Best Practice & Research Clinical Endocrinology & Metabolism 28 (2014) 453461

Contents lists available at ScienceDirect

Best Practice & Research Clinical

Endocrinology & Metabolism
journal homepage: www.elsevier.com/locate/beem

12

Emerging therapies for raising high-density

lipoprotein cholesterol (HDL-C) and augmenting
HDL particle functionality
Marcin Barylski, MD, PhD, Assistant Professor of Medicine a,
Peter P. Toth, MD, PhD, Professor of Clinical Family and
Community Medicine b, c, *, Dragana Nikolic, MD, Doctoral
Candidate d, Maciej Banach, MD, Professor of Medicine e,
Manfredi Rizzo, MD, PhD, Professor of Medicine d, f,
Giuseppe Montalto, MD, Professor of Medicine d
a

Department of Internal Medicine and Cardiological Rehabilitation, Medical University of Lodz, Lodz, Poland
CGH Medical Center, Sterling, IL 61081, USA
c
University of Illinois School of Medicine, Peoria, IL, USA
d
Biomedical Department of Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
e
Nephrology and Hypertension, Medical University of Lodz, Zeromskiego 113, 90-549 Lodz, Poland
f
Euro-Mediterranean Institute of Science and Technology, Palermo, Italy
b

Keywords:
apoA-I mimetic
coronary artery disease
delipidation
endothelial lipase inhibitor
farnesoid X receptor
high-density lipoproteins
liver X receptor
reverse cholesterol transport
RVX-208

High-density lipoprotein (HDL) particles are highly complex polymolecular aggregates capable of performing a remarkable range
of atheroprotective functions. Considerable research is being performed throughout the world to develop novel pharmacologic
approaches to: (1) promote apoprotein A-I and HDL particle
biosynthesis; (2) augment capacity for reverse cholesterol transport so as to reduce risk for the development and progression of
atherosclerotic disease; and (3) modulate the functionality of HDL
particles in order to increase their capacity to antagonize oxidation, inammation, thrombosis, endothelial dysfunction, insulin
resistance, and other processes that participate in arterial wall
injury. HDL metabolism and the molecular constitution of HDL
particles are highly complex and can change in response to both
acute and chronic alterations in the metabolic milieu. To date,
some of these interventions have been shown to positively impact
rates of coronary artery disease progression. However, none of
them have as yet been shown to signicantly reduce risk for

* Corresponding author. University of Illinois School of Medicine, Peoria, IL, USA. Tel.: 1 (815) 632 5093; Fax: 1 (815) 626 5947.
E-mail addresses: mbarylski3@wp.pl (M. Barylski), peter.toth@cghmc.com (P.P. Toth), draggana.nikolic@gmail.com (D.
Nikolic), maciejbanach@aol.co.uk (M. Banach), manfredi.rizzo@unipa.it (M. Rizzo), giuseppe.montalto@unipa.it (G. Montalto).
1521-690X/$ see front matter 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.beem.2013.11.001

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M. Barylski et al. / Best Practice & Research Clinical Endocrinology & Metabolism 28 (2014) 453461

cardiovascular events. In the next 35 years a variety of pharmacologic interventions for modulating HDL metabolism and functionality will be tested in large, randomized, prospective outcomes
trials. It is hoped that one or more of these therapeutic approaches
will result in the ability to further reduce risk for cardiovascular
events once low-density lipoprotein cholesterol and non-HDLcholesterol targets have been attained.
2013 Elsevier Ltd. All rights reserved.

