Bempedoic Acid (ETC-1002): an Investigational Inhibitor of ATP Citrate Lyase
Curr Atheroscler Rep
Bempedoic Acid (ETC-1002): an Investigational Inhibitor of ATP Citrate Lyase
Ozlem Bilen 0 1 2 3
Christie M. Ballantyne 0 1 2 3
0 Cardiology, Department of Medicine, Baylor College of Medicine , Houston, TX , USA
1 Cardiovascular Research, Department of Medicine, Baylor College of Medicine , Houston, TX , USA
2 Christie M. Ballantyne
3 Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart and Vascular Center , Houston, TX , USA
Bempedoic acid (ETC-1002), a novel therapeutic approach for low-density lipoprotein cholesterol (LDL-C) lowering, inhibits ATP citrate lyase (ACL), an enzyme involved in fatty acid and cholesterol synthesis. Although rodent studies suggested potential effects of ACL inhibition on both fatty acid and cholesterol synthesis, studies in humans show an effect only on cholesterol synthesis. In phase 2 studies, ETC-1002 reduced LDL-C as monotherapy, combined with ezetimibe, and added to statin therapy, with LDL-C lowering most pronounced when ETC-1002 was combined with ezetimibe in patients who cannot tolerate statins. Whether clinically relevant favorable effects on other cardiometabolic risk factors such as hyperglycemia and insulin resistance occur in humans is unknown and requires further investigation. Promising phase 2 results have led to the design of a large phase 3 program to gain more information on efficacy and safety of ETC-1002 in combination with statins and when added to ezetimibe in statin-intolerant patients.
ETC-1002; Low-density lipoprotein cholesterol
Cardiovascular disease (CVD) is a major health problem
and the leading cause of mortality and morbidity
worldwide . Alterations in lipid and lipoprotein
metabolisms play an important role in pathogenesis of CVD.
Low-density lipoprotein cholesterol (LDL-C)–lowering
with statins inhibits progression of coronary
atherosclerosis and reduces cardiovascular mortality and morbidity
]. However, a large number of individuals still do
not take high-efficacy doses of statins and continue to
have elevated levels of LDL-C [
]. One of the major
reasons for the lack of adherence to high- or
moderatedose statin therapy as recommended in the guidelines is
the concern of both patients and physicians about
adverse events with high-efficacy statins. The most
common adverse events of statins are muscle-related adverse
events, which range from myalgia to rare, but
lifethreatening, rhabdomyolysis [
], followed by
asymptomatic elevation in hepatic transaminases [
recent evidence suggests that high-dose statins may
increase the risk of developing type 2 diabetes [
Although such side effects are rare, they reduce patient
compliance and medication adherence. Despite the
proven benefits and wide availability of statins, because of
their dose-dependent side effect profile, a considerable
proportion of patients with elevated cholesterol fail to
achieve guideline-recommended targets [
underlines the importance of developing alternative
cholesterol-lowering therapies with good efficacy and
tolerability beyond statins.
Bempedoic acid (ETC-1002) is one such novel
cholesterollowering drug. It is an inhibitor of adenosine triphosphate
(ATP) citrate lyase (ACL), a cellular enzyme responsible for
production of precursors for fatty acid and cholesterol
synthesis. ETC-1002 effectively reduces LDL-C and
apolipoprotein (apo) B–containing lipoproteins [
]. In this article,
we will review the cardiometabolic effects of ETC-1002 and
the underlying proposed mechanism of action in the light of
the most recent evidence.
ETC-1002 Mechanism of Action and Pharmacology
ACL is an important enzyme with significant effects on fatty
acid and cholesterol metabolism. It is a cytosolic enzyme
highly expressed in lipogenic tissues such as the liver and
white adipose tissue [
] and is positioned upstream from
HMG-CoA reductase in the mammalian cholesterol
biosynthesis pathway [Fig. 1]. It links energy metabolism from
carbohydrates to the production of fatty acids through catalyzing
acetyl CoA synthesis, the fundamental substrate for the
biosynthesis of both fatty acids and cholesterol [
13, 14, 15
crucial role in lipid biosynthesis makes ACL a potential target
for lipid-lowering intervention. Historically, several compounds
have proven capable of inhibiting ACL in vitro, including
(2),(2),2,2 difluorocitrate, several benzonesulfonamides, and the
naturally occurring compound hydroxycitrate. Nevertheless,
their development as pharmacologic agents has been limited
due to poor ability to cross cell membranes, poor affinity for
ACL, and poor specificity leading to undesirable inhibition of
other essential enzymes in vivo. Among several ACL inhibitors
that were tested, ETC-1002
(8-hydroxy-2,2,14,14tetramethylpentadecaned–ioic acid; bempedoic acid) is in the
most advanced stage of clinical development and has improved
bioavailability and specificity compared with earlier compounds.
