01008

QUARTERLY FOCUS ISSUE: PREVENTION/OUTCOMES State-of-the-Art Paper
High-Density Lipoprotein and Coronary Heart Disease

Current and Future Therapies
Pradeep Natarajan, MD,* Kausik K. Ray, MD, Christopher P. Cannon, MD*
Boston, Massachusetts; and Cambridge, England
Coronary heart disease remains a major cause of worldwide morbidity and mortality despite therapeutic ad-
vances that control many risk factors such as low-density lipoprotein cholesterol to levels lower than previously
possible. Population studies have consistently demonstrated an inverse association between high-density li-
poprotein cholesterol (HDL-C) levels with the risk of coronary heart disease. As a result, HDL-C is gaining increas-
ing interest as a therapeutic target. In this review, we explore the protective mechanisms of HDL and how cur-
rent and future therapies harness these benecial properties. We offer a biological framework to understand
treatment strategies as well as their resultant successes and failures to guide management and future direc-
tions. At present, raising HDL-C level holds great promise, on the basis of epidemiology and initial trials, but we
await the outcomes of the many large clinical outcomes trials currently under way to dene the clinical role of
older and novel therapies to raise HDL-C level. (J Am Coll Cardiol 2010;55:128399) 2010 by the American
College of Cardiology Foundation
Currently, our therapy for lipid modication for atheroscle-
rosis treatment and prevention focuses on lowering low-
density lipoprotein cholesterol (LDL-C). Lipid-lowering
treatment directed at LDL-C with standard doses of
3-hydroxy-3-methylglutaryl coenzyme A reductase inhibi-
tors (statins) has resulted in a relative risk reduction of
one-third in major vascular events as compared with placebo
(1). In patients at very high risk for vascular events, intensive
lipid-lowering has been shown to be benecial compared
with standard therapy (24). However, despite such notable
progress, cardiovascular disease continues to be the leading
cause of death and disease worldwide. As a result, novel
strategies to address this residual risk have been sought.
The Framingham Heart Study in the 1980s demon-
strated that the risk of coronary heart disease (CHD) was
signicantly lower among persons with higher levels of
high-density lipoprotein cholesterol (HDL-C) (normal
range 40 to 60 mg/dl) (5). A number of studies have
supported this inverse correlation between HDL-C and
CHD (59); hence, HDL-C has quickly evolved as one of
the traditional risk factors used by clinicians to predict risk
of incident CHD (4). An estimated 1 mg/dl higher
HDL-C is associated with a 2% lower risk of CHD for men
and a 3% lower risk for women (10). Current guidelines
recommend lowering nonHDL-C as a secondary target
after LDL-C lowering in recognition of the atherogenicity
of lipoproteins associated with hypertriglyceridemia (4).
Traditional lipid-lowering therapy appears to lower LDL-C
and nonHDL-C similarly, and these parameters are often
not distinguished in trials. Even after LDL-C is aggressively
controlled to very low levels with statin therapy, low
HDL-C still remains a signicant cardiovascular risk factor
(11,12). As a result, there has been increasing interest in
HDL-C as a therapeutic target (13).
Prevalence
The prevalence of low levels of HDL-C (e.g., 40 mg/dl)
varies geographically (14) and is particularly high in Latin
American countries, where the prevalence is as high as 46%
in men (15). Over a 7-year period, this prevalence has
continued to rise in Mexico by 2% to 3% (16). Approxi-
mately 25% of men in the United Kingdom have low levels
of HDL-C (17). A more recent Pan-European survey
suggests that the prevalence throughout Europe is similar to
that in the U.S., with low HDL-C levels in nearly one-half
of the Dutch (18). Although a signicant number in China
have low HDL-C levels, the prevalence is much lower than
in North America, with 7% of men and 2% of women
having low levels (19). In the international study evaluating
From the *Department of Medicine and the TIMI Study Group, Cardiovascular
Division, Brigham & Womens Hospital/Harvard Medical School, Boston, Massa-
chusetts; and the Department of Public Health and Primary Care, University of
Cambridge, Cambridge, England. Dr. Natarajan receives royalties from Artery
Therapeutics. Dr. Ray receives research grant support from Bristol-Myers Squibb and
Pzer, and honoraria for lectures and/or consultancy from Merck SP, MSD,
AstraZeneca, Pzer, Lilly, Daiichi Sankyo, Roche, Novartis, and Novo Nordisk. Dr.
Cannon receives research grant support from Accumetrics, AstraZeneca, Bristol-
Myers Squibb/Sano Partnership, GlaxoSmithKline, Intekrin Therapeutics, Merck,
Merck/Schering-Plough Partnership, Novartis, and Takeda, and is a clinical advisor
to and has equity holdings in Automedics Medical Systems.
Manuscript received November 25, 2009; revised manuscript received January 4,
2010, accepted January 4, 2010.
Journal of the American College of Cardiology Vol. 55, No. 13, 2010
2010 by the American College of Cardiology Foundation ISSN 0735-1097/10/$36.00
Published by Elsevier Inc. doi:10.1016/j.jacc.2010.01.008
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risk factors for acute myocardial
infarction known as the INTER-
HEART study, it was recently
shown that there is specically a
higher prevalence of low HDL-C
levels in South Asians compared
with other Asians (20).
Biological Role of High-
Density Lipoprotein (HDL)
The equilibrium between athero-
genic lipoproteins, such as low-
density lipoprotein (LDL), and
antiatherogenic HDL can affect
endothelial dysfunction and in-
ammation (21). In the face of
elevated LDL-C levels, HDL-C
appears to progressively protect
against atherosclerosis (21).
Circulating HDL particles are
greatly heterogeneous with a very
complex metabolic prole (Table 1).
The various HDL subclasses vary
in quantitative and qualitative content of lipids, apolipopro-
teins, enzymes, and lipid transfer proteins, resulting in
differences in shape, density, size, charge, and antigenicity.
Discoid HDL particles are small, lipid-poor particles made
of apolipoprotein in a monolayer of phospholipids and free
cholesterol (2123). Spherical HDL particles are larger, are
made from discoid HDL, and contain a hydrophobic core of
cholesterol esters (2123).
Reverse cholesterol transport, the process of transporting
excess cholesterol from the arterial walls foam macrophages
to the liver, bile, and feces is one of HDLs antiatherogenic
properties (24,25) (Fig. 1). Lipid-free HDL, or apolipopro-
tein A-I, mediates this through the adenosine triphosphate
(ATP)-cassette binding transporter (ABC) A1. Then ester-
ication of HDL-C by lecithin-cholesterol acyltransferase
(LCAT) generates more mature HDL particles, including
small, dense spherical HDL3 and large, less dense spherical
HDL2 (22,24). These mature HDL particles may induce
further cholesterol efux through ABCG1 and ABCG4
(21,24,26). HDL-C measures the cholesterol content of
nascent HDL, HDL2, and HDL3 particles and is, there-
fore, a crude marker of reverse cholesterol transport. The
smaller HDL3 particles more efciently promote cholesterol
efux through the ABCA1 pathway than do their larger
counterparts, but they are equally as effective through the
ABCG1 pathway (2729).
