HDL-Cholesterol; an inverse risk predictor for CVD

Low levels of high density lipoprotein (HDL)-cholesterol (HDL-C) are defined as less than 40 mg/dL (<1.03 mmol/L) according to current National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guidelines [1] (see High Cholesterol Knol). By this definition, low HDL-C levels are relatively common in the United States, occurring in approximately 35% of men and 15% of women in the general population [2]. Comparatively, patients with coronary heart disease (CHD) are even more likely to have low HDL-C. Low HDL-C levels (<35 mg/dL) (<0.90 mmol/L) are more common in men with CHD compared with those without CHD (50% vs. 30%, respectively).

HDL Cholesterol: an inverse risk predictor for CVD 

Low HDL-C levels can confer additional risk for cardiovascular disease (CVD) irrespective of total cholesterol levels. An independent reduction in CHD risk of 2% to 3% has been estimated for every 1-mg/dL (0.03-mmol/L) increase in HDL-C. In a 12-year follow-up of the Framingham study, individuals with high HDL-C (80th percentile) were at 50% lower risk of CHD than those with low HDL-C (20th percentile) [3]. Similarly, the Prospective Cardiovascular Münster study participants with HDL-C ≥35 mg/dL (>0.90 mmol/L) were found to have 4-times less risk of CHD at 6-year follow-up than patients with HDL-C <35 mg/dL (<0.90 mmol/L) [4].

Importantly, baseline HDL-C level has been shown in several statin trials to predict CVD risk [5]. For example, the Treating to New Targets (TNT) trial included 9,770 s   coronary heart disease patients with mean LDL-C levels <70 mg/dL (<1.81 mmol/L). Low HDL-C levels in that subgroup remained a significant predictor of major cardiovascular events. The cardiovascular event rate was 40% lower for patients in the highest quintile (>55 mg/dL) (>1.42 mmol/L) versus the lowest quintile (<38 mg/dL) (<0.98 mmol/L) of HDL-C [6].


Multiple Risk Factor Adjusted Analysis of the Relationship between Major Cardiovascular Events and Categories of HDL Cholesterol Levels in Coronary Heart Disease Patients with LDL-C Levels <70 mg/dL [6]


Anti-atherogenic properties of HDL particles

Atherosclerosis is one form of hardening of the arteries that involves large arteries. This disorder of large arteries is responsible for most arterial disease in industrialized societies. The clinical complications of

atherosclerosis may lead to heart attack, stroke, lower extremity arterial disease and aneurysms. The ability of HDL particles to protect against atherosclerosis is believed to be the result of numerous anti-atherogenic properties as described in the next sections.


HDL plays a pivotal role in reverse cholesterol transport (RCT), a process whereby excess cholesterol in cells and in atherosclerotic plaques is removed [7]. The steps involved in RCT are depicted in the   (  2).


Reverse cholesterol transport (RCT) [7]


Triglycerides and cholesterol are transported by chylomicrons and remnant lipoproteins from the intestine and by very low density lipoprotein (VLDL) and low density lipoprotein (LDL) from the liver (white arrows). Apo A-1 is synthesized by the liver and, after interaction with ABCA1, is secreted into plasma as lipid-poor apo A-1 (yellow arrow). In RCT, newly synthesized lipid-poor apo A-1 interacts with ABCA1, removing excess cellular cholesterol and forming pre-beta-HDL (green arrow). Pre-beta-HDL is converted into mature alpha-HDL by lecithin cholesterol: acyltransferase (LCAT) (black arrow). HDL-C is returned to the liver through two pathways: selective uptake of cholesterol by the hepatic SR-B1 (blue arrow), or the transfer of cholesteryl ester by CETP to VLDL-LDL, with uptake by the liver through the LDL receptor (red arrows).

•      Another protein, ABCA1 (also called cholesterol efflux regulatory protein [CERP]), also plays an important role in the HDL-mediated uptake of cellular cholesterol by promoting the transfer of intracellular cholesterol to the cell membrane. ABCA1 expression on the cell surface is induced by cholesterol loading and reduced after the cholesterol has been removed by apolipoproteins.

•      After acquisition of free cholesterol by HDL, the cholesterol is esterified to cholesterol esters by lecithin: cholesterol acyl transferase (LCAT), a plasma enzyme that is activated primarily by apo A-I. By a similar mechanism, HDL can act as an acceptor for cholesterol released during lipolysis of triglyceride-containing lipoproteins.

•      Lipid transfer proteins, such as cholesteryl ester transfer protein facilitate movement of the cholesterol esters to apo B-containing lipoproteins (VLDL, IDL, and LDL). This cholesterol can then be delivered to the tissues for steroid synthesis or storage.

