New Therapy Update

Anacetrapib: A Potential New Therapy for Dyslipidemia

Lacey B. Robinson, MD* and William H. Frishman, MD

Abstract: Anacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor

currently in Phase III of development as a treatment for those with dyslipidemia and the risk of cardiovascular disease. The agent acts by inhibiting the
CETP, which mediates the transfer of cholesterol esters from high-density
lipoprotein cholesterol (HDL-C) to other lipoproteins. HDL-C has been
inversely linked to cardiac risk and is thus a potential target for decreasing
residual cardiovascular risk, which remains despite aggressive low-density
lipoprotein cholesterol therapy with statin drugs. Anacetrapib has been shown
to raise HDL-C by up to 138% and decrease low-density lipoprotein cholesterol by up to 39% compared with placebo. The HDL-C molecules treated
with anacetrapib have also been shown to retain their function in cholesterol
efflux and reverse cholesterol transport and their anti-inflammatory properties. Unlike the previously tested CETP inhibitor torcetrapib, anacetrapib has
not been shown to elevate blood pressure, alter electrolytes, or cause any significant side effects. Future studies will determine whether these alterations in
the lipid profile decrease the cardiovascular risk of morbidity and mortality. If
these studies show promising results, anacetrapib could become a vital pharmacologic therapy for decreasing cardiovascular risk in patients.
Key Words: anacetrapib, cholesterol ester transfer protein, high-density
lipoprotein, dyslipidemia
(Cardiology in Review 2014;22: 253261)

ardiovascular disease (CVD) is the leading cause of mortality in

the United States accounting for 1 in every 3 deaths.1,2 It is estimated that 82 million adults have one or more forms of CVD. Over
the next 20 years, without changes to our current therapeutic and
preventive modalities, the incidence of CVD will continue to rise and
>40% of adults, or 116 million people, will experience CVD.3 High
levels of low-density lipoprotein cholesterol (LDL-C) and low levels
of high-density lipoprotein cholesterol (HDL-C) are associated with
increased cardiovascular risk.4 Pharmacologic lowering of LDL-C
with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors
(statins) significantly decreases the risk of morbidity and mortality associated with major cardiovascular events.5 However, patients
treated with statins to LDL-C levels <70mg/dL still have a residual
risk of CVD.69
Because this residual risk remains even after statin therapy,
it is important to look at other lipids that play a role in the development of CVD. HDL-C is inversely related to the risk of developing
coronary heart disease (CHD).1014 The Framingham Study showed
that low HDL-C was not only a risk factor for developing CHD but
that it was a stronger risk factor than high LDL-C.15 In a subsequent
analysis of the Framingham Study and 3 other prospective studies,

From the *Department of Medicine, New York Presbyterian-Columbia University

Medical Center, New York, NY; and Department of Medicine, New York
Medical College/Westchester Medical Center, Valhalla, NY.
Disclosure: The authors have no conflicts of interest to report.
Correspondence: William H. Frishman, MD, Department of Medicine, New York
Medical College, Valhalla, NY 10595. E-mail: William_Frishman@nymc.edu.
Copyright 2014 Lippincott Williams & Wilkins
ISSN: 1061-5377/14/2205-0253
DOI: 10.1097/CRD.0000000000000023