After cholesterol efux from the plaque, reverse cholesterol
transport is completed by transport back to the liver. Through
the scavenger receptor B1, hepatocytes and steroid-producing
cells can uptake these mature HDL particles (25,30). Further-
more, cholesterol esters from these particles may be trans-
ferred to apolipoprotein B-containing particles, such as
LDL or very low-density lipoprotein (VLDL), through the
cholesterol ester transfer protein (CETP) (22,24,25). He-
patic LDL receptors can then scavenge these apolipoprotein
Bcontaining particles enriched with cholesterol esters,
further contributing to reverse cholesterol transport (25).
The subsequent HDL particle enriched with triglycerides
may regenerate small HDL particles through hydrolysis
from hepatic lipase (21,24,25).
In addition to HDL protecting against atherosclerosis
through reverse cholesterol transport, HDLs antioxidative ac-
tivity further protects against atherosclerosis (21,31) (Table 2).
Apolipoprotein A-I is a major factor in this process (31). In
addition to HDL-C esterication, LCAT can also hydrolyze
oxidized phospholipids of LDL (22,31,32).
For monocytes to gain entry into the subendothelial space
to promote atherosclerosis, their circulation must be ar-
rested, which is accomplished by binding to adhesion
molecules in the blood vessel wall (33,34). Expression of
these adhesion molecules depends on inammatory cyto-
kines and vascular injury, and is up-regulated in atheroscle-
rosis (3538). Animal models have demonstrated that HDL
inhibits the expression of adhesion molecules (39,40). HDL
can also directly inhibit the migration of these monocytes
into the subendothelial space (41). In the endothelium,
nitric oxide protects against inammation and activation
(42). HDL promotes vasoprotection by enhancing nitric
oxide synthase and thereby increasing the production of
nitric oxide (42,43). In addition to protection against
platelet activation through endothelial protection, HDL
inhibits the coagulation cascade through serine protease
protein C, which inactivates factors Va and VIIa (42,4446).
Dysfunctional HDL
Structural and functional changes accompany HDL in the
setting of acute or chronic inammation. Leukocyte myelo-
peroxidase may alter the function of normally atheroprotec-
tive molecules into so-called dysfunctional HDL with
proinammatory properties (47). During inammation,
HDL-C levels can be reduced because of increased HDL
catabolism, decreased apolipoprotein A-I synthesis, and
displacement of apolipoprotein A-I from HDL with serum
amyloid A, an acute-phase protein (48,49). Additionally,
platelet-activating acetylhydrolase and LCAT can become
dysfunctional or diminished during inammation, and
among persons with low HDL-C levels such as those with
Abbreviations
and Acronyms
ABC ATP-binding
cassette transporter
ACAT acyl-coenzyme A
cholesterol acyltransferase
ATP adenosine
triphosphate
CETP cholesterol ester
transfer protein
CHD coronary heart
disease
HDL-C high-density
lipoprotein cholesterol
LCAT lecithin-cholesterol
acyltransferase
LDL-C low-density
lipoprotein cholesterol
PPAR peroxisome
proliferator-activated
receptor
VLDL very low-density
lipoprotein
Physical Properties of HDL Particles
Table 1 Physical Properties of HDL Particles
Particle Diameter, nm Density, g/ml
Discoid HDL 8
Spherical HDL3 89 1.1251.21
Spherical HDL2 910 1.0631.125
Discoid high-density lipoprotein (HDL) is quickly degraded when extracted fromplasma. As a result,
when human HDL is processed through density gradient ultracentrifugation, the predominant
subfractions include HDL2 and HDL3. HDL3 is smaller and denser, and is relatively protein rich and
lipid poor (2123).
1284 Natarajan et al. JACC Vol. 55, No. 13, 2010
HDL Therapies March 30, 2010:128399
type 2 diabetes mellitus and CHD (31,41,5052). Further-
more, in the metabolic syndrome, hypertriglyceridemic
states and the acute-phase response, largely through CETP,
enrich the triglyceride content of HDL-C (48,53). In turn,
triglyceride-rich HDL-C particles result in a lowering of
circulating HDL-C levels through their inherent instability
and subsequent degradation as well as through hydrolysis
from hepatic lipase (53). Furthermore, triglyceride-rich
HDL-C cannot be taken by hepatocytes through scavenger
receptor B1 as readily, resulting in reduced efcacy of reverse
cholesterol transport (53,54). Therefore, a combination of
metabolic abnormalities and inammatory milieu may result
in dysfunctional HDL (31,55).
Nonpharmacological Interventions
Observational and interventional studies have assessed the
relationship between lifestyle factors and circulating
HDL-C levels.
Aerobic exercise. In young adult women, moderate activity
was shown to signicantly increase HDL-C over the course
of 6 months (56). In a population of men and women
ranging from 50 to 65 years of age, however, an increased
frequency of exercise resulted in the highest HDL-C levels
Figure 1 Reverse Cholesterol Transport and Therapeutic Targets
Reverse cholesterol transport is one of the primary antiatherogenic properties of high-density lipoprotein (HDL) (24,25). This efux of cholesterol is largely facilitated
through adenosine triphosphate-binding cassette transporters (ABC) as lecithin-cholesterol acyltransferase (LCAT) helps modify these particles into more mature HDL2
and HDL3 particles (22,24). Furthermore, cholesterol ester transfer protein (CETP) transfers additional cholesterol esters from apolipoprotein B-containing particles to
HDL (22,24,25). Subsequently, these HDL particles are taken up by hepatocytes through scavenger receptor B1 (SRB1) (25,30). The various current pharmacologic
agents attempt to increase HDL-C levels by affecting different steps involved in reverse cholesterol transport. ACAT acyl-coenzyme A cholesterol acyltransferase;
CE cholesterol ester; FC free cholesterol; LDL low-density lipoprotein; PL phospholipid; PPAR peroxisome proliferator-activated receptor; TG triglycerides;
VLDL very low-density lipoprotein.
Properties of HDL
Table 2 Properties of HDL
Function Mechanism
Reverse cholesterol transport Cholesterol efux through ABCA1, ABCG1,
ABCG4 (21,22,2429)
LDL antioxidation Activation of LCAT (29,31,32)
Endothelial protection Inhibition of adhesion molecule expression
(39,40), prevention of monocyte
chemotaxis (41), nitric oxide synthase
stimulation (42,43)
Antiplatelet activity Protection against endothelial injury (42)
Anticoagulation Inhibition of factors Va and VIIa (4446)
ABC adenosine triphosphate-binding cassette transporter; HDL high-density lipoprotein;
LCAT lecithin-cholesterol acyltransferase; LDL low-density lipoprotein.
