Author + information
- Received February 20, 2013
- Revision received April 23, 2013
- Accepted May 14, 2013
- Published online September 24, 2013.
- Christie M. Ballantyne, MD∗,†∗ (, )
- Michael H. Davidson, MD‡,
- Diane E. MacDougall, MS§,
- Harold E. Bays, MD‖,
- Lorenzo A. DiCarlo, MD§,
- Noah L. Rosenberg, MD§,
- Janice Margulies, MS§ and
- Roger S. Newton, PhD§
- ∗Department of Medicine, Baylor College of Medicine, Houston, Texas
- †Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart and Vascular Center, Houston, Texas
- ‡Pritzker School of Medicine, University of Chicago, Chicago, Illinois
- §Esperion Therapeutics, Inc., Plymouth, Michigan
- ‖Louisville Metabolic and Atherosclerosis Research Center, Louisville, Kentucky
- ↵∗Reprint requests and correspondence:
Dr. Christie M. Ballantyne, Department of Medicine, Baylor College of Medicine, 6565 Fannin Street, Suite A656, MS A601, Houston, Texas 77030.
Objectives The aim of this study was to assess the lipid-altering efficacy and safety of ETC-1002 in subjects with hypercholesterolemia.
Background ETC-1002 is a small molecule that modulates pathways of cholesterol, fatty acid, and carbohydrate metabolism and may have therapeutic benefits in treating hypercholesterolemia and other cardiometabolic risk factors.
Methods This multicenter, randomized, double-blind, placebo-controlled, parallel-group trial evaluated patients (n = 177) with elevated low-density lipoprotein cholesterol (LDL-C) (130 to 220 mg/dl), who were stratified by baseline triglycerides (not elevated [<150 mg/dl] or elevated [150–<400 mg/dl]) and randomized to receive 40, 80, or 120 mg of ETC-1002 or placebo once daily for 12 weeks. Outcomes included changes in LDL-C (primary endpoint), other lipids, and cardiometabolic risk factors; and safety.
Results ETC-1002 40, 80, and 120 mg lowered least-squares mean ± SE LDL-C levels by 17.9 ± 2.2%, 25.0 ± 2.1%, and 26.6 ± 2.2%, respectively, versus a reduction of 2.1 ± 2.2% with placebo (all, p < 0.0001); LDL-C lowering was similar between the subgroups with nonelevated and elevated triglycerides. ETC-1002 also lowered non–high-density lipoprotein cholesterol (non–HDL-C), apolipoprotein B, and LDL particle number (all, p < 0.0001) in a dose-dependent manner; HDL-C and triglyceride levels were relatively unchanged. Post-hoc analyses suggest that ETC-1002 may have favorable effects on other cardiometabolic risk factors. The ETC-1002 and placebo groups did not demonstrate clinically meaningful differences in adverse events or other safety assessments.
Conclusions ETC-1002 significantly lowered LDL-C levels up to 27% across a broad range of baseline triglycerides and was generally safe and well tolerated. ETC-1002 has a novel mechanism of action and may be useful for reducing LDL-C. (A Study to Assess the Efficacy and Safety of ETC-1002 in Subjects With Elevated Blood Cholesterol and Either Normal or Elevated Triglycerides; NCT01262638)
Epidemiological studies, Mendelian genetic disorders, genome-wide association studies with more common genetic variants, and clinical trials have clearly established low-density lipoprotein cholesterol (LDL-C) as the major target for lipid-modifying therapy. Statins are the standard of care, supported by a large body of data demonstrating robust effectiveness in lowering LDL-C and in reducing the risk for cardiovascular disease (1,2). However, many individuals at risk for cardiovascular disease fail to achieve LDL-C goals (3,4). Only a relatively few number of alternative, nonstatin agents have been approved for lowering LDL-C levels, and their LDL-C–lowering efficacy is modest. Therefore, physicians and their patients are looking for additional therapeutic options.