it was found that with each 1mg/dL increase in HDL-C, there is a

23% decrease in the risk of developing CHD.12 This evidence makes
HDL-C an attractive target for lipid-modifying therapies that may
reduce the risk of CHD.
Before the advent of cholesteryl ester transfer protein (CETP)
inhibitors, 2 other therapies, niacin and fibrates, were tested in clinical trials in an attempt to raise HDL-C and decrease the risk of CHD.
Fibrates are a class of lipid-modulating therapy capable of raising
HDL-C by acting as peroxisome proliferatoractivator receptor-
agonists.16 Niacin modifies lipids by raising HDL-C levels and lowering LDL-C, total cholesterol, and triglycerides.17 While these therapies are effective in raising the HDL-C level, clinical trials have
yielded mixed results on their ability to decrease the risk of CHD.1823
The Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) found that with each 5mg/dL increase in
HDL-C with gemfibrozil, the risk of CHD decreased by 11%.22
Similarly, the Helsinki Heart Study found that gemfibrozil increased
HDL-C, decreased LDL-C, and led to a 34% decrease in CHD compared with placebo.23 The results of these studies showed promise
for decreasing CHD risk by raising HDL-C, whereas other studies
produced conflicting results. The Bezafibrate Infarction Prevention
(BIP) study showed that bezafibrate increased HDL-C by 18% compared with placebo but failed to decrease the rate of fatal myocardial
infarction (MI), nonfatal MI, or sudden death.19 The FIELD study
showed that although the use of fenofibrate in patients with type 2
diabetes mellitus was able to decrease the rate of total cardiovascular
events, it failed to reduce the rate of coronary events.18 More recently,
the ACCORD study examined the ability of statins used alone compared with a statin plus a fibrate to decrease CHD and CVD death.21
The analysis of 5518 patients showed that the addition of a fibrate
to statin therapy added no additional benefit and did not reduce the
rate of either CHD or CVD. The AIM-High trial,20 the largest trial to
date examining the use of niacin in dyslipidemic patients, examined
3414 patients with LDL-C levels <70mg/dL assigned to either statin
and extended-release niacin or statin alone. The niacin group showed
an increase in HDL-C by an average of 7mg/dL, and a decrease of
LDL-C by an average of 12mg/dL, but failed to decrease the risk of
CHD or CVD. The trial was terminated after 3 years due to lack of
efficacy.20 To date, the trials on fibrates and niacin have failed to give
a clear answer as to whether increasing HDL-C pharmacologically
can reduce CVD risk.
Fueled by the epidemiological evidence of HDL-Cs inverse
relationship to CHD and a discovery of the link between CETP
activity and HDL-C, another class of pharmacologic therapy was
createdthe CETP inhibitors. CETP inhibitors include torcetrapib
(Pfizer, CP-529), dalcetrapib (Hoffmann-LaRoche, JTT-705), evacetrapib (Eli Lilly & Company, LY2484595) and the focus of this articleanacetrapib (Merck & Co., Whitehouse Station, MK-0859).24

HDL-C AND CHOLESTEROL METABOLISM

Lipoproteins, such as LDL-C and HDL-C, are macromolecules composed of lipids and proteins whose function is to transport lipids in the plasma. They are composed of a hydrophobic
core containing cholesteryl esters and triglycerides with a surrounding hydrophilic layer of apolipoproteins (apo), free cholesterol, and phospholipids.25 HDL-C, a small, dense lipoprotein,

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is primarily associated with apo-AI and is largely synthesized in

the liver. LDL-C is primarily associated with apo-B.26 It is proposed that HDL-Cs inverse relationship to the development of
CHD is directly related to its ability to decrease atherosclerosis.
The main mechanism of decreased atherosclerosis is believed to
occur through HDL-Cs pivotal role in reverse cholesterol transport
(RCT).25,2733 Other mechanisms by which HDL-C is antiatherogenic include its anti-inflammatory, antioxidant,34 antithrombotic,35
and anti-infectious properties, and its promotion of improved endothelial function.34,3639
The maintenance of cholesterol in homeostatic balance is an
extremely complex process requiring the transport of cholesterol in
the plasma and synthesis and catabolism of lipoproteins. Apo-B-containing lipoproteins, including LDL-C and very lowdensity lipoproteins (VLDL), are involved in transporting cholesterol from the liver
to peripheral cells. And in opposition, apo-A containing lipoproteins,
primarily HDL-C, are responsible for transporting cholesterol from
the cells in the periphery to the liver for metabolism and excretion
(RCT, as noted earlier).31,32 RCT begins with an efflux of excess
cholesterol from peripheral cells, including macrophage foam cells,
by the membrane transporter ATP-binding cassette transporter-1
(ABCA1).30,31 This ABCA1 is considered a vital component of the
RCT as evidenced by the fact that patients with Tangier disease and
experimental animals with ABCA1 deficiency or dysfunction have
little or no plasma HDL.40 The cholesterol is transferred to the newly
formed but lipid-poor nascent HDL particle. Once inside the HDL-C
molecule, the enzyme lecithin cholesterol acyltransferase converts
the free cholesterol obtained from the peripheral cells into their esterified form. The HDL-C is now mature and can participate in lipid
exchange with other molecules. CETP is a glycoprotein,41,42 which
mediates the exchange of CEs and triglycerides between HDL and
apo-B-containing lipoproteins (LDL-C and VLDL).42,43 The mature
HDL is also capable of accepting free cholesterol and phospholipids.44 When the particle reaches the liver, it can interact with the

SR-B1 receptor for uptake into the liver where the excess cholesterol
can then be catabolized or excreted in the bile (Fig.1).25
Studies in transgenic mice made to overexpress apo-A1 and
in humans infused with apo-A1 and phospholipids showed that these
interventions not only halted the progression of atherosclerosis but
also caused regression of the atherosclerotic plaque.45,46 These data,
coupled with epidemiological data and HDL-Cs potential involvement in multiple beneficial processes and pathways, including RCT,
made the idea of pharmacologically raising HDL-C a promising
treatment for decreasing the risk of CHD.