1285 JACC Vol. 55, No. 13, 2010 Natarajan et al.
March 30, 2010:128399 HDL Therapies
(57). Meanwhile, over the short term, such as within the
rst month of aerobic exercise, the anti-inammatory ben-
ets of HDL predominate (58). For example, over the
course of only 3 weeks of exercise, although HDL-C levels
did not increase, HDL preferentially converted to an anti-
inammatory state (58).
Diet. The dietary consumption of saturated fats, unlike
polyunsaturated and monounsaturated fats, promotes ath-
erosclerosis (59). A high saturated fat diet has been shown
to diminish the ability of HDL to protect the endothelium
and reduces vasoreactivity (60,61). In contrast, a high
polyunsaturated fat diet enhances these features (62). In
vitro, HDL suppresses the chemokines that attract inam-
matory cells to the vessel wall (6365).
Purely low fat diets have been shown to decrease
HDL-C to a similar degree as LDL-C is reduced. How-
ever, when unsaturated fat replaces saturated fat and trans-
fats, LDL-C decreases proportionally more, thereby de-
creasing the LDL-to-HDL ratio (62,66). Diets high in
monounsaturated fats, including olive oil and canola oil,
have been shown to reduce LDL-C without adversely
affecting HDL (67). Certain polyunsaturated fats, including
n-3-polyunsaturated fatty acids, largely found in sh oil, can
elevate levels of HDL-C, especially among persons with high
triglycerides (68,69). Grapeseed oil, a byproduct of winemak-
ing, that contains a mixture of polyunsaturated vegetable oils
may increase HDL-C levels by nearly 13% (70).
Glycemic index measures how much a carbohydrate-
containing food increases blood sugar levels and is deter-
mined by ber content, glucose content, and digestibility.
Data suggest that the carbohydrate quality, or glycemic
index, may affect HDL-C levels (71). For instance, the
favorable effect of low glycemic index foods on increases in
HDL-C levels was observed in both the U.S. and Europe
(72,73). In the Nurses Health Study, persons particularly
susceptible to insulin resistance had increases in their
HDL-C when eating foods with low glycemic index (74).
Weight loss. Obesity is the central abnormality that con-
tributes to the metabolic syndrome and is associated with
low HDL-C and high triglyceride levels. Losing weight
through diet or aerobic exercise equally results in an increase
in HDL-C, without signicant differences between the 2
strategies (75). The effect of weight loss from caloric
restriction and regular exercise is particularly benecial for
overweight or obese men and women (76). In a meta-
analysis, subjects actively losing weight initially experience a
reduction in HDL-C levels, but subjects at a stabilized,
reduced weight have HDL-C levels inversely proportional
to their weight (77). This nding is consistent with the
observation that lipoprotein lipase decreases with acute
caloric restriction but increases with weight loss, especially
when the weight is stabilized (78,79). A sustained reduction
in weight can be achieved through various mechanisms, but
all have similar favorable effects on HDL-C levels.
Tobacco cessation. The Framingham study group showed
that cigarette smoking accounted for a drop in HDL-C by
4 mg/dl in men and 6 mg/dl in women (80). A meta-
analysis demonstrated that smokers generally have a 9%
lower HDL-C level and a 6% lower apolipoprotein A-I
level compared with matched nonsmokers (81). This inverse
association of cigarette smoking and HDL-C levels is dose
dependent (8184). Increased CETP activity and the re-
sultant transfer of cholesterol esters from HDL to apoli-
poprotein B-containing particles mediate tobacco smokings
atherogenic lipoprotein changes (85,86). Furthermore, in a
meta-analysis of 27 studies, it was observed that when
participants quit smoking tobacco, their HDL-C levels rose
by 4 mg/dl without a signicant effect on total cholesterol,
LDL-C, or triglyceride levels (87). Additionally, smoking
cessation results in an increase in apolipoprotein A-I (88).
These favorable effects on the lipid prole can be seen as
early as 30 days after quitting smoking (89).
Alcohol. While heavy alcohol intake is associated with
increased all-cause mortality and cardiovascular-related
mortality (9094), moderate alcohol intake appears to have
a protective effect on CHD (9599). Part of this protection
may be mediated by an associated increase in HDL-C
(100103). An increase in both the HDL2 and HDL3
subfractions, but with relatively larger increase in HDL2, is
observed with moderate alcohol consumption (103,104). A
systematic review showed that all forms of alcohol (e.g.,
beer, wine, and spirits) had a favorable cardioprotective
effect (105). However, data suggest that wine consumption
provides more cardioprotection (106). Some of this additive
benet may be from avonoids such as resveritrol that act
as lipoprotein antioxidants (107). The recommendation of
alcohol consumption for cardiovascular protection is limited
by the potential for abuse, dependence, and caloric intake.
Pharmacological Interventions
Various randomized controlled trials have evaluated the
efcacy and safety of pharmacologically modifying HDL
(Table 3).
Statins. The reduction of LDL-C with statins has a
positive effect on the occurrence of cardiovascular events
(108112). A decrease in LDL-C levels from statin therapy
is associated with a decrease in the progression of athero-
sclerosis (113115). Increases in HDL-C between 5% and
15% have been reported with statin-mediated therapy, with
an average increase of 9% (108,110,111,116). However,
the data regarding the clinical signicance of this are
unclear. The statin-induced HDL-C effects are relatively
small compared with the LDL-C effects, so the effects of
statins on HDL-C are likely to be small. Nevertheless, a
recent meta-analysis of statin therapy demonstrated that, in
patients with CHD in whom LDL-C levels are aggressively
reduced to 87.5 mg/dl, an increase in HDL-C by 7.5% is
independently associated with a regression in coronary
atherosclerosis (116). Statins also promote the formation of
a more favorable HDL subfraction prole by creating more
cholesterol-rich HDL particles, perhaps through the reduc-
tion of cholesterol transfer from HDL (117120). That may
occur through the reduction in available apolipoprotein
B-containing atherogenic particles to accept cholesterol
esters and down-regulation of CETP expression (121,122).
Niacin. Currently, niacin (vitamin B3) is the most effective
available pharmacologic means to raise HDL-C levels.
Interest in niacin developed 50 years ago when it was
noted to decrease total cholesterol, lower LDL-C, and
raise HDL-C (123,124). Niacin increases HDL-C levels by
15% to 35% with a nonlinear dose-dependent response
(125129). Therefore, the majority of the benecial effects
of niacin occurs at doses of 1 to 1.5 g per day (126,129).