It is a novel, oral, once-daily, small molecule with a half-life of
15–24 h. It is rapidly absorbed in the small intestine, and,
importantly, the cell surface receptors through which this molecule
enters the liver are different from statin transporters, thus there
is no competitive liver uptake with statins [
]. ETC-1002 itself
is a prodrug, which is converted to an active metabolite
(ETC1002–CoA) by endogenous liver acyl-CoA synthetase activity,
which then inhibits ACL [Fig. 1]. By inhibiting cholesterol
synthesis in the liver, ETC-1002 induces upregulation of the LDL
] and stimulates the uptake of LDL particles by the
liver, which contributes to reductions of LDL-C levels in the
]. In addition, because the prodrug is converted to the
active drug specifically in the liver, theoretically this may avoid
potential adverse muscle effects as seen with inhibition of
cholesterol by statins in muscle. Although the precise mechanism of
statin-induced myopathy is not agreed upon, cerivastatin had the
highest systemic exposure (including muscle tissue) of all
approved statins and the highest rate of myopathy. In animal
studies, inhibition of ACL also led to reductions in fatty acids and
Initial animal experiments showed that, in addition to
inhibiting ACL, ETC-1002 also activates AMP-activated
protein kinase (AMPK), a master kinase that regulates whole
body energy metabolism and inhibits fatty acid and
cholesterol synthesis pathways by inhibiting HMG-CoA reductase and
acetyl-CoA carboxylase, the rate-limiting enzymes for
cholesterol and fatty acid synthesis, respectively [
]. In a mouse
model of diabetes and obesity, ETC-1002 improved hepatic
steatosis; lowered plasma non-high-density lipoprotein
cholesterol (non-HDL-C), triglycerides, and free fatty acids; and
lowered glucose levels and improved glucose intolerance
. In addition, in human monocyte-derived macrophages
treated with ETC-1002, it was shown that increased levels of
AMPK phosphorylation reduced production of
proinflammatory cytokines and chemokines . Further, in a mouse
model of diet-induced obesity, ETC-1002 restored adipose AMPK
activity, reduced JNK phosphorylation, and diminished
expression of macrophage-specific marker 4F/80. These data
were consistent with decreased epididymal fat-pad mass and
interleukin-6 release by inflamed adipose tissue . Based
on these studies, it was proposed that ETC-1002 may have
potential benefits on systemic inflammation, glycemic control
parameters, insulin resistance, and vascular complications of
To date, ETC-1002 has been studied in more than 10
clinical trials across different patient populations [Table 1].
Although rodent studies suggested potential effects of ACL
inhibition with ETC-1002 on both fatty acid and cholesterol
synthesis, the clinical profile in humans shows an effect on
cholesterol synthesis with no effect on fatty acid metabolism.
Moreover, as discussed later in this article, although clinical
studies showed a reduction in high-sensitivity C-reactive
protein (hs-CRP) with ETC-1002, overall, there was a neutral
effect on other cardiometabolic parameters such as weight,
glucose metabolism, insulin resistance, and blood pressure,
indicating that the effect of ETC-1002 on AMPK activation
in humans is likely not clinically relevant.
Another important approach to gain further insights into
the effects of ACL inhibiton in humans would be to examine
the association between genetic variants and metabolic
parameters and cardiovascular outcomes in large epidemiological
studies as has been done recently for a number of potential
targets for lipoprotein metabolism.
Phase 1 Studies
A first-in-human, phase 1a single-dose clinical trial,
ETC1002-001  evaluated safety, tolerability, and
pharmacokinetics of ETC-1002 in 18 healthy subjects. Similarly,
ETC1002-002  was a staged 2-week and 4-week phase 1b
multiple dose tolerance clinical trial in 53 subjects, with 39
receiving ETC-1002 and 23 receiving placebo. The subjects
were divided into four different cohorts of six subjects with
each receiving 20, 60, 100, or 120 mg of ETC-1002 or
placebo once daily for 14 days. This was followed by studying
a larger cohort that was treated for 28 days during which
subjects lived outside of the clinical site for the duration of
their treatment. ETC-1002 was safe, well tolerated, and
associated with no dose-limiting side effects.