CHOLESTERYL ESTER TRANSFER PROTEIN

CETP became a target for developing pharmacologic therapies to raise HDL and reduce CHD risk after epidemiological evidence suggested that those with CETP deficiency had high levels of
HDL-C. In 1989, the connection between CETP deficiency and high
HDL-C was discovered in a Japanese family who had a homozygous splice site mutation leading to CETP deficiency and high levels
of HDL-C.47 Other studies in the Japanese not only confirmed that
CETP deficiency was associated with high HDL-C levels but they
also detected multiple other mutations that cause CETP deficiency.48,49
CETP can theoretically function as both proatherogenic and
antiatherogenic depending on its role in cholesterol metabolism. If
CETP transfers cholesterol from LDL-C and VLDL to HDL-C, and
these HDL-C particles are subsequently taken up by the liver and
catabolized, CETP could function as a stimulant of the RCT pathway
and thus serve an antiatherogenic function. However, if cholesterol
esters are preferably transferred to LDL-C or VLDL or if the hepatic
receptors for HDL-C are not properly functioning, the excess cholesterol may be transported back to peripheral cells where it may contribute to atheroma formation.50 Both human and animal studies have
yielded conflicting results regarding the relationship between CETP
activity and CHD risk.

FIGURE 1. Role of cholesteryl ester transfer protein (CETP). CETP mediates the transfer of CE and TG between lipoproteins. The
transfer of CE into apolipoprotein Bcontaining LDL particles contributes to the maturation of VLDL particles to more atherogenic, more readily oxidized LDL particles, which contribute to macrophage foam cell formation. ABCA1, ABCG1, and SR-BI
mediate efflux of cholesterol out of the peripheral macrophage to nascent, pre- HDL, which matures to larger HDL via the
esterification of cholesterol by LCAT. CE indicates cholesterol ester; CETP, cholesteryl ester transfer protein; HDL, high-density
lipoprotein; IDL, intermediate-level density lipoprotein; LCAT, lecithin cholesterol acyltransferase; LDL, low-density lipoprotein;
TG, triglycerides; VLDL, very lowdensity lipoprotein. Reproduced with permission from Gutstein et al.24
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Cardiology in Review Volume 22, Number 5, September/October 2014

CETP is present in humans, nonhuman primates, and rabbits,

but it is absent in most other species, including rodents.51 Studies
performed in rabbits provide the strongest evidence that CETP plays
a role in the formation of atherosclerosis. Rabbits express high levels
of CETP activity and, like humans, are prone to develop diet-induced
atherosclerosis.51 CETP activity can be increased in rabbits by feeding them a high-fat diet.52 CETP inhibition in rabbits has been shown
to raise HDL-C.53 Studies have shown that inhibiting CETP by antiCETP vaccines, antisense oligonucleotides, and molecular CETP
inhibition have all shown the ability to decrease atherosclerosis.5456
Conversely, the evidence from transgenic mice studies is conflicting.
Studies show that mice expressing CETP have altered lipid profiles,
including low HDL-C, and experience increased atherogenesis, especially in the background of dysfunctional LDL-C receptors, suggesting that CETP functions in a proatherogenic role.57,58 Other studies
have suggested that in certain settings, CETP serves an antiatherogenic role.5961 For example, in the db/db mouse model for diabetes
and obesity, the expression of CETP actually prevented the formation
of atherosclerosis.60 One study suggests that although CETP expression lowers HDL-C, it may actually serve a role in promoting RCT in
mice with hypertriglyceridemia.61
In humans, the relationship between CETP activity and CHD
risk is still unclear. Multiple epidemiological studies have been conducted, examining those with genetic variants that lead to CETP
deficiency or decreased activity mimicking the effect of CETP
inhibition. The original analysis of the Honolulu Heart Study,62 the
Ludwigshafen Risk,63 and Cardiovascular Health Study,64 and a
prospective analysis of participants in the Framingham Study and
the VA-HIT Study65 found that low CETP activity was associated
with increased risk of CHD. However, the Framingham Off-spring
Study,66 the Copenhagen City Heart Study,67 the 7-year follow-up of
the Honolulu Heart Study,68 the REGRESS Study,69 and the Womens
Genome Health Study,70 all found the opposite; that low CETP activity is associated with decreased CHD risk. The 7-year follow-up of
the Honolulu Heart Study and one other study showed that low CETP
activity is associated with low CHD risk only when the HDL-C is
>60mg/dL.68,71 A large meta-analysis of 92 studies, which analyzed
data from 113,883 participants, found that those with decreased
CETP activity and high HDL-C had a decreased risk of CVD.72
Other studies have suggested that specific metabolic background determines whether CETP activity is proatherogenic or
antiatherogenic. For example, the EPIC-Norfolk Population Study
suggested that hypertriglyceridemia has the ability to augment the
effect of CETP on CVD risk.73 Another meta-analysis found that
decreased CETP activity raised HDL-C and lowered LDL-C and
resulted in decreased risk of CHD. However, the results of this metaanalysis are difficult to interpret, as the decreased risk of CHD may be
attributable to either the decrease in LDL-C or the increase in HDLC.74 This body of evidence leaves us with no clear-cut understanding
of the relationship between CETP inhibition and CVD risk, but it is
reasonable to assume that the relationship is very complex and can be
altered by a variety of factors, including altered metabolism.