Introduction
The high-density lipoproteins (HDLs) are functionally highly versatile and have the capacity to drive
reverse cholesterol transport and exert a variety of other atheroprotective functions [1]. Elevated
serum levels of high-density lipoprotein cholesterol (HDL-C) are highly correlated with reduced risk for
cardiovascular events [24]. Given these data, it is quite logical to ask the question: does raising HDL-C,
increasing HDL particle number, or modulating HDL functionality impact risk for cardiovascular events
and can any of these changes impact the development and progression of atherosclerotic disease?
A variety of post hoc results from clinical trials and a number of meta-analyses suggest that raising
HDL-C does correlate with reductions in both cardiovascular event rates as well as progression of
atherosclerotic disease [57]. Unfortunately, large prospective randomized outcomes trials in patients
with established cardiovascular disease performed with cholesterol ester transfer protein inhibitors
[8,9] and niacin [10,11] failed to demonstrate incremental benet when tested against a background of
statin therapy. These studies have raised serious issues regarding the value of raising HDL-C in
modulating risk in the secondary prevention setting. Despite these setbacks, newer forms of pharmacologic interventions targeted at HDL metabolism and functionality are being developed and tested
at a rapid rate. It is hoped that one or more of these novel approaches will help to reduce residual risk
for cardiovascular events once atherogenic lipoprotein burden in serum is controlled to guidelinedened levels.
Directly augmenting apoA-I and apoA-I/phospholipid complexes
Another approach to increasing serum levels of HDL is by infusing reconstituted HDL (rHDL) or recombinant HDL particles into the circulation, rather than increasing HDL indirectly by modulating HDL
metabolism. One approach uses recombinant apoA-IMilano. Individuals with the apoA-IMilano mutation
(R173C) have low HDL-C levels (1030 mg/dl), and no apparent increased cardiovascular disease (CVD) risk
[12]. Early studies indicated that recombinant apoA-IMilano, when delivered by intravenous infusion,
promotes regression of atherosclerotic lesions to a greater extent than wild type apoA-I as measured by
intravascular ultrasound with 5 once weekly treatments [13]. Procedural difculties complicated the
development of ETC-216 (clinical denomination of apoA-IMilano) and no further clinical trials with this
formulation have been reported [14]. More recently, it was shown that recombinant HDL containing apoAIMilano exerts greater anti-inammatory and plaque stabilizing properties rather than antiatherosclerotic
properties [15]. Another rHDL compound, CSL-111, consists of apoA-I puried from human plasma and
complexed with phosphatidylcholine derived from soybeans. The rst trial of CSL-111 examined the effect
of rHDL in the Atherosclerosis Safety and Efcacy (ERASE) trial conducted in 183 patients with acute
coronary syndrome (ACS) [16]. Four weekly infusions of CSL-111 to 111 individuals randomized to the
40 mg/kg proved to be well tolerated and failed to meet its primary end-point. The high dose regimen
(80 mg/kg) was discontinued because of abnormal liver transaminase elevations. However, there was no
signicant change in atheroma volume, as measured by intravascular ultrasound (IVUS), compared with
the placebo group. Another study investigated the effect of CSL-111 on surrogate cardiovascular marker in
patients following ACS [17]. In this trial 29 patients were randomized to a single infusion of CSL-111
(80 mg/kg over 4 h) or albumin. Following signicant increases of HDL-C (64%) and reductions in lowdensity lipoprotein cholesterol (LDL-C) (23%), human rHDL did not improve vascular function compared to
placebo. A modied version CSL-111 (CSL-112) is currently in phase II trials.

