High-density lipoprotein cholesterol (HDL-C) has long been recognized
as an inverse predictor of atherosclerotic events, yet remains elusive as a
therapeutic target in reducing vascular risk.1,2 As coronary disease is a
phenomenon of recent centuries, it seems improbable that HDL evolved as a
function of its ability to slow atherosclerotic disease. More likely, the role
of HDL in the body’s innate immune system has afforded a survival
advantage, and its protective cardiovascular effects stem from a convenient but
complex interplay between its numerous enzymatic and other protein
substituents, its lipid composition, and its interaction with the arterial
vessel wall and other lipoproteins. These characteristics of HDL, including its
cholesterol content, change in the context of both acute and chronic
Although the epidemiology of HDL-C and cardiovascular risk has been
fairly consistent, clinical trials of pharmacologic interventions to raise
HDL-C have yielded under-whelming results.2,3 Furthermore, the functional characteristics of HDL are
impaired in patients with atherosclerosis and inflammatory disorders.4 The lack of consensus concerning which aspects of HDL
function are most important has contributed to controversy over whether HDL
quantity or HDL quality is the most relevant target of treatment.
HDL particles are surrounded by an outer amphipathic layer containing
free cholesterol, phospholipid and apolipoproteins (in decreasing order, AI,
AII, C, E, AIV, J, and D) on the surface, with a triglyceride- and cholesterol
ester–rich hydrophobic core. Apolipoprotein AI (apo AI) is the principal
protein of HDL. The “cargo” carried by HDL particles includes enzymes
such as paraoxonase, platelet-activating factor acetylhydrolase (both
anti-oxidants), lecithin cholesterol acyltransferase (LCAT), and cholesteryl
ester transfer protein (CETP). HDL subtypes can be separated and quantified on
the basis of ultracentrifugation, electrophoresis or nuclear magnetic
resonance; these particle classes include HDL-2 and HDL-3. The differences in
particle size primarily result from the number of apolipoprotein molecules and
the volume of the cholesterol ester in the particle core.5
Functional Roles of HDL
HDL possesses multiple potentially atheroprotective characteristics,
although the relative importance of these characteristics remains the subject
of debate. Participation of HDL in reverse cholesterol transport (RCT), the
process through which intracellular lipids are mobilized onto apo AI for
hepatic elimination, is the most elucidated and least controversial
In RCT, cholesterol and other lipids in the macrophages (foam cells)
of the arterial wall plaque are transported either to lipid-poor apo AI or
immature forms of HDL through ATP-binding cassette transporter A1 (ABCA1), or
to more mature HDL via ATP-binding cassette subfamily G, member 1, present on
the cell membrane. LCAT present within HDL catalyzes the conversion of this
cholesterol to cholesteryl ester (CE). CE is either passed to the liver via the
scavenger receptor B1 on the hepatocyte surface or transferred to particles
containing apolipoprotein B, predominantly very low-density lipoprotein (VLDL)
and low-density lipoprotein (LDL), through the HDL-associated enzyme
CETP.6 In type 2 diabetes and metabolic
syndrome, CETP activity is relatively high, in association with the clinical
phenotype of low HDL-C, elevated triglycerides, and small, dense
cholesterol-rich LDL particles.7
Beyond RCT, HDL has other properties that appear to contribute to
reduced vascular risk. Among these are anti-inflammatory capabilities,
including reducing chemoattraction of monocytes to vascular endothelial cells
by reducing the chemokine monocyte chemotaxis protein-1 (MCP-1),
down-regulating cellular adhesion molecule expression on endothelial cell
membranes (to which monocytes attach), and decreasing differentiation of
subendothelial macrophages into foam cells within plaque.8
One of the major drivers of atherosclerosis and many associated
inflammatory pathways is the oxidation of lipids within lipoproteins and
plaque.9 Under normal circumstances, HDL reduces
production of oxidized lipids within macrophages and LDL.10 This anti-oxidative capacity is anti-inflammatory in
that HDL decreases the significant stimulus of monocyte attraction and
foam-cell development.9 Even RCT may be
considered anti-inflammatory, since it promotes efflux of lipids—many of
which are oxidized and promote vascular inflammation—from within the
artery wall. This may explain the observation that the ability of HDL to
inhibit monocyte chemotaxis highly correlates with its capacity to promote
The apolipoprotein content of HDL also seems to be related to the
apparent clinical relevance of HDL in regulation of platelet
aggregation.12 HDL is believed to be protective
against both arterial and venous thrombosis.13
In these ways, HDL could well mitigate the entire course of atherothrombosis,
from fatty streak (its earliest stage) to acute coronary syndrome.
