Low HDL Cholesterol (Hypoalphalipoproteinemia) Treatment & Management

Most individuals are diagnosed with hypoalphalipoproteinemia (HA) based on the results of a routine lipid profile measurement. This finding of a low high-density lipoprotein (HDL) cholesterol level can be useful as an independent factor in assessing coronary artery disease (CAD) risk and further management. Guidelines in the ATP III report emphasized the importance of HDL cholesterol; the level of HDL considered to be a significant risk factor was changed from less than 35 mg/dL to less than 40 mg/dL. ^{[3, 4, 5, 6, 29]}

The basic purpose of the management of HA and related lipid abnormalities is to reduce the risk of atherosclerosis, which is the main mechanism of increased morbidity and mortality. With regard to HA, the ATP III report stated, "Low HDL cholesterol is a strong independent predictor of CHD [coronary heart disease]. In ATP III, low HDL cholesterol is defined categorically as a level < 40 mg/dL, a change from the level of < 35 mg/dL in ATP II [1993]. In the present guidelines, low HDL cholesterol both modifies the goal for LDL-lowering therapy and is used as a risk factor to estimate 10-year risk for CHD." ^{[3, 4, 5, 6]}

The document also reported that there are several causes of low HDL cholesterol levels and that a number of these—including type II diabetes, overweight, obesity, elevated triglycerides (TGs), and a lack of physical activity—are associated with insulin resistance. The study also cited cigarette smoking, a very high carbohydrate intake (>60% of calories), and certain agents (such as progestational drugs, anabolic steroids, and beta blockers) as causes of low HDL levels.

• Follow an appropriate management strategy. The ATP III report did not provide a specific level to which a low HDL concentration should be raised. According to the study's executive summary, "Although clinical trial results suggest that raising HDL will reduce risk, the evidence is insufficient to specify a goal of therapy. Furthermore, currently available drugs do not robustly raise HDL cholesterol." The panel stated that low HDL levels should be managed in the following manner:

  • Reducing low-density lipoprotein (LDL) levels is the primary goal.

  • Metabolic syndrome is the second target. According to the ATP III executive summary, "After the LDL goal has been reached, emphasis shifts to weight reduction and increased physical activity (when the metabolic syndrome is present)." Metabolic syndrome is diagnosed in patients with at least 3 of the following risk factors:

    • Abdominal obesity, with a waist circumference of over 35 inches (females) or above 40 inches (males)

    • TG levels of 15 mg/dL or greater

    • HDL cholesterol levels of below 40 mg/dL (males) or less than 50 mg/dL (females)

    • Blood pressure at or above 130 mm Hg systolic and greater than or equal to 85 mm Hg diastolic

    • Fasting glucose levels at or above 110 mg/dL

  • An association between low HDL and hypertriglyceridemia requires attention. The ATP III reported, "When a low HDL cholesterol is associated with high triglycerides (200-499 mg/dL), secondary priority goes to achieving the non-HDL cholesterol goal." For example:

    • In the patients with established CHD or a CHD risk equivalent (10-year risk for CHD >20%), the LDL goal is under 100 mg/dL, and the goal for non-HDL cholesterol (LDL plus very–low-density lipoprotein [VLDL]) is below 130 mg/dL.

    • In persons with multiple (2+) risk factors and 10-year risk of equal to or less than 20%, the LDL goal is < 130 mg/dL, while the non-HDL goal is < 160 mg/dL.

    • In persons with 0-1 risk factor, the LDL goal is < 160 mg/dL, and that for the non-HDL is < 190 mg/dL.

  • Managing isolated low HDL cholesterol is also important. According to the ATP III, if a patient's TG levels are below 200 mg/dL (isolated low HDL cholesterol), the administration of drugs that increase HDL (fibrates or nicotinic acid) can be considered. Statins have only a modest effect. Treatment for isolated low HDL cholesterol is provided mainly to patients with CHD and CHD risk equivalents.

• Identify patients whose diet is very low in fat. A low HDL cholesterol level in this setting is rarely associated with an increased risk for premature CHD.

