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Review Article |

New Perspectives on the Management of Low Levels of High-Density Lipoprotein Cholesterol FREE

Charles R. Harper, MD; Terry A. Jacobson, MD
[+] Author Affiliations

From the Department of Medicine (Drs Harper and Jacobson) and Office of Health Promotion and Disease Prevention (Dr Jacobson), Emory University, Atlanta, Ga.


Arch Intern Med. 1999;159(10):1049-1057. doi:10.1001/archinte.159.10.1049.
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Published online

  A low serum high-density lipoprotein cholesterol (HDL-C) level is a potent predictor of coronary heart disease (CHD). It has been estimated that 11% of US men have isolated low HDL-C levels, and there is uncertainty regarding the management of these patients. A cause-and-effect relationship between low HDL-C levels and CHD is supported by epidemiological, animal, and human clinical studies. We reviewed the structure and function of HDL-C and its role in preventing atherosclerosis. We then suggested an approach to the patient with isolated low HDL-C that may be useful to the primary care physician. An algorithm was proposed for use in patients with existing CHD, while the decision to treat patients without CHD was based on their score on the Framingham Heart Study risk prediction chart.

Figures in this Article

A low serum high-density lipoprotein cholesterol (HDL-C) level is a potent predictor of premature coronary heart disease (CHD).13 There are numerous epidemiological and interventional studies that substantiate HDL-C as a major independent risk factor for CHD.4 Isolated low HDL-C (ILHDL-C) has been defined as HDL-C levels less than 35 mg/dL (0.91 mmol/L), low-density lipoprotein cholesterol (LDL-C) levels less than 160 mg/dL (4.14 mmol/L), and triglyceride levels less than 250 mg/dL (2.82 mmol/L).5 The National Cholesterol Education Program II (NCEP II) guidelines focus on using LDL-C levels and the number of CHD risk factors to treat patients with dyslipidemia. Patients with ILHDL-C are quite common yet are only minimally addressed in the guidelines.6 New evidence suggests that patients with low HDL-C levels should be treated more aggressively.7 This article reviews the available evidence that supports the importance of both diagnosing and treating ILHDL-C. The epidemiology and prevalence of ILHDL-C in various populations are addressed. Then a review of HDL-C biochemistry and its theoretical role in preventing atherogenesis is provided. Finally, an approach to treating patients with ILHDL-C is discussed.

Although there is strong epidemiological evidence that HDL-C protects against CHD, a cause-and-effect relationship has not been proven. The Framingham Heart Study was one of the first epidemiological studies to show the relationship between CHD and low HDL-C levels (Figure 1).8 Of note, a low LDL-C level did not completely remove the risk imparted by a low HDL-C level, while a high HDL-C level seemed to offset some of the risk of a high LDL-C level. Finally, an aggregate analysis of 4 of the largest US epidemiological studies (Framingham Heart Study, Lipid Research Clinics Prevalence Mortality Follow-up Study, Lipid Research Clinics Primary Prevention Trial, and Multiple Risk Factor Intervention Trial) suggested that for each 1-mg/dL (0.02-mmol/L) increase in HDL-C, a 2% decrease in CHD risk in men and a 3% decrease in women may occur.9

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Figure 1.

Risk of coronary heart disease (CHD) by high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels (from the Framingham Heart Study8).

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A review of the National Health and Nutrition Examination Survey III data, a population-based survey of noninstitutionalized US adults, revealed that 11% of US men older than 20 years have ILHDL-C.10 In Canada, the Quebec Cardiovascular Study, which measured lipoprotein levels in more than 2000 men free of CHD, also found a similar frequency of ILHDL-C in 13% of adult men.11 When examining higher-risk populations, such as men with CHD, the incidence of patients with ILHDL-C is much greater. The prevalence of ILHDL-C in CHD populations has been found to range from 17% to 36%.1215

In addition to epidemiological evidence, rodent studies suggest raising HDL-C levels may inhibit atherosclerosis. Mice that are genetically manipulated to overproduce HDL-C apolipoprotein A-I were protected against diet-induced atherosclerosis.16 In a second experiment, a different strain of mice with premature atherosclerosis were genetically altered to express the "human" HDL-C apolipoprotein A-I gene. These mice had a marked decrease in the development of atherosclerosis.17 Finally, in another animal model, rabbits intravenously infused with HDL-C exhibited regression of atherosclerotic lesions.18 Although animal models provide presumptive evidence that genetically altering HDL-C may be useful in slowing atherosclerosis, they do not necessarily generalize to humans or replace the need for human interventional trials.

In addition to the data in animal studies, there is clinical trial evidence in humans that therapy directed at raising HDL-C levels may decrease CHD risk.19 The Helsinki Heart Study was a randomized, placebo-controlled primary prevention trial using gemfibrozil therapy in more than 4000 high-risk men with dyslipidemia. The treatment group received gemfibrozil, 600 mg twice daily. During a 5-year interval, the intervention group demonstrated a decrease in LDL-C and triglyceride levels by 11% and 35%, respectively, while the HDL-C levels increased by 11%. Although this was a primary prevention study designed to reduce CHD risk in men with high LDL-C levels, the study demonstrated that for every 1-mg/dL (0.02-mmol/L) increase in HDL-C, there was a 2% to 3% decrease in CHD risk, independent of changes in LDL-C level. These numbers are based on a post hoc subgroup analysis, since the Helsinki Heart Study was not specifically designed to look at therapy directed toward raising HDL-C levels. Fibrates may have other beneficial effects besides raising HDL-C levels, such as reducing atherogenic remnants of triglyceride-rich lipoproteins or changing LDL-C particle size. It was shown, however, that patients with low HDL-C levels and high LDL-C levels had significantly greater risk reduction than any other subset.

The HDL-C subfractions are small, dense, spherical lipid-protein complexes synthesized in the liver and small intestine. The lipids that make up this complex include phospholipid, cholesterol, cholesterol esters, and triglycerides. The proteins are apoproteins A-I, A-II, E, and C. The HDL-C lipid protein complex is built around a hydrophobic core that contains cholesterol ester and triglycerides. The surface is hydrophilic and consists of phospholipids, unesterified cholesterol, and apolipoproteins20 (Figure 2).

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Figure 2.