Niacin accomplishes this effect on HDL through multi-
ple mechanisms. It selectively inhibits hepatic clearance of
HDLs apolipoprotein A-I and not the cholesterol esters
(130,131). As a result, the cholesterol-decient apolipopro-
tein A-Icontaining HDL particles are recycled into the
circulation and freed for further reverse cholesterol transport
(130,132). Furthermore, niacin directly inhibits the transfer
of cholesterol esters through CTEP from HDL to apoli-
poprotein B-containing particles by directly inhibiting
CTEP activity as well as by reducing the hepatic synthesis
of CTEP (133). Niacin also targets this pathway by reduc-
ing the lipolysis in adipose tissue. That reduces the release of
free fatty acids into plasma, with a consequent decrease in
free fatty acid uptake by the liver that leads to a secondary
decrease in hepatic triglyceride synthesis. The resulting
decrease in concentration of plasma VLDL results in a
reduction in the transfer of cholesteryl esters from HDL to
VLDL, and hence an increase in concentration of HDL-C
(134). At a more local level, through the cyclic adenosine
monophosphate/protein kinase A secondary messengers,
niacin promotes the transcription of ABCA1 to provide
HDL particles with targets for reverse cholesterol transport
(135). Moreover, niacin tends to promote the formation of
HDL2 through its inhibition of hepatic lipase (136).
The CDP (Coronary Drug Project) evaluated the effect
of niacin on 8,341 men with a history of myocardial
infarction during 1966 to 1975 (137). Over a 5-year
follow-up period, the incidence of nonfatal reinfarction was
reduced by 27%. Even more compelling is that 15 years
later, niacin contributed to a signicant decrease in all-cause
mortality by 9% (138).
Additional clinical studies of niacin have typically been in
the setting of combination therapy. When combined with
colestipol, a bile-acid sequestrant, in the FATS (Familial
Pharmacotherapy and Effects on HDL-C
Table 3 Pharmacotherapy and Effects on HDL-C
Medication Class Mechanism Phase II/III Trials HDL-C Increase Ongoing Large Trials
Statins Reduced cholesterol transfer from HDL through
decreased ApoB-containing particles and
reduced CETP expression (117122)
* 5%15%
Niacin Inhibition of hepatic clearance of ApoA-I, CETP
inhibition, reduced CETP synthesis, reduced
adipose tissue lipolysis, ABCA1 transcription
promotion, hepatic lipase inhibition
(130136)
CDP (137), FATS (139), CLAS (141), Stockholm
Ischaemic Heart Disease Secondary
Prevention Study (143), ARBITER 2 (154),
ARBITER 6-HALTS (155)
15%35% AIM-HIGH (156);
HPS2-THRIVE (157)
Fibrates PPAR agonism resulting in ABCA1
up-regulation and synthesis, and ApoA-I
transcription (122,162167)
Helsinki Heart Study (168), VA-HIT (169),
BIP (171), FIELD (173)
10%15% ACCORD (188)
Thiazolidinediones PPAR agonism resulting in cellular
differentiation in vascular tissue and
adipocytes (190)
PROACTIVE (193), CHICAGO (194),
PERISCOPE (195), RECORD (197)
5%10%
Glitazars PPAR and PPAR agonism (199201) Kendall et al. (205) 15%30% Aleglitazar (211)
CETP inhibitors CETP inhibition (122,212219) ILLUMINATE (228), ILLUSTRATE (232),
RADIANCE1 (234), RADIANCE2 (235)
40%130% dal-OUTCOMES (241),
dal-VESSEL (242),
dal-PLAQUE (243),
DEFINE (246)
ACAT inhibitors ACAT-1 and ACAT-2 inhibition reducing
intracellular cholesterol esterication
(247,248)
ACTIVATE (253), CAPTIVATE (254) 0%5%
Recombinant
HDL infusion
Reverse cholesterol transport (259), increased
nitric oxide bioavailability (257,258)
ERASE (260)
ApoA-I Milano
infusion
Antioxidation from free cysteine residues
(264266)
Nissen et al. (270)
ApoA-I mimetics Saponication by amphipathic alpha-helices
(273,274), ABCA1-dependent reverse
cholesterol transport (273), antioxidation
(281)

ApoA-I up-regulators Promotion of ApoA-I transcription (287)
*There are several phase III trials with statins targeted specically to low-density lipoprotein cholesterol (LDL-C) lowering, which is outside the scope of this review. High-density lipoprotein cholesterol
(HDL-C) levels after infusions were not routinely measured in the ERASE study or in apolipoprotein (Apo) A-I trials (258,268). Only phase I safety data in humans are currently available for the Apo A-I
mimetic, 4F, and the Apo A-I up-regulator, RVX-208 (281,288,289).
ACAT acyl-coenzyme A cholesterol acyltransferase; CETP cholesterol ester transfer protein; PPAR peroxisome proliferator-activated receptor; other abbreviations as in Table 2.
Atherosclerosis Treatment Study), HDL-C increased by
43%, with angiographic atherosclerotic regression in 39%
and a 73% reduction in CHD rates over a 2.5-year
follow-up period (139). After 10 years of niacin combined
with both colestipol and lovastatin, there was an 18.5%
absolute risk reduction in all-cause mortality (140). The
CLAS (Cholesterol-Lowering Atherosclerosis Study) also
evaluated the effect of combining colestipol with niacin in
162 men who had prior coronary artery bypass graft surgery,
and demonstrated an HDL-C increase by 37%, with an-
giographic regression of atherosclerosis of 16% at 2 years
and 18% at 4 years (141,142).
Combining niacin with a brate has also been shown to
be effective. In the Stockholm Ischaemic Heart Disease
Secondary Prevention Study, 554 post-myocardial infarc-
tion patients were randomly assigned to placebo or to a
combination of niacin and clobrate, and those in the active
treatment arm experienced a 26% reduction in all-cause
mortality and a 36% reduction in CHD mortality (143).
However, this benecial effect was more correlated with the
extent of reduction in serum triglyceride levels. When
examined among patients with CHD and low HDL-C
levels, triple therapy with cholestyramine, a bile-acid se-
questrant, gembrozil, and niacin resulted in a 36% increase
in HDL-C and a 13.7% reduction in CHD events (144).
A common limiting side effect of niacin is facial pruritis
and ushing caused by prostaglandin-mediated vasodilation
through the G-coupled protein receptor, GPR109A
(132,145). This pathway additionally, at least partially,
mediates the niacin-mediated antilipolytic effects in murine
models (145). Interestingly, ushing may be a marker of an
increased lipid response to niacin (146). Paradoxically, the
presence of ushing as a surrogate for niacins efcacy may
promote adherence through appropriate patient education.