ETC-1002 (8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid) is currently in Phase II clinical development, primarily to treat hypercholesterolemia, with early support for potentially favorable effects on other cardiometabolic risk factors, such as insulin sensitivity, inflammatory markers, and blood pressure. ETC-1002 modulates two distinct and complementary molecular targets: 1) hepatic adenosine triphosphate-citrate lyase (ACL) and 2) adenosine monophosphate-activated protein kinase (AMPK) (5). Inhibition of ACL by ETC-1002 rapidly reduces levels of acetyl coenzyme A (CoA) (5), the final common substrate for both fatty acid and sterol synthesis, at a point in the lipid synthesis pathway well upstream of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase—the molecular target of statins. In a manner complementary to the effects of ACL, activation of AMPK results in inhibitory phosphorylation of acetyl-CoA carboxylase and HMG-CoA reductase (5). ETC-1002, via effects at multiple points within the lipid-synthesis pathway, inhibits sterol and fatty acid synthesis and increases mitochondrial long-chain fatty acid oxidation. Furthermore, ETC-1002–mediated AMPK activation also improves glucose regulation (5). In animal models, ETC-1002 improved plasma cholesterol and triglycerides; hepatic fat; inflammatory markers; glycemic control; blood pressure; and, notably, atherosclerosis (5–8). Phase I human studies of single-dose tolerability up to 250 mg and multiple-dose tolerability up to 220 mg/day (n = 77) revealed no dose-limiting adverse effects, and the drug was generally well tolerated (data on file). The aim of this first Phase II clinical trial was to evaluate the lipid-altering efficacy and safety of a range of doses of ETC-1002 in individuals with hypercholesterolemia with or without elevated triglyceride levels. Subgroup analyses were also performed regarding other cardiometabolic risk factors.
Between December 2010 and August 2011, this randomized, double-blind, placebo-controlled, parallel-group trial (NCT01262638) was conducted at 11 sites in the United States. The four treatment arms included ETC-1002 40, 80, and 120 mg and placebo once daily for 12 weeks. Clinic visits were conducted at weeks –6 (required only for those washing out of lipid-altering drugs), –2, –1, 0, 2, 4, 8, and 12. The protocol and informed-consent document were approved by the appropriate institutional review boards, the study was conducted according to the guidelines for Good Clinical Practice, and study participants underwent the informed-consent process prior to the conduct of any study-related procedures.
Study participant inclusion and exclusion criteria
Eligibility criteria included men and naturally post menopausal or surgically sterile women age 18 to 80 years with qualifying LDL-C (130 to 220 mg/dl) and triglycerides (<400 mg/dl) and a body mass index between 18 and 35 kg/m2. Lipid value qualification was determined following a 6-week washout of all lipid-altering drugs and supplements, with the baseline LDL-C and triglyceride values being the means of measurements obtained on two separate visits prior to randomization. Eligible subjects were then stratified, based on triglyceride level, into “not elevated” (<150 mg/dl) and “elevated” (150 to <400 mg/dl) triglyceride strata, and were then randomized to receive, with equal probability (1:1:1:1), ETC-1002 40, 80, or 120 mg or matching placebo once daily for 12 weeks.
Exclusion criteria included a history of diabetes mellitus, clinically significant cardiovascular disease, systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥95 mm Hg, clinically significant liver disease or dysfunction, alanine aminotransferase/aspartate aminotransferase >2 × the upper limit normal (ULN) or total bilirubin >1.5 × ULN, clinically significant renal dysfunction (including calculated creatinine clearance <60 ml/min), unexplained creatine kinase >3 × ULN, or a hematologic or coagulation disorder (including hemoglobin <12 g/dl).
The primary endpoint was the percent change in LDL-C level from baseline to week 12 in each ETC-1002 dose group versus placebo. Secondary endpoints were percent changes in non–high-density lipoprotein cholesterol (non–HDL-C), apolipoprotein (apo)B, LDL particle number, total cholesterol, triglycerides, HDL-C, apoA1, HDL particle number, lipoprotein(a), free fatty acids, and high-sensitivity C-reactive protein (hsCRP). Post-hoc endpoints were changes in fasting insulin, diastolic and systolic blood pressure, and hsCRP.
Lipid and lipoprotein efficacy parameters and safety laboratory tests were performed after 12-hour overnight fasts (water only). Medpace Reference Laboratories (Cincinnati, Ohio), which maintained Part III certification by Centers for Disease Control and Prevention (CDC) Lipid Standardization Program (9) and accreditation by the College of American Pathologists (10), was the central laboratory that performed the analyses. Triglycerides and cholesterol were measured with enzymatic colorimetric tests (Olympus AU2700 or AU5400 Analyzer, Olympus, Center Valley, Pennsylvania), with calibration directly traceable to CDC reference procedures. ApoB-containing lipoproteins were precipitated with dextran sulfate, and HDL-C was measured on the supernatant (11). The Friedewald formula (12) was used to calculate LDL-C unless triglycerides were >400 mg/dl, in which case it was measured after preparative ultracentrifugation (beta quantification) (13). Non–HDL-C was calculated by subtracting HDL-C from total cholesterol. ApoA1, ApoB, lipoprotein(a), and hsCRP were measured with rate immunonephelometry (Dade Behring BNII nephelometer, Siemens Healthcare Diagnostics, Deerfield, Illinois). Lipoprotein particle number was measured using proton nuclear magnetic resonance spectroscopy (LipoScience, Inc., Raleigh, North Carolina) (14). Free fatty acids were measured using an enzymatic photometry assay (Wako Chemicals USA, Inc., Richmond, Virginia) adapted to a Randox Daytona instrument (Randox, Ltd., Crumlin, United Kingdom). Homocysteine was measured on an Olympus analyzer using an enzymatic photometry assay (Diazyme Laboratories, Poway, California), and insulin was measured on an Elecsys_E170 analyzer using an electrochemiluminescence immunoassay (Roche Diagnostics Corporation, Indianapolis, Indiana). Investigators were blinded to lipid, apo, and hsCRP values after subjects were randomized and dosing was commenced.