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Delipidated HDL infusions

Another novel approach to HDL therapeutics is to raise levels of HDL particles by intravenous
infusion with the use of autologous delipidated HDL [18]. Preclinical evaluation of selective delipidated
HDL in dyslipidemic monkeys achieved a signicant 6.9% reduction in aortic atheroma volume assessed
by IVUS [19]. The process involves the selective removal of apoA-I HDL particles from plasma, delipidating them, and then reinfusing the cholesterol-depleted functional pre-b HDL. In a human trial, 28
patients with ACS received 5 weekly infusions of delipidated HDL (n 14) or placebo (n 14).
Selectively increasing preb-HDL was associated with decreased total atheroma volume by 5.2% from
baseline. [18] However, it is not yet established whether or not acute regression of atherosclerotic
plaque volume is associated with decreased clinical cardiovascular events. Autologous delipidated HDL
infusions do not induce liver toxicity or hypersensitivity reactions. In the study HDL apheresis resulted
in hypotension in one-third of the participants undergoing treatment. A delipidation system for human
use is now available from Lipid Sciences Plasma Delipidation System-2 (PDS-2), which converts aHDL
to preb-like HDL by selectively removing cholesterol from HDL in samples of plasma collected from
patients by apheresis. This approach remains under investigation.
HDL mimetics
ApoA-I mimetic peptides drugs
ApoAI mimetics are short synthetic peptides that mimic the amphipathic a-helix of apoA-I. The
rst apoA-I mimetic peptide consisted of 18 amino acids (compound 18A). Based on the structure of
18A, additional improved peptides were generated by increasing the number of phenylalanine residues on the hydrophobic face (referred to as 2F, 3F, 4F, 5F, 6F, and 7F) of the polypeptide. [20] Among
them only apoA-I mimetic peptide 4F showed promise in a number of animal models and in early
human trials [21] leading to a phase I/II study in humans with high risk CVD [22]. In this study, the 4F
peptide (synthesized from L-amino acids for L-4F) was delivered at low doses (0.0421.43 mg/kg) by
intravenous or subcutaneous administration [23]. Very high plasma peptide levels were achieved, but
there was no improvement in HDL anti-inammatory function [23]. On the other hand, previous
studies showed that L-4F restores vascular endothelial function in murine models of hypercholesterolemia [24]. In another clinical trial the 4F peptide synthesized from all D-amino acids (making it
resistant to hydrolysis by gastrointestinal peptidases) for D-4F was administered orally at higher doses
(0.437.14 mg/kg). Interestingly, despite very low plasma peptide levels, it was associated with a
signicantly improved HDL inammatory index [22]. In humans with signicant cardiovascular risk, a
single dose of D-4F was found to improve the inammatory index of HDL with modest oral
bioavailability [25].
Given concerns regarding possible cytotoxicity through ABCA1-independent lipid efux, additional
peptide mimetics have been engineered [26]. Peptides comprised of twenty-two amino acids based on
domains of apolipoprotein A-I that have a higher afnity for ABCA1 have been shown to promote
cholesterol efux without cytopathic effects [2628]. Furthermore, such domains are conserved across
other apolipoproteins, and similarly designed peptides from apolipoprotein E promote ABCA1mediated reverse cholesterol transport [29]. 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. The 5A peptide had increased ABCA1-dependent cholesterol efux and decreased
hemolysis compared with its parent compound [30].
ATI-5261 synthetic peptide
Native apoA-I is a 243 amino acid protein that contains multiple a-helical segments repeated in
tandem and separated by proline residues. In vitro, ATI-5261 exerts its effects through ABCA1 in a
fashion similar to that of HDL and successfully enhances cholesterol efux from macrophages and
reduces aortic atherosclerosis by up to 45% after intraperitoneal injection in mice. ATI-526 increases
reverse cholesterol transport in mice [31]. The compound presently awaits early phase clinical trials in
humans.

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Endothelial lipase inhibitors

Endothelial lipase (EL) inhibition may represent potential future therapies to reduce apoA-I
catabolism and to increase plasma apoA-I and HDL-C levels. Human genetic studies have conrmed
that variation of the EL gene is an important determinant of plasma HDL-C level [32]. However, how
changes in HDL-C level attributed to EL may affect atherosclerosis is still not clear. Some human studies
propose an atherogenic role for EL, with a positive association of plasma level of EL mass and coronary
artery calcication [33]. Carriers of EL variants associated with increased HDL-C levels have been reported to have decreased risk of coronary artery disease [34], but this association has not been
observed in other studies [35]. Studies in mice showed that EL overexpression reduces HDL-C and
apoA-I levels [36] due to increased renal catabolism. Conversely, gene deletion of EL results in
increased HDL-C and apoA-I levels [37]. Although EL inactivation was expected to inhibit atherosclerosis by raising HDL-C, the effect of EL inactivation seems more complex than expected. The enthusiasm for EL inhibitors is somewhat tempered by Mendelian randomization data showing that
variations in the gene loci for EL and cholesterol ester transfer protein (CETP) that increase HDL-C are
not associated with protection against the development of atherosclerotic disease and its complications [38].
Lecithin-cholesterol acyltransferase modulators
Several drug development approaches have recently been initiated for modulating lecithincholesterol acyltransferase (LCAT) activity. Early studies for the treatment of atherosclerosis by
raising HDL-C through plasma LCAT enzyme activity were initiated by Zhou et al. in a rabbit model [39].
It was shown that recombinant LCAT administration may represent a novel approach for the treatment
of atherosclerosis and the dyslipidemia associated with low HDL. Intravenous infusion of human rLCAT
in rabbits was found to raise HDL-C, to increase fecal excretion of cholesterol, and to reduce atherosclerosis [40]. Another potential alternative to LCAT injection for treatment of human LCAT deciency
was recently reported in which adipocytes transfected with LCAT were transplanted into mice and
were found to raise HDL-C [41]. Only one LCAT modulator has reached early clinical development, ETC642, but little data are available on the vascular effects of treatment with this agent [42].
Apo A-I upregulator
Reservelogix-208
Reservelogix-208 (RVX-208) is a small molecule that increases endogenous synthesis of apoA-I. In
African green monkeys, oral administration of RVX-208 resulted in increased levels of plasma apoA-I
and HDL-C [43]. Serum from human subjects treated with RVX-208 exhibited increased cholesterol
efux capacity despite a relatively modest increase in HDL-C levels [44]. In a phase II trial, modest
changes in HDL-C and apoA-I were reported in 299 statin-treated patients with stable coronary artery
disease (CAD) [45]. One Phase IIb study is ongoing and involves 172 statin-treated patients randomized
for RVX-208 100 mg or placebo twice daily for 24 weeks [46]. The ASSURE trial investigated the effect of
RVX-208 on coronary atherosclerosis assessed by intravascular ultrasound [47]. The trial was negative
with no demonstrable differences in percent atheroma volume or normalized total atheroma between
patients treated either with placebo or RVX-208.
Synthetic liver X receptor agonists
Synthetic liver X receptor (LXR) agonists including LXRa/b are known to induce the transcription of
ABCA1 and ATP-binding cassette transporter G1 (ABCG1). As potent activators of cellular cholesterol
efux, these compounds have been shown to raise HDL-C levels and to reduce atherosclerosis in
transgenic mouse models [48]. Thus, LXR agonist activation may be a promising pharmacologic target
for the treatment of dyslipidemia and atherosclerosis. Unfortunately, the development of rst generation LXR compounds has been hampered by their capacity to increase expression of lipogenic genes in
the liver, which increase levels of triglycerides and promote hepatic steatosis [49]. Various synthetically engineered LXR agonists have been developed and tested in animal models. They all show high
potency for interacting with LXRa/b receptors, but none of them shows selectivity for ABCA1 and
ABCG1 [49,50]. T091317 is a LXR activator, which consistently decreases atherosclerosis in mouse