Meanwhile, these ushing symptoms can be ameliorated
with the once-daily extended-release formulation, which is
equally as efcacious as the immediate-release formulation
(147). This ushing can also be addressed by taking aspirin
30 min before dosing and by avoiding spicy foods. Niacin in
its immediate-release or extended-release form is safe and
tolerable for diabetic patients as well (148). However, higher
doses of niacin resulted in a slight worsening of glycemic
control (p 0.048) in the ADVENT (Assessment of
Diabetes Control and Evaluation of the Efcacy of Niaspan
Trial) of type 2 diabetic patients randomly assigned to
niacin or placebo (148). When niacin is given at doses 2.5
g, it is associated with a 4% to 5% increase in ngerstick
glucose levels and may or may not have effects on hemo-
globin A1c, and these effects on hemoglobin A1c may be
transient only during uptitration of doses (149). Guidelines
from the National Cholesterol Education Program, Amer-
ican Heart Association, American Diabetes Association,
and National Lipid Association all consider niacin at doses
2 g daily safe for diabetic patients to manage dyslipidemia,
and the cardiovascular benets may outweigh the risks
(14,150152). Additionally, the National Lipid Association
further asserts that patients with impaired glucose tolerance
without overt diabetes mellitus (e.g., fasting glucose 110 to
125) can safely take niacin with careful monitoring of glycemic
control, similar to that for diabetic patients when niacin
therapy is initiated (152).
Both formulations have been evaluated in combination
with statins. In the HATS (HDL-Atherosclerosis Treat-
ment Study), patients with CHD, HDL-C 35 mg/dl, and
LDL-C 145 mg/dl treated with both simvastatin and
extended-release niacin had an increase in HDL-C levels by
26%, slight regression in proximal coronary artery stenosis
by angiography, and a 90% reduction in CHD events versus
dual placebo, although this represented 9 versus 1 events
(153). In the ARBITER 2 (Arterial Biology for the Inves-
tigation of Treatment Effects of Reducing Cholesterol 2)
trial, extended-release niacin was given to patients with
CHD, HDL-C 45 mg/dl, and LDL-C 120 mg/dl who
were already receiving statin therapy (154). This treatment
resulted in a 21% increase in HDL-C and a trend toward a
decrease in the progression of carotid intima media thick-
ness as assessed by ultrasonography over a 1-year follow-up
period (154). The follow-up study, ARBITER 6 (HDL and
LDL Treatment Strategies in Atherosclerosis), was de-
signed to compare the effects of HDL-Clowering therapy
with extended-release niacin versus additional LDL-C
lowering therapy with ezetimibe on atherosclerosis progres-
sion in patients already receiving statin therapy (155). This
trial was stopped early in 2009 with just 208 evaluable
patients when it was seen that patients receiving niacin had
a signicant reduction in carotid-intima media thickness at
both 8 months and 14 months (155).
Currently, the AIM-HIGH (Atherothrombosis Inter-
vention in Metabolic Syndrome with Low HDL/High
Triglycerides and Impact on Global Health Outcomes)
study has enrolled 3,300 patients with CHD and evidence
of the metabolic syndrome with HDL-C 40 mg/dl and
triglycerides 150 mg/dl not already given statin therapy
(156). In this U.S.Canadian, multicenter, randomized,
double-blind, parallel-group, controlled clinical trial, pa-
tients have been randomly allocated to therapy with simva-
statin alone or simvastatin and extended-release niacin and
are being evaluated over a 5-year period to better dene the
additive effect of HDL-raising therapies. Another trial, the
HPS2-THRIVE (Heart Protection Study 2 Treatment on
HDL to Reduce the Incidence of Vascular Events) is
recruiting 25,000 patients with a history of CHD, stroke, or
peripheral arterial disease and randomizing them to placebo
or a new tablet containing extended-release niacin plus a
specic blocker of prostaglandin D2, called laropiprant, to
prevent the ushing associated with niacin (157).
Fibrates. Fibrates are peroxisome proliferator-activated re-
ceptor (PPAR)- agonists that lower LDL-C by 10% to
20%, lower triglycerides by 25% to 45%, and increase
HDL-C modestly by 10% to 15% (158161). Through the
activation of PPAR, ABCA1 is up-regulated as well as
hepatic HDL synthesis (162,163). The HDL production is
largely mediated through PPARs stimulation of the apo-
lipoprotein A-I genes promoter (164166). PPAR ago-
nism may also decrease CETP gene expression, resulting in
lower levels of plasma CETP (122). Additionally, by reduc-
ing triglyceride-rich lipoproteins available to accept choles-
terol esters, HDL-C levels are boosted (122,167).
In the Helsinki Heart study, 4,081 healthy men without
CHD with nonHDL-C 200 mg/dl were randomly
assigned to gembrozil versus placebo (168). LDL-C de-
creased by 11%, triglycerides decreased by 35%, and
HDL-C increased by 11%. Although the more pronounced
effect was on triglycerides, the 34% reduction in CHD
events was signicantly associated with both LDL-C low-
ering and HDL-C elevation. The VA-HIT (Veterans
Affairs High-Density Lipoprotein Cholesterol Intervention
Trial) evaluated patients with CHD, LDL-C 140 mg/dl,
triglycerides 300 mg/dl, and HDL-C 40 mg/dl on
gembrozil (160). LDL-C levels did not differ signicantly
between the study groups over the 5-year study period, so
the 22% reduction in CHD events was attributed to the 6%
increase in HDL-C in a subsequent multivariable analysis
(160,169). It was the rst trial that demonstrated a relation-
ship between HDL-C increase and CHD event reduction
in patients with moderate LDL-C levels. Another analysis
of the VA-HIT study demonstrated that gembrozil ther-
apy for patients with CHD and low HDL-C was cost
effective in terms of the cost of quality-adjusted life-years
saved (170).
The effects of the brates on coronary events have been
variable. Although bezabrate therapy in patients with
CHD and low HDL-C levels increases HDL-C by 18%,
there was only a trend toward the reduction of CHD events
in the BIP (Bezabrate Infarction Protection) study (171).
A 16-year follow-up of this trial demonstrated that subjects
with the highest HDL-C response to therapy had a signif-
icant reduction in the risk of death (172). In the FIELD
(Fenobrate Intervention and Event Lowering in Diabetes)
study, the authors studied the effect of fenobrate therapy
on 9,795 randomized patients with type 2 diabetes mellitus
not receiving statin therapy and with a total cholesterol level
of 251 mg/dl (173). However, fenobrate did not signif-
icantly alter HDL-C levels but it did lower LDL-C and
triglyceride levels. There was no signicant effect on total
coronary events, but a signicant 24% reduction in nonfatal
myocardial infarction was observed. Overall, the FIELD
trial failed to demonstrate a signicant benet of an agent
that predominantly reduces triglycerides in a high-risk
population. That may have resulted from a greater use of
open-label statin therapy for subjects allocated to placebo.
Studies of clobrate have been plagued with concerns
regarding potential safety (174176).
The brates are primarily excreted renally, and there are
retrospective observational data suggesting that they may
result in reversible worsening renal function in patients with
baseline renal impairment (177,178). In severe renal impair-
ment, the drugs half-life is prolonged and is not dialyzable,
and there is concern regarding permanent renal dysfunction
in kidney transplant patients (177,179). Although the
mechanism of inducing renal dysfunction is unclear, inter-
esting data propose that brates result in increased creati-
nine levels from increased creatinine production without an
actual change in creatinine clearance (180). Renal function
in patients with severe nondialysis-dependent renal disease
should be monitored during the initiation of brate therapy
for dyslipidemia, but brates are not contraindicated in
patients with baseline renal impairment.