Basic structure of high-density lipoprotein.64

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Plasma HDLs are not homogeneous. Subclasses of HDL-C can be defined based on density or apolipoprotein composition. When classified by density, HDL-C is separated into 2 major subclasses, HDL2 (larger and less dense) and HDL3 (smaller and more dense).21 Classification by apolipoprotein composition reveals 2 subclasses. A-I HDLs are composed of apolipoprotein A-I without apolipoprotein A-II. A-I/A-II HDLs contain both apolipoprotein A-I and apolipoprotein A-II.20 The recognition of these subclasses has become important because of studies that suggest size and apolipoprotein composition may alter HDL's cardioprotective properties.16

There are 3 events that are key to the formation of early atherosclerotic lesions. The first is infiltration of native LDL-C particles through the endothelium into the intimal layer of the arterial wall. It is thought that these LDL-C particles are then oxidized.22 Macrophages in the intima can ingest a limited number of native LDL-C particles. Once LDL-C is oxidized, however, macrophage uptake is increased and leads to foam cell formation. Foam cells are a major component of the early atherosclerotic lesion.22 The focal accumulation of monocytes and macrophages is also thought to be critical to the formation of the early atherosclerotic lesion. Endothelial cells express glycoproteins that allow monocyte adhesion to the endothelial surface. Oxidized LDL-C then stimulates endothelial cells to produce the monocyte chemotactic factor. As a result monocytes enter the intima and differentiate into macrophages. These macrophages produce cytokines that stimulate endothelial cells to produce adhesive glycoproteins and thus the recruitment of more monocytes. Macrophages also produce growth factors that result in the proliferation of smooth muscle cells. The composite of these events is the formation of a fatty streak or an early atherosclerotic lesion22 (Figure 3).

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Figure 3.

Schematic diagram of events thought to be involved in the formation of an early atherosclerotic lesion.21 HDL indicates high-density lipoprotein; LDL, low-density lipoprotein; HDL+, an enhancement by HDL; and HDL−, an inhibition by HDL.

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The cardioprotective effect of HDL-C has been attributed to its role in reverse cholesterol transport. In reverse cholesterol transport, cholesterol is accepted from peripheral tissues by small cholesterol-poor HDL3 particles.20 As the HDL3 accepts more free cholesterol, it is esterified and moved to the core of the particle. The continued uptake of cholesterol by HDL3 results in the formation of a larger, less dense HDL2 particle. The HDL2 particle can then transfer cholesterol esters to apolipoprotein B-100 lipoproteins or directly to the liver. High-density lipoprotein cholesterol is thought to have the ability to remove cholesterol from macrophages, thus preventing the formation of foam cells. Recently, it has been suggested that HDL's effect on atherogenesis may be mediated through other mechanisms as well.23 Potential mechanisms include the following: (1) HDL-C prevents the oxidation of LDL-C, (2) HDL-C prevents the adhesion of monocytes to the endothelium, and (3) HDL-C prolongs the half-life of prostacycline and preserves its vasodilatory effect.24

Before initiating a treatment plan for low HDL-C, a search should be made for secondary conditions that spuriously depress HDL-C. Acute illnesses such as a myocardial infarction, burns, surgical procedures, acute viral illness, or any inflammatory condition that results in an acute phase response will alter lipid levels.25 Typically, the total cholesterol, LDL-C, and HDL-C levels will decrease while triglyceride levels increase. Two to 5 days after a myocardial infarction, HDL-C levels start to decrease. A 12% to 32% decrease can be seen in HDL-C, and this depression may last up to 30 days. Lipid measurement should not be performed within 60 days of a myocardial infarction or major surgical procedure.25

The contribution of other chronic diseases also needs to be considered. The most common secondary causes of altered lipids include hypothyroidism, diabetes, uremia, and liver disease.26 Elevated triglyceride level is one of the leading causes of depressed HDL-C levels, and thus a fasting lipid profile, a thyroid-stimulating hormone level, blood glucose level, creatinine level, and liver enzyme levels are necessary to first rule out these secondary causes.4,26 In addition, certain commonly prescribed drugs also may lower HDL-C levels. Diuretics, progestins, androgens, and β-adrenergic blocking agents without intrinsic sympathomimetic activity are commonly prescribed drugs that decrease HDL-C levels.27 However, the use of these drugs may have other benefits that outweigh their risk of lowering HDL-C levels. On the other hand, estrogen replacement and phenytoin have been found to have a potent effect on raising HDL-C levels.28 Finally, there are rare familial dyslipoproteinemias that result in low HDL-C levels.29 Most of these genetic disorders are quite uncommon and are not always associated with premature atherosclerosis in affected families.30

Numerous studies have documented the value of lifestyle modification in improving HDL-C levels. The patient's weight, diet, exercise habits, and use of cigarettes should be addressed. Weight loss in obese men has been found to increase HDL-C levels.31 This is clearly depicted in a Dutch study32 of 315 men followed up for 10 years. The data from this study revealed that HDL-C levels increased 0.8 mg/dL (0.02 mmol/L) for every unit decrease in body mass index (a measure of weight in kilograms divided by the square of height in meters). The Framingham Offspring Study33 demonstrated a similar relationship. These studies indicate even modest weight loss can have a significant impact on HDL-C levels. The most important consideration in diet is energy (caloric) restriction with subsequent weight loss. Also, certain types of fats, called trans fatty acids, have been shown to lower HDL-C levels, whereas monounsaturated fats are thought to have a neutral effect on HDL-C.34 In recommending a diet to a patient with ILHDL-C not only should the total energy be restricted if the patient is overweight but so should the consumption of energy-dense saturated and polyunsaturated fats. Saturated fats and trans fatty acids may be substituted with unhydrogenated monounsaturated fats, such as olive oil or canola oil.35 These recommendations are based on studies that show that saturated fat raises LDL-C levels, whereas trans fatty acids lower HDL-C levels.34,35 Although some studies have shown that low-fat diets may lower HDL-C levels, total fat reduction is still thought to be overwhelmingly cardioprotective through mechanisms involving the lowering of LDL-C and its oxidation as well as possible effects on thrombosis.

Exercise in sedentary men increases HDL-C levels, but there is a threshold effect.36 It appears that moderate exercise is needed to result in a significant increase of HDL-C levels. Joggers who ran 16 km per week for 10 months showed a 10% increase in HDL-C levels. Exercise might not have as large an impact on HDL-C in women.37 Although a mechanism of HDL-C modulation has been proposed, it is still difficult to ascertain how much of the HDL-C response to exercise is derived from weight loss.35

In addition to diet and exercise, cigarette and alcohol use significantly affect HDL-C levels. Cigarette smoking has a "dose-dependent" negative effect on HDL-C even with consumption of less than 1 pack per day. After adjusting for other variables, including alcohol intake, cigarette smoking caused a 5- to 9-mg/dL (0.13- to 0.23-mmol/L) reduction in HDL-C when compared with matched controls.38 Moderate use of alcohol can increase HDL-C levels. Multiple epidemiological studies have demonstrated that CHD is lower in moderate daily drinkers. Fifty percent of the cardioprotective effect of alcohol may be attributed to HDL-C. Other contributors to alcohol's cardioprotective effect include LDL-C lowering, inhibition of platelet aggregation, decrease in fibrinogen, and enhancement of prostacyclin formation.39 It appears that men who consume 1 drink per day (12 oz of beer, 5 oz of wine, or 1.5 oz of 80-proof liquor) or less do not experience an increase in HDL-C level. Women, however, can consume 1 drink per day or less and still experience an increase in HDL-C level.39

Many patients will not achieve an adequate HDL-C level with nonpharmacologic therapy. There are several classes of drugs available for physicians to use in patients who do not respond to nonpharmacologic therapy. These classes include niacin, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, fibric acids, and estrogens.