Finally, ETC-1002-004  was a 2-week, phase 1b,
multiple dose tolerance clinical trial in 24 subjects, of whom 18
received ETC-1002. This clinical trial was designed to
evaluate the safety and tolerability of escalating, multiple oral doses
of ETC-1002 above 120 mg/day. Subjects in this clinical trial
received 140, 180, or 220 mg of ETC-1002 or placebo once
daily for 14 days. LDL-C levels were reduced by an average
of 36 % for subjects receiving 220 mg/day of ETC-1002 as
compared to a 4 % increase for subjects receiving placebo
(p < 0.0001). No serious adverse events were observed in the
subjects dosed with ETC-1002. ETC-1002 was safe, well
tolerated, and associated with no dose-limiting side effects.
Phase 2 Studies
ETC-1002 as Monotherapy in Patients with Hypercholesterolemia
The first phase 2 study, ETC-1002-003 [26 ], was a 12-week
phase 2a proof-of-concept study in 177 patients, of whom 133
were treated with ETC-1002, across 11 participating clinical
recruitment sites in the USA. This clinical study was designed
to evaluate the LDL-C–lowering efficacy and safety of
ETC1002 versus placebo in patients with hypercholesterolemia
(LDL-C of 130 to 220 mg/dL) and either normal triglycerides
(less than 150 mg/dL) or elevated triglycerides (150 to 400 mg/
dL). The four arms were placebo and 40-, 80-, and 120-mg
protein kinase (AMPK) activation. ACL ATP citrate lyase, Acetyl-CoA
acetyl coenzyme A, HMG-S HMG-CoA synthase, HMG-R HMG-CoA
doses of ETC-1002 once daily. LDL-C levels were reduced
by an average of 18, 25, and 27 % for patients treated with
ETC-1002 40, 80, and 120 mg, respectively, compared with
an average of 2 % for patients treated with placebo
(p < 0.0001). ETC-1002’s lowering of LDL-C levels was
maintained across a range of baseline triglyceride levels. ETC-1002
also lowered levels of the atherogenic biomarkers apo B,
nonHDL-C, and LDL particle number (p < 0.0001) in a
dosedependent manner. Patients treated with ETC-1002
demonstrated a trend in hs-CRP reduction of 20 to 26 % compared with
2 % in patients treated with placebo. In a subgroup of patients
with elevated hs-CRP, patients treated with ETC-1002
demonstrated a trend in hs-CRP reduction of 43 to 64 %, compared
with a decrease of 7 % in patients treated with placebo.
ETC-1002-005  was a 4-week phase 2a
proof-ofconcept clinical study at a single site that was designed to
evaluate the LDL-C–lowering efficacy and safety of
ETC1002 in patients with type 2 diabetes. One treatment arm
was placebo and the other was 80 mg of ETC-1002 once daily
for 2 weeks followed by 120 mg of ETC-1002 once-daily for
2 additional weeks. LDL-C levels after 4 weeks of treatment
with ETC-1002, which was the primary endpoint, were
reduced by an average of 43 % in patients receiving the
120mg dose of ETC-1002, compared with an average of 4 % in
patients receiving placebo (p < 0.0001). Approximately 80 %
of the patients were not at their National Cholesterol
Education Program Adult Treatment Panel III LDL-C goal
of less than 100 mg/dL at the beginning of the study. Of these,
88 % of the patients treated with ETC-1002 achieved their
goal by study end as compared with 4 % of patients treated
with placebo (p < 0.0001). Levels of hs-CRP were reduced by
41 % with the 120-mg dose of ETC-1002 versus 11 % with
placebo (p = 0.001). Non-HDL-C decreased by 32 % in
Dose range (mg)
Up to 17 %
Up to 27 %
Up to 36 %
patients treated with ETC-1002 as compared with an increase
of 1 % in patients treated with placebo (p < 0.0001). A 24-h
continuous glucose monitoring assessment showed a
nonsignificant trend of improved glycemic control with
ETC1002 treatment. Overall, 24-h ambulatory blood pressure
monitoring showed no differences between treatment groups
in mean changes from baseline to day 28.
