HDL Cholesterol and Protective Factors in Atherosclerosis
Gerd Assmann, MD; Antonio M. Gotto, Jr, MD, DPhil
Abstract—A low level of high-density lipoprotein cholesterol (HDL-C) is an important risk factor for cardiovascular
disease. Epidemiological and clinical studies provide evidence that HDL-C levels are linked to rates of coronary events.
The cardioprotective effects of HDL-C have been attributed to its role in reverse cholesterol transport, its effects on
endothelial cells, and its antioxidant activity. Although some clinical trials suggest a benefit of raising HDL-C to reduce
risk, further studies are needed, and HDL-C is still not considered a primary target of therapy in the National Cholesterol
Education Program guidelines. However, HDL-C should be considered as part of the patient’s overall profile of
established risk factors in determining treatment strategies. (Circulation. 2004;109[suppl III]:III-8 –III-14.)
Key Words: atherosclerosis 䡲 cardiovascular diseases 䡲 cholesterol 䡲 high-density lipoprotein (HDL)
䡲 lipoproteins 䡲 risk factors
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T
particles. These lipid-poor particles are increased in extravascular compartments where reverse cholesterol transport takes
place. 3 The origin of HDL particles with pre– ␤ electrophoretic mobility is not entirely clear. Several mechanisms have been proposed, including direct secretion into
plasma from hepatocytes or enterocytes; release during the
interconversion of various HDL subpopulations by phospholipid transfer protein (PLTP), cholesteryl ester transfer protein (CETP), or hepatic lipase (HL); or direct interaction of
free apolipoproteins with cell membrane.4
he association between low levels of high-density lipoprotein cholesterol (HDL-C) and an increased risk for
cardiovascular disease has been well established through
epidemiological and clinical studies.1 This relationship is
supported by the potential antiatherogenic properties of HDL,
including its mediation of reverse cholesterol transport, in
which cholesterol from peripheral tissues is returned to the
liver for excretion in the bile.2 This review considers the
potential mechanisms by which HDL-C may exert its antiatherogenic effects, discusses disorders of HDL and how to
interpret them in the clinical setting, and presents current and
potential treatment strategies for patients with low HDL-C.
HDL and Reverse Cholesterol Transport
Mechanisms. Reverse cholesterol transport describes the
transfer of cholesterol from nonhepatic cells to the liver.3,4
Lipid-free apo A-I or lipid-poor pre–␤-HDL particles produced in the intestine or liver or shed during lipolysis of
triglyceride-rich lipoproteins (TGRL) initiate efflux of phospholipids and cholesterol from cell membranes in a process
facilitated by PLTP. Cholesterol in these nascent discoidal
HDL particles is then esterified by lecithin-cholesterol acyltransferase (LCAT). Cholesteryl esters readily move to the
core of HDL particles, producing a steady gradient of free
cholesterol and enabling HDL to accept cholesterol from
various donors. The reciprocal exchange of cholesteryl ester
for triglycerides mediated by CETP moves the bulk of the
cholesteryl esters to lipoprotein remnant particles, which are
subsequently cleared by the liver. At the same time, HDL
becomes enriched with triglycerides, which are substrates for
HL. The concerted action of CETP-mediated cholesteryl ester
transfer and HL-mediated hydrolysis of triglycerides and
phospholipids helps to form the smaller HDL particles that
are the preferred binding partners for scavenger receptor type
B1 (SR-B1), the major HDL receptor on hepatocytes. The
Structure and Metabolism of HDL and Relation to
Potential Mechanisms of Benefit
Overview of HDL Structure and Heterogeneity
HDL is a class of heterogeneous lipoproteins containing
approximately equal amounts of lipid and protein.1 HDL
particles are characterized by high density (⬎1.063 g/mL)
and small size (Stoke’s diameter ⫽5 to 17 nm). The various
HDL subclasses vary in quantitative and qualitative content
of lipids, apolipoproteins, enzymes, and lipid transfer proteins, resulting in differences in shape, density, size, charge,
and antigenicity. Most of apolipoprotein A-I (apo A-I), the
predominant HDL protein, migrates in agarose gels with
␣-electrophoretic mobility and is designated ␣–LpA-I. This
fraction accounts for almost all of the cholesterol quantified
in the clinical laboratory as HDL-C. ␣-HDL can be further
fractionated by density into HDL2 and HDL3, by size, or by
apolipoprotein composition. Approximately 5% to 15% of
apo A-I in human plasma is associated with particles with
pre–␤-electrophoretic mobility. These can be further differentiated into pre–␤1-LpA-I, pre–␤2-LpA-I, and pre–␤3-LpA-I
From the Institute of Clinical Chemistry and Laboratory Medicine (G.A.), Central Laboratory, Westphalian Wilhelms-University, and the Institute of
Arteriosclerosis Research at the University of Münster (G.A.), Münster, Germany; and Weill Medical College of Cornell University (A.M.G.), New York, NY.