Safety was assessed by reported adverse events; physical examination, including vital sign measurement, electrocardiogram readings, weight, and ankle circumference measurements; and clinical laboratory testing for safety parameters, including hematology, blood chemistry, and urinalysis. Blood pressure was measured in duplicate 3 minutes apart after the patient had been sitting quietly for 5 minutes. The relationships between study drug and adverse events were assessed by the investigator, with consideration of temporal association and other potential etiologies.
This proof-of-concept study was designed to assess the lipid-altering effects of ETC-1002 and to explore additional parameters that may merit investigation in future clinical studies. The primary endpoint was the percent change in LDL-C level from baseline to week 12 in each ETC-1002 dose group versus placebo in the modified intent-to-treat (mITT) population, which was assessed within and across each triglyceride stratum using an analysis of covariance (ANCOVA) model, with the effects of treatment and baseline values as covariates to generate least-squares means and p values. The mITT population was defined as all randomized subjects who received at least one dose of study medication with at least one before- and after-baseline assessment using the last-observation-carried-forward approach, excluding assessments taken more than 2 days after last dose of study medication. All statistical testing was 2-sided and conducted at the 5% level of significance, with no adjustment for multiple comparisons. A sample size of 176 subjects was selected to provide 80% power to detect a 20% change in LDL-C in each ETC-1002 treatment group within each triglyceride stratum (n = 22) versus placebo, assuming an SD of 21% and a dropout rate of 10%. Assessment of secondary endpoints (non–HDL-C, apoB, LDL-C particle number, total cholesterol, triglycerides, HDL-C, apoA1, HDL particle number, lipoprotein[a], free fatty acids, and hsCRP) and post-hoc analyses (fasting insulin, diastolic and systolic blood pressures, and hsCRP [in a relevant subgroup only]) were assessed as with the primary endpoint, except that post-hoc analyses were completed in relevant subgroups rather than by triglyceride stratum. All statistical procedures for the primary and secondary endpoints were pre specified prior to database lock and unblinding; post-hoc analyses were designed following initial data review and should be viewed as exploratory. Data for those secondary and post-hoc endpoints that were found to have been not normally distributed based on graphical assessment and the Shapiro-Wilk test (triglycerides, apoA1, lipoprotein[a], hsCRP, and fasting insulin in all subjects only, and free fatty acids) were summarized with medians and then assessed using a nonparametric analysis (rank ANCOVA with p values obtained from the Cochran-Mantel-Haenszel test). Analyses were performed using SAS software version 9.1.3 (SAS Institute Inc., Cary, North Carolina) run in a Windows XP (Microsoft Corporation, Redmond, Washington) environment. Safety analyses included all subjects receiving at least one dose of study medication, and adverse events were coded using the Medical Dictionary for Regulatory Activities version 13.1.
Study subject disposition and baseline demographics
The study subject disposition is summarized in Figure 1. Of the 177 individuals randomized, 15% (n = 26) discontinued prior to completion of the trial, most commonly due to an adverse event. Among randomized subjects, the mean age was 57 years, and the body mass index was 28 kg/m2. Subjects were mostly white (86%), and almost half were women (45%). Patient characteristics across treatment groups (Table 1) and triglyceride strata were generally similar, with the exception of baseline lipid parameters, which, as expected, differed across triglyceride strata (nonelevated/elevated triglyceride strata: LDL-C, 161 ± 21/172 ± 26 mg/dl; triglycerides, 103 ± 30/215 ± 56 mg/dl; HDL-C, 57 ± 13/47 ± 10 mg/dl) (data not shown).
Primary endpoint and other efficacy endpoints
Regarding the primary endpoint, ETC-1002 decreased LDL-C levels in a dose-dependent manner (Table 2, Fig. 2). Within the overall study population, LS mean ± SE percent changes from baseline to week 12 were –17.9 ± 2.2%, –25.0 ± 2.1%, and –26.6 ± 2.2% in the ETC-1002 40-, 80-, and 120-mg treatment groups, respectively, compared with –2.1 ± 2.2% in the placebo group (all, p < 0.0001 vs. placebo). ETC-1002 similarly reduced LDL-C levels at all doses (all, p < 0.05) across the nonelevated- and elevated-triglyceride strata (Fig. 2). Maximum LDL-C lowering appeared to have occurred within 2 weeks (the first post-treatment assessment) and was maintained for the remainder of the trial (Fig. 2). ETC-1002 reductions in LDL-C were accompanied by similar reductions in non–HDL-C, apoB, and LDL particle number at all dose levels (all, p < 0.0001 vs. placebo). ETC-1002 numerically decreased triglycerides and increased HDL parameters; however, these changes were neither consistently statistically significant nor dose related. ETC-1002 also numerically reduced hsCRP at all doses, but these changes were not statistically significant.
