HDL Cholesterol: What Is Its True Clinical Significance?

Although the cardioprotective effect of high-density lipoprotein cholesterol (HDL-C) has been recognized since 1950, research data on the long-term effects of treatments designed to raise serum HDL-C have only begun to emerge in the past two years. The authors explain how HDL-C fits into the pathogenesis of coronary heart disease and lay out a practical approach to the patient whose HDL-C may be too low.

By Analia Castiglioni, MD, and W. Richey Neuman, MD, MPH

Since 1950, researchers have recognized the cardioprotective effect of high-density lipoprotein cholesterol (HDL-C). Subsequent epidemiologic and clinical data demonstrate the important role of HDL-C in coronary heart disease (CHD) risk. Notably, elevated HDL-C reduces the risk of CHD, while low HDL-C is a strong independent risk factor for CHD. In spite of this convincing evidence, however, there is still controversy as to whether treatment of low HDL-C reduces the risk of CHD.

In this article, we will discuss the role of HDL-C in the pathogenesis of CHD. We will also review the evidence underscoring the importance of diagnosing and treating patients with low HDL-C. Lastly, we will provide a clinically useful approach to treating such patients.
 

HDL-C AND ATHEROGENESIS

High-density lipoprotein cholesterol subfractions are small, dense particles containing lipids (phospholipids, cholesterol, and triglycerides) and proteins (apolipoproteins, enzymes, and lipid transfer proteins). These particles are heterogeneous, classified according to their lipid and apolipoprotein content and their density. The recognition of different HDL-C subclasses is important; some studies suggest that particle size and apolipoprotein composition may alter HDL-C's cardioprotective properties.

Those cardioprotective properties have been attributed to HDL-C's role in reverse cholesterol transport. Through this mechanism, cholesterol is accepted from peripheral tissues by small, cholesterol-poor HDL particles, which then transfer cholesterol esters back to apolipoprotein B-100 lipoproteins or directly to the liver. High-density lipoprotein cholesterol is also thought to remove cholesterol from macrophages, thus preventing the formation of foam cells. Other hypothesized anti-atherogenic mechanisms of HDL-C include prevention of low-density lipoprotein cholesterol (LDL-C) oxidation, prevention of the adhesion of monocytes to the endothelium, and prolongation of prostacycline half-life and subsequent preservation of vasodilatory effect.

It is estimated that 11% of American men who are older than 20 years of age have isolated low HDL-C, defined as a level below 40 mg/dl in the absence of elevated LDL-C and triglyceride levels. Among all patients with CHD, the prevalence of isolated low HDL-C ranges from 17% to 36%. Compared to Caucasian men, African-American men with CHD have substantially higher HDL-C levels (45 versus 38 mg/dl).

Low levels of HDL-C have several causes, many of which are associated with insulin resistance and the metabolic syndrome, such as elevated triglyceride levels, overweight and obesity, physical inactivity, and type 2 diabetes. (The metabolic syndrome is defined as the presence of three or more of the following conditions: abdominal obesity, hypertension, an HDL-C level below 40 mg/dl, a triglyceride level above 150 mg/dl, and insulin resistance.) Other causes of low HDL-C include cigarette smoking, very high carbohydrate intake (more than 60% of calories consumed), and certain drugs (such as androgens and related steroids, beta blockers, diuretics, and progestins). There are rare familial dyslipoproteinemias that result in low HDL-C levels, such as familial hypoalphalipoproteinemia; however, they are not necessarily associated with premature atherosclerosis.

In contrast to low levels of HDL-C, elevated HDL-C is associated with use of estrogen and phenytoin, smoking cessation, high saturated fat diet, regular aerobic exercise, and alcohol consumption. There is also a genetic syndrome, called the syndrome of high HDL-C, that is characterized by high levels of HDL-C and associated with decreased incidence of CHD and with longevity.
 

EVIDENCE FOR TREATING LOW HDL-C

The Framingham Heart Study was one of the first epidemiologic studies to show an inverse association between HDL-C levels and CHD. In the Framingham population, HDL-C levels were independent predictors of CHD risk, regardless of low LDL-C levels. In addition to the Framingham data, an aggregate analysis of several large epidemiologic studies suggested that for each 1 mg/dl increase in HDL-C, a 2% decrease in CHD risk in men and a 3% decrease in women may occur.