• Identify and correct secondary factors. Instruct patients who smoke to stop smoking, tell persons who are overweight to manage their weight, and encourage individuals who are sedentary to engage in regular exercise. Whenever possible, eliminate medications associated with low HDL cholesterol levels. Control diabetes optimally, and aggressively treat LDL cholesterol, regardless of HDL cholesterol levels.

• Consider estrogen replacement therapy for postmenopausal women, because this can substantially raise HDL cholesterol levels.

• It is unclear whether pharmacologic agents should be used to raise the HDL cholesterol level in otherwise healthy persons, because no published clinical trials are available that demonstrate a benefit. Nonetheless, individuals at high risk require further assessment for CHD risk, with an evaluation that includes a family history, measurements of apo and lipoprotein Lp(a), and electron beam CT scanning.

  • Niacin is the most effective agent currently available. However, many patients with isolated HA do not respond well to niacin. Most patients who receive niacin also have high LDL cholesterol levels that are being managed pharmacologically, and niacin is added to raise their HDL cholesterol level if it is low.

  • Gemfibrozil and fenofibrate modestly raise the HDL cholesterol level. They are most effective in the setting of concomitant hypertriglyceridemia.

  • Statins only mildly raise HDL cholesterol levels. They are not recommended for this purpose alone.

  • Alcohol tends to raise some HDL subfractions. However, no clinical trial data are available to demonstrate any positive role for raising HDL levels with alcohol in order to reduce cardiovascular events in patients with CHD.

HDL-raising therapies

Low HDL levels often reflect a genetic abnormality, although they can also be pushed downward by a high blood level of TGs or by cigarette smoking, inactivity, or hypertension, as well as by a diet very high in carbohydrates or polyunsaturated fats.

Another pharmacologic approach geared towards raising HDL levels involves inhibiting cholesteryl ester transfer protein (CETP). CETP helps to exchange cholesterol between lipoproteins and can transfer it from HDL to LDL and VLDL. Individuals with a genetic mutation that causes the loss of all CETP activity have very high levels of HDL cholesterol. These individuals appear to be at lower risk of coronary disease. ^{[30, 31]}

A small study in 2004 involving the CETP inhibitor torcetrapib showed that the drug markedly increased HDL levels and decreased LDL levels when taken alone and also when taken in combination with a statin. The increases in HDL levels were much higher than can be achieved with existing lipid drugs. Although this points researchers in a promising direction, therapy with torcetrapib needs to be tested in a larger population; it must be shown through outcome studies that the drug not only to increases HDL levels, but that it also prevents heart problems. ^[32]

HDL infusion therapy studied in a group of 40 Italian villagers led to the discovery of a rare type of HDL that seemed to protect against heart disease even when the levels of HDL were not very high. People in the study had a protein in their HDL, the aforementioned apo A-I Milano, that seemed to be better at stimulating the removal of cholesterol from plaques than was HDL containing the normal protein, called apo A-I.

Nissen and colleagues tested whether a synthetic version of apo A-I Milano (recombinant apo A-1 Milano/phospholipid complexes, ETC-216) infused into the blood of people who did not naturally have this protein would have the same effect. ^[33] The small trial randomly assigned 47 people who had recently had a heart attack to receive either a placebo or a low or high dose of the synthetic protein.

Studying ultrasonograms of the arteries, the researchers found that from the beginning to the end of the 5-week trial, the plaque in the treatment groups shrank by 4%, while that of the placebo group increased by a small amount. Although these were exciting results, a larger trial employing synthetic HDL infusion therapy is needed.

Estrogen replacement or hormone replacement therapy (HRT) raises HDL by about 8% in postmenopausal women, but its use is controversial; such treatment is not recommended for CAD prevention due to a demonstrated lack of benefit and the possible risk of increased thrombosis.