In a variety of clinical circumstances that manifest features of
either acute or systemic inflammation, composition and function of HDL can
become impaired, resulting in a particle with less ability to reduce or with a
paradoxical tendency to increase evidence of vascular inflammation.14
The latter, specifically HDL that promotes lipid oxidation, cellular adhesion
molecule expression, and monocyte attraction to the vessel wall, has been
isolated from patients with coronary disease and other forms of
atherosclerosis;4 patients following a single
ingestion of a meal predominantly consisting of saturated fat;15 and patients with type 2 diabetes,16 rheumatoid arthritis,17 systemic lupus, renal disease,18 and uremia.19
Other measures of HDL function have shown the same paradoxical
reversal of HDL protective capacity in Crohn’s disease (impaired HDL
protection against lipid oxidation)20 and
obstructive sleep apnea (paradoxically increased lipid oxidation),21 and after elective non-vascular surgery (increased
HDL-mediated monocyte chemotaxis).22 In
patients with rheumatoid arthritis, the degree of HDL dysfunction correlated
with disease activity,23 while in patients with
metabolic syndrome and diabetes, the impairment in HDL activity was highly
associated with the degree of hyperglycemia.16
In sepsis, HDL-C content is reduced as much as 50% as part of the acute phase
response.24 In addition, low levels of apo AI
independently predict 30-day mortality and are highly correlated with the
degree of HDL-mediated platelet activation in sepsis.12
This change in HDL is associated with a change in the structure and
content of HDL particles. Concentrations of apo AI and the key antioxidant
enzyme paraoxonase are reduced, while the levels are increased of other
“acute phase proteins” such as serum amyloid A, apolipoprotein J and
ceruloplasmin.25 Moreover, the remaining apo AI
is itself often oxidized due to the release of the enzyme myeloperoxidase (MPO)
by phagocytic mononuclear cells.26 This
oxidation occurs at specific amino acid residues within apo AI, and is often
followed by a chemical process known as nitrotyrosination, which impedes the
ability of HDL to facilitate ABCA1-mediated lipid transport.26
Another acute phase reactant, secretory phospholipase A2 (sPLA2),
reduces HDL-C concentrations and particle size by hydrolyzing phospholipids,
including those in HDL. Activity of sPLA2 releases from lipoproteins highly
proinflammatory oxidized fatty acids that reduce HDL’s ability to promote
cholesterol efflux and decrease macrophage expression of ABCA1 by accelerating
Interpretation of Clinical Trials
Interpretation of published clinical trials on the relationship
between modification of HDL-C and HDL itself has been challenging for a number
of reasons. Therapeutic interventions (lifestyle or pharmacologic) that affect
HDL-C also typically affect other lipoproteins and vascular risk factors
(including blood pressure, fasting glucose levels, and inflammatory markers).
The ability to modulate HDL-C levels has been modest relative to the ability to
modulate other risk factors. Several promising therapies have failed to achieve
clinical acceptance because of tolerability, toxicity, absence of
cardiovascular benefits, and clear evidence of harm in some circumstances.