Given the benets of statin therapy for diabetic patients,
there is little evidence to recommend brates as an alternative
rst-line treatment to statins for the management of dyslipi-
demia among diabetic patients (181,182). The combination of
statins and brates bears the risk of myotoxicity with an
incidence of 0.12%, but there are some data suggesting the
benets of combined statin and brate therapy, particularly for
diabetic patients (14,183185). All brates have been associ-
ated with reports of creatinine kinase elevations and myopathy
when given with statins, but that appears to occur more
frequently with gembrozil than with fenobrate (186). Gem-
brozil, more than fenobrate, inhibits hepatic glucoronida-
tion of various statins, thereby preventing statin clearance and
increasing serum levels of statins in their active form (187).
The ACCORD (Action to Control Cardiovascular Risk in
Diabetes) study is a large-scale trial that is currently prospec-
tively evaluating the safety and efcacy of the combination of
simvastatin and fenobrate in managing dyslipidemia in type 2
diabetes (188).
Thiazolidinediones. The insulin-sensitizing thiazolidinediones,
which include pioglitazone and rosiglitazone, were approved
in the U.S. in the late 1990s for the treatment of type 2
diabetes mellitus. Troglitazone was also a member of this
class but was withdrawn because of idiosyncratic liver injury
(189). These agents are agonists of peroxisome proliferator-
activated receptor (PPAR)-, a nuclear receptor involved in
cellular differentiation, largely in vascular tissue and adipo-
cytes (190). Insulin resistance contributes to the metabolic
syndrome, which includes hyperglycemia, elevation in tri-
glycerides, and reductions in HDL-C levels. As a result,
insulin-sensitizers such as thiazolidinediones were proposed
to not only correct dysglycemia but also to potentially
correct lipid abnormalities (189).
A meta-analysis of 23 randomized trials demonstrated
that pioglitazone increased HDL-C levels by 4.6 mg/dl and
that rosiglitazone increased HDL-C levels by 2.7 mg/dl
(191). However, unlike pioglitazone, rosiglitazone increased
LDL-C and total cholesterol and did not decrease triglyc-
erides (191). Even in patients without overt diabetes mel-
litus but with evidence of insulin resistance, pioglitazone
increases HDL-C levels (192). The PROACTIVE (Pro-
spective Pioglitazone Clinical Trial in Macrovascular
Events) assessed the benet of pioglitazone in a higher risk
population, type 2 diabetes with a hemoglobin A1c level
6.5%, and stable macrovascular disease (193). Pioglita-
zone increased HDL-C by 8.9% and decreased triglycerides
by 9.6% without a signicant reduction in the primary end
point but with a 16% reduction in the combined secondary
end point of mortality and nonfatal myocardial infarction
and stroke (193). Given the modest 0.6% decrease in
hemoglobin A1c, many have speculated that part of the
clinical benets of these agents could be related to the
HDL-Craising benets of these agents.
Pioglitazone has been recently tested against other oral
hypoglycemic agents, including glimepiride, a sulfonylurea
that acts as an insulin secretagogue. In the CHICAGO
(Carotid Intima Media Thickness in Atherosclerosis Using
Pioglitazone) trial, type 2 diabetic patients treated with
pioglitazone had a decrease in the progression of carotid
intima media thickness compared with type 2 diabetic
patients treated with glimepiride (194). More recently, the
PERISCOPE (Pioglitazone Effect on Regression of Intra-
vascular Sonographic Coronary Obstruction Prospective
Evaluation) study randomly allocated type 2 diabetic pa-
tients with CHD to pioglitazone or glimepiride (195).
Patients treated with pioglitazone had a 4.6 mg/dl increase
in HDL-C levels and a decrease in CHD progression as
evaluated by intravascular ultrasonography (195).
The effects of pioglitazone may not extend to thiazo-
lidinediones, in general. Rosiglitazone does not result in the
same favorable lipid prole (191). Furthermore, a recent
meta-analysis suggested that rosiglitazone treatment results
in a signicant risk of myocardial infarction (196). How-
ever, in the large, randomized RECORD (Rosiglitazone
Evaluated for Cardiac Outcomes and Regulation of Gly-
caemia in Diabetes) trial, an interim analysis subsequently
showed no difference in myocardial infarction or cardiovas-
cular deaths (197). A meta-analysis of pioglitazone, largely
involving the PROACTIVE trial, demonstrated a decrease
in mortality, myocardial infarction, or stroke (198). With
the currently available data, this class is generally not used
for HDL modication.
Glitazars. A new class of agents called glitazars with
combined PPAR- and PPAR- agonism is being evalu-
ated (199201). These drugs would theoretically combine
the lipid benets of PPAR activation with the insulin-
sensitizing effects of PPAR activation to optimally treat
the metabolic syndrome.
Ragaglitazar increased HDL-Cby 31%, decreased triglycerides
by 62%, and decreased hemoglobin A1c by 1.3%, but the
adverse events of edema, anemia, and leukopenia have
drawn concern (202,203). Muraglitazar increases HDL-C
by as much as 16% in type 2 diabetic patients, but, as with
ragaglitazar and the thiazolidinediones, weight gain and
edema were more common with muraglitazar therapy
(204,205). An analysis of muraglitazars phase 2 and 3 data
revealed an increase in risk of death, cardiovascular events,
and congestive heart failure associated with muraglitazar
(206). Tesaglitazar, a third agent in this drug class, can
increase HDL-C by 13% (207209). Recently, a phase 2
trial of aleglitazar was shown to increase HDL-C by 20%
and also decrease hemoglobin A1c in a dose-dependent
manner, with an increase in edema but not congestive heart
failure or myocardial infarction (210). As a result, a phase 3
study of aleglitazar in type 2 diabetic patients with a recent
acute coronary syndrome has been announced (211).
CETP inhibitors. Humans with CETP deciency due to
molecular defects in the CETP gene have markedly elevated
plasma levels of HDL-C and apolipoprotein A-I (212,213).
Studies regarding the association of lower CETP levels and
atherosclerosis are mixed, but patients with CETP de-
ciency and higher HDL-C levels tend to have lower rates of
atherosclerotic disease (214217). There was initial concern
that the larger, cholesterol-rich HDL particles formed
through CETP inhibition would not as efciently allow for
reverse cholesterol transport (218). In response, a study
showed that these larger particles promote cholesterol efux
through the ABCG transporter (219). Such observations
led to the concept that pharmacological CETP inhibition
might favorably increase HDL-C levels (122).