Niacin

Niacin is the most efficacious drug for raising HDL-C levels.40 Its mechanism of action is not completely understood, but it is thought that niacin decreases hepatic production of very low-density lipoprotein levels and leads to an increase in HDL-C levels.26 Significantly lower doses of niacin are required to raise HDL-C levels than those required to lower LDL-C levels. Studies have shown that an increase in HDL-C of greater than 20% can be expected from doses of 1000 to 1500 mg/d.41 At higher doses niacin has been shown to lower triglyceride, LDL-C, and lipoprotein(a) levels. Full-dose niacin has been shown to decrease LDL-C levels 10% to 25%, increase HDL-C levels 15% to 35%, and decrease triglyceride levels 20% to 50%. The crystalline niacin is less expensive and appears to be more effective at increasing HDL-C levels than the sustained-release niacin. Sustained-release niacin is better tolerated and more effective at lowering LDL-C levels. An increased frequency of hepatotoxicity has been reported with sustained-release preparations.42 Niacin can be purchased at health food stores without a prescription, and there can be great variation in the quality of the preparations. Once a patient's dose and lipid level have been maintained, the patient should be instructed to avoid changing brands.6 Once-a-day, prescription-based niacin preparations (Niaspan; KOS Pharmaceuticals) have recently been approved by the Food and Drug Administration and may improve patient tolerance and lower the number of adverse effects.

Although niacin has a desirable effect on several lipoprotein subfractions, it has several unpleasant but benign side effects. In the Coronary Drug Project, 1119 men were randomized to 3 g/d of niacin or placebo, and there was a 66% adherence rate at the end of 5 years. Flushing and vasomotor symptoms were common and the most frequent reason for discontinuance.43 Gastrointestinal complaints include dyspepsia, nausea, abdominal pain, and activation of peptic ulcer. Niacin can result in dose-dependent hyperuricemia and hyperglycemia and should be used with greater caution or not at all in patients with uncontrolled diabetes, gout, or peptic ulcer disease.44 Dose-dependent hepatotoxicity has occurred but is more common with sustained-release preparations.45 Less common adverse effects include acanthosis nigricans and retinal edema. These adverse effects are less severe and less common at doses needed to increase HDL-C.43

Crystalline niacin can be given 3 to 4 times per day. Patients can take 325 mg of enteric-coated aspirin 30 minutes before the morning dose to reduce the prostaglandin-mediated flushing. Patients can begin treatment with 100 mg of niacin 3 times daily. The dose can be increased to 200 mg 3 times daily after 1 week and then increased by 100 mg weekly until a daily dose of 1500 mg (500 mg 3 times daily) is reached. The patient's HDL-C level should be measured after 1 month at the 1500-mg dose and then increased slowly if needed. Niacin should be taken with food to reduce dyspepsia or nausea. Serum transaminase levels should be measured before treatment and then every 3 months during the first year. Niacin is absolutely contraindicated in patients with chronic active liver disease.6 There are no large randomized clinical event trials that have examined the use of niacin in the treatment of ILHDL-C. The Coronary Drug Project, however, which used niacin in 1119 men with moderate hyperlipidemia after myocardial infarction, showed a 27% reduction in nonfatal myocardial infarction at the end of 5 years and a total mortality reduction of 11% at the end of 15 years.46

Fibrates

Gemfibrozil, 600 mg twice a day, increases HDL-C levels by an average of 11%. This drug is generally well tolerated; however, reported adverse effects include cholesterol gallstones, myopathy, liver enzyme elevations, dyspepsia, and leukopenia.19 There is increasing angiographic evidence that the fibrates may play a role in secondary prevention in patients with ILHDL-C. The Bezafibrate Coronary Atherosclerosis Intervention Trial study involved young survivors of myocardial infarctions with low HDL-C levels randomized to either bezafibrate or placebo. Ninety-two patients were followed up for 5 years. Treatment reduced triglyceride levels by 36% and increased HDL-C levels by 9%, whereas LDL-C levels did not change significantly. In addition to treatment that reduced triglyceride levels and increased HDL-C levels, there was a significant reduction in fibrinogen and remnant lipoproteins as well, which may account for the slowing of the atherosclerotic disease process. Treatment with bezafibrate not only slowed the progression of atherosclerosis, but also reduced coronary events.47 The Lipid Coronary Angiography Trial, a Finnish angiographic study, examined 372 patients after coronary artery bypass graft surgery who had ILHDL-C. Treatment with gemfibrozil decreased progression of CHD in native vessels and decreased graft lesions after an average of 32 months of therapy. VLDL triglyceride levels decreased by 40%, HDL-C levels increased by 15%, and LDL-C levels decreased by 10%.48 Although these angiographic trials have suggested some benefit for patients with CHD and ILHDL-C, the long-term follow-up of the secondary prevention component of the Helsinki Heart Study did not show clinical CHD event reduction with gemfibrozil. In addition, long-term follow-up of the primary prevention component of the Helsinki Heart Study showed that all-cause mortality was 20% higher in the gemfibrozil group when compared with placebo. This finding raises questions about the role of fibrates in CHD prevention.49

Two new trials using fibrates in patients with CHD and ILHDL-C will report their results in the next year. In the Veterans Affairs HDL-C Intervention Trial (VA HIT), 2500 men with CHD and HDL-C levels less than 40 mg/dL (1.03 mmol/L), LDL-C levels less than 140 mg/dL (3.62 mmol/L), and triglyceride levels less than 300 mg/dL (3.39 mmol/L) were recruited from 20 Veterans Affairs medical centers. These men were randomized to either gemfibrozil or placebo.50 The Bezafibrate Infarction Prevention Trial examined 3000 patients after myocardial infarction from 19 cardiac departments in Israel who had HDL-C levels less than 45 mg/dL (1.16 mmol/L), triglyceride levels less than 300 mg/dL (3.39 mmol/L), and LDL-C levels less than 180 mg/dL (4.65 mmol/L). The subjects were randomized to bezafibrate, 400 mg/d, or placebo, and will be followed up for 5 years.51 A new more potent fibrate, fenofibrate, has recently become FDA approved, with clinical event data pending.