Finally, ETC-1002-014  was a 6-week, multicenter,
randomized, double-blind, placebo-controlled, parallel group
phase 2 study that evaluated the safety and efficacy of
ETC1002 versus placebo in 143 patients with both
hypercholesterolemia and hypertension. After washout of any
lipidmodifying and blood pressure therapies, 71 patients received
ETC-1002 180 mg and 72 patients received placebo.
ETC1002-treated patients achieved LDL-C lowering of 21 % at
6 weeks, compared with an increase in LDL-C of 3 % in the
placebo group (p < 0.0001). The reduction occurred within the
first 2 weeks of initiating therapy and continued throughout
the treatment period. Levels of hs-CRP were reduced by 25 %
with ETC-1002, compared with an increase of 20 % in the
placebo group (p < 0.0001). ETC-1002 had a neutral effect on
blood pressure and was safe and well tolerated. Despite
effective LDL-C lowering with ETC-1002, HDL-C and
triglyceride levels were unchanged across all treatment arms in these
studies. No serious adverse events were observed in patients
treated with ETC-1002. ETC-1002 was safe, well tolerated,
and associated with no dose-limiting side effects.
ETC-1002 Added on a Background of Statin Therapy in Patients with Hypercholesterolemia
ETC-1002-007  was an 8-week phase 2a clinical study in
58 patients, of whom 42 were treated with ETC-1002, across
six clinical recruitment sites in the USA. For the primary
endpoint of number of subjects with adverse events, clinical lab
abnormalities, and other safety findings, ETC-1002 as an
addon to 10 mg of atorvastatin was well tolerated and did not result
in any serious adverse events. Although the trial was not
designed to assess LDL-C lowering with ETC-1002, this was
measured as a secondary endpoint to determine whether
incremental LDL-C lowering would occur with ETC-1002 added on
a background of statin therapy. In patients on a background of
atorvastatin, ETC-1002 reduced LDL-C levels by an average of
22 versus 0 % change with placebo (p < 0.0001).
ETC-1002-009  was a double-blind, parallel-group,
placebo-controlled multicenter trial that evaluated 134 patients
with baseline LDL-C of 115–220 mg/dL while taking
atorvastatin ≤20 mg, simvastatin ≤20 mg, rosuvastatin ≤10 mg, or
pravastatin ≤40 mg randomized to receive ETC-1002 120 mg,
ETC-1002 180 mg, or placebo once daily for 12 weeks.
ETC1002 lowered LDL-C by up to 24 % (p < 0.0001), significantly
more than placebo, as an add-on to statin therapy. ETC-1002
also lowered (p < 0.05) apo B, non-HDL-C, and total
cholesterol levels and LDL particle number by more than placebo.
Nonsignificant reductions in hs-CRP were observed with
ETC1002 120 mg (22 %, p = 0.26) and 180 mg (30 %, p = 0.08)
versus 0 % with placebo. No significant changes in HDL-C or
triglyceride levels were observed in either study. Adverse
events, muscle-related adverse events, discontinuations due to
adverse events, and levels of clinical safety labs were generally
similar compared with placebo.
Overall, the LDL-C–lowering effect of ETC-1002 added
on background statin therapy appeared to be less pronounced
as compared to ETC-1002 monotherapy. This is likely due to
the overlapping mechanism of action of both drugs [Fig. 1].
Whether the additive cholesterol-lowering effect of ETC-1002
would be less with higher dose background statin therapy will
require further investigation in phase 3 studies.
ETC-1002 as Monotherapy and in Combination with Ezetimibe in Patients with Statin Intolerance
ETC-1002-006  was an 8-week phase 2a proof-of-concept
clinical study in 56 patients, of whom 37 were treated with
ETC-1002, across five clinical recruitment sites in the USA.
This clinical study was designed to evaluate the
LDL-C–lowering efficacy, tolerability, and safety of ETC-1002 versus
placebo in patients with hypercholesterolemia and a history of
intolerance to one or more statins, defined as new myalgia,
muscle cramps, muscle aches, or muscle weakness that
developed during statin treatment and resolved or markedly
improved of muscle symptoms within 4 weeks of statin
discontinuation. After completing a washout of lipid-lowering therapy
and 2 weeks of treatment with placebo, eligible patients were
randomized to receive ETC-1002 or placebo in a 2:1 ratio for
8 weeks. Patients were given either increasing doses of
ETC1002 of 60, 120, 180, and 240 mg for 2 weeks each or placebo
only for the full 8 weeks. The primary endpoint of this clinical
study was LDL-C lowering from baseline to end of study.