Statins have only a modest (4%–10%) ability to raise HDL-C30 but appear to more substantially improve the
anti-inflammatory functions of HDL. In patients with coronary disease or risk
equivalents, treatment with simvastatin resulted in partial reversion of
pro-inflammatory HDL to a more neutral phenotype, in contrast to HDL isolated
from patients receiving a placebo.4 In patients
with active rheumatoid arthritis but no known vascular disease, high-dose
atorvastatin resulted in a 15% reduction of HDL-associated lipid oxidation in a
cell-free assay in significant contrast to placebo, which had no effect.31 Increases in HDL-C have correlated with
statin-induced regression of plaque measurements as determined using
intravascular ultrasonography (IVUS), so the relatively slight increase of
HDL-C with statins may be relevant.32
Clinically, fibrates are typically used as a means to reduce levels of
VLDL-C, chiefly triglycerides. However, the modest effects of fibrates in
elevating HDL-C may be more relevant to cardiovascular disease
prevention.33 The Helsinki Heart Study showed a
34% reduction in coronary events in dyslipidemic men treated with gemfibrozil,
but subjects in the lowest baseline HDL-C tertile experienced the largest
benefit from the drug.34 Changes in plasma
triglycerides did not correlate with outcome, but increases in HDL-C (+14%
overall) and decreases in LDL-C (–15% overall) were each associated with
significant coronary event reduction with gemfibrozil compared with
placebo.35 In the Veterans Affairs HDL
Intervention Trial (VA-HIT), use of gemfibrozil to treat male patients who have
coronary heart disease (CHD) with low HDL-C levels resulted in a 22% reduction
in coronary events. Multivariate analysis revealed that the changes in LDL-C or
triglyceride levels were not related to this outcome.33 Rather, for each 5 mg/dL rise in HDL-C, a
significant 11% reduction in coronary events occurred.33 The small (6%) rise in HDL-C only partially
accounted for the benefit of drug treatment in VA-HIT. Notably, similar
findings have not been demonstrated to date with fenofibrate.
Niacin and HDL-C
Niacin has long been the staple of pharmacologic efforts to raise
HDL-C, a construct bolstered by the results of the Coronary Drug Project, which
showed a significant but small reduction in recurrent coronary events after 6
years and an 11% relative risk reduction in total mortality after 15-year
follow-up in survivors of myocardial infarction who were receiving niacin
monotherapy. A smaller angio-graphic trial indicated 70% to 90% reduction in a
composite of cardiovascular events in CHD patients with low HDL-C who received
high-dose nicotinic acid in combination with low-dose simvastatin treatment
However, neither study was designed or subsequently analyzed in a manner that
could attribute the clinical benefits observed to any change in HDL-C distinct
from reduction in LDL-C or VLDL-C.
More widespread use of niacin has been limited in no small part due to
intolerable side effects. For this reason, extended-release niacin (ER-niacin)
is the most widely used formulation in practice. Recently, the National Heart,
Lung, and Blood Institute’s (NHLBI) AIM-HIGH study was prematurely
terminated after its data safety monitoring board projected futility of
detecting any cardiovascular benefits of ER-niacin versus placebo in CHD
patients with low HDL-C and aggressively treated LDL-C levels.3 The study organizers and NHLBI have noted that an
unexpected increase in stroke rate was also seen in the ER-niacin group.3 The results of AIM-HIGH challenge the treatment role
of niacin in the context of contemporary LDL-C targets.
The results of the Heart Protection Study 2-THRIVE (HPS2- THRIVE) are
expected in several years. The study is assessing whether the addition of
ER-niacin with the flush-blocking agent laropiprant will affect the rate of
cardiovascular disease relative to placebo in 20,000 patients with symptomatic
atherosclerotic disease who are simultaneously receiving simvastatin.37
A group of investigational agents that inhibit CETP have generated
great interest because this mechanism raises HDL-C significantly, lowers LDL-C
in some cases, and shows promise in animal models of atherosclerosis.38 The development of one CETP inhibitor, torcetrapib,
was abruptly halted due to evidence of a significant 58% relative increase in
the risk of all-cause mortality associated with its use in a large
placebo-controlled trial of patients at high-risk for cardiovascular disease
who were also receiving atorvastatin.39
Torcetrapib treatment was associated with an additional 25% reduction in LDL-C
and 72% increase in HDL-C compared with atorvastatin treatment alone, but also
with a median increase in blood pressure of 5.4 mm Hg.40
Whether this increase in blood pressure (later shown to correlate with