Hormone Replacement Therapy

Randomized control trials are also needed to further delineate the role of hormone replacement therapy in the management of women with ILHDL-C. Estrogen is thought to reduce coronary risk by a variety of mechanisms, including raising HDL-C levels, lowering LDL-C levels, decreasing lipoprotein(a) levels, and decreasing fibrinogen levels and through beneficial effects on the arterial wall. Progestogens, however, typically decrease HDL-C levels.52 A recent, small, randomized, crossover trial demonstrated that in postmenopausal women treatment with the combination of estrogen and medroxyprogesterone acetate resulted in a 7% increase in HDL-C, a decrease in lipoprotein(a) levels, and a reduction in LDL-C.53 In the Coronary Drug Project, which used conjugated estrogen in men who had survived myocardial infarctions, the estrogen arm was discontinued because of unacceptable thrombotic complications. The doses of estrogen used in this study were 2.5 and 5.0 mg, which are much higher than those used for hormone replacement therapy today (0.625 mg).43 The recent Heart and Estrogen/Progestin Replacement Study (HERS) trial54 in postmenopausal women with CHD found that conjugated equine estrogen, 0.625 mg, combined with medroxyprogesterone acetate, 2.5 mg, had no effect on CHD end points and resulted in an increased incidence of thromboembolic complications. Preliminary results of VA-HIT suggest a modest benefit with gemfibrozil with CHD event rates reduced by 22%.50

HMG-CoA Reductase Inhibitors

The HMG-CoA reductase inhibitors act by inhibiting the conversion of HMG-CoA to mevalonic acid. This conversion is the rate-limiting step in cholesterol production and requires the enzyme HMG-CoA reductase. The HMG-CoA reductase inhibitors act in the liver by inhibiting HMG-CoA reductase, which reduces the cholesterol level in the liver cell. The reduced hepatocyte cholesterol levels result in an increase in the synthesis of LDL-C receptors.26 The HMG-CoA reductase inhibitors act predominantly by reducing LDL-C, but also have moderate effects on HDL-C and endothelial function. A study with lovastatin in patients with ILHDL-C revealed a 6% increase in HDL-C levels.40 The HMG-CoA reductase inhibitor drugs are well tolerated by patients. Adverse effects include increased liver enzyme levels, dyspepsia, and myopathy.25

Preliminary data from several primary and secondary CHD prevention trials suggest that HMG-CoA reductase inhibitors may reduce the adverse consequences of low HDL-C levels and result in significant morbidity and mortality reductions. For example, in the landmark HMG-CoA reductase inhibitor trials, such as the Scandinavian Simvastatin Survival Study, the West of Scotland Coronary Prevention Study, and the Cholesterol and Recurrent Events study, subgroup analysis of those with low HDL-C levels but with elevated LDL-C levels demonstrated similar CHD risk reductions compared with those with normal HDL-C levels.5557

In the recently published Air Force/Texas Coronary Atherosclerosis Prevention Study, a randomized, double-blind, placebo-controlled primary prevention trial involving 6605 men and women, the benefits of HMG-CoA reductase inhibitors were demonstrated in patients with low HDL-C and "average" LDL-C values.7 This study was designed to evaluate whether lipid-lowering therapy with lovastatin, 20 to 40 mg per day, was more effective than placebo in reducing acute major coronary events in a healthy, middle-aged cohort with normal to mildly elevated total cholesterol levels (180-264 mg/dL [4.65-6.83 mmol/L]) and LDL-C levels (130-190 mg/dL [3.36-4.91 mmol/L]) and low HDL-C levels (<45 mg/dL [1.16 mmol/L] for men and <47 mg/dL [1.22 mmol/L] for women) levels. About 35% of the Air Force/Texas Coronary Atherosclerosis Prevention Study cohort had HDL-C levels less than 35 mg/dL (0.90 mmol/L). Lovastatin was found to reduce major coronary events by 37% in this low-risk population that had a mean LDL-C level of 150 mg/dL (3.88 mmol/L) and a mean HDL-C level of 36 mg/dL (0.93 mmol/L). The acute major coronary event rate in the low HDL-C subgroup was reduced by lovastatin to a rate similar to that found in the desirable HDL-C subgroup.

Secondary Prevention

A decision should not be made to start drug therapy until all the patient's risk factors for CHD have been considered. Patients with established CHD are considered high risk and should be treated with drugs if an inadequate response to nonpharmacologic therapy is seen.58 Given the NCEP II recommendations for a target LDL-C level of less than 100 mg/dL (2.59 mmol/L) in CHD, patients with ILHDL-C should probably start treatment with a statin first. If these patients reach their target LDL-C level but their HDL-C level remains less than 35 mg/dL (0.90 mmol/L), then niacin or gemfibrozil could be considered as an addition to their regimen. The patient should be instructed to report myalgias, because this combination has a 2% risk of myositis myopathy or rhabdomyolysis.6 If the patient has an LDL-C level of less than 100 mg/dL (2.59 mmol/L) after nonpharmacologic therapy and the HDL-C level remains less than 35 mg/dL (0.90 mmol/L), then monotherapy with niacin may be considered (Figure 4).

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Figure 4.

An algorithm for the treatment of isolated low high-density lipoprotein (HDL). CHD indicates coronary heart disease; LDL, low-density lipoprotein; plus sign, positive; and minus sign, negative. ILHDL-C is defined as HDL ≤35 mg/dL, LDL ≤160 mg/dL, and TG ≤250 mg/dL.

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Primary Prevention

In patients without established CHD, nonlipid risk factors should be accounted for, and only the patients at the highest absolute risk of CHD should be treated with drugs.59 For primary prevention, an improved risk prediction tool other than the NCEP II guidelines (Table 1) may assist the provider in determining which patients are at high enough risk to start pharmacotherapy. Although more cumbersome, the Framingham risk prediction chart (Figure 5) is a more inclusive assessment of CHD risk than the NCEP II guidelines. The risk prediction chart is derived from the Framingham population and more precisely estimates CHD risk based on the interrelationship of other CHD risk factors (age, sex, smoking, hypertension, and diabetes) with lipoprotein levels, including total cholesterol and HDL-C.60 The risk prediction chart will assign the patient an absolute risk of CHD during a 10-year period. Based on international guidelines, such as those of the European Atherosclerosis Society, patients with a greater than 20% risk of CHD during a 10-year period should then be considered for treatment.61

Table Graphic Jump LocationTable 1. National Cholesterol Education Program II Treatment Decisions Based on LDL-C Levels*
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Figure 5.

