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Back: Evaluation and Management of Patients with Low HDL Cholesterol

Jeff Unger Picture


   Jeff Unger, MD
   PCMG Steering Committee Member
   Charlotte, North Carolina 
   Associate Director for Metabolic Studies
   Catalina Research Institute
   Chino, California

The Role of HDL Cholesterol in Reducing Cardiovascular Risk

Low levels of high-density lipoprotein cholesterol (HDL-C) can significantly increase one’s cardiovascular risk and be challenging to treat. Coronary artery disease risk remains elevated in patients with low HDL-C even after metabolic improvement for obesity, blood pressure, total cholesterol and LDL-C. The term “isolated low HDL cholesterol” refers to the situation in which total  cholesterol or LDL-C are in the “ideal range” but the HDL-C is low. Although infrequently encountered clinically, several genetic diseases are associated with low HDL including Tangiers disease, familial hypoalphalipoproteinemia, fish-eye disease, and lecithin:cholesterol acyl transferase deficiency.  Only Tangier’s disease and familial hypoalphalipoproteinemia are associated with premature coronary artery disease.

A low HDL-C level is thought to accelerate the development of atherosclerosis because of impaired reverse cholesterol transport and possibly because of the absence of other protective effects of HDL-C, such as decreased oxidation of other lipoproteins.

Cells within peripheral tissues produce all the cholesterol needed for cellular homeostasis. However, the liver is the only organ capable of degrading cholesterol. Therefore, cholesterol must be transported through blood to the liver for processing, degradation, and secretion into bile. Because cholesterol is an insoluble molecule, it must be packaged and transported by special particles in the plasma called lipoproteins. High-density lipoproteins are responsible for movement of most cholesterol from peripheral tissues back to the liver. Because the liver is the center of cholesterol homeostasis in the body, cholesterol that moves from peripheral tissues to the liver is considered to be moving in the reverse direction. HDL-C is believed to protect against atherosclerosis in part through the process of reverse cholesterol transport, whereby excess free cholesterol (FC) is removed from cells in peripheral tissues (such as macrophages within the arterial wall) and returned to the liver for excretion in the bile. FC is generated in part by the hydrolysis of intracellular cholesteryl ester (CE) stores.

Several key molecules play a role in reverse cholesterol transport, including ATP-binding cassette protein A1 (ABCA1), lecithin:cholesterol acyltransferase (LCAT), and scavenger receptor class-B, type I (SR-BI). Pharmacological enhancement of this pathway could, in theory, help reduce atherosclerosis. Elevated levels of HDL-C have been associated with a reduced risk for CHD, which may occur by at least three mechanisms: (1) promotion of peripheral cholesterol transport, (2) enhanced antioxidant/anti-inflammatory effects, and (3) favorable antithrombotic effects.

Diagnosing and Managing Low HDL Cholesterol

Low HDL-C is defined as a level < 40 mg/dL by the Adult Treatment Panel III [Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults [Adult Treatment Panel III. JAMA 2001;285(19):2486-97]. ATP III also reported several conditions commonly observed in conjunction with low HDL-C such as type 2 diabetes, obesity, lack of physical activity and elevated triglycerides are associated with insulin resistance. Cigarette smoking, very high carbohydrate intake (> 60 % of total daily calories), certain medications (progestational drugs, anabolic steroids and beta blockers) can potentiate low HDL-C levels.  Low HDL-C is the strongest predictor of subsequent cardiovascular events in patients with angiographically proven CAD and “desirable” levels of total cholesterol.

Unfortunately, the ATP III report did NOT provide guidelines suggesting a specific level to which a low HDL-C should be raised. According to the study's executive summary: "Although clinical trial results suggest that raising HDL-C will reduce risk, the evidence is insufficient to specify a goal of therapy. Furthermore, currently available drugs do not robustly raise HDL-C."

The panel stated that low HDL levels should be managed in the following manner:

  • Reducing LDL cholesterol levels is the primary goal.
  • Identify patients whose diet is very low in fat. A low HDL-C 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-C levels.
    • Control diabetes optimally, and aggressively treat LDL-C, regardless of HDL-C levels.
  • When a low HDL-C is associated with high triglycerides (200-499 mg/dL), secondary priority goes to achieving the non- HDL-C goal.
    • For example, for patients with established CHD or a CHD risk equivalent (10-year risk for CHD >20%), the LDL-C goal is under 100 mg/dL, and the goal for non- HDL-C (Total cholesterol minus HDL cholesterol) 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-C goal is <130 mg/dL, while the non- HDL-C goal is <160 mg/dL.
    • In persons with 0-1 risk factor, the LDL-C goal is <160 mg/dL, and that for the non- HDL-C is <190 mg/dL.
  • Managing isolated low HDL-C is also important. According to the ATP III, if a patient's TG levels are below 200 mg/dL, the administration of drugs that increase HDL-C (fibrates or nicotinic acid) can be considered. Treatment for isolated low HDL cholesterol is provided mainly to patients with CHD and CHD risk equivalents.
    • Niacin is the most effective agent currently available. However, many patients with isolated low HDL-C do not respond well to niacin. Most patients who receive niacin also have high LDL-C levels that are being managed pharmacologically, and niacin is added to raise their HDL-C level if it is low.
    • Gemfibrozil and fenofibrate modestly raise the HDL-C level. They are most effective in the setting of concomitant hypertriglyceridemia.
    • Statins only mildly raise HDL-C levels. They are not recommended for this purpose alone.
    • Alcohol tends to raise some HDL-C subfractions. However, no clinical trial data are available to demonstrate any positive role for raising HDL-C levels with alcohol in order to reduce cardiovascular events in patients with CHD.
    • Consider estrogen replacement therapy for postmenopausal women, because this can substantially raise HDL-C levels.
  • It is unclear whether pharmacologic agents should be used to raise the HDL-C 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 cardiac CT imaging.

Final Thoughts

Always consider secondary causes of low HDL-C levels, especially medications, smoking habits, dietary patterns, and physical activity. Patients with elevated triglyceride levels (>500 mg/dL) commonly have low HDL-C levels; address hypertriglyceridemia first in such patients. Patients with moderately reduced HDL-C levels (20-35 mg/dL) usually have secondary causes that should be addressed. Individuals with severely reduced HDL-C 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.

Jeff Unger, MD


Further Reading:

1. Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III Final Report). US Department of Health and Human Services; May 2001
2. Tall AR. Plasma high density lipoproteins. Metabolism and relationship to atherogenesis. J Clin Invest. Aug 1990;86(2):379-84
3. Tai E.-Shyong Tai, Emmanuel SC, Chew S-K, et al. Isolated low HDL Cholesterol. An Insulin-Resistant State Only in the Presence of Fasting Hypertriglyceridemia. Diabetes. 1999. 48:1008-1092.
4. Ashen Dominique M, Blumenthal Roger S. Low HDL Cholesterol Levels. NEJM. 2005. 353: 1252-1260.