Correspondence to Prof. Dr Gerd Assmann, Institute of Arteriosclerosis Research, University of Münster, Domagkstrasse 3, D-48149 Münster,
Germany. E-mail [email protected]
© 2004 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/01.CIR.0000131512.50667.46
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Assmann and Gotto
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Pathways involved in the generation and
conversion of HDL. ABC1 indicates
adenosine triphosphate-binding cassette
transporter 1; apo A-I, apolipoprotein A-I;
apo E, apolipoprotein E; CE, cholesteryl
ester; CETP, cholesteryl ester transfer
protein; HDL, high-density lipoprotein;
HL, hepatic lipase; IDL, intermediatedensity lipoprotein; LCAT, lecithin-cholesterol acyltransferase; LDL, low-density
lipoprotein; LDL-R, low-density lipoprotein receptor; LDL-RRP, low-density
lipoprotein receptor-related protein; Lyso
PC, lysophosphatidylcholine; PC, phosphatidylcholine; PGN, proteoglycans; PL,
phospholipids; PLTP, phospholipid transfer protein; SR-B1, scavenger receptor
B1; UC, unesterified cholesterol; and
VLDL, very-low-density lipoprotein.
Adapted from Toth PP. Curr Atheroscler
Rep. 2003;5:386 –393.
binding of HDL with SR-B1 mediates the selective uptake of
cholesteryl esters that have not undergone CETP-mediated
transfer to apo B– containing particles (intermediate-density
lipoprotein and low-density lipoprotein [LDL]). Lipid-free
apolipoproteins or lipid-poor pre–␤-HDL are formed in
reactions catalyzed by PLTP, CETP, and HL. Thus, as shown
in the Figure, reverse cholesterol transport can be envisioned
as a cycle in which acceptors of cellular cholesterol (ie, apo
A-I, pre–␤-HDL) are perpetually regenerated to undertake
their function of inducing cholesterol efflux.
Experiments with transgenic animals suggest that disruption of one or more steps in reverse cholesterol transport
results in accelerated atherosclerosis, whereas overexpression
of pivotal proteins in reverse cholesterol transport, such as
apo A-I, PLTP, LCAT, and SR-B1, exerts atheroprotective
effects.4 The important lesson from these experimental approaches is that disruption of reverse cholesterol transport
and resulting atherosclerosis may occur in the presence of
either decreased or increased HDL-C levels, depending on
which step of reverse cholesterol transport is dysfunctional.