Framingham Heart Study risk prediction chart. HDL indicates high-density lipoprotein; SBP, systolic blood pressure; and ECG, electrocardiogram; LVH, left ventricular hypertrophy. Estimated risk of CHD over a 10-year period, based on Framingham experience in patients aged 30 to 74 years at baseline. To convert cholesterol to millimoles per liter, multiply by 0.02586. High risk >20%.

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The utility of the risk prediction chart is illustrated by the following cases of 2 patients free of CHD but with low HDL-C levels (Table 2). Patient 1 is a 46-year-old man with a total cholesterol level of 260 mg/dL (2.72 mmol/L), an LDL-C level of 190 mg/dL (4.91 mmol/L), an HDL-C level of 34 mg/dL (0.88 mmol/L), and a triglyceride level of 180 mg/dL (2.03 mmol/L). The patient has no other CHD risk factors. Patient 2 is a 55-year-old man who smokes and has diabetes and hypertension (average systolic blood pressure, 139 mm Hg), and who has a total cholesterol level of 191 mg/dL (4.94 mmol/L), an LDL-C level of 131 mg/dL (3.39 mmol/L), an HDL-C level of 34 mg/dL (0.88 mmol/L), and a triglyceride level of 130 mg/dL (1.47 mmol/L).

Table Graphic Jump LocationTable 2. Comparison of CHD Risk for 2 Sample Patients With Low HDL-C Levels*

In case 1, the patient would be treated by the NCEP II guidelines by virtue of having an LDL-C level greater than 160 mg/dL (4.14 mmol/L) and 2 CHD risk factors. His 10-year risk for CHD derived from the risk prediction chart is 10%. In case 2, the patient would not meet NCEP II criteria for drug therapy, since his LDL-C level is less than 160 mg/dL (4.14 mmol/L) but his 10-year risk is 27% when using the risk prediction chart. Thus, despite patient 2 having a much lower LDL cholesterol level than patient 1, patient 2 remains at 3 times greater absolute risk of CHD than patient 1 given the multitude and intensity of other CHD risk factors. When applying these numbers to the European Atherosclerosis Society Guidelines based on the patient's absolute risk of CHD, patient 2 would be considered for drug therapy while patient 1 would not. These 2 cases illustrate that patients with ILHDL-C may not have their true CHD risk adequately expressed when using the NCEP II guidelines. The risk prediction chart allows the primary care physician to make a more informed decision about starting drug therapy in patients with ILHDL-C. A newer, more simplified Framingham risk prediction chart has recently been published.62

Another way to assess CHD risk aside from the Framingham Heart Study risk prediction tool is to use additional lipid and nonlipid CHD risk markers. Other markers if available, such as lipoprotein(a), apolipoprotein B, and dense LDL-C, may help identify higher-risk patients for treatment. In addition, nonlipid risk factors that may identify higher-risk patients include homocysteine, fibrinogen, or C-reactive protein.63 However, at present, their utility in the primary care setting has not been demonstrated and they can only be considered as research tools. Finally, another important nonlipid risk factor in treating patients with ILHDL-C is the presence of premature familial atherosclerosis in parents or siblings who also have relatively normal lipid levels or risk factor profiles. Since CHD is a multifactorial disease, members of high-risk families should be targeted more aggressively by either raising HDL-C levels or lowering LDL-C levels.

The existing evidence from epidemiological studies, transgenic animal studies, and subgroup analysis of human intervention trials supports the treatment of patients with ILHDL-C. The physician should determine the patient's absolute risk for CHD. In those without existing CHD, the Framingham Heart Study risk prediction chart is suggested as a possible tool for improved risk prediction in the patient with ILHDL-C. Separate approaches for both primary and secondary CHD prevention have been proposed. Large randomized controlled trials evaluating the treatment of ILHDL-C in patients with CHD are still pending. Although no interventional trial to date has demonstrated that modulating HDL-C in patients with ILHDL-C will result in CHD risk reduction, the available clinical, epidemiological, and animal evidence supports a role for intervention in those deemed at high risk for CHD events. The approach suggested in this review may help physicians treat this common lipid abnormality.

Accepted for publication September 1, 1998.

We thank Michael Lubin, MD, for advice and feedback and Betty Webb and Peggy Harper for help with manuscript preparation.

Reprints: Terry A. Jacobson, MD, Emory University, Thomas Glenn Building, 69 Butler St SE, Atlanta, GA 30303 (e-mail: tjaco02@emory.edu).