The Heart and Estrogen/progestin Replacement Study (HERS) found no net decrease in secondary prevention of CHD events over 4 years. ^[34] Events increased 50% with HRT during year 1 but then progressively decreased to 33% lower by the study's end. The early increase may have resulted from prothrombotic and/or pro-inflammatory effects of HRT, while the later decrease may have reflected the 8% increase in HDL cholesterol and/or other antiatherosclerotic mechanisms. ^[35] Results of HRT in primary prevention await completion of the Women's Health Initiative in 2007.

Because an increase in the consumption of cold-water fish (eg, salmon) rich in polyunsaturated fats may help to raise HDL, fish oil capsules (capsules containing omega-3 fatty acids, ie, 1.48 grams of docosahexaenoic acid and 1.88 grams of eicosapentaenoic acid) have been studied in small trials. In a study in patients with familial combined hyperlipidemia, treatment with this formulation for 8 weeks increased HDL by 8%, particularly the more buoyant HDL-2 subfraction. levels of paraoxonase, an HDL-associated, antioxidant enzyme, were also increased by 10%. ^[36]

None of these HDL-raising therapies have been studied in Asian Indians. Therefore, no particular treatment recommendations can be made at this juncture. Nonetheless, the treatment strategies appear to be well suited for this subpopulation, which has a high prevalence of HA.

Niacin, fibrates, and statins

Multiple studies have shown that niacin, fibrates, and statins can decrease the risk of cardiovascular disease and atherosclerosis progression by affecting multiple lipid parameters. In a study by AIM-HIGH Investigators et al, the addition of niacin to statin therapy did not provide any clear benefit to patients with cardiovascular disease and low HDL levels. ^[37] The much larger HPS2-THRIVE study (N=25,673) confirmed these findings. Additionally, adding niacin to statins increased risk for serious adverse events. ^[38]

Overall, fibrates reduce the risk for major coronary events by 25%, whereas currently available data for niacin suggest about a 27% reduction. Statins do have modest affects on HDL, increasing concentrations by 5% to 10%, providing a secondary benefit to this therapy beyond LDL reduction.

Completion of trials with clinical endpoints (eg, AIM-HIGH and HPS2-THRIVE clinical trials) have shown that the addition of niacin that decreased TGs and/or increased HDL-C levels in statin-treated patients does not cause further reduction in risk of CV events. Consistent with this conclusion, the FDA has determined that the benefits of niacin ER tablets for coadministration with statins no longer outweigh the risks, and the approval for this indication should be withdrawn. Additionally, the combination products that include simvastatin or lovastatin plus long-acting niacin (ie, Advicor, Simcor) were withdrawn from the U.S. market at the beginning of 2016 and are no longer available. ^[39]

ADVOCATE study

In the ADvicor Versus Other Cholesterol-Modulating Agents Trial Evaluation (ADVOCATE), 315 patients with high LDL (≥160 mg/dL without CAD, or ≥130 mg/dL with CAD) and low HDL (< 45 mg/dL in men, and < 50 mg/dL in women) were randomized to 16 weeks of a combination of niacin/lovastatin versus standard doses of atorvastatin or simvastatin. Niacin/lovastatin increased HDL significantly more than did statin alone at all dose combinations (P< 0.001). In addition, a significant decrease in LDL (42% vs 34%; P< 0.001) and significant improvements in TGs, lipoprotein(a), apo A-I, and apo B were seen in those patients receiving niacin/lovastatin (no longer on U.S. market).

HATS study

A niacin/statin combination was also evaluated in the HDL-Atherosclerosis Treatment Study (HATS). ^[40] In this investigation, LDL levels fell by 42% (P< 0.001) and HDL levels increased by 26% (P< 0.001). Angiographic analysis revealed that the combination therapy significantly enhanced stenosis regression. The statin/niacin combination also resulted in a 60-90% reduction in the incidence of major coronary events.

ARBITER 2 study

In the ARterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER 2) study, a double-blind, placebo-controlled trial was performed on an extended-release niacin/statin therapy. ^[41] One group of patients received the combination therapy, while another group received only statin. HDL levels in the combination group rose 21% higher (P = 0.002) than they did in the statin-only group, and TGs decreased significantly (P = 0.009). The primary endpoint of ARBITER 2 was change in common carotid intima-media thickness (CIMT). CIMT progression was 68% lower in the niacin/statin group than in the other patients. The end result was a 50% reduction in the composite cardiovascular endpoint for the niacin/statin patients.