For instance, decreased HDL levels associated with increased
accumulation of cholesterol in peripheral tissues and/or atherosclerosis were observed in humans and animals with apo
A-I or adenosine triphosphate– binding cassette transporter
A1 (ABCA1) deficiency, in which the initial steps of reverse
cholesterol transport are impaired. By contrast, animals with
dysfunctional SR-B1 presented with enhanced arteriosclerosis combined with increased HDL concentrations.4
Cholesterol Efflux and ABCA1. As a result of efflux of
cholesterol and phospholipid from cells induced by apo A-I,
apo A-II, apo A-IV, and apo E, HDL-like lipoproteins with
pre–␤-mobility are produced. Apolipoprotein-mediated cholesterol efflux involves specific interactions with plasma
membrane proteins, with subsequent generation of intracellular signals and translocation of cholesterol from endoplasmic reticulum, the trans-Golgi network, or endosomes to the
plasma membrane. Several lines of evidence suggest that apo
A-I– binding protein may be directly linked to ABCA1,
defects of which have been identified in patients with familial
analphalipoproteinemia (Tangier disease, familial HDL deficiency).5–7 Membrane topological models of ABCA1 predict
the presence of 2 exocytoplasmic domains that could act as
apo A-I docking sites.8 Furthermore, the number of apo A-I
membrane binding sites correlates closely with ABCA1
expression levels.9,10 However, other mechanisms underlying
ABCA1-mediated cholesterol efflux have also been proposed. As a member of a large family of membrane transporters, ABCA1 may move cellular lipids across the bilayer
in a process requiring hydrolysis of adenosine triphosphate
(ATP). As ABCA1 does not seem to bind cholesterol, it is
more likely that ABCA1 induces translocation of phospholipids and thereby facilitates the lipidation of apo A-I and the
generation of effective cholesterol acceptors such as pre–␤HDL.11 The identity of the preferred phospholipid substrate
for ABCA1 remains a matter of debate, but phosphatidylserine (PS) and phosphatidylcholine (PC) are major candidates.
Phosphatidylserine could influence the arrangement of lipids
in a way that favors apo A-I binding.12 On the other hand,
PC-enriched domains have been identified that serve as a
primary source of phospholipids and cholesterol for ABCA1mediated efflux.13
Although abundant evidence suggests that ABCA1 acts as
a phospholipid translocase, no rigorous proof has been
presented as yet. Immunocytochemical studies suggest that
ABCA1 shuttles between the plasma membrane and late
endosomes.14 Furthermore, ABCA1 appears to interact with
several important components of vesicular traffic machinery
such as cdc42, a small G protein, and the beta-subunit of coat
protein I (COPI-I) coatomer complex essential for the formation of transport vesicles.15,16 It seems, therefore, that ABCA1
may regulate cholesterol and/or phospholipid sorting in the
endosomal compartment. The regulation of endosomal vesi-
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cle formation by ABCA1 may also be important to exocytosis
of apo E, which is able to initiate cholesterol efflux locally
and thereby to promote reverse cholesterol transport.17
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ABCA1, HDL-C, and Atherosclerosis. The most prominent
abnormality observed in an ABCA1⫺/⫺ mouse model was the
lack of HDL-C and apo A-I, accompanied by accumulation of
lipid-laden macrophages in the lungs.18 In ABCA1-deficient
hypercholesterolemic animals (ABCA1⫺/⫺/apo E⫺/⫺ or
ABCA1⫺/⫺/ LDL-receptor⫺/⫺ double knockout mice), the
accumulation of foam cells in peripheral tissue was especially
pronounced.19 However, no accelerated development of atherosclerotic lesions could be observed in ABCA1 knockout
mice. It is possible that the reduced cholesterol efflux
resulting from ABCA1 deficiency could be balanced by
decreased cholesterol influx caused by a less atherogenic
profile (lower total and LDL-cholesterol [LDL-C], lower
triglycerides), because ABCA1-deficient mice also seem to
have decreased cholesterol synthesis.19 Experiments with
ABCA1 transgenic animals produced equally contradictory
results. Transgenic mice strongly expressing ABCA1 showed
an antiatherogenic lipid profile with elevated levels of
HDL-C and apo A-I, and significantly less aortic atherosclerosis.20,21 However, selective overexpression of ABCA1 in
macrophages had minimal effect on plasma HDL-C.22 The
major cholesterol contribution to HDL generation presumably comes from ABCA1 in hepatocytes. As macrophages
comprise a very small portion of peripheral cells in the body,
the cholesterol efflux contributed by these cells may be too
low to affect the efficiency of the overall reverse cholesterol
transport. However, ABCA1 in macrophages may have an
antiatherogenic effect that is independent of plasma HDL. A
recent study has reported increased recruitment of ABCA1deficient leukocytes (monocytes/macrophages) into the arterial wall of LDL-receptor– deficient mice.23
HDL and Endothelial Function
Endothelial dysfunction characterized by decreased bioavailability of nitric oxide (NO), a potent vasodilator, and increased affinity of the endothelial surface for leukocytes is
often encountered in the early stages of atherosclerosis. In
advanced plaques, denudation of the endothelium as a consequence of increased apoptotic cell death can be observed.