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Sempos  CTCleeman  JICarroll  MD  et al.  Prevalence of high blood cholesterol among US adults. JAMA. 1993;2693009- 3014
Lamarche  BDespres  J-PMoorjani  S  et al.  Prevalence of dyslipidemic phenotypes in ischemic heart disease (prospective results from the Quebec Cardiovascular Study). Am J Cardiol. 1995;751189- 1195
Genest  JMcNamara  JROrdovas  JM  et al.  Lipoprotein cholesterol, apolipoprotein A-I and B and lipoprotein (a) abnormalities in men with premature coronary artery disease. J Am Coll Cardiol. 1992;19792- 802
Genest  JJMartin-Munley  SSMcNamara  JR  et al.  Familial lipoprotein disorders in patients with premature coronary artery disease. Circulation. 1992;852025- 2033
Ginsburg  GSSafran  CPasternak  RC Frequency of low serum high-density lipoprotein cholesterol levels in hospitalized patients with desirable total cholesterol levels. Am J Cardiol. 1991;68187- 192
Lien  WLai  LShyu  K  et al.  Low-serum, high-density lipoprotein cholesterol concentration is an important coronary risk factor in Chinese patients with low serum levels of total cholesterol and triglyceride. Am J Cardiol. 1996;771112- 1115
Rubin  EMKrauss  RMSpangler  EA  et al.  Inhibition of early atherogenesis in transgenic mice by human apolipoprotein A1. Lett Nature. 1991;353265- 267
Plump  ASScott  CJ Human apolipoprotein A-I gene expression increases high density lipoprotein and suppresses atherosclerosis in apolipoprotein E deficient mice. Proc Natl Acad Sci U S A. 1994;919607- 9611
Badimon  JJBadimon  LFuster  V Regression of atherosclerotic lesions by high density lipoprotein plasma fraction in the cholesterol-fed rabbit. J Clin Invest. 1990;851234- 1241
Frick  MNElo  OHaapa  K  et al.  Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. N Engl J Med. 1987;3171237- 1245
Tall  AR Plasma high density lipoproteins. J Clin Invest. 1990;86379- 384
Barter  PJRye  KA High density lipoproteins and coronary. Atherosclerosis. 1996;1211- 12
Fernanez-Ortiz  AFuster  V Pathophysiology of coronary artery disease: coronary artery disease in the elderly. Clin Geriatr Med. 1996;121- 21
Maier  JABarcenghi  LPagani  F  et al.  The protective role of high density lipoprotein on oxidized low density lipoprotein induced U937/endothelial cell interactions. Eur J Biochem. 1994;22135- 41
Mackness  MIArrol  SAbbott  CADuringhton  PN Protection of low-density lipoprotein against oxidative modification by high-density lipoprotein associated paraoxonase. Atherosclerosis. 1993;104129- 135
Rosenson  RS Low levels of high-density lipoprotein cholesterol (hypoalphalipoproteinemia). Arch Intern Med. 1993;1531528- 1538
Stone  NBlum  CWinslon  E Management of Lipids in Clinical Practice.  Caddo, Okla Professional Communications Inc1997;
Wallace  RBHunningake  DBReiland  S  et al.  Alterations of plasma high-density lipoprotein cholesterol levels associated with consumption of selected medications. Circulation. 1980;62 ((suppl 4)) 77- 82
Walsh  BWSchiff  IRosner  B  et al.  Effects of postmenopausal estrogen replacement on the concentration and metabolism of plasma lipoproteins. N Engl J Med. 1991;3251196- 1204
Funke  H Genetic determinants of high density lipoprotein levels. Lipidology. 1997;8189- 196
Rader  DJIkewaki  KDuverger  N  et al.  Very low high-density lipoproteins without coronary atherosclerosis. Lancet. 1993;3421455- 1458
Wood  PDStefanick  MLDreon  DM  et al.  Changes in plasma lipids and lipoproteins in overweight men during weight loses through dieting as compared with exercise. N Engl J Med. 1988;3191173- 1179
Berns  MADevries  JHKatan  MB Increase in body fatness as a major determinant of changes in serum total cholesterol and HDL cholesterol in young men over a 10 year period. Am J Epidemiol. 1984;1301109- 1122
Anderson  KMWilson  PWFGarrison  RJCastelli  WP Longitudinal and secular trends in lipoproteins: the Framingham Offspring Study. Artherioscler Thromb. 1983;3273- 281
Mensink  RPKatan  MB Effect of dietary trans fatty acids on high-density and low-density lipoprotein cholesterol levels in healthy subjects. N Engl J Med. 1990;323439- 445
Hu  FBStumpfer  MJManson  SE  et al.  Dietary fat intake and the risk of coronary heart disease in women. N Engl J Med. 1997;3371491- 1499
Milani  RVLavie  CJ Prevalence and effects of nonpharmacologic treatment of isolated low-HDL cholesterol in patients with coronary artery disease. J Cardiopulm Rehabil. 1995;15439- 444
Sagiv  MGoldbourt  U Influence of physical work on high density lipoprotein cholesterol: implications for the risk of coronary heart disease. Int J Sports Med. 1994;15261- 266
Criqui  MHWallace  RBHeiss  G  et al.  Cigarette smoking and plasma high-density lipoprotein cholesterol: the Lipid Research Clinics Program Prevalence Study. Circulation. 1980;62 ((suppl 4)) 70- 76
Stampfer  MJColditz  GAWillett  WC  et al.  A prospective study of moderate alcohol consumption and the risk of coronary disease and stroke in women. N Engl J Med. 1988;319267- 273
Vega  GLGrundy  SM Lipoprotein responses to treatment with lovastatin, gemfibrozil, and nicotinic acid in normolipidemic patients with hypoalphalipoproteinemia. Arch Intern Med. 1994;15473- 82
Martin-Jadraque  RTato  FMostaza  JM  et al.  Effectiveness of low-dose crystalline nicotinic acid in men with low high-density lipoprotein cholesterol levels. Arch Intern Med. 1996;1561081- 1088
McKenney  JMProctor  JHarris  SChinchili  VM A comparison of the efficacy and toxic effects of sustained vs immediate-release niacin in hypercholesterolemic patients. JAMA. 1994;271672- 677
The Coronary Drug Project Research Group, Clofibrate and niacin in coronary heart disease. JAMA. 1975;231360- 381
Garg  AGrundy  SM Nicotinic acid as therapy for dyslipidemia in non–insulin-dependent diabetes mellitus. JAMA. 1980;264723- 726
Gibbons  LWGonzales  VBSGordon  N  et al.  The prevalence of side effects with regular and sustained-released nicotine acid. Am J Med. 1995;99378- 385
Canner  PLBerge  KGWenger  NK  et al.  Fifteen year mortality in coronary drug project patients: long-term benefit with niacin. J Am Coll Cardiol. 1986;81245- 1255
Ericsson  C-GHamsten  ANilsson  J  et al.  Angiographic assessment of effects of bezafibrate on progression of coronary artery disease in young male postinfarction patients. Lancet. 1996;347849- 853
Frick  MHMikko  SNieminen  MS  et al.  Prevention of the angiographic progression of coronary and vein-graft atherosclerosis by gemfibrozil after coronary bypass surgery in men with low levels of HDL cholesterol. Circulation. 1997;962137- 2143
Huttunen  JKHeinonone  OPManninen  V  et al.  Helsinki Heart Study: 8.5 year safety and mortality follow-up. J Intern Med. 1994;23531- 39
Rubins  HVA HIT Study Group, Veterans' Administration HDL Intervention Trial (VA HIT). American Heart Association Scientific Session, November 1998. Am J Cardiol. 1993;7145- 52
Goldbourt  UBehar  SReicher-Reiss  H  et al.  Rationale and design of a secondary prevention trial of increasing serum high-density lipoprotein cholesterol and reducing triglycerides in patients with clinically manifest atherosclerotic heart disease (The Bezafibrate Infarction Prevention Trial). Am J Cardiol. 1993;71909- 915
Denke  MA Hormone replacement therapy: benefit and safety issues. Lipidology. 1996;7369- 373
Darling  GMJohns  JAMcCloud  PI  et al.  Estrogen and progestin compared with simvastatin for hypercholesterolemia in postmenopausal women. N Engl J Med. 1997;337595- 601
Hulley  SGrady  DBush  T  et al.  Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women: Heart and Estrogen/Progestin Replacement Study (HERS) Research Group. JAMA. 1998;280605- 613
Not Available, The Scandinavian Simvastatin Survival Study (4S): randomized trial of cholesterol lowering in 4444 patients with coronary heart disease. Lancet. 1994;3441383- 1389
Shepherd  JCobbe  SMFord  I  et al.  Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 1995;3331301- 1307
Sacks  FMPfeffer  MAMoye  LA  et al.  The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;3351001- 1009
Smith  SCBlair  SNCriqui  MH  et al.  Preventing heart attack and death in patents with coronary disease. Circulation. 1995;922- 4
Grundy  SMBalady  GJCriqui  MH  et al.  Guide to primary prevention of cardiovascular disease. Circulation. 1997;952329- 2331
Anderson  KMWilson  PWOdell  PM  et al.  An updated coronary risk profile. Am Heart Assoc Statement Circ. 1991;83356- 362
Pyorala  KDe Backer  GGraham  I  et al.  Prevention of coronary heart disease in clinical practice. Eur Soc Cardiol. 1994;151300- 1331
Wilson  PWD'Agustino  RBLevy  DA  et al.  Prediction of Coronary Heart Disease Risk Using Risk Factor Categories. Circulation. 1998;971837- 1847
Boushey  CJBersford  SAOmenn  GSMotulsky  AG A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA. 1995;2741049- 1057
Grundy  SM Etiology and Treatment of Hyperlipidemia.  London, England Mosby-Wolfe Medical Communications1996;

Figures

Place holder to copy figure label and caption
Figure 1.