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models and induces gene expression of Niemann-Pick C1 (NPC1) and NPC2 in macrophages resulting in
enriched cholesterol content in the outer layer of plasma membranes [51]. The LXR agonist LXR-623 is
associated with increased expression of ABCA1 and ABCG1 in cells [52], but adverse central nervous
system-related effects were noted in more than half of patients, leading to termination of the study
[53]. Other agonists (AZ876 and GW3965) were shown to reduce the number of atherosclerotic lesions
[54]. The LXR agonist GW6340, an intestine specic LXRa/b agonist, promoted macrophage specic
cellular cholesterol efux and increased intestinal excretion of HDL-derived cholesterol [50]. More
recently, a novel synthetic LXR agonist, ATI-111, that is more potent than T0901317, inhibited atherosclerosis progression and prevented atheromatous plaque formation in mice [55]. Research on more
selective LXR ligands is an active area of experimental pharmacology.
Synthetic farnesoid X receptor agonists
The farnesoid X receptor (FXR) is a bile acid-activated nuclear receptor that plays an important role
in the regulation of cholesterol and, more specically, HDL homeostasis [56]. Preclinical studies
showed that activation of FXR leads to both pro- and antiatherosclerotic effects and a major metabolic
effect of FXR agonists in animal models is a reduction of plasma HDL [56,57]. Hambruch et al. showed
that FXR agonists promote HDL-derived cholesterol excretion into feces in mice and monkeys [57]. For
these reasons, FXR agonists have received attention as a potential therapeutic target [58], and different
agonists have been generated as a strategy for HDL-C raising therapies. These include GW4064, 6ECDCA, FXR-450, and PX20606 [57]. GW4064 has potential cell toxicity and uncertain bioavailability
prevents its development for clinical studies [58]. In normolipidemic monkeys treated with PX20606,
HDL2 is decreased without changing apoA-I levels. In these studies, the basic mechanisms of FXR
mediating HDLC clearance are conserved in mice and monkeys. These observations will support further
studies to investigate the potential roles of FXR activation on HDL metabolism and speciation.
Gene therapy
Animal experiments with apoA-I transgenes have yielded benecial results for the prevention of
atherosclerosis [59,60]. To date, this approach has little application in man. Animal data supports novel
Table 1
Summary of selected strategies to increase HDL/apoA-I and potential compound under development.
Pharmacotherapeutic strategy

Drug

Aim

Recombinant apoA-I
Milano/phospholipids
Puried native apoA-I/phospholipids
Upregulators of endogenous apoA-I
production
ApoA-I mimetic peptides