LDLC levels after 8 weeks of treatment with ETC-1002 were
reduced by an average of 32 % in patients treated with ETC-1002,
compared with an average of 3 % in patients treated with
placebo (p < 0.0001). Drop-out rates and muscle-related adverse
events were comparable between ETC-1002 and placebo, and
no patients treated with ETC-1002 discontinued the trial
because of muscle-related adverse events. hs-CRP levels were
reduced by 42 % after 8 weeks of ETC-1002 therapy versus
0 % on placebo (p = 0.0022). No significant changes in HDL-C
or triglyceride levels were observed.
ETC-1002-008 [32 ] was a phase 2b study of the treatment
of elevated LDL-C levels in approximately 348 patients either
with (n = 177) or without (n = 171) statin intolerance across 70
clinical sites in the USA. The purpose was to assess the dose
response of ETC-1002, directly compare the
LDL-C–lowering efficacy of ETC-1002 versus ezetimibe, and assess safety
and tolerability, including muscle-related adverse events, in
patients with or without statin intolerance, defined as inability
to tolerate two or more statins because of muscle pain,
weakness, or cramping that began or increased during statin therapy
and resolved with statin discontinuation, including at least one
statin at the lowest approved daily dose (rosuvastatin 5 mg,
atorvastatin 10 mg, simvastatin 10 mg, lovastatin 20 mg,
pravastatin 40 mg, fluvastatin 40 mg, pitavastatin 2 mg) or less.
With a parallel-group design and 12-week duration,
ETC1002-008 compared two doses of ETC-1002 (120 and
180 mg) with ezetimibe, a common treatment in patients with
statin intolerance. The LDL-C–lowering efficacy of
ETC1002 in combination with ezetimibe was also assessed. In
patients receiving ETC-1002 monotherapy, compared with
patients receiving ezetimibe monotherapy, significantly
greater LDL-C lowering of up to 30 % was observed. LDL-C
reduction occurred within the first 2 weeks of treatment and
was sustained over the treatment period. ETC-1002 lowered
LDL-C similarly in both statin-intolerant and statin-tolerant
patients. Lowering of atherogenic lipids and lipoproteins
was consistent with LDL-C lowering. Significantly more
hsCRP lowering of up to 40 % was seen with ETC-1002
compared with ezetimibe. In patients receiving both ETC-1002
and ezetimibe, LDL-C lowering of up to 48 % was observed
and the combination appeared to be safe and well tolerated.
HDL-C decreased with ETC-1002 treatment by up to 6 % and
increased with ezetimibe alone by 5 % (p < 0.0001 to p < 0.05
for ETC-1002 groups vs. ezetimibe alone). In patients treated
with ETC-1002, including those with statin intolerance, there
were no increases in muscle-related adverse events as
compared with ezetimibe.
Overall, ETC-1002 and ezetimibe in combination seems to
be a safe and effective regimen in patients with statin
intolerance. Long-term studies are needed to assess the effect of this
combination on cardiovascular outcomes.
Currently, available results of clinical trials suggest that
bempedoic acid (ETC-1002) may represent a novel
therapeutic approach for LDL-C lowering. In seven phase 2 studies
which randomized a total of 977 participants of whom 669
received active drug, ETC-1002 has been shown to reduce
LDL-C as monotherapy, combined with ezetimibe, and added
to statin therapy, with LDL-C lowering most pronounced
when ETC-1002 was combined with ezetimibe in patients
with a history of statin intolerance. Although rodent studies
had suggested potential effects of inhibition of ACL on both
fatty acid synthesis and cholesterol synthesis, the clinical
profile in humans is consistent with a major effect on cholesterol
synthesis but not on fatty acid synthesis. Whether clinically
relevant favorable effects on other cardiometabolic risk factors
such as hyperglycemia and insulin resistance occur in humans
is unknown and requires further investigation in studies that
are primarily designed to test such effects. The current results
on efficacy and tolerability have led to the design of a large
phase 3 program to gain more information on both efficacy
and safety in combination with statins and also when added to
ezetimibe in statin-intolerant patients.