Risk of coronary heart disease (CHD) by high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels (from the Framingham Heart Study8).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Basic structure of high-density lipoprotein.64

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Schematic diagram of events thought to be involved in the formation of an early atherosclerotic lesion.21 HDL indicates high-density lipoprotein; LDL, low-density lipoprotein; HDL+, an enhancement by HDL; and HDL−, an inhibition by HDL.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

An algorithm for the treatment of isolated low high-density lipoprotein (HDL). CHD indicates coronary heart disease; LDL, low-density lipoprotein; plus sign, positive; and minus sign, negative. ILHDL-C is defined as HDL ≤35 mg/dL, LDL ≤160 mg/dL, and TG ≤250 mg/dL.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 5.

Framingham Heart Study risk prediction chart. HDL indicates high-density lipoprotein; SBP, systolic blood pressure; and ECG, electrocardiogram; LVH, left ventricular hypertrophy. Estimated risk of CHD over a 10-year period, based on Framingham experience in patients aged 30 to 74 years at baseline. To convert cholesterol to millimoles per liter, multiply by 0.02586. High risk >20%.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. National Cholesterol Education Program II Treatment Decisions Based on LDL-C Levels*
Table Graphic Jump LocationTable 2. Comparison of CHD Risk for 2 Sample Patients With Low HDL-C Levels*