ETC-216

Directly augmenting apoA-I/HDL pool

CSL-111 and CSL 112

RVX-208

Directly augmenting apoA-I/HDL pool

Directly augmenting apoA-I/HDL pool

D-4F
L-4F
ATI-5261
Selective HDL delipidated
miR-33

Mimicking apoA-I functionality

Autologous delipidated HDL

Gene therapy
Liver X receptor agonists

Niacin receptor agonists

Farnesoid X receptor
Cholesteryl ester transfer inhibitors
Endothelial lipase inhibition
LCAT activators

LXRa/b agonists
LxR-623
T0901317, GW3965
ATI-111
ARI-3037MO
FxR-450
Anacetrapib MK-0859
Evacetrapib LY248595
Boronic acid inhibitors
Selective sulfonylfuran urea
rLCAT
ETC-642

Directly augmenting apoA-I/HDL pool

Modulating HDL levels and
cholesterol efux expression
Enhancing RCT & Macrophage
cholesterol efux

Indirectly augmenting apoA-I and

HDL-cholesterol
Modulate HDL levels
Indirectly augmenting apoA-I and
HDL-cholesterol
Increasing HDL-cholesterol
Enhancing RCT

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gene-based approaches to increase HDL-C. A potential mechanism to increase of HDL-C is increasing

ABCA1 and ABCG1 expression through the therapeutic manipulation of microRNA metabolism (inhibition of miR-33 being the most promising candidate to date). Overexpression of antisense miR-33
using a lentivirus vector in mice showed a 50% increase in hepatic ABCA1 protein levels and a
concomitant 25% increase in plasma HDL levels after 6 days [61]. Marquart et al. showed that injection
of an anti-miR-33 oligonucleotide in mice resulted in a substantial increase in ABCA1 expression and
HDL levels [62]. Furthermore, it was shown in mice that miR-33 decreases cholesterol efux [63]. These
data suggest that miR-33 might be a possible target for the treatment of cardiovascular and metabolic
disorders. Table 1 summarizes selected strategies to increase HDL/apoA-I and describes potential
compounds under development.
Conclusion
Unlike the path taken to therapeutically modulate LDL-C levels, that for HDL-C has turned out to be
much more difcult and complicated. Two CETP inhibitors, RVX-208, and multiple other agents have
failed in clinical trials. Is the apparent protectiveness of HDL-C suggested by epidemiology simply an
epiphenomenon? Is it possible that the exceptional complexity of HDLs proteome and lipidome really
have little bearing on the structural and functional integrity of arterial walls? It is hoped that these and
many other questions concerning HDL therapeutics will be answered in the years ahead with the
innovative approaches summarized herein. In the meantime, we will await the results of clinical trials
testing the ability of these various agents to impact rates of atherosclerotic disease progression and risk
for cardiovascular events.

Practice points
At the present time, HDL-C is not a target of therapy.
The HDL hypothesis (i.e., that raising HDL-C, HDL particles, or modulating HDL functionality
impacts risk for CV events) is a matter of intensive investigation.
A variety of new pharmacologic interventions are being developed that:
1. Increase serum HDL particle concentration by infusing autologous delipidated HDL, human
native apoA-I and apoA-I(Milano) incorporated into liposomes, and apoA-I mimetics.
2. The regulation of RCT is being studied by agonizing nuclear transcription factors (LXR-alpha
and FXR) and modulating the activity of enzymes responsible for HDL metabolism in serum
(LCAT, CETP, endothelial lipase).
Gene therapy is being tested in a murine model to evaluate the safety and efcacy of an
antisense molecule to miR-33. Antisense technology is already being used in humans to treat
familial hypercholesterolemia with mipomersen, an antisense oligonucleotide directed against
the mRNA for apoprotein B.

Research agenda
HDL particles are highly heterogeneous with diverse lipid and protein cargos. It will be
important to establish:
1. How specic HDL interventions impact both the serum concentration of HDL particles and
their functionality.
2. If functionality is greatly increased, is it even necessary to robustly elevate serum levels of
HDL?

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3. If specic functions (e.g., RCT, anti-oxidative capacity) are augmented or even adversely
affected despite elevations in serum levels of HDL?
4. Long-term safety of these agents in humans.
5. Whether or not they can safely be used in combination with other lipid modifying drugs such
as the statins or brates
6. The impact of specic agents on rates of atherosclerosis disease progression and cardiovascular events (myocardial infarction, ischemic stroke, death, need for coronary and peripheral
revascularization) will have to be assessed in large prospective outcomes and imaging trials.

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