.H., Department of Family Medicine, East Dayton Health Center 2132 E Third St., Dayton, OH 45403. Reprints are not available from the authors.

COPYRIGHT 1998 American Academy of Family Physicians
COPYRIGHT 2000 Gale Group

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