CHOLESTERYL ESTER TRANSFER PROTEIN

INHIBITORS
To date, 3 CETP inhibitors have been tested in humans: torcetrapib, dalcetrapib, and anacetrapib. Torcetrapib and anacetrapib are
3,5-bis-trifluoro-methyl-benzene derivatives and dalcetrapib is a benzenethiol derivative (Fig.2).75

Torcetrapib
The first CETP inhibitor tested in humans was torcetrapib.
Three clinical trials of torcetrapib were conducted: Rating Atherosclerotic Disease Change by Imaging with a New CETP Inhibitor
2014 Lippincott Williams & Wilkins

Anacetrapib Therapy for Dyslipidemia

FIGURE 2. The chemical structures of cholesteryl ester

transfer protein inhibitors. Reproduced with permission from
Smith et al.25
(RADIANCE 1), RADIANCE 2, and the Investigation of Lipid
Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation trial
(ILLUSTRATE). All these studies showed that torcetrapib was able
to raise HDL-C by up to 61% and lower LDL-C by up to 20%. However, they were unable to show any benefit over statin therapy on
reducing or halting the progression of atherosclerotic plaques.7678 A
subsequent large clinical trial, the ILLUMINATE study, showed that
torcetrapib raised HDL-C by 72.1% and lowered LDL-C by 24.9%.
However, there was also a 5.4 mmHg increase in systolic blood
pressure, a decrease in serum potassium, and increases in serum
sodium, bicarbonate, and aldosterone. Most importantly, there was
an increased risk of cardiovascular events and death from all causes
leading to termination of the trial.7980a At the completion of the trial,
it was unknown whether these deleterious effects of torcetrapib were
related to the CETP inhibitors as a class or due to off-target effects
specific to the torcetrapib molecule. Post hoc analyses of the ILLUMINATE trial indicated that the cause of these deleterious effects,
which resulted in increased mortality, was related to off-target
effects. These effects promoted aldosterone and cortisol release and
subsequently caused torcetrapib to act as a pressor.4,81 Torcetrapib
also induced endothelial dysfunction, which contributed to the detrimental cardiovascular outcomes.82 These off-target effects have been
shown to be unrelated to the mechanism of CETP inhibition.82,83 The
mechanism by which these effects occurred is thought to be due to
torcetrapibs activation of L-type calcium channels.84 No other CETP
inhibitors, including anacetrapib or dalcetrapib, have been shown
to function as pressors or to have any effect on serum electrolytes.
80a,81,85,86
The results of the torcetrapib studies also cast doubt about
the functionality of the HDL-C particles after treatment with CETP
inhibitors. The HDL-C particle from torcetrapib-treated patients has
been shown to not only retain functionality but to actually be more
efficient at promoting efflux of cholesterol from peripheral cells
than the HDL-C particles from untreated patients.87,88 Another post
hoc analysis of the ILLUSTRATE trial also found that those with
the highest levels of HDL-C, treated with torcetrapib plus a statin,
demonstrated regression of coronary atherosclerosis.89 Although the
outcome of the torcetrapib trial was disappointing, it is now clear that
its off-target effects are not related directly to CETP inhibition and
there is once again hope for CETP inhibition as a therapy to decrease
CVD risk.