Emerging treatment strategies

Several novel approaches to increasing HDL cholesterol that have been under investigation include the following:

• The aforementioned partial CETP inhibitor, torcetrapib, may increase HDL by as much as 46%.

• The glitazones, which are PPAR (peroxisome proliferator-activated receptor) agonists, act by lowering free fatty acid (FFA) and TG levels and by raising HDL. Rosiglitazone appears to increase the size of small LDL particles.

• Recombinant apo A-1 Milano mimics the activity of nascent HDL and has shown promise in early trials in patients with acute coronary syndromes.

CETP inhibition therapy

CETP mediates the transfer of cholesteryl ester for TGs from HDL to VLDL and LDL. It may be proatherogenic if the VLDL-LDL cholesteryl ester is taken up by arterial macrophages. Blocking CETP prevents the transfer of cholesterol from HDL2 to the apo B–containing lipoproteins, and therefore, the HDL concentration in terms of cholesterol rises.

Two pharmacologic inhibitors of CETP have undergone phase 3 clinical trials: torcetrapib and JTT-705. The 2 drugs differ in chemical structure. With torcetrapib, the CETP activity is inhibited by only about 50% to 60%, to avoid the fact that patients with complete CETP deficiency, mostly found in Japan, exhibit a paradoxically increased risk of CAD. The effect of torcetrapib is dose-dependent; for example, increasing the dose from 10 mg to 120 mg twice daily is associated with an almost 90% CETP inhibition and a greater rise in HDL. In addition, LDL is reduced by torcetrapib, by as much as 40%.

Torcetrapib was looked at in a phase 3 global study called the Investigation of Lipid level management to Understand its iMpact IN ATherosclerotic Events (ILLUMINATE) trial. The study utilized 15,067 patients (mean age 61 years; 78% male, 93% white) with CHD or CHD risk equivalent (type 2 diabetes). ^[42] Patients received either torcetrapib and atorvastatin or atorvastatin alone.

At 12 months follow-up, patients who received torcetrapib demonstrated a mean increase of 72.1% in HDL cholesterol and a mean decrease of 24.9% in LDL cholesterol, as well as a mean decrease of 9% in TGs compared with baseline (all P< .001 vs atorvastatin-only patients). Beginning early in the trial, however, the 2 patient groups diverged with regard to the study's primary endpoint, a composite of first major cardiovascular events (CHD death, nonfatal myocardial infarction, stroke, and hospitalization for unstable angina).

By the study's termination, the torcetrapib group demonstrated a 25% elevation in risk over the patients who received only atorvastatin (hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.09-1.44; P = .001). This included a greater risk of death from cardiovascular causes (49 in the torcetrapib group in comparison with 35 in the atorvastatin-only patients) and from noncardiovascular causes (40 in the torcetrapib group vs 20 in the atorvastatin-only patients). At 12 months follow-up, systolic blood pressure (SBP) in the torcetrapib patients had risen from baseline by a mean of 5.4 mm Hg, a significantly greater increase than that (0.9 mm Hg) found in the atorvastatin group (P< .001).

A significant (albeit small) change in serum electrolytes—a reduction in potassium and increases in sodium and serum bicarbonate—was also found in the torcetrapib patients. These changes may have indicated that mineralocorticoid excess accounted for the blood pressure increase.

A trial by Roche Pharmaceuticals using an agent similar to torcetrapib is underway. This drug reportedly does not raise blood pressure. The study's results should be available within a few years.

ApoA-1 Milano complexes

Apo A-I Milano, an apo A-I variant identified in a rural Italian population, is associated with cardioprotection due to its "super-HDL" properties. Individuals possessing apo Milano were found to have very low levels of HDL and yet, as a group, had a very low prevalence of atherosclerotic disease because most of their HDL was apo A-I Milano.