The long-term clinical benefits of decreasing CHD risk by reducing elevated levels of LDL-C has been demonstrated by several well-designed primary and secondary prevention trials. But even with the established benefit of up to a 30% reduction in coronary events through LDL-C reduction seen in these trials, 70% of patients at risk for myocardial infarction (MI) who received treatment experienced coronary events. These findings, together with the strong epidemiologic data showing a cardioprotective effect of high HDL-C independent of other risk factors, have led to the emergence of the so-called HDL hypothesis, which proposes that high levels of HDL-C have a cardioprotective effect and low HDL-C levels have a risk-promoting effect.

Clinical trials and angiographic studies have lent support to this HDL hypothesis. Two primary prevention trials of LDL-C lowering—the Lipid Research Clinics Primary Prevention trial and the Helsinki Heart Study—both demonstrated that increasing HDL-C levels reduced CHD events, independent of the effect of LDL-C lowering. Another study demonstrated that in otherwise normocholesterolemic patients with angiographically documented CHD, patients with an HDL-C level below 34.8 mg/dl had significantly more CHD events over a 13-year follow-up period than patients with an HDL-C equal to or more than that level. In an angiographic study evaluating the effects of HDL-C on CHD, an association was seen between decreasing levels of HDL-C and the severity of CHD, as indicated by the number and type of coronary vessels involved.

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CLINICAL TRIALS TARGETING HDL-C

Within the last two years, the first large-scale, secondary prevention clinical trials looking at the long-term outcomes of increasing HDL-C in patients with CHD and normal cholesterol levels were released. They are the Bezafibrate Infarction Prevention (BIP) study and the Veterans Affairs High-density Lipoprotein Intervention Trial (VA-HIT).

The BIP was a multicenter secondary prevention study that included 3122 men and women with documented CHD. It examined the effect of bezafibrate, a fibric acid derivative, on CHD-related death and nonfatal MI among patients who had total cholesterol levels between 180 and 250 mg/dl, normal triglyceride levels (below 300 mg/dl), and low HDL-C (below 45 mg/dl). After 12 months, patients treated with bezafibrate had a mean 15% increase in their HDL-C levels and an 18% reduction in triglyceride levels compared with placebo. A 9% reduction in the primary CHD and MI endpoints was observed but was not considered statistically significant. However, patients with diabetes, who represent a large subgroup of patients with CHD that may benefit more than most from increased HDL-C levels, were largely excluded from the study. This may well have precluded the possibility of demonstrating a significant treatment effect.

The second trial, VA-HIT, was the first major clinical trial to examine the benefits of lipid therapy in patients whose primary lipid abnormality was a low HDL-C level. Another secondary prevention trial, it was a randomized, double-blind, placebo-controlled, multicenter study evaluating the effect of the fibrate gemfibrozil on CHD-related death and nonfatal MI in men with documented CHD who had low HDL-C levels (below 40 mg/dl), triglyceride levels below 300 mg/dl, and LDL-C levels below 140 mg/dl. Unlike the BIP trial, this study included patients with diabetes.

A total of 2531 men were followed for a mean 5.1 years. After one year, gemfibrozil-treated patients had a 6% increase in their HDL-C levels and a 31% decrease in triglycerides compared with placebo (p=0.001). Importantly, both the gemfibrozil and placebo groups had identical LDL-C levels at one year. These lipid alterations were associated with a significant (p=0.05) reduction of 22% in the combined primary end point of CHD-related death and nonfatal MI, a 22% reduction in nonfatal MI alone, and a 27% reduction in stroke.

This was the first trial to show that raising HDL-C and decreasing triglyceride levels, in the absence of LDL-C lowering, yields a clinical benefit. The results of VA-HIT not only substantiate the HDL-C hypothesis but also indicate that the therapeutic benefit associated with increased HDL-C in this population is similar to, or perhaps even greater than, that of LDL-C lowering in patients whose primary abnormality is high LDL-C. The trial also demonstrated that for every 1 mg/dl increase in HDL-C, there was an 11% decrease in CHD-related death or nonfatal MI.
 

ATP III RECOMMENDATIONS

The Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on the Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III [ATP III]) was released in May 2001. It defined low HDL-C as a serum level below 40 mg/dl, a change from the level of less than 35 mg/dl described in NCEP/ATP II. Conversely, high HDL-C is defined as HDL-C serum levels above 60 mg/dl, which imparts a negative risk factor for CHD.