Animal models of CETP inhibitors using a variety of
different pharmacological strategies have resulted in an increase
in HDL-C and an attenuation of atherosclerosis (220226).
Early small studies of torcetrapib, a direct CETP inhibitor, in
healthy subjects and patients with HDL-C 40 mg/dl dem-
onstrated signicant increases in HDL-C levels of 50% to 60%
(218,227). Torcetrapib was evaluated on a much larger scale
through the ILLUMINATE (Investigation of Lipid Level
Management to Understand its Impact in Atherosclerotic
Events) trial (228). In that trial, 15,067 patients with a history
of cardiovascular disease or type 2 diabetes mellitus receiving
atorvastatin were randomly assigned to torcetrapib or placebo.
Patients receiving torcetrapib experienced a 72.1% increase in
HDL-C, a 24.9% decrease in LDL-C, and a 9% decrease in
triglycerides over 1 year. However, the ILLUMINATE trial
was prematurely terminated because of an increase in cardio-
vascular events (hazard ratio: 1.25; 95% condence interval:
1.09 to 1.44) and all-cause mortality (hazard ratio: 1.58; 95%
condence interval: 1.14 to 2.19). Off-target toxic effects
including hyperaldosteronism as reected by the observed
hypokalemia, hypernatremia, and increase in systolic blood
pressure by a median of 5.4 mm Hg specic to the molecule
itself may have been the culprits (228,229). Additionally, there
is speculation that the HDL particles formed by torcetrapib
may not participate in reverse cholesterol transport and other
cardioprotective qualities, but recent data suggest that these
particles do participate in reverse cholesterol transport
(229231).
The ILLUSTRATE (Investigation of Lipid Level Man-
agement Using Coronary Ultrasound to Assess Reduction
of Atherosclerosis by CETP Inhibition and HDL Eleva-
tion) study concurrently did not show an effect of torce-
trapib on coronary atherosclerosis (232). A post-hoc analysis
suggested that patients who experienced the highest level of
HDL-C increase did have some regression of coronary
atherosclerosis (233). Patients with familial hypercholester-
olemia treated with torcetrapib in the RADIANCE1 (Rat-
ing Atherosclerotic Disease Change by Imaging With a
New CETP Inhibitor 1) study did not demonstrate a
change in carotid intima media thickness despite a 55.5%
increase in HDL-C (234). There was also progression of
disease in the common carotid segment, raising the concern
of a directly toxic effect of torcetrapib on the endothelium
(229,234). In the RADIANCE2 trial, patients with mixed
dyslipidemia also had a similar increase in HDL-C, without
an effect on carotid intima media thickness (235). Similar to
in the ILLUMINATE trial, torcetrapib was associated with
a small increase in blood pressure in the ILLUSTRATE,
RADIANCE1, and RADIANCE2 studies (232,234,235).
Dalcetrapib (also known as R1658, JTT-705, and
RO460731) is another CETP inhibitor (236). A phase 2
trial involving healthy subjects demonstrated a 34% increase
in HDL-C (237). Another phase 2 trial involving patients
with dyslipidemia on pravastatin therapy showed an associ-
ated 28% increase in HDL-C with dalcetrapib (238).
Neither study had an increase in blood pressure or cardio-
vascular adverse events, as seen in the torcetrapib trials
(237239). In vitro, dalcetrapib does not activate the renin-
angiotensin-aldosterone pathway (240). Currently, the
phase 3 dal-OUTCOMES trial is recruiting 15,600
patients with recent acute coronary syndromes to further
study dalcetrapibs effect on cardiovascular morbidity and
mortality as well as its safety prole (241). Also, the phase
2b dal-VESSEL study will further evaluate dalcetrapibs
favorable effect on endothelial function in hypercholester-
olemic patients with a low baseline HDL-C level (242).
And the phase 2b dal-PLAQUE study plans to characterize
its effects on atherosclerotic plaque with magnetic resonance
imaging and positron emission tomography/computed to-
mography (243).
Anacetrapib (also known as MK-0859) is a novel, potent
CETP inhibitor also being studied. A phase 1 trial involving
healthy subjects documented an increase in HDL-C up to
129% without an effect on blood pressure (244). Recently, a
phase 2 trial showed that 589 patients with dyslipidemia
receiving atorvastatin randomly assigned to anacetrapib had
a 130% increase in their HDL-C levels and a decrease of
40% in their LDL-C levels without an effect on blood
pressure (245). The DEFINE (Efcacy and Tolerability of
CETP Inhibition With Anacetrapib) trial has recruited
1,623 patients with CHD already receiving statin therapy
for an anacetrapib phase 3 safety trial, and a larger outcomes
study is planned (246).
ACAT inhibitors. A target for treating atherosclerosis has
been the inhibition of acyl-coenzyme A cholesterol acyl-
transferase (ACAT), which esteries cholesterol in a range
of tissues (247,248). Theoretically ACAT, specically
ACAT-1, inhibition would slow the progression of foam
macrophage cells in theory (249). Subsequently, free cho-
lesterol would be available for reverse cholesterol transport
(250). ACAT-2, the other identied ACAT isoform, is
present in the liver and intestine, so inhibition of this
enzyme would reduce LDL formation (251).
Avasimibe, a nonselective ACAT inhibitor, was assessed
in 639 randomized patients with CHD in the phase 2
A-PLUS (Avasimibe and Progression of Lesions on Ultra-
Sound) study (252). Unfortunately, avasimibe did not alter
HDL-C levels, and it did not have an impact on coronary
atherosclerosis as assessed by intravascular ultrasonogra-
phy (252). Pactimibe, another nonselective ACAT inhib-
itor, was evaluated by intravascular ultrasonography in
the ACTIVATE (ACAT Intravascular Atherosclerosis
Treatment Evaluation) trial of 408 patients with CHD
(253). Pactimibe resulted in a 5.4% (p 0.04) increase in
HDL-C, but although there was no difference compared
with placebo with respect to atherosclerosis progression,
secondary variables suggested that pactimibe limited athero-
sclerosis regression compared with placebo (253). Further-
more, the more recent CAPTIVATE (Carotid Atheroscle-
rosis Progression Trial Investigating Vascular ACAT
Inhibition Treatment Effects) evaluated the effects of pac-
timibe on carotid atherosclerosis using ultrasonography of
carotid intima media thickness in 892 patients with familial
atherosclerosis (254). There was no change in HDL-C
levels, and although there was no change in maximum
carotid intima media thickness, but there was an increase in
mean carotid intima media thickness by 2.9% (p 0.05)
after 1 year, and, notably, there was a signicant absolute
risk increase of 2.1% of cardiovascular death, myocardial
infarction, and stroke with pactimibe (254). Potential ex-
planations for this proatherogenic effect of ACAT inhibi-
tion is that the accumulation of free cholesterol in macro-
phages results in ABCA1 degradation, limiting reverse
cholesterol transport, and such free cholesterol abundance
causes cellular death, stimulating and intensifying the de-
velopment of atherosclerosis (255,256).