Dalcetrapib
Dalcetrapib was tested in clinical trials through Phase III,
which were terminated in 2012 due to futility. A key safety and
efficacy study of dalcetrapib on endothelial function using brachial
artery flow-mediated vasodilatation, the dal-VESSEL Study, found
that dalcetrapib increased HDL-C by up to 31%, decreased CETP
activity, and found no increases in blood pressure or deleterious
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effects on endothelial function.90 The subsequent safety and efficacy of dalcetrapib on atherosclerotic disease using novel noninvasive multimodality imaging, dal-PLAQUE trial, also found
that dalcetrapib raised HDL-C and halted the progression of atherosclerosis.91 Although these studies eased fears about the adverse
effects of CETP inhibitors, they had yet to demonstrate that the
CETP inhibitors could decrease CVD risk. The large Phase III clinical trial efficacy and safety or dalcetrapib in patients with recent
acute coronary syndromes, the dal-OUTCOMES Study,92 set out
to discover if dalcetrapib could indeed reduce the rate of death from
coronary disease, nonfatal MI, ischemic stroke, unstable angina, or
cardiac arrest with resuscitation. The trial enrolled nearly 16,000
subjects, and those receiving dalcetrapib experienced increases in
their HDL of up to 29%. Unfortunately, the trial was terminated at
the interim analysis due to futility. The dalcetrapib group did not
show any decrease in mortality compared with placebo. The failure
of this trial to demonstrate the ability to reduce CVD mortality begs
the question if dalcetrapib is ineffective or are all CETP inhibitors
ineffective? Only time will tell if other more potent CETP inhibitors,
such as anacetrapib, which raise HDL-C to a significantly higher
degree and simultaneously lower the LDL-C, will be able to successfully decrease CVD risk.

than dosing with low-fat meals. They hypothesized that this phenomenon may be related to the lipophilicity of the molecule and its
solubility. Consistent with previous results, a clinical follow-up study
of a Phase IIb trial found that the terminal half-life of anacetrapib
is 34 weeks and that 85% of steady state can be reached within 2
weeks. This long terminal half-life may be because anacetrapib is
highly lipophilic and may use adipose tissue as a drug depot, as well
as the fact that anacetrapib forms a stable complex with HDL-C and
CETP in the plasma.98

Anacetrapib

Anacetrapib has been tested in multiple Phase I and II clinical

trials to date and is currently undergoing Phase III trials.

The remainder of our discussion will focus on anacetrapibs

development, the unique properties of the drug, its history through
preclinical and clinical trials, and the potential for this therapy.
Anacetrapib is a small-molecule 3,5-bis-trifluoro-methybenzene derivative CETP inhibitor.75 The exact mechanism of action
of anacetrapib has not yet been elucidated, but it is known that
anacetrapib reversibly binds to CETP and mediates the formation
of a complex between HDL-C and CETP to inhibit the transfer of
CEs.93 The structure of anacetrapib was designed through a series
of structure-activity studies examining different substitutions on the
oxazolidinone ring of the 5-aryloxazolidinone system. Ultimately,
these studies led to the development of anacetrapib, which is a potent
inhibitor of CETP capable of raising HDL-C levels in transgenic
mice expressing CETP.25