Several in vivo studies provide evidence for the beneficial
effects of HDL on endothelial function. Compared with
normocholesterolemic patients, those with hypercholesterolemia appear to have reduced NO-dependent vasodilation, and
restoration of endothelial function has been observed after
infusion of cholesterol-free reconstituted HDL in hypercholesterolemic subjects.24 Elevation of plasma HDL concentrations reduced interleukin (IL)-1–induced expression of leukocyte adhesion molecules such as E-selectin.25 The
expression of vascular cell adhesion molecule (VCAM)-1,
which binds leukocytes in early atheroma, and the formation
of neointima were also inhibited by reconstituted HDL in a
mouse model of carotid artery injury.26
HDL functions as an autonomous protective factor for the
endothelium. HDL-induced activation of endothelial nitric
oxide synthase (eNOS), NO release, and vasorelaxatory
effects were documented in 2 recent studies.27,28 Other studies
confirmed that HDL attenuates expression of VCAM-1,
intracellular adhesion molecule (ICAM)-1, and E-selectin, as
well as cytokines such as IL-8 that promote leukocyte
extravasation.26,29 Endothelial apoptosis was prevented in the
presence of HDL, and this effect was associated with inhibition of typical apoptosis pathways such as the activation of
caspases.30,31 In addition, HDL activates protein kinase Akt, a
ubiquitous mediator of antiapoptotic signaling.30
The observation that only binding of native HDL is
associated with generation of NO, whereas binding of apo A-I
is without any effect, suggests that some distinct biological
activity stimulating NO production is present in HDL particles. Several groups of investigators demonstrated that HDL
serves as a carrier of bioactive lysosphingolipids such as
sphingosine-1-phosphate (S-1-P), sphingosylphosphorylcholine (SPC), and lysosulfatide (LSF).30 –32 The intracellular
signaling events initiated by lysosphingolipids and HDL
show striking similarities. Furthermore, these substances
fully mimic HDL in their ability to induce vasorelaxation and
inhibit apoptosis. Because of their lipophilicity, lysosphingolipids were thought to act primarily in a paracrine fashion.
However, defining HDL as a carrier for lysosphingolipids
suggests that whole endothelium may constitute an important
physiological target for these substances.
HDL and Antioxidative Mechanisms
A growing body of evidence suggests that HDL exerts part of
its antiatherogenic effect by counteracting LDL oxidation.
Some hints pointing to the antioxidant effects of HDL come
from epidemiological studies. For example, although smokers
in the Prospective Cardiovascular Münster (PROCAM) study
experienced more major coronary events than did nonsmokers, increasing HDL levels were associated with greater
reduction in the number of events in the smoker versus the
nonsmoker populations.33 HDL inhibits the oxidation of LDL
by transition metal ions, but also prevents 12-lipooxygenase–
mediated formation of lipid hydroperoxides.34 Inhibition of
LDL oxidation by HDL is usually attributed to the high
content of antioxidants in this lipoprotein; to antioxidative
properties of apo A-I; and to the presence of several enzymes,
such as paraoxonase (PON), platelet activating factor acetylhydrolase (PAF-AH), and glutathione peroxidase (GPX),
which prevent LDL oxidation or degrade its bioactive products. Apo A-I was shown to reduce peroxides of both
phospholipids and cholesteryl esters and to remove hydroperoxyeicosatetraenoic acid (HPETE) and hydroperoxyoctadecadienoic acid (HPODE), which are products of 12-lipooxygenase, from native LDL.35,36 Both HPETE and HPODE are
examples of so-called “seeding molecules,” compounds necessary for induction of the nonenzymatic oxidation of lipoprotein phospholipids.37 Oxidized phospholipids found in
LDL, including 1-palmitoyl-2(5-oxovaleroyl)-sn-glycero-3phosphorylcholine (POVPC) and 1-palmitoyl-2-glutaroyl-snglycero-3-phosphorylcholine (PGPC), have been shown to
stimulate production of cytokines (monocyte chemotactic
protein-1, IL-8, macrophage colony-stimulating factor) and to
induce adhesion of monocytes to the endothelial surface.