a compound-specific rise in serum aldosterone levels and decrease in potassium
levels) is adequate explanation for the increased mortality in the trial
remains controversial. A post hoc analysis suggested that the subgroup of the
trial that experienced the greatest rise in HDL-C showed the lowest mortality
rate.40 However, approximately half of the
excess total mortality observed in the trial was related to incident cancer and
serious infections, which could suggest abnormal immune function of the HDL
produced in association with torcetrapib. A separate study indicated no
advantage of the use of torcetrapib versus placebo in addition to atorvastatin
treatment, as assessed by carotid intima-media thickness measurement.41
The effects on hypertension and aldosterone levels seen with
torcetrapib have not been seen with two other investigational CETP inhibitors,
anacetrapib and dalcetrapib.42 Although direct
comparisons have not been studied, the former appears to raise HDL-C levels
more than the latter. In addition to increasing HDL-C levels by 140%, in
comparison to placebo anacetrapib 100 mg daily was associated with a 40%
reduction in LDL-C.43 Serious safety concerns
were not evident in 1,623 patients treated with anacetrapib 100 mg daily for 76
weeks.43 Several smaller studies have also
shown no increased blood pressure or cardiovascular toxicity with
dalcetrapib.44,45 With the
exception of minor gastrointestinal complaints, tolerance of both compounds has
been similar to that for placebo.42
Dalcetrapib treatment in patients with CHD or at high risk for
developing CHD did not result in any difference (in comparison with placebo) in
arterial plaque measurement by MRI and FDG-positron emission tomography.46 The dal-OUTCOMES trial is comparing the effect of
initiating dalcetrapib and placebo treatment in >15,000 patients following
recent acute coronary events on the risk of recurrent cardiovascular
events.47 The study has no predefined HDL-C
The REVEAL (Randomized EValuation of the Effects of Anacetrapib
Through Lipid-modification) study is currently enrolling an anticipated 30,000
subjects with clinical vascular disease to evaluate the effects of anacetrapib
100 mg daily on cardiovascular outcomes and lipid parameters.48 Results are not expected until 2017 at the
Other therapeutic approaches have not targeted HDL-C per se, but
rather attempted to increase the amount of circulating functional HDL, or
HDL-like particles. Two areas of investigation (infusion therapy and apo AI
mimetics) have been scaled back following disappointing clinical trial
Six weekly infusions of recombinant apo AI Milano to survivors of
myocardial infarction was associated with reduction in atheroma volume as
measured by IVUS, but the treatment proved to be impractical for commercial
development, in part because of hypotension related to difficulty with the
purification process for the recombinant apo AI.49 Reconstituted HDL using wild-type apo AI and
soybean-derived phospholipid showed an insignificant trend toward angio-graphic
plaque regression in coronary disease patients.50
Apo AI Mimetics
Animal models of small peptide apo AI “mimetics” indicated
that oral ingestion or infusion of these synthetic compounds, similar in amino
acid structure to apo AI, improved anti-inflammatory and antioxidative
functionality of HDL.51 However, oral
administration of D-4F to humans with cardiovascular disease resulted in highly
variable plasma concentrations of the peptide and insignificant changes in HDL
function overall. Subsequently, neither intravenous nor subcutaneous treatment
of patients with cardiovascular disease with L-4F, a related mimetic, resulted
in meaningful changes in assays of HDL function.52
To be effective in mitigating cardiovascular risk, the ideal
HDL-directed therapy would increase the amount of functional HDL available to
antagonize lipid deposition, oxidation, inflammation and potential for
thrombosis in the arterial wall. Reversing the epidemiology of low HDL-C has
proven inadequate to ensure coronary risk reduction. Improving measures of HDL
function in human subjects has not been as practical or demonstrable as in
animal models, although statin therapy is a notable exception. The role of
niacin in management of patients with low HDL-C is under reconsideration in
light of recent evidence. Evaluation of dalcetrapib and anacetrapib is now
ongoing, and the case in favor of their use is somewhat bolstered by the
absence of aldosterone-like effects that coincided with the demise of
torcetrapib. Demonstrating the effect of HDL interventions on clinically
relevant outcomes will be necessary to earn CETP inhibitors a place in patient
management. In the meantime, we must consider the possibility that raising
HDL-C is neither sufficient, nor perhaps even necessary, to reduce HDL-mediated
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