In the current guidelines, low HDL-C both modifies the goal for LDL-C lowering therapy and is used as a risk factor to estimate 10-year risk of CHD. Low levels of HDL-C can be present with elevated total cholesterol and LDL-C or as the primary lipid abnormality. The ATP III recommends that in all patients with low HDL-C, the primary therapeutic target should be lowering LDL-C, followed by weight reduction and increased physical activity. Next, elevated triglyceride levels should be addressed, with medication if necessary. Attention should then turn to low HDL-C. Although ATP III does not specify a target goal for HDL-C levels, the panel does acknowledge that raising HDL-C will likely reduce the risk of CHD. It also recommends raising HDL-C through lifestyle modifications and, when necessary, medication. It does comment that treatment for isolated low HDL-C should be reserved for patients with CHD and CHD risk equivalents, such as diabetes and other clinical forms of atherosclerotic disease.

Numerous studies have documented the value of lifestyle modifications in improving HDL-C levels. Weight, diet, exercise, and smoking should all be addressed in the patient with low HDL-C. Studies show that even a weight loss of only 5 to 10 kg in obese patients can increase HDL-C levels, and HDL-C can increase by as much as 0.8 mg/dl for every unit decrease in body mass index. The most important dietary consideration is restricting caloric intake, with subsequent weight loss. Saturated fat and trans fatty acids should be avoided; saturated fat raises LDL-C levels and trans fatty acids lower HDL-C levels. Patients should be encouraged to use unhydrogenated monounsaturated fat (such as canola oil or olive oil), which is thought to have a neutral effect on HDL-C.

Moderate exercise in men increases HDL-C levels, as much as 10% in those who run 10 miles a week. Exercise might not have such an impact on HDL-C in women, however, and it is still difficult to know how much of the HDL-C response to exercise is derived from weight loss.

Cigarette smoking has a dose-dependent negative effect on HDL-C levels, even in those who smoke less than a pack a day. Smokers have been found to have HDL-C levels 5 to 9 mg/dl lower than matched controls. On the other hand, moderate alcohol intake increases HDL-C levels. Men who have only one to two drinks a day and women who have only one drink a day can expect their HDL-C to rise. Although this is considered one of the most important mechanisms by which alcohol decreases the risk of cardiovascular disease, encouraging alcohol intake to treat isolated low HDL-C is not recommended. 

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DRUG THERAPY FOR LOW HDL-C

For patients whose HDL-C levels do not respond to lifestyle changes, several classes of drugs that raise HDL-C are available. These drugs include niacin, fibrates, statins, and hormone replacement therapy (HRT).

Niacin. Niacin (or nicotinic acid) is the most effective drug for raising HDL-C levels. Its ability to decrease hepatic production of very-low-density lipoproteins results in an increase in HDL-C and also favorably alters LDL-C and triglyceride levels. Niacin is available in both a crystalline formulation (Niacor, a prescription drug, and the over-the-counter drugs Nicolar, Nicotinex, and Slo-Niacin) and a sustained-release formulation (Niaspan). At full doses (1.5 to 6 gm/day in three divided doses for the crystalline form and 2 gm/day for the sustained-release form), niacin increases HDL-C by 20%, decreases LDL-C by 10% to 25%, and decreases triglycerides by 20% to 50%. There are currently no large clinical trials looking at the effect of niacin in reducing CHD related to isolated low HDL-C, but the use of niacin in patients with hyperlipidemia after MI has shown an 11% decrease in mortality and 27% decrease in recurrent cardiac events.

Common side effects include flushing and vasomotor symptoms; dyspepsia, nausea, abdominal pain, hyperglycemia, and hyperuricemia may also occur but are less common. Dose-dependent hepatotoxicity is rare, occurring in only about 1% of patients. Vasomotor symptoms and flushing can be minimized by using the sustained-release formulation, gradually increasing the dose, and encouraging the patient to take an aspirin 30 minutes before the dose to reduce the prostaglandin-mediated flushing. Significantly lower doses of niacin are required to raise HDL-C than those required to decrease LDL-C; the usual daily maintenance dose is 1500 to 2000 mg.

Fibrates. In patients with isolated low HDL-C, evidence exists for the use of fibrates in both primary and secondary CHD prevention, as demonstrated by the Helsinski Heart Study and the VA-HIT trial. Fibrates should also be used as first-line therapy in patients who have low HDL-C associated with hypertriglyceridemia. In addition, fibrates may be used as an alternative to niacin in patients with isolated low HDL-C after lifestyle modifications have been initiated. In the United States, fibrates are available in two forms: gemfibrozil (Lopid) and fenofibrate (Tricor). They are well known for their ability to lower triglycerides by up to 60%, but they also increase HDL-C by 10% to 15%. Their effect on LDL-C is minimal.