Paraoxonase catalyzes the breakdown of oxidized phospholipids in LDL. Studies have found that transgenic animals
Assmann and Gotto
deficient in this enzyme are significantly more susceptible to
the development of diet-induced atherosclerosis.38,39 On the
other hand, expression of PON transgene in mice produces
HDL resistant to oxidation.40 Degradation of oxidized phospholipids has also been attributed to PAF-AH. Overexpression of human apo A-I in apo E knockout mice increases
PAF-AH activity and simultaneously reduces oxidative stress
in plasma, decreases ICAM and VCAM expression, and
decreases monocyte recruitment into the arterial wall.41
HDL-C as a Risk Factor and a Therapeutic Target
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Epidemiological Evidence
In general, large prospective epidemiological studies such as
the Framingham Heart Study in the United States and the
PROCAM study in Europe have found that low HDL-C is
independently associated with increased risk for coronary
artery disease (CAD).1,42 However, exceptions to this association1 suggest that the atherogenicity of HDL-C may be
influenced by unmeasured variables, including genetic and
acquired factors, or that the concentration of HDL subclasses
and the kinetics of HDL metabolism, not the absolute
quantity of HDL, may contribute to the antiatherogenic
effect.3,43
Studies in different patient populations have shown that the
higher risk for coronary heart disease (CHD) at lower HDL
levels is multifactorial in causation.42 Other lipid abnormalities that tend to accompany low HDL include elevated
triglyceride levels, especially in the presence of a high ratio of
LDL-C to HDL-C;44,45 increased concentrations of remnant
lipoproteins;46 and small, dense LDL particles.47 In many
persons, these characteristics occur as part of the metabolic
syndrome, a constellation of risk factors that also includes
abdominal obesity, insulin resistance, elevated fasting glucose, hypertension, and prothrombotic/proinflammatory
states.42,45 Low HDL-C is also caused by cigarette smoking,
very high carbohydrate intake, and the use of certain drugs
(eg, progestational agents, anabolic steroids).42
Clinical Guidelines
In the National Cholesterol Education Program (NCEP)
Adult Treatment Panel III (ATP III) guidelines, LDL-C is the
primary target of CHD risk-reduction therapy.42 Low HDL-C
(ⱕ40 mg/dL) is one of 5 major CHD risk factors, and HDL
level is also a component of the Framingham scoring system,
the method used to estimate 10-year CHD risk and determine
the intensity of lipid-lowering therapy. The guidelines do not
regard low HDL-C as a therapeutic target, stating that there is
insufficient clinical trial evidence to support a numeric goal
and also a lack of available drugs that can robustly modify
HDL levels. To raise HDL-C, the guidelines recommend
increased physical activity, particularly in patients with the
metabolic syndrome.42
For patients with low HDL-C levels accompanied by high
triglycerides (200 to 499 mg/dL; ⱖ150 mg/dL in the metabolic syndrome), non–HDL-C (ie, LDL-C plus very-lowdensity lipoprotein cholesterol) is a secondary target of
therapy after the LDL-C goal has been achieved. Drug
therapy to raise HDL-C may be considered in patients
without triglyceride elevations (“isolated” low HDL-C), a
HDL-C in Atherosclerosis
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strategy reserved primarily for high-risk individuals.42 However, an increasing number of experts believe that low
HDL-C may warrant treatment in a wider range of patients,
even when LDL-C or non–HDL-C levels have not yet been
reduced to target levels.
Clinical Trial Evidence
In an analysis of 4 American studies (2 observational studies
and the control groups of 2 clinical trials), CHD risk was
found to decrease by 2% to 3% with each increment of 1
mg/dL in HDL-C levels.48 However, clinical trials do not yet
provide strong and consistent evidence concerning the benefit
of raising HDL levels.