While RCT is often cited as the primary anti-atherogenic mechanism, HDL also protects LDL particles from oxidation. Oxidized LDL increases atherosclerosis by several mechanisms, such as facilitating the transformation of macrophages into foam cells (see High Cholesterol Knol). Additional mechanisms by which HDL may confer protection against atherosclerosis include the inhibited production of the proteins on the lining of the blood vessels that tether inflammatory cells to the vessel wall thereby stopping the migration of these inflammatory cells into the vessel walls, and reduced platelet activation, which are the primary cells involved in blood clotting. HDL can also improve vessel wall dilation and reduced stickiness of blood platelets to the vessel wall. It was recently shown that HDL carries a previously unidentified range of proteins that may contribute to its anti-inflammatory and cardioprotective activities.



Low HDL levels can occur in one of three ways: impaired synthesis of apo A-I (apo A-I deficiency, apo A-I/C-III deficiency, apo A-I structural variants); increased turnover or catabolism (familial HDL deficiency and Tangier disease); or enzymatic changes affecting HDL metabolism. The enzymatic changes are either genetically determined or, as with decreased activity of lipoprotein lipase, secondary to insulin resistance.

Low HDL-C levels: A marker of atherogenic dyslipoproteinemia?

LDL also consists of a heterogeneous spectrum of particles that differ in size, density, and composition. Elevated concentrations of small LDL particles are associated with a greater risk for CHD and are frequently found in patients with type 2 diabetes or metabolic syndrome [8]. Furthermore, evidence suggests that the CHD risk associated with low HDL-C may, in part, reflect a previously unrecognized shift in LDL size from large LDL to small LDL particles. Data from the Framingham Offspring Study showed that, in individuals with low HDL-C (<40 mg/dL) (<1.03 mmol/L), there was a substantial increase in the level of small LDL particles [9] [  3].

HDL-Cholesterol Issues

Additionally, the lipoprotein profile in patients with type 2 diabetes or metabolic syndrome may be characterized by the formation of small, dense HDL with altered physicochemical properties, such as abnormal composition (triglyceride-rich) and dysfunctional anti-atherogenic activity. Thus, while HDL-C level is a strong, independent, and inverse predictor of CVD, other factors that are closely associated with low HDL-C levels may also contribute to CVD risk.


Framingham Offspring Study: Clinical Implications of the Disconnect Between LDL-C and LDL Particles in Patients with Low HDL-C [9]


HDL-C and existing guideline recommendations

The NCEP guidelines recognize elevated LDL-C as the primary target for lipid modification [1] (see High Cholesterol Knol). Recommended targets reflect clear evidence from clinical trials that large reductions in LDL-C are associated with significant decreases in CV events. Nonetheless, the guidelines do recognize the importance of low HDL-C as a CHD risk factor and state that:

•      In addition to intensive LDL-C lowering, risk assessment should cover high triglyceride and low HDL-C levels (low HDL-C being defined as <40 mg/dL) (<1.03 mmol/L).

•      Low HDL-C modifies the goal for LDL-C lowering and should be used as a risk factor to estimate the 10-year CHD risk.

•      HDL-C is a secondary therapeutic target in patients with isolated low HDL-C (where triglycerides are ≥200 mg/dL (>2.26 mmol/L) or as a component of the metabolic syndrome).

However, NCEP guidelines have not established a target level for HDL-C [1]. This is likely due to the absence of pharmacotherapies that can robustly raise HDL-C and a consequent lack of direct evidence from clinical outcomes trials. In contrast, other influential guidelines do suggest target levels for HDL-C. The American Diabetes Association recommends an optimal target of 40 mg/dL (1.03 mmol/L) for men and 50 mg/dL (1.29 mmol/L) for women with type 2 diabetes [10]. Similarly, a target of ≥40 mg/dL (>1.03 mmol/L) is recommended by the Expert Group on HDL-C as a goal for patients with CVD and those without clinical CVD at high risk (eg, patients with type 2 diabetes or metabolic syndrome) [11]. As has been the case with LDL-C targets, HDL-C targets will be reassessed as more clinical trial data emerges.

What are the current therapeutic options for raising LOW HDL-C levels?

Treatment of low HDL-C disorders — Treatment of low HDL disorders involve both lifestyle modifications and appropriate medications [1,5,10,11]. Exercise, weight loss (in overweight subjects), smoking cessation, and substitution of monounsaturated for saturated fatty acids all can raise HDL-C.


Efficacy of Lifestyle Strategies for Increasing HDL-C [5]


Different classes of hypolipidemic drugs have different effects on HDL-C as described in the next sections.