Reconstituted HDL infusion. Short-term infusions of
reconstituted HDL have been a target of reverse cholesterol
transport therapy. The HDL infusions also increase nitric
oxide bioavailability for endothelial protection (257,258). In
a small study of healthy subjects, these intravenous infusions
promoted reverse cholesterol transport (259).
On the basis of these data, the ERASE (Effect of rHDL
on AtherosclerosisSafety and Efcacy) study randomly
assigned 183 patients within 2 weeks of an acute coronary
syndrome to 4 weekly infusions of CSL-111, reconstituted
HDL made of puried human apolipoprotein A-I and
soybean phosphatidylcholine (260). There was a nonsignif-
icant trend toward an improvement in coronary atheroma
volume when measured by intravascular ultrasonography,
but the study was prematurely terminated because of a high
incidence of liver function test abnormalities (260). None-
theless, there is some evidence that reconstituted HDL
infusion promotes a favorable change in the quality of
coronary atheroma (260,261). In type 2 diabetic patients,
recent data suggest that reconstituted HDL infusion not
only suppresses the expression of inammatory markers and
enhances reverse cholesterol efux, but also augments gly-
cemic control by increasing plasma insulin and activating
adenosine monophosphate-activated protein kinase in skel-
etal muscle (262,263).
Apolipoprotein A-I Milano infusion. In 1980, a group in
Milano described 40 persons in a small village in northern
Italy called Limone sul Garda who, despite very low
HDL-C levels (10 to 30 mg/dl), had a reduced atheroscle-
rotic disease burden and longer lives (264266). This was
attributed to an arginine to cysteine mutation at position
173 of apolipoprotein A-I, termed apolipoprotein A-I
Milano, allowing for disulde bond dimer formation
(264266). Not all of the cysteine residues dimerize, and
the free thiol groups have antioxidant properties (267).
Recombinant apolipoprotein A-I Milano infusions in ani-
mals demonstrated evidence of atherosclerosis regression,
which can occur in as little as 48 h (268,269).
This therapy was piloted in humans when ETC-216,
recombinant apolipoprotein A-I Milano complexed with
phospholipid, was randomly infused in 57 patients within 2
weeks of an acute coronary syndrome over 5 weekly treat-
ments (270). There was signicant reduction in intravascu-
lar ultrasound-measured coronary atheroma burden with
ETC-216, with 1 patient reported to have a signicant rise
in transaminases (270). In a trial of 47 patients after an acute
coronary syndrome, recombinant apolipoprotein A-I Mi-
lano infusion was associated with reverse coronary remod-
eling whereby atheroma burden was reduced but luminal
size was unchanged (271).
Apolipoprotein A-I mimetics. Apolipoprotein A-I is a
protein with 243 amino acids and consists of a tandem
assortment of amphipathic helices (272). Reverse choles-
terol transport by the ABCA1 pathway is mediated by the
detergent-like properties of these amphipathic helical seg-
ments (273,274).
The development of smaller peptides that retain such
activity began with the development of peptide mimetic
18A, consisting of 18 amino acids, which does not share
sequence homology of apolipoprotein A-I but can form a
similar amphipathic helix (275). Multiple modications
have been studied, but the most studied is 4F, which is a
dimerized version of 18A with 2 phenylalanine substitutions
(273,275278).
An orally active 4F peptide made with D-amino acids,
D-4F, given to mice decreases atherosclerotic lesions and
promotes reverse cholesterol transport (279,280). Phase I data
suggest that D-4F may be safe for humans with CHD, and
although it does not alter lipoprotein levels, it may improve the
HDL anti-inammatory index, but further clinical studies are
needed to elucidate this signicance (281).
Given concerns regarding possible cytotoxicity through
ABCA1-independent lipid efux, additional peptide mi-
metics have been engineered (282). Twenty-two amino acid
peptides based on domains of apolipoprotein A-I that have
a higher afnity for ABCA1 have been shown to promote
cholesterol efux without cytopathic effects (282284). Fur-
thermore, such domains are conserved across other apoli-
poproteins, and similarly designed peptides from apoli-
poprotein E promote ABCA1-mediated reverse cholesterol
transport (285). Recently, 5A, an asymmetric bihelical
peptide based on 2F, with 1 of the domains containing more
alanine residues and thereby reducing its helical content, has
been constructed to more closely reect the combination of
low- and high-afnity helices on apolipoprotein A-I (286).
The 5A peptide had increased ABCA1-dependent choles-
terol efux and decreased hemolysis compared with its
parent compound (286).
The strategy of using peptide mimetics to treat athero-
sclerotic disease is in its infancy but carries the potential to
treat disease through specic, endogenous pathways.
Apolipoprotein A-I up-regulators. Recently, a novel par-
ticle called RVX-208 that increases the transcription of
apolipoprotein A-I to promote reverse cholesterol transport
has been announced (287). This transport was facilitated
through the ABCA1, ABCG1, and SR-B1 pathways
through apolipoprotein A-I up-regulation (288). Phase I
data from 24 healthy subjects have shown a dose-dependent
increase in apolipoprotein A-I, and thereby HDL function-
ality (288,289). Further data and investigation are needed to
fully examine the ability of small molecules up-regulating
apolipoprotein A-I to impact the burden of atherosclerosis.
Conclusions
There is overwhelming evidence that high levels of HDL-C
in nature are associated with a lower risk of CHD. Unlike
LDL-C, the mechanisms controlling HDL-C are more
complex. Lifestyle interventions are safe but only modestly
increase HDL-C. The best treatments available currently
are the niacin derivatives, although the newer CETP
inhibitors, apolipoprotein mimetics, and apolipoprotein up-
regulators hold much promise. The next 5 years should
provide information on whether the ux or cycling of HDL
is more important than HDL-C levels and also whether we
should target raising specic HDL subclasses rather than
HDL-C itself.
Acknowledgment
The authors would like to thank Philip Barter, MD, PhD,
for his thoughtful and helpful review of this manuscript.
Reprint requests and correspondence: Dr. Christopher P. Can-
non, Brigham and Womens Hospital, Cardiovascular Division,
TIMI Study, 350 Longwood Avenue, First Floor Ofce, Boston,
Massachusetts 02115. E-mail: cpcannon@partners.org.
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289. Johansson J, Jahagirdar R, Genest J. Use of RVX-208 to increase
apolipoprotein A-I and HDL in animals and phase I clinical trials.
Paper presented at: Annual Conference of Arteriosclerosis, Throm-
bosis, and Vascular Biology; April 16, 2008; Atlanta, GA.
Key Words: high-density lipoprotein y coronary artery disease y
prognosis y prevention.

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QUARTERLY FOCUS ISSUE: PREVENTION/OUTCOMES State-of-the-Art Paper

High-Density Lipoprotein and Coronary Heart Disease

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