Pharmacokinetics and Pharmacodynamics of Anacetrapib

The first pharmacokinetic studies performed in rats and rhesus
monkeys show that anacetrapib exhibits low-to-moderate absorption
after oral dosing and has a long half-life of 1224 hours. It is primarily metabolized through a series of CYP34A-oxidative reactions
leading to excretion through the biliaryfecal route.94,95
The first study of anacetrapibs metabolism in humans examined single-dose pharmacokinetics after oral dosing and the impact
of fed and fasted state, food, age, gender, and obesity. Anacetrapib was rapidly absorbed and reached its maximum concentration
approximately 4 hours after dose. The terminal half-life ranged from
9 to 83 hours after dose and was generally shorter in the fasted state.
Steady state was reached after 7 days. Food increases exposure to
anacetrapib, but age, gender, and obesity did not significantly affect
the pharmacodynamic or pharmacokinetic profiles. The data support
that anacetrapib can be dosed once daily. The researchers believed
that the apparent effect of food, especially the fat content in meals,
may be related to the solubility and absorption of anacetrapib.96
A subsequent trial examining the pharmacokinetic and pharmacodynamic profiles of multidoses of anacetrapib in healthy subjects97 also found that a peak maximum concentration was reached
approximately 4 hours after dose, with a long terminal half-life of
6080 hours. Anacetrapib was amenable to once-daily dosing. Once
again, Krishna et al97 found that dosing with meals containing a highfat content affected the exposure of anacetrapib more significantly
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Drug Interactions
It is important to ascertain any potential drug interactions for
new therapies of dyslipidemia. An ideal therapy would have minimal-to-no interactions with other cardiovascular medications. Many
medications are metabolized through the CYP3A system, but anacetrapib does not induce or inhibit CYP3A. Anacetrapib is, however,
a moderately sensitive substrate of CYP3A.99 Co-administration of
anacetrapib with simvastatin or atorvastatin was well tolerated.85,100
Warfarin, which is metabolized by the CYP2C9 system, was not
affected by the co-administration of anacetrapib, nor were digoxin or
diltiazem. Therefore, dosage adjustment was not required.101103

Clinical Trials of Anacetrapib

Phase I
Two double-blind, randomized, placebo-controlled Phase I
clinical trials were conducted to examine the effects of monotherapy
with anacetrapib on lipid levels and blood pressure.104
In the first trial, 50 patients with dyslipidemia defined as
LDL-C of 100190mg/dL were enrolled, and 10 participants were
assigned to each of the following groups: placebo, 10, 40, 150, and
300mg of anacetrapib. Each participant received a once-daily dose
for 28 days with a meal. Serum lipids and lipoproteins were obtained
at baseline, predose, and postdose. There were significant decreases in
LDL-C with anacetrapib doses of 10, 40, 150, and 300mg compared
with placebo. All doses of anacetrapib led to significant increases in
HDL-C levels compared with placebo. The 10mg dose increased the
HDL-C by 41% and the 300mg dose increased the HDL-C by 129%
and the LDL-C decreased by 38%.
The second study was a 2-period crossover study that evaluated the 24-hour ambulatory blood pressure of 22 healthy subjects.
The participants were randomly assigned to receive either placebo
or 150mg of anacetrapib with a low-fat meal daily for 10 days. The
results showed that the 24-hour ambulatory blood pressures were
similar for those on placebo and those receiving anacetrapib (Fig.3).
Anacetrapib was generally well tolerated in both of these clinical trials, and there were no significant abnormalities found on routine laboratory testing, including complete blood count and serum
chemistry, electrocardiogram, and physical examination. No doserelated increases were seen in serum electrolytes.104

Phase II
A Phase II study examined the efficacy and safety of anacetrapib alone versus anacetrapib co-administered with atorvastatin
in patients with dyslipidemia.85 This randomized, double-blind,
placebo-controlled, parallel-group dose-ranging study to assess the
efficacy, safety, and tolerability of anacetrapib enrolled 589 dyslipidemic patients who were then randomized into 10 different treatment
groups. Half of the participants received atorvastatin 20mg daily,
and all the participants were randomized to receive either placebo or
anacetrapib at 10, 40, 150, or 300mg daily for the 8-week duration of
the study. The results of the study found that all doses of anacetrapib
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Anacetrapib Therapy for Dyslipidemia

aspartate aminotransferase, and creatine kinase, which did not appear

to be dose related.85
A follow-up study analyzed safety and efficacy in the 8 weeks
following the treatment period.98 The study found that at 8 weeks
post-treatment, there were persistent decreases in the LDL-C level and
increases in the HDL-C level in those participants treated with anacetrapib, particularly in the higher doses. The study did not detect any differences in blood pressure in any of the treatment arms. However, they did
find isolated nondose-related increases in alanine aminotransferase,
aspartate aminotransferase, and creatine kinase. Eight weeks after drug
discontinuation, those treated with anacetrapib also showed persistent
decrease in CETP activity and increases in CETP mass.97