In a study, ETC-216, a recombinant form of apo A-I Milano–phospholipid complex, was found to be effective in reducing coronary atheroma volume as measured by intravascular ultrasonography. The investigation showed that the atherosclerosis in the coronary vessel wall could be modified in a much shorter time than anticipated, ie, within 5-6 weeks. ^{[43, 44, 45]}

An apo A-I mimetic peptide under development, D-4F, is targeted not at raising HDL but at changing pro-inflammatory HDL into anti-inflammatory HDL in high-risk patients.

Hypoalphalipoproteinemia (HA) may not require any surgical intervention. However, its association with and promotion of atherosclerosis may require a variety of surgical interventions, as follows:

• Cardiac catheterization, coronary angiography, and various percutaneous interventions for coronary heart disease (CHD)

• Coronary bypass grafting surgery for patients with CHD

• Percutaneous interventions and bypass procedures for peripheral vascular disease

• Carotid endarterectomy for carotid disease

• Gastric stapling and other related intestinal surgeries for weight reduction and the management of metabolic syndrome

Always consider secondary causes of low HDL levels, especially medications, smoking habits, dietary patterns, and physical activity. Patients with elevated triglyceride levels (>500 mg/dL) commonly have low HDL cholesterol levels; address hypertriglyceridemia first in such patients. Patients with moderately reduced HDL levels (20-35 mg/dL) usually have secondary causes that should be addressed. Individuals with severely reduced HDL levels (< 20 mg/dL) may have a specific genetic etiology, such as familial lecithin-cholesterol acetyltransferase (LCAT) deficiency, Tangier disease, or mutations in apo A-I. Ironically, these disorders are not commonly associated with an increased risk of atherosclerosis. Refer patients who may possibly have one of these diagnoses to a specialized lipid center for advanced management. Consultation with the following specialists may be required:

• Lipidologist

• Endocrinologist

• Cardiologist

• Vascular specialist

• Cardiovascular surgeon

• Dietitian

Diet

Diets that are very low in fat are associated with low high-density lipoprotein (HDL) cholesterol levels. However, because no data are available that show a reduction in the risk of coronary heart disease (CHD) upon raising HDL cholesterol levels, no particular dietary interventions are needed for this specific purpose. In fact, increasing the fat content of a patient's diet is not recommended. Dietary management should follow the NCEP guidelines for lowering frequently associated low-density lipoprotein (LDL) cholesterol, which is the primary target in lipid management ^{[3, 4, 5, 6]} ; lowering LDL levels has been demonstrated to reduce CHD morbidity and mortality in multiple randomized clinical trials.

The NCEP has recommended a therapeutic lifestyle-change diet, which should be incorporated in the treatment of all patients. The following are recommendations:

• Patients should reduce their intake of saturated fats to less than 7% of their total calorie (energy) intake. Their cholesterol intake should be reduced to less than 200 mg/d. Trans fatty acids (the HDL-lowering, LDL-raising fats) should be kept to a minimum. Polyunsaturated fats should constitute up to 10% of total energy intake, and monounsaturated fats, up to 20% of total energy intake. Total fat intake, therefore, should be in the range of 25-35% of total energy intake.

• Carbohydrates (complex carbohydrates from grains, whole grains, fruits, and vegetables) should constitute 50-60% of total energy intake.

• Patients should consume 20-30 g/d of fiber.

• The protein content should be approximately 15% of total energy intake.

• In order to maintain a desirable body weight and to prevent weight gain, the total amount of energy consumed must be balanced in terms of energy intake and expenditure.

Activity

Strongly encourage increased physical activity, especially in persons with sedentary habits. According to the NCEP guidelines, daily activity and energy expenditure should include at least moderate physical activity, with the patient expending approximately 840 kJ/d.

In a Spanish study that included 296 adults at high cardiovascular risk, leisure-time physical activity was associated with increased circulating levels of HDL, as well as improvement in several markers of HDL functionality. ^[46]