Fibric acid derivatives are widely used to treat low HDL-C
levels. In the Helsinki Heart Study of 4081 asymptomatic
middle-aged men,49 gemfibrozil increased HDL-C levels by
more than 10% from baseline. Overall, there was a 34%
reduction in coronary risk compared with placebo (P⬍0.05).
Despite decreases of 10% and 43% in LDL-C and triglyceride
levels, respectively, the association between the change in
triglyceride levels and the risk for CHD was not statistically
significant in the gemfibrozil group.50 This implies that the
reduction in CHD risk was mediated by changes in HDL-C
and LDL-C. Both the increase in HDL-C and in the HDL-C/
total cholesterol ratio with gemfibrozil were inversely associated with CHD risk (P⬍0.01).50
The Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) compared the effect of gemfibrozil
versus placebo on coronary risk in 2531 middle-aged men
with CHD and a primary lipid abnormality of low HDL-C.51
After 1 year, there was a 6% increase in HDL-C levels,
accompanied by a significant 22% reduction (P⫽0.006) in
CHD death or nonfatal myocardial infarction.51 Further analysis found a strong correlation between CHD event reduction
and treatment levels of HDL-C, but not of triglycerides or
LDL-C.52 Moreover, during treatment HDL-C was the only
major lipid to predict a significant reduction in CHD events
based on both univariate and multivariate analyses. Despite
the independent inverse association between HDL-C levels
and CHD events, regression analysis revealed that lipid
concentrations achieved with gemfibrozil accounted for just
23% of the treatment benefit. This suggests that other effects
of fibrates are partly responsible for their clinical benefit, and
that similar increases in HDL-C with other types of drugs
might not produce the same reduction in risk.52
In the Bezafibrate Infarction Prevention (BIP) study, 3039
men and women with CHD were randomized to the study
drug or placebo.53 Despite an increase of 18% in HDL-C and
a decrease of 21% in triglycerides, the reduction of 9.4% in
coronary end points was not significant (P⫽0.26). One
explanation for this unexpected outcome may be the possibility that an HDL-C increase from a lower baseline level (as
in VA-HIT) may be more cardioprotective than a similar
increase from a higher initial level.54
Refinement of Risk Assessment and Treatment Strategies
Although 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors, or statins, are primarily used to
lower LDL-C levels, the 6 available drugs in this class also
raise HDL-C levels by 5% to 15%.42,55 Moreover, HDL-C
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levels have been found to predict response to statin therapy.
The Air Force/Texas Coronary Atherosclerosis Prevention
Study (AFCAPS/TexCAPS)56,57 was the first primaryprevention trial in a population (N⫽6605) with average total
cholesterol (mean, 221 mg/dL) and LDL-C (mean, 150 mg/dL)
and below-average HDL-C (mean, 36 mg/dL for men, 40 mg/dL
for women). After a mean 5.2 years of follow-up, treatment with
lovastatin reduced the risk for a first acute major coronary event
by 37% versus placebo.57 Participants in the 2 lowest tertiles of
baseline HDL-C showed the greatest relative risk reduction with
lovastatin therapy, and apo A-I was the only significant predictor
of risk for the 3 categories of level at baseline, level at year 1,
and percent change from baseline at year 1.56 These data suggest
that HDL-C and apo A-I may help refine CHD risk assessment
in primary-prevention patients with average LDL-C levels.
Low HDL-C may also predict the benefit of therapy, as
evaluated angiographically, in CHD patients with LDL-C
levels traditionally deemed mildly to moderately elevated.
The Lipoprotein and Coronary Atherosclerosis Study (LCAS)
of fluvastatin enrolled men and postmenopausal women aged
35 to 75 years with LDL-C levels of 115 to 190 mg/dL and
angiographic evidence of CAD.58 One fifth of the 339
evaluable subjects also had HDL-C levels ⬍35 mg/dL.