Phase III

FIGURE 3. Hourly mean systolic, A, and diastolic, B, blood

pressure (SE) over 24h postdose on day 10 after administration of anacetrapib (or matching placebo) in healthy middleaged and elderly people (N = 22). Reproduced with permission from Krishna et al.104
caused significantly lower LDL-C levels and significantly higher
HDL-C levels than placebo at the conclusion of the study. However,
there were no differences in the lipid-altering capacity of the 150
and 300mg doses of anacetrapib. Similarly, all doses of anacetrapib when co-administered with atorvastatin resulted in significantly
greater decreases in LDL-C than placebo and atorvastatin alone. The
increases in HDL-C in co-administration of atorvastatin and anacetrapib were similar to the administration of anacetrapib alone. The
LDL-C lowering and HDL-C raising effects of anacetrapib were
not affected by age, gender, or baseline LDL-C level. However, in
those with triglyceride levels above the median level, the decrease in
LDL-C with anacetrapib was smaller.
Anacetrapib was generally well tolerated. There were no significant changes in serum sodium, potassium, chloride, or aldosterone
levels with the administration of anacetrapib alone or with atorvastatin. There were also no significant changes in blood pressure compared with placebo. The most common adverse events reported were
constipation, diarrhea, dyspepsia, and myalgia. The only laboratory
abnormalities reported were increases in alanine aminotransferase,
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The largest completed Phase III clinical trial to date investigating anacetrapib is the Determining the Efficacy and Tolerability of
CETP Inhibition with Anacetrapib (DEFINE) Study, which aimed
to analyze the safety and efficacy of anacetrapib.105 The randomized,
double-blind, placebo-controlled trial enrolled 1623 subjects with
CHD or at high risk for developing CHD. Subjects were required
to be on a statin drug before study entry and were subsequently
randomized to receive either anacetrapib 100mg or placebo for the
18-month duration of the study. The study primarily aimed to assess
the change in LDL-C from baseline to 24 weeks, as well as the safety
and tolerability of anacetrapib.
The results of the study found that those receiving anacetrapib
had a 39% greater decrease in LDL-C than placebo and a 138% greater
increase in HDL-C than placebo; 17.6% of participants receiving anacetrapib experienced 2 consecutive LDL-C measurements of 25mg/
dL or less. These participants were then discontinued from the study
due to the currently unknown effects of extremely low LDL-C. The
anacetrapib treatment groups also showed a decrease in apo-B by 21%
compared with placebo and an increase in apo-A1 by 44.7% compared
with placebo (Fig.4). Anacetrapib plus a statin showed fewer elevations in liver function tests compared with statin use alone.
There were no changes seen in blood pressure, serum electrolytes, or aldosterone levels throughout the duration of the study.
Anacetrapib was not related to an increased risk of cardiovascular
events, and in fact the data show a 94% positive predictive value
that anacetrapib would not increase all-cause cardiovascular mortality. In contrast to the 8-week safety follow-up of the Phase II trials,
this study found that significantly fewer subjects in the anacetrapib
group had elevations in their alanine aminotransferase and aspartate
aminotransferase levels compared with placebo.105
The next large Phase III study of anacetrapib is the Randomized Evaluation of the Effects of Anacetrapib through Lipid Modification (REVEAL) study that began in 2011 and aims to assess the
effect of treatment with anacetrapib on cardiovascular outcomes
(www.clinicaltrials.gov/ct2/show/NCT01252953). This study aims
to enroll 30,000 participants older than 50 years with at least one of
the following: history of MI, cerebrovascular atherosclerotic disease,
peripheral artery disease, or diabetes with other evidence of symptomatic CHD. The specific cardiovascular outcomes that will be followed include coronary death, MI, and coronary revascularization.
The study is expected to be completed in January 2017.

Dose Selection of Anacetrapib

Before the initiation of Phase III studies, a model-based study
was performed to determine the appropriate dose of anacetrapib.106
Using the model-based approach, they were able to use pharmacokinetic and pharmacodynamic information obtained from Phase I
and IIb studies for varying doses and modes of delivery. The analysis included data from 8 studies and 576 subjects. The results of the
study led to selection of the 100mg dose administered in a hot-melt
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Cardiology in Review Volume 22, Number 5, September/October 2014