Nicotinic Acid (Niacin)

Nicotinic acid is the most effective HDL-C–raising drug currently available, and it also favorably affects LDL-C, LDL particle size, and triglyceride levels. Extended-release form of nicotinic acid 3,000 mg has been shown to increase HDL-C by 30% in patients with primary hyperlipidemia, although a pooled analysis of randomized trials using various nicotinic acid preparations indicates HDL increases by an average of 16% [  5] [12]. Nicotinic acid is, however, associated with tolerability problems, side-effects include disruption of glucose control and liver toxicity and skin flushing that can occur in up to 80% of patients [12]. The extended-release formulation has improved tolerance, producing significantly less flushing than immediate-release nicotinic acid.


Summary data of nicotinic acid (niacin) effects on HDL-C [12]


Fibrates or Fibric Acid Derivatives

Fibrates (peroxisome proliferator-activated receptor-alpha agonists) stimulate the formation of HDL in the serum by increasing the expression of proteins involved in HDL metabolism (for example, apolipoproteins A-I and A-II, ABCA1, and SR-B1). Fibrates can increase HDL-C an average of 10% [  6] as well as substantially lower triglyceride levels [12]. Beneficial changes in the size and distribution of HDL and LDL subclasses are also produced [8]. Gemfibrozil, for example, raises the HDL concentration via both direct stimulation of the hepatic synthesis of apo A-I and reduced cholesterol transfer from HDL to VLDL due to a decline in VLDL levels.


Summary data of fibrate effects on HDL-C [12]



Statins produce small increases in HDL-C (5% to 15%) in addition to a significant impact on LDL-C. The underlying mechanism is not well understood, but may involve a reduction in CETP activity.


Percent Change in HDL-C Across Statin Treatment in Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin (STELLAR) (Week 6) [13]


HDL-C in Clinical Trials of LDL-C Lowering with Statin Therapy

Additional support for the treatment of low HDL-C is provided by inference from clinical trials of LDL-C lowering strategies in which patients were further stratified by change in HDL-C. Although the effect of these small changes in HDL-C on reducing CHD risk is difficult to determine, given the larger simultaneous decreases in LDL-C, evidence suggests that the reduction in morbidity seen in at least some statin trials can be partly attributed to changes in HDL-C [5]. Furthermore, statins may be especially beneficial in individuals with low HDL-C at baseline. In the AFCAPS/TexCAPS study, lovastatin 20 to 40 mg/day increased HDL-C by 6% after 1 year in patients with an average risk for CHD [14]. Individuals whose baseline HDL-C was <40 mg/dL (<1.03 mmol/L) experienced a 3-fold reduction (45% to 15%) in risk for first-time, CHD-related events after 5.2 years compared with those with HDL-C ≥40 mg/dL (>1.03 mmol/L).

More recently, a pooled analysis of four prospective studies [Reversal of Atherosclerosis with Lipitor (REVERSAL), Comparison of Amlodipine versus Enalapril to Limit Occurrences of Thrombosis (CAMELOT), Acyl-CoA: Cholesterol Acyltransferase Intravascular Atherosclerosis Treatment Evaluation Study (ACTIVATE), and A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden (ASTEROID)] that used intravascular ultrasound (IVUS) to determine changes in atherosclerotic progression in statin-treated patients with angiographic coronary disease showed that a ≥5% reduction in atheroma volume was observed in those patients in which a 7% increase in HDL-C was accompanied by a reduction in LDL-C to <87.5 mg/dL (<2.26 mmol/L) [15]. Despite these observations, no significant difference was found with regard to clinical events.


Two studies have found that raising HDL-C in patients with a low baseline serum concentration may be effective for the prevention of recurrent CHD events:

The Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) included 2531 with CHD who had an LDL-C (<140 mg/dL or <3.62 mmol/L), an HDL-C (<40 mg/dL or <1.03 mmol/L), and triglycerides <300 mg/dL (<3.38 mmol/L); the patients were randomly assigned to treatment with gemfibrozil or placebo [16]. At one year, the following differences in plasma lipids were noted in the gemfibrozil group:

•      The average HDL-C level was 6 percent higher (34 versus 32 mg/dL for placebo [0.88 versus 0.83 mmol/L])

•      The average total cholesterol was 4 percent lower (170 versus 177 mg/dL [4.39 versus 4.57 mmol/L])

•      The mean triglyceride concentration was 31 percent lower (115 versus 166 mg/dL [1.30 versus 1.87 mmol/L])

These differences persisted throughout the study and the mean LDL-C concentration was the same in both groups. At five years, the combined primary end point of cardiac death and nonfatal myocardial infarction occurred less often in the gemfibrozil-treated group (17.3 versus 21.7 percent for placebo). Patients taking gemfibrozil also had a lower rate of stroke (4.6 versus 6 percent for placebo), transient ischemic attacks (1.7 versus 4.2 percent), and carotid endarterectomy (1.3 versus 3.5 percent).

Multiple risk factor adjusted analysis of the VA-HIT trial found that the reduction in nonfatal myocardial infarction and cardiac death was strongly correlated with the serum HDL-C concentration achieved with gemfibrozil therapy independent of changes in LDL-C or triglycerides [17].