According to a post hoc analysis, placebo patients with low
baseline HDL-C had significantly more angiographic progression than those with higher HDL-C, and the effect of
fluvastatin versus placebo on angiographic progression was
significantly greater in patients with low HDL-C. With
fluvastatin, HDL-C levels increased by 15.9% and 7.4% in
the low and high HDL-C groups, respectively. Although
LCAS was not designed to evaluate clinical outcomes, there
was a significant trend toward improved event-free survival
in the fluvastatin-treated low–HDL-C patients, compared
with no benefit of fluvastatin in the higher HDL-C group.
Lipid lowering alone cannot explain the difference in benefit
between HDL categories, because the LDL-C reduction was
similar in all patients.58 These results suggest that treatment
of CAD patients with low HDL-C levels, and LDL-C levels
traditionally regarded as mildly to moderately elevated,
should address both lipid abnormalities.
Although niacin is considered to be the most effective
pharmacological agent for raising HDL-C,42 few trials have
evaluated its effect on clinical outcomes. Recently, a new
formulation combining extended-release (ER) niacin and
lovastatin was evaluated in a 28-week, double-blind, multicenter trial that randomized 237 patients to 1 of 4 treatment
groups: niacin ER 1000 mg/lovastatin 20 mg, niacin ER 2000
mg/lovastatin 40 mg, niacin ER 2000 mg, or lovastatin 40
mg. In this study, both of the combination regimens were
significantly more effective than lovastatin alone in raising
HDL-C levels.59 There was also a strong dose–response
relationship between niacin ER/lovastatin and improvements
in LDL-C and HDL-C.
Treatment Strategies: Present and Future
As low HDL-C levels are often associated with the presence
of other risk factors for atherosclerosis, it is difficult to assess
the impact of raising HDL-C on CAD. Pharmacological
interventions that increase HDL-C levels usually improve
other lipid parameters as well. For example, the contribution
of increased HDL-C levels is not easily distinguishable from
that of decreased LDL-C and/or triglyceride levels.43
Strategies for increasing low HDL-C levels include therapeutic lifestyle changes such as exercise, smoking cessation,
weight loss, and reduction of saturated fat and cholesterol in
the diet.42 Of the 4 classes of pharmacological agents currently approved for lipid-modifying therapy (resins [bile-acid
sequestrants], nicotinic acid [niacin], fibric acid derivatives
[fibrates], and statins), resins have little effect on HDL-C
levels42,43 and are not discussed further in this review.
Treatment with estrogen plus progestin (medroxyprogesterone) as hormone replacement therapy is no longer recommended for the prevention of CHD. Pharmacological strategies that may be developed in the future include agents
designed specifically to inhibit CETP, peroxisome
proliferator-activated receptor (PPAR) agonists, and exogenous HDL mimetics.
Niacin
In addition to raising HDL-C, niacin lowers both LDL-C and
triglycerides. No large, randomized clinical trials have evaluated the treatment of isolated low HDL-C with niacin. Side
effects include potential hepatotoxicity; flushing, which is
very prevalent; hyperglycemia; hyperuricemia; and upper
gastrointestinal distress.42,43 When a switch is made from
immediate-release niacin to ER formulations, equivalent
doses should not be substituted; rather, the ER regimen
should be initiated at a low dose and titrated to the desired
therapeutic response.60
Fibrates
Fibrates raise HDL-C by 10% to 20%, modestly lower
LDL-C, and substantially lower triglycerides.42 These agents
are absolutely contraindicated in patients with severe renal or
hepatic disease.42,43 Moreover, because of the risk for myotoxicity, including rhabdomyolysis, the combination of a
fibrate, particularly gemfibrozil, with a statin requires extreme caution and monitoring of creatine kinase levels.61
Fibrates as PPAR Agonists. PPARs are a subfamily of nuclear
receptors that act as transcription factors, altering the expression
of target genes by binding to peroxisome proliferator response
elements. Through activation of PPAR-␣, fibrates influence the
expression of 5 key gene-encoding proteins involved in HDL-C
metabolism: apo A-I, apo A-II, lipoprotein lipase, SR-B1, and
ABCA1. PPAR-␣ thereby increases HDL synthesis and affects
reverse cholesterol transport by accelerating the efflux of cholesterol from peripheral cells and its uptake by the liver.62
Further understanding of the mechanism of action of PPAR
agonists may lead to the design of more specific agents with
fewer side effects.