Fibrates are generally well tolerated. Common side effects include mild gastrointestinal upset and arthralgias. When used in combination with statins, there is an increased risk of myalgias and rhabdomyolysis.

Statins. The most commonly prescribed cholesterol-lowering drugs in the United States, statins act by blocking the rate-limiting step in cholesterol synthesis, which causes an increase in LDL-C synthesis and a subsequent decrease in serum levels. They are highly efficacious in reducing LDL-C but only minimally effective in elevating HDL-C, raising levels by only 6% to 8%. Nevertheless, when used in patients with isolated low HDL-C, statins have been shown to decrease the adverse consequences of low HDL-C levels and to result in significant reductions in morbidity and mortality. Currently only two statins—atorvastatin (Lipitor) and simvastatin (Zocor)—are approved by the U.S. Food and Drug Administration for HDL-C raising.

Statins are generally well tolerated. Rare side effects include gastrointestinal upset, myalgias, headache, and rash. About 1% of patients experience liver function abnormalities. Rhabdomyolysis is extremely rare, occurring in only 0.01% of patients, but the risk increases with concomitant use of fibrates, niacin, erythromycin, and certain antifungals.

Hormone replacement therapy. Among the various mechanisms by which HRT was thought to decrease CHD risk were raising HDL-C, lowering LDL-C, and decreasing lipoprotein(a) and fibrinogen levels. Postmenopausal women receiving HRT show an average 16% increase in HDL-C levels. In recent large clinical trials, however, this effect has not been shown to be clinically beneficial. In the Women's Health Initiative (WHI) trial, women aged 50 to 79 without prior CHD were randomized to receive estrogen and/or progesterone versus placebo. In an average follow-up of 5.2 years, women on HRT showed an unadjusted increased risk of 29% for development of CHD (with most of the risk involving nonfatal MI) and a 41% increased risk for stroke. In the Heart and Estrogen/Progestin Replacement Study (HERS) trial, no benefit was seen in the secondary prevention of CHD in women receiving HRT, despite a favorable lipid profile. In fact, HRT was shown to possibly impart some increased risk in women with established CHD. Thus, HRT is no longer recommended for primary or secondary prevention of CHD.
 

APPROACH TO THE PATIENT WITH LOW HDL-C

Before initiating a treatment plan for the patient with low HDL-C, pre-existing conditions that depress HDL-C should be identified and addressed. Medical conditions associated with low HDL-C levels, for example, include acute illnesses (such as MI, surgery, burns, and viral infections), inflammatory conditions that result in an acute-phase reaction, elevated triglyceride levels, hypothyroidism, diabetes mellitus, chronic renal failure, and liver disease. In addition, medications such as beta blockers, thiazides, androgens, and progestins can also decrease HDL-C. Finally, lifestyle-related causes of low HDL-C include cigarette smoking, obesity, inactivity, and a very low-fat diet. Initial evaluation of the patient with low HDL-C, therefore, should include a detailed history and physical examination, fasting lipid profile, and thyroid-stimulating hormone, creatinine, and liver enzyme levels to rule out such causes. In addition, weight reduction, smoking cessation, and physical activity should be encouraged for all patients with low HDL-C.

Further evaluation of the patient with low HDL-C that is not the result of a pre-existing condition, medication, or a lifestyle-related cause should include the following steps:

•   The ATP III recommends that in all persons with low HDL-C, the primary target of therapy should be reducing LDL-C to target levels. After this goal has been reached, emphasis should shift to HDL-C, triglycerides, and the metabolic syndrome, if present.
   
•   When low HDL-C is associated with high triglycerides (200 to 499 mg/dl), the priority should be lowering the triglyceride levels. In patients with hypertriglyceridemia, reduction of triglyceride levels is generally associated with an increase in HDL-C. The use of a fibrate is indicated in such cases.
   
•   When isolated low HDL-C is present, weight reduction, smoking cessation, and physical activity should be tried first, with a target HDL-C level of 40 mg/dl or higher. Pharmacologic therapy should be reserved for persons with CHD or CHD risk equivalents. If such therapy is necessary, niacin or a fibrate should be used.

The algorithm above summarizes the key points to keep in mind in managing the patient with low HDL-C levels.

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