References

Castelli  WPGarrison  RJWilson  PW  et al.  Incidence of coronary heart disease and lipoprotein cholesterol levels. JAMA. 1986;2562835- 2838
Jacobs  DRMebane  ILBangdiwala  SI  et al.  High density lipoprotein cholesterol as a predictor of cardiovascular disease mortality in men and women: the follow-up study of the Lipid Research Clinics Prevalence Study. Am J Epidemiol. 1990;13132- 47
Kannel  WBCastelli  WPGordon  T Cholesterol in the prediction of atherosclerotic diseases: new perspectives on the Framingham Study. Ann Intern Med. 1979;9085- 91
NIH Consensus Conference, Triglyceride, high-density lipoprotein, and coronary heart disease. JAMA. 1993;269505- 510
Lavie  CJMailander  LMilani  RV Marked benefit with sustained-release niacin therapy in patients with isolated very low levels of high-density lipoprotein cholesterol and coronary artery disease. Am J Cardiol. 1992;691083- 1085
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, 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). Circulation. 1994;891329- 1445
Downs  JRClearfield  MWeis  S  et al.  Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. JAMA. 1998;2791615- 1622
Gordon  TCastelli  WPHjortland  MC  et al.  High density lipoprotein as a protective factor against coronary heart disease. Am J Med. 1977;62707- 714
Gordon  DJProbstfield  JLGarrison  RJ  et al.  High-density lipoprotein cholesterol and cardiovascular disease. Circulation. 1989;798- 15
Sempos  CTCleeman  JICarroll  MD  et al.  Prevalence of high blood cholesterol among US adults. JAMA. 1993;2693009- 3014
Lamarche  BDespres  J-PMoorjani  S  et al.  Prevalence of dyslipidemic phenotypes in ischemic heart disease (prospective results from the Quebec Cardiovascular Study). Am J Cardiol. 1995;751189- 1195
Genest  JMcNamara  JROrdovas  JM  et al.  Lipoprotein cholesterol, apolipoprotein A-I and B and lipoprotein (a) abnormalities in men with premature coronary artery disease. J Am Coll Cardiol. 1992;19792- 802
Genest  JJMartin-Munley  SSMcNamara  JR  et al.  Familial lipoprotein disorders in patients with premature coronary artery disease. Circulation. 1992;852025- 2033
Ginsburg  GSSafran  CPasternak  RC Frequency of low serum high-density lipoprotein cholesterol levels in hospitalized patients with desirable total cholesterol levels. Am J Cardiol. 1991;68187- 192
Lien  WLai  LShyu  K  et al.  Low-serum, high-density lipoprotein cholesterol concentration is an important coronary risk factor in Chinese patients with low serum levels of total cholesterol and triglyceride. Am J Cardiol. 1996;771112- 1115
Rubin  EMKrauss  RMSpangler  EA  et al.  Inhibition of early atherogenesis in transgenic mice by human apolipoprotein A1. Lett Nature. 1991;353265- 267
Plump  ASScott  CJ Human apolipoprotein A-I gene expression increases high density lipoprotein and suppresses atherosclerosis in apolipoprotein E deficient mice. Proc Natl Acad Sci U S A. 1994;919607- 9611
Badimon  JJBadimon  LFuster  V Regression of atherosclerotic lesions by high density lipoprotein plasma fraction in the cholesterol-fed rabbit. J Clin Invest. 1990;851234- 1241
Frick  MNElo  OHaapa  K  et al.  Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. N Engl J Med. 1987;3171237- 1245
Tall  AR Plasma high density lipoproteins. J Clin Invest. 1990;86379- 384
Barter  PJRye  KA High density lipoproteins and coronary. Atherosclerosis. 1996;1211- 12
Fernanez-Ortiz  AFuster  V Pathophysiology of coronary artery disease: coronary artery disease in the elderly. Clin Geriatr Med. 1996;121- 21
Maier  JABarcenghi  LPagani  F  et al.  The protective role of high density lipoprotein on oxidized low density lipoprotein induced U937/endothelial cell interactions. Eur J Biochem. 1994;22135- 41
Mackness  MIArrol  SAbbott  CADuringhton  PN Protection of low-density lipoprotein against oxidative modification by high-density lipoprotein associated paraoxonase. Atherosclerosis. 1993;104129- 135
Rosenson  RS Low levels of high-density lipoprotein cholesterol (hypoalphalipoproteinemia). Arch Intern Med. 1993;1531528- 1538
Stone  NBlum  CWinslon  E Management of Lipids in Clinical Practice.  Caddo, Okla Professional Communications Inc1997;
Wallace  RBHunningake  DBReiland  S  et al.  Alterations of plasma high-density lipoprotein cholesterol levels associated with consumption of selected medications. Circulation. 1980;62 ((suppl 4)) 77- 82
Walsh  BWSchiff  IRosner  B  et al.  Effects of postmenopausal estrogen replacement on the concentration and metabolism of plasma lipoproteins. N Engl J Med. 1991;3251196- 1204
Funke  H Genetic determinants of high density lipoprotein levels. Lipidology. 1997;8189- 196
Rader  DJIkewaki  KDuverger  N  et al.  Very low high-density lipoproteins without coronary atherosclerosis. Lancet. 1993;3421455- 1458
Wood  PDStefanick  MLDreon  DM  et al.  Changes in plasma lipids and lipoproteins in overweight men during weight loses through dieting as compared with exercise. N Engl J Med. 1988;3191173- 1179
Berns  MADevries  JHKatan  MB Increase in body fatness as a major determinant of changes in serum total cholesterol and HDL cholesterol in young men over a 10 year period. Am J Epidemiol. 1984;1301109- 1122
Anderson  KMWilson  PWFGarrison  RJCastelli  WP Longitudinal and secular trends in lipoproteins: the Framingham Offspring Study. Artherioscler Thromb. 1983;3273- 281
Mensink  RPKatan  MB Effect of dietary trans fatty acids on high-density and low-density lipoprotein cholesterol levels in healthy subjects. N Engl J Med. 1990;323439- 445
Hu  FBStumpfer  MJManson  SE  et al.  Dietary fat intake and the risk of coronary heart disease in women. N Engl J Med. 1997;3371491- 1499
Milani  RVLavie  CJ Prevalence and effects of nonpharmacologic treatment of isolated low-HDL cholesterol in patients with coronary artery disease. J Cardiopulm Rehabil. 1995;15439- 444
Sagiv  MGoldbourt  U Influence of physical work on high density lipoprotein cholesterol: implications for the risk of coronary heart disease. Int J Sports Med. 1994;15261- 266
Criqui  MHWallace  RBHeiss  G  et al.  Cigarette smoking and plasma high-density lipoprotein cholesterol: the Lipid Research Clinics Program Prevalence Study. Circulation. 1980;62 ((suppl 4)) 70- 76
Stampfer  MJColditz  GAWillett  WC  et al.  A prospective study of moderate alcohol consumption and the risk of coronary disease and stroke in women. N Engl J Med. 1988;319267- 273
Vega  GLGrundy  SM Lipoprotein responses to treatment with lovastatin, gemfibrozil, and nicotinic acid in normolipidemic patients with hypoalphalipoproteinemia. Arch Intern Med. 1994;15473- 82
Martin-Jadraque  RTato  FMostaza  JM  et al.  Effectiveness of low-dose crystalline nicotinic acid in men with low high-density lipoprotein cholesterol levels. Arch Intern Med. 1996;1561081- 1088
McKenney  JMProctor  JHarris  SChinchili  VM A comparison of the efficacy and toxic effects of sustained vs immediate-release niacin in hypercholesterolemic patients. JAMA. 1994;271672- 677
The Coronary Drug Project Research Group, Clofibrate and niacin in coronary heart disease. JAMA. 1975;231360- 381
Garg  AGrundy  SM Nicotinic acid as therapy for dyslipidemia in non–insulin-dependent diabetes mellitus. JAMA. 1980;264723- 726
Gibbons  LWGonzales  VBSGordon  N  et al.  The prevalence of side effects with regular and sustained-released nicotine acid. Am J Med. 1995;99378- 385
Canner  PLBerge  KGWenger  NK  et al.  Fifteen year mortality in coronary drug project patients: long-term benefit with niacin. J Am Coll Cardiol. 1986;81245- 1255
Ericsson  C-GHamsten  ANilsson  J  et al.  Angiographic assessment of effects of bezafibrate on progression of coronary artery disease in young male postinfarction patients. Lancet. 1996;347849- 853
Frick  MHMikko  SNieminen  MS  et al.  Prevention of the angiographic progression of coronary and vein-graft atherosclerosis by gemfibrozil after coronary bypass surgery in men with low levels of HDL cholesterol. Circulation. 1997;962137- 2143
Huttunen  JKHeinonone  OPManninen  V  et al.  Helsinki Heart Study: 8.5 year safety and mortality follow-up. J Intern Med. 1994;23531- 39
Rubins  HVA HIT Study Group, Veterans' Administration HDL Intervention Trial (VA HIT). American Heart Association Scientific Session, November 1998. Am J Cardiol. 1993;7145- 52
Goldbourt  UBehar  SReicher-Reiss  H  et al.  Rationale and design of a secondary prevention trial of increasing serum high-density lipoprotein cholesterol and reducing triglycerides in patients with clinically manifest atherosclerotic heart disease (The Bezafibrate Infarction Prevention Trial). Am J Cardiol. 1993;71909- 915
Denke  MA Hormone replacement therapy: benefit and safety issues. Lipidology. 1996;7369- 373
Darling  GMJohns  JAMcCloud  PI  et al.  Estrogen and progestin compared with simvastatin for hypercholesterolemia in postmenopausal women. N Engl J Med. 1997;337595- 601
Hulley  SGrady  DBush  T  et al.  Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women: Heart and Estrogen/Progestin Replacement Study (HERS) Research Group. JAMA. 1998;280605- 613
Not Available, The Scandinavian Simvastatin Survival Study (4S): randomized trial of cholesterol lowering in 4444 patients with coronary heart disease. Lancet. 1994;3441383- 1389
Shepherd  JCobbe  SMFord  I  et al.  Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 1995;3331301- 1307
Sacks  FMPfeffer  MAMoye  LA  et al.  The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;3351001- 1009
Smith  SCBlair  SNCriqui  MH  et al.  Preventing heart attack and death in patents with coronary disease. Circulation. 1995;922- 4
Grundy  SMBalady  GJCriqui  MH  et al.  Guide to primary prevention of cardiovascular disease. Circulation. 1997;952329- 2331
Anderson  KMWilson  PWOdell  PM  et al.  An updated coronary risk profile. Am Heart Assoc Statement Circ. 1991;83356- 362
Pyorala  KDe Backer  GGraham  I  et al.  Prevention of coronary heart disease in clinical practice. Eur Soc Cardiol. 1994;151300- 1331
Wilson  PWD'Agustino  RBLevy  DA  et al.  Prediction of Coronary Heart Disease Risk Using Risk Factor Categories. Circulation. 1998;971837- 1847
Boushey  CJBersford  SAOmenn  GSMotulsky  AG A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA. 1995;2741049- 1057
Grundy  SM Etiology and Treatment of Hyperlipidemia.  London, England Mosby-Wolfe Medical Communications1996;

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