Gemofibrozil Treatment Effects in VA-HIT [17]


In accordance with the interrelationships between low HDL-C levels, low levels of small HDL and high levels of small LDL particles were even more predictive of cardiovascular events in VA-HIT [17].


Lipoprotein Particles predict Coronary Heart Disease Events


The HDL Atherosclerosis Treatment Study (HATS) was a second study that suggested additional cardiovascular benefits may be observed in patients with low HDL-C by combining a statin (which not only lowers LDL-C but may have additional cardiovascular benefits beyond lipid lowering) with a drug that increases HDL-C [18]. This three year trial included 160 patients with clinical and angiographic evidence of CHD who had an HDL-C less than 35 mg/dL (0.90 mmol/L) and an LDL-C less than 145 mg/dL (3.75 mmol/L) [18]. In the simvastatin plus niacin group the LDL-C fell by 42% and the HDL-C increased by 20%. Compared with placebo, patients receiving simvastatin plus niacin were significantly less likely to sustain a cardiovascular event (death, myocardial infarction, stroke, or revascularization) and experienced angiographic regression (compared with progression for the placebo group) of the most significant coronary stenosis.

The ARterial Biology for the Investigation of the Treatment Effects of Reducing cholesterol (ARBITER) 2 study was a randomized trial that examined the effects of extended-release (ER) nicotinic acid 1000 mg daily in 167 patients with known CHD and an HDL-C concentration below 45 mg/dL (1.16 mmol/L) who were already receiving a statin [19]. Patients treated with ER nicotinic acid experienced a mean increase in HDL-C of 8 mg/dL (0.21 mmol/L) and, compared with those receiving placebo, had a trend toward decreased progression of carotid intima-media thickness.


Low HDL-C currently represents one of the strongest independent predictors of CHD risk. Targeting HDL-C is a promising strategy for combating CVD, and one that may help address the residual CV risk in statin-treated patients. In particular, pharmacologic elevation of HDL-C may also be associated with additional beneficial effects, such as a reduction in overall LDL particle number. This results from the redistribution of highly-atherogenic, cholesterol-depleted small LDL to larger, less atherogenic, cholesterol-enriched LDL particles that improves LDL particle-LDL receptor interaction and facilitates LDL clearance. However, there remains a lack of trial data confirming the clinical benefit of independently raising HDL-C to protective levels.


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3.     Castelli, WP, Garrison, RJ, Wilson, PW, Abbott, RD, Kalousdian, S, Kannel, WB. Incidence of coronary heart disease and lipoprotein cholesterol levels. The Framingham Study. JAMA 1986;256:2835.

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6.     Barter, P, Gotto, AM, LaRosa, JC, Maroni, J, et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med. 2007;357:1301.

7.     Brewer, HB, Jr., Increasing HDL Cholesterol Levels. N Engl J Med. 2004;350:1491.

8.     Kathiresan, S, Otvos, JD, Sullivan, LM, Keyes, MJ, Schaefer, EJ, Wilson, PW, D'Agostino, RB, Vasan, RS, Robins, SJ. Increased small low-density lipoprotein particle number: a prominent feature of the metabolic syndrome in the Framingham Heart Study. Circulation 2006;113:20.

9.     Otvos, JD, Jeyarajah, EJ, Cromwell, WC. Measurement issues related to lipoprotein heterogeneity. Am J Cardiol 2002;90:22i.

10.    Haffner, SM. Dyslipidemia management in adults with diabetes. Diabetes Care 2004;27 Suppl 1:S68.

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12.    Birjmohun, RS, Hutten, BA, Kastelein, JJ, Stroes, ES. Efficacy and safety of high-density lipoprotein cholesterol-increasing compounds: a meta-analysis of randomized controlled trials. J Am Coll Cardiol 2005;45:185.

13.    Jones, PH, Davidson, MH, Stein, EA, Bays, HE, McKenny, JM. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial), Am J Cardiol 2003;92:152.

14.    Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAP/TexCAPS. Air force/Texas Coronary Atherosclerosis Prevention Study JAMA 1998;279:1615.

15.    Nicholls, SJ, Tuzcu, EM, Sipahi, I, Grasso, AW, Schoenhagen, P, Hu, T, Wolski, K, Crowe, T, Desai, MY, Hazen, SL, Kapadia, SR, Nissen, SE. Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis. JAMA 2007;297:499.

16.    Rubins, HB, Robins, SJ, Collins, D, et al, for the Veterans Affairs High-density lipoprotein cholesterol Intervention Trial study group. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999; 341:410.

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19.    Taylor, AJ, Sullenberger, LE, Lee, HJ, et al. Arterial biology for the investigation of the treatment effects of reducing cholesterol (ARBITER) 2. A double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation 2004; 110:3512.

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