Compliance with Ethical Standards
Conflict of Interest Ozlem Bilen declares no conflict of interest.
Christie M. Ballantyne declares consultant fees, grants, and research
support from Esperion, paid to her institution, during the conduct of the
study; she also declares grants, research support, and/or consultant fees
from Amarin, Amgen, Eli Lilly, Otsuka, Novartis, Pfizer, Regeneron,
Sanofi-Synthelabo, Takeda, National Institutes of Health, American
Heart Association, and American Diabetes Association; she also declares
consultant fees from AstraZeneca, Ionis, Genzyme, Matinas BioPharma,
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
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Papers of particular interest, published recently, have been
Of major importance
1. Kolansky DM. Acute coronary syndromes: morbidity, mortality, and
pharmacoeconomic burden. Am J Manag Care. 2009;15:S36–41.
2. Wiviott SD , Cannon CP , Morrow DA , et al. Can low-density lipoprotein be too low? The safety and efficacy of achieving very low low-density lipoprotein with intensive statin therapy: a PROVE ITTIMI 22 substudy . J Am Coll Cardiol . 2005 ; 46 : 1411 - 6 .
3. Schwartz GG , Olsson AG , Ezekowitz MD , et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial . JAMA . 2001 ; 285 : 1711 - 8 .
4. de Lemos JA , Blazing MA , Wiviott SD , et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial . JAMA . 2004 ; 292 : 1307 - 16 .
5. Virani SS , Woodard LD , Akeroyd JM , et al. Is high-intensity statin therapy associated with lower statin adherence compared with lowto moderate-intensity statin therapy? Implications of the 2013 American College of Cardiology/American Heart Association Cholesterol Management Guidelines . Clin Cardiol . 2014 ; 37 : 653 - 9 .
6. Harper CR , Jacobson TA . The broad spectrum of statin myopathy: from myalgia to rhabdomyolysis . Curr Opin Lipidol . 2007 ; 18 : 401 - 8 .
7. Alberton M , Wu P , Druyts E , et al. Adverse events associated with individual statin treatments for cardiovascular disease: an indirect comparison meta-analysis . QJM . 2012 ; 105 : 145 - 57 .
8. Culver AL , Ockene IS , Balasubramanian R , et al. Statin use and risk of diabetes mellitus in postmenopausal women in the Women's Health Initiative . Arch Intern Med . 2012 ; 172 : 144 - 52 .
9. Wong ND , Chuang J , Zhao Y , Rosenblit PD . Residual dyslipidemia according to low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B among statin-treated US adults: National Health and Nutrition Examination Survey 2009-2010 . J Clin Lipidol . 2015 ; 9 : 525 - 32 .
10. Gao F , Zhou YJ , Hu da Y , et al. Contemporary management and attainment of cholesterol targets for patients with dyslipidemia in China . PLoS One . 2013 ; 8 : e47681 .
11. Lemus HN , Mendivil CO . Adenosine triphosphate citrate lyase: emerging target in the treatment of dyslipidemia . J Clin Lipidol . 2015 ; 9 : 384 - 9 . Review of the function of ACL and its clinical implications .
12. Wang Q , Li S , Jiang L , et al. Deficiency in hepatic ATP-citrate lyase affects VLDL-triglyceride mobilization and liver fatty acid composition in mice . J Lipid Res . 2010 ; 51 : 2516 - 26 .
13. Daikuhara Y , Tsunemi T , Takeda Y. The role of ATP citrate lyase in the transfer of acetyl groups in rat liver . Biochim Biophys Acta . 1968 ; 158 : 51 - 61 .
14. Ameer F , Scandiuzzi L , Hasnain S , et al. De novo lipogenesis in health and disease . Metabolism . 2014 ; 63 : 895 - 902 .
15. Groot PHE , Pearce NJ , Gribble AD . ATP-citrate lyase: a potential target for hypolipidemic intervention . Curr Med Chem Immunol Endocr Metab Agents . 2003 ; 3 : 211 - 7 . Review of the role of ACL in lipogenesis .
16. Esperion Therapeutics . Understanding key pathways . Available at: http://www.esperion.com/ourpathways-approach/understandingkey-pathways/. Accessed 20 January 2016 .
17. Berkhout TA , Havekes LM , Pearce NJ , Groot PH . The effect of (-)- hydroxycitrate on the activity of the low-density-lipoprotein receptor and 3-hydroxy-3-methylglutaryl-CoA reductase levels in the human hepatoma cell line Hep G2 . Biochem J . 1990 ; 272 : 181 - 6 .