Statins
In addition to decreasing LDL-C concentrations through inhibition
of HMG-CoA reductase, the enzyme involved in the rate-limiting
step of cholesterol biosynthesis, statins lower triglycerides and
modestly increase HDL-C. Compared with fibrates, statins as a
class have a slightly lesser effect on HDL-C, decrease LDL-C levels
to a much greater extent, and, in some patient populations, may be
less effective in decreasing triglyceride levels.42,63
Assmann and Gotto
Depending on the dose, all statins produce similar increases in HDL-C. The effect of statins on HDL level,
composition, and functionality is not well understood, but
appears to involve multiple mechanisms. For example, atorvastatin at a daily dose of 10 mg can beneficially shift the
HDL subspecies profile and induce changes in CETP activity.63 Statins are contraindicated in patients with active or
chronic liver disease.42
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CETP Inhibition
Because CETP enriches the cholesterol content of LDL and
depletes that of HDL, it was originally considered to be a
proatherogenic modulator of HDL metabolism. However, the
generation of pre–␤-HDL and the involvement in reverse
cholesterol transport suggest antiatherogenic properties. Data
from genetic studies show that CETP polymorphisms can be
associated either with increased or decreased CAD risk. It
seems, therefore, that CETP can be either proatherogenic or
antiatherogenic depending on the metabolic setting. Inhibition of CETP would be expected to impair reverse cholesterol
transport but at the same time to extend the biological lifetime
of mature HDL particles and thereby to increase the bioavailability of antioxidants and lysosphingolipids associated with
HDL particles. Animal models suggest that long-term inhibition of CETP reduces susceptibility to atherosclerosis,
although the effect of such action in humans is not known.2
Specific statins affect CETP activity in different ways.
Atorvastatin and simvastatin both reduce CETP mass; however, the major effect of atorvastatin on CETP is to decrease
CETP activity through a reduction in the number of cholesteryl ester acceptor particles.63 It is possible that long-term
inhibition of CETP may be accomplished in the future by use
of vaccines or small-molecule inhibitors as a means of
altering the metabolism and concentration of HDL and other
lipoproteins to prevent coronary disease.2
Exogenous HDL Mimetic
Apo A-I Milano is a naturally occurring variant of apo A-I.
Found in a small number of inhabitants of a rural Italian
village, it appears to be atheroprotective. Carriers have very
low HDL-C levels, but are noted for their longevity and low
incidence of atherosclerosis.64 In a recent randomized,
double-blind study, recombinant apo A-I Milano (ETC-216)
was administered weekly to 123 patients via intravenous
infusion after an acute coronary syndrome. Results showed a
significant decrease of 1.06% (SD ⫽3.17%) in mean atheroma volume, as evaluated by intravascular ultrasound, over 5
weeks. These results require confirmation in a larger population with a longer follow-up, as well as evaluation of the
effect of therapy on clinical outcomes.64
Conclusions
Reducing LDL-C levels can lower the incidence of CHD by
up to one third. Although impressive, these results also raise
the question of how to decrease the 65% to 70% of major
cardiac events that still occur. Therefore, investigators are
seeking other modifiable CHD risk factors.
HDL is one important target of investigation. The cardioprotective effect of HDL has been recognized since 1950,65 and low levels
of HDL are now identified as a major independent risk factor for
HDL-C in Atherosclerosis
III-13
CHD. Although epidemiological data show an inverse relation
between HDL-C levels and CHD risk, the outcomes of clinical trials
evaluating HDL-C–raising therapies lack the strength and consistency of the statin trial data. Nevertheless, observational, biological,
and clinical evidence strongly suggests that HDL is a promising
target of therapeutic intervention. In the future, a more complete
understanding of HDL metabolism could lead to the development
of drugs that enhance atheroprotection by robustly increasing levels
of HDL and/or enhancing its functionality.
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HDL Cholesterol and Protective Factors in Atherosclerosis
Gerd Assmann and Antonio M. Gotto, Jr
Circulation. 2004;109:III-8-III-14
doi: 10.1161/01.CIR.0000131512.50667.46
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