FIGURE 4. Changes in cholesterol levels and blood pressure during the DEFINE trial. A, Low-density lipoprotein (LDL) and highdensity lipoprotein (HDL) cholesterol levels in the anacetrapib and placebo groups from baseline to week 76. Horizontal bars indicate standard errors. To convert the values for LDL and HDL cholesterol to millimoles per liter, multiply by 0.02586. B, Systolic
and diastolic blood pressure from baseline to week 76. Boxes indicate the interquartile ranges; the lines within the boxes are
medians. The vertical lines represent 1.5 times the interquartile range (above the upper end of the range and below the lower
end of the range); the short horizontal lines indicate the last data points that fall within 1.5 times the interquartile range. The
dots beyond those lines indicate outliers. Reproduced with permission from Cannon et al.105
extruded tablet for all future Phase III studies. Because the absorption of anacetrapib is affected by meals, they also analyzed the effects
of dietary indiscretion on the effects of anacetrapib. It was found that
the effects of anacetrapib were robust as long as the patients generally adhered to a low-fat diet.106

Safety and Tolerability of Anacetrapib

Due to the failure of the previously tested CETP inhibitor
torcetrapib, the main safety concerns for anacetrapib before human
testing included increased cardiovascular mortality, elevations in
blood pressure, and changes in electrolytes consistent with hyperaldosteronism.79 There has been no evidence that anacetrapib causes an
increase in blood pressure, alterations in electrolytes, or an increase
in aldosterone,85,104,105 and it has been well tolerated in all clinical
studies, without an associated increase in mortality. The most common side effects reported are mild and include constipation, diarrhea,
dyspepsia, and myalgia.85 Further studies will continue to analyze the
safety and side effect profile of anacetrapib, but at this time no major
safety concerns have been identified.

HDL Particle Functionality

Although it is obvious that anacetrapib substantially raises
HDL-C, many have questioned whether or not the HDL-C particles
retain their functional ability. It is important to ascertain the effects
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of pharmacologic CETP inhibition on HDL-C participation in RCT,

change in lipoprotein composition and anti-inflammatory properties.
It has previously been identified that CETP inhibition raises HDLC, raises apo-A1, and also increases the size of HDL-C particles.105
Torcetrapib was shown to cause an increase in cholesterol efflux to
HDL-C particles, showing that the HDL-C molecules not only retain
their function in RCT, but also may have increased functionality.
The increased functionality of the HDL-C molecule was associated
with an increase in apo-E, cholesteryl esters, lecithin cholesterol
acyltransferase.88
A subsequent study of RCT in Syrian golden hamsters
found that anacetrapib promotes not only RCT but also net excretion of cholesterol, indicating that the HDL-C particles treated with
anacetrapib are not only functional, but are more functional than
nontreated HDL-C particles.107 A study examined the effects of
anacetrapib on the change in lipoprotein subfraction concentrations
of 30 subjects treated with variable doses of anacetrapib.108 As was
expected, the results showed that those treated with 150mg of anacetrapib had significant decreases in LDL-C of 26% and apo-B of 29%,
and increases in HDL-C by 82%. The primary increase in HDL-C
was in the very large HDL 2d particles. The decreased LDL-C levels
are due to decreases in the medium and small LDLs. These particles
showed some moderate triglyceride depletion and an increase in
phospholipid content.108 The full clinical impact of these alterations
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Cardiology in Review Volume 22, Number 5, September/October 2014

of lipoprotein subfractions is still unclear, but further clinical studies

examining the cardiovascular impact of anacetrapib treatment may
help to clarify the role of these specific changes.
One of HDL-Cs potential benefits is its protective role against
endothelial inflammation, and thus one must question if HDL-C
particles treated with anacetrapib can retain their anti-inflammatory
properties. A recent in vitro study found that HDL-C from humans
and hamsters treated with anacetrapib was still able to suppress the
inflammatory processes in endothelial cells in vitro.109

CONCLUSIONS
Anacetrapib is a CETP inhibitor that has been shown to safely
and effectively alter the lipid profile by lowering LDL-C by up to 39%
and raising HDL-C by up to 138%. Unlike its predecessor, torcetrapib,
anacetrapib has not been shown to raise blood pressures, alter serum
electrolytes, or raise serum aldosterone.85,98,104,105 Dalcetrapib failed to
show any effect on cardiovascular outcomes. Importantly, anacetrapib
is a unique molecule from dalcetrapib and is a significantly more potent
CETP inhibitor with greater effects on HDL-C and LDL-C.93 Although
anacetrapib clearly alters the lipid profile in a beneficial way, it has yet
to be determined whether or not these alterations will translate into
clinical cardiovascular benefits. The REVEAL study will provide these
answers after its completion in 2017. If shown to be effective, anacetrapib will most likely be used in addition to statins or possibly as
monotherapy in patients who cannot tolerate statins.
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