18. Hamilton JG , Sullivan AC , Kritchevsky D. Hypolipidemic activity of (-)-hydroxycitrate . Lipids . 1977 ; 12 : 1 - 9 .
19. Pearce NJ , Yates JW , Berkhout TA , et al. The role of ATP citratelyase in the metabolic regulation of plasma lipids . Hypolipidaemic effects of SB-204990 , a lactone prodrug of the potent ATP citratelyase inhibitor SB-201076 . Biochem J. 1998 ; 334 (Pt 1): 113 - 9 .
20. Pinkosky SL , Filippov S , Srivastava RA , et al. AMP-activated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism . J Lipid Res . 2013 ; 54 : 134 - 51 .
Hanselman JC , Bradshaw CD , Brant AF , et al. ETC -1002 reduces circulating and hepatic triglyceride content and improves glycemic control in KKAy mice (abstract 657) . Presented at ATVB Scientific Sessions 2011 , Chicago, IL, 28 - 30 April 2011 .
Filippov S , Pinkosky SL , Lister RJ , et al. ETC -1002 regulates immune response, leukocyte homing, and adipose tissue inflammation via LKB1-dependent activation of macrophage AMPK . J Lipid Res . 2013 ; 54 : 2095 - 108 .
Esperion Therapeutics I. Form 10-K - Annual report United States Securities and Exchange Commission. 10 March 2015 . Available a t : h t t p : / / w w w. s e c . g o v / A r c h i v e s / e d g a r / d a t a / 1 4 3 4 8 6 8 /000104746915001908/0001047469-15-001908-index.htm.
Accessed 20 January 2016 .
ClinicalTrials.gov. A multiple ascending dose study of ETC-1002 in subjects with mild dyslipidemia . Available at: https://clinicaltrials.
gov/ct2/show/NCT01105598. Accessed 20 January 2016 .
ClinicalTrials.gov. A multiple ascending dose study of ETC-1002 in healthy subjects . Available at: https://clinicaltrials.gov/ct2 /show/NCT01485146. Accessed 20 January 2016 .
Ballantyne CM , Davidson MH , Macdougall DE , et al. Efficacy and safety of a novel dual modulator of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase in patients with hypercholesterolemia: results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial . J Am Coll Cardiol . 2013 ; 62 : 1154 - 62 . First phase 2 trial which studied LDL-C-lowering efficacy and safety of ETC-1002 versus placebo in patients with hypercholesterolemia .
Gutierrez MJ , Rosenberg NL , Macdougall DE , et al. Efficacy and safety of ETC-1002, a novel investigational low-density lipoprotein-cholesterol-lowering therapy for the treatment of patients with hypercholesterolemia and type 2 diabetes mellitus .
Arterioscler Thromb Vasc Biol . 2014 ; 34 : 676 - 83 .
ClinicalTrials.gov. Evaluation of ETC-1002 in patients with hypercholesterolemia and hypertension . Available at: https://clinicaltrials.
gov/ct2/show/NCT02178098. Accessed 20 January 2016 .
ClinicalTrials.gov. A study of the safety, pharmacokinetic drug interaction and efficacy of ETC-1002 and atorvastatin in subjects with hypercholesterolemia . Available at: https://clinicaltrials.gov/ct2 /show/study/NCT01779453. Accessed 20 January 2016 .
Ballantyne CM , Macdougall DE , Margulies JR , et al. ETC -1002 incrementally lowers low density lipoprotein-cholesterol in patients with hypercholesterolemia receiving stable statin therapy [abstract 17499] . Circulation. 2015 ; 132 : A17499 .
Thompson PD , Rubino J , Janik MJ , et al. Use of ETC-1002 to treat hypercholesterolemia in patients with statin intolerance . J Clin Lipidol . 2015 ; 9 : 295 - 304 .
Thompson PD , Macdougall DE , Newton RS , et al. Treatment with ETC-1002 alone and in combination with ezetimibe lowers LDL cholesterol in hypercholesterolemic patients with or without statin intolerance . J Clin Lipidol . 2016 ; 10 : 556 - 67 . Study showed that LDL-C lowering was most pronounced when ETC-1002 was combined with ezetimibe in patients with a history of statin intolerance .