Other cardiometabolic risk factors
A post-hoc, exploratory analysis evaluated the effects of ETC-1002 on fasting insulin, diastolic blood pressure, and hsCRP (Table 3). In all subjects, treatment with ETC-1002 had minimal effect on fasting insulin. However, in the subgroup of subjects with elevated baseline fasting insulin ≥12 μIU/ml, ETC-1002 40 mg (p = 0.005) and 80 mg (p = 0.03) significantly reduced fasting insulin levels. The ETC-1002 40- and 80-mg groups trended toward a decrease in diastolic blood pressure of 2.5 mm Hg in all subjects and 5 to 6 mm Hg in a small subgroup with mildly elevated baseline diastolic blood pressure (≥80 mm Hg). ETC-1002 had a similar effect on systolic blood pressure, though lesser in magnitude (data not shown). The magnitude of change in hsCRP was also greater in subjects with elevated hsCRP (≥2 mg/l) at baseline. In that subgroup, treatment with ETC-1002 lowered hsCRP by 43% to 63.5% versus a 7.0% reduction with placebo.
ETC-1002 was generally safe and well tolerated in this trial (Table 4). Approximately three-fourths of subjects experienced at least one adverse event during the 12-week treatment period, with headache being the most common. Myalgia was reported in 4%, 5%, and 7% of subjects in the ETC-1002 40-, 80-, and 120-mg treatment groups, respectively, and in none of the placebo-treated subjects. Further investigation of the seven ETC-1002 subjects reporting myalgia showed that a single subject receiving 80 mg of ETC-1002 was withdrawn from the trial due to this adverse event, whereas all other subjects completed 12 weeks of treatment. None of the individuals reporting myalgia experienced concurrent creatine kinase elevations >2 × ULN.
A minority of subjects (from 7% to 9% across treatment groups, including placebo) discontinued trial participation due to one or more adverse events, which included abdominal discomfort, abdominal pain, and muscle tightness in the ETC-1002 40-mg group; gastroesophageal reflux disease, nausea, elevated alanine aminotransferase, elevated aspartate aminotransferase, arthralgia, myalgia, and headache in the 80-mg group; abdominal distension, nausea, arthralgia, headache, and pollakiuria in the 120-mg group; and flatulence, pain, arthralgia, gouty arthritis, muscle spasms, headache, hyperesthesia, and somnolence in the placebo group. Approximately one-third of subjects in the trial experienced at least one adverse event that was considered by the investigator to have been related to the study medication, with the lowest rate (32%) in the ETC-1002 120-mg group and the highest rate (39%) in the placebo group; none of the adverse events considered related to the study medication appeared to have demonstrated a dose-related trend. Adverse events considered by the investigator to have been related to the study medication included abdominal discomfort, abdominal distension, abdominal pain, diarrhea, dyspepsia, nausea, asthenia, increased energy, fatigue, increased blood creatine kinase, abnormal red blood cell count, arthralgia, muscle spasms, muscle tightness, musculoskeletal stiffness, myalgia, dizziness, headache, milia, and macular rash in the ETC-1002 40-mg group; anemia, visual impairment, diarrhea, gastroesophageal reflux disease, nausea, vomiting, urinary tract infection, decreased hematocrit, increased hepatic enzyme, increased international normalized ratio, abnormal prothrombin level, decreased white blood cell count, arthralgia, myalgia, dizziness, dysgeusia, headache, nightmare, cough, and rash in the 80-mg group; abdominal distension, abdominal pain, upper abdominal pain, constipation, dental discomfort, dyspepsia, nausea, fatigue, hunger, pain, increased blood creatine kinase, increased gamma-glutamyltransferase, arthralgia, muscle spasms, pain in extremity, headache, paraesthesia, pollakiuria, pruritus, papular rash, and inadequately controlled blood pressure in the 120-mg group; and abdominal discomfort, upper abdominal pain, diarrhea, dyspepsia, flatulence, nausea, vomiting, peripheral edema, pain, weight increase, arthralgia, gouty arthritis, muscle spasms, postural dizziness, headache, hyperesthesia, somnolence, sleep disorder, and dyspnea in the placebo group. No deaths occurred during the study, and a single serious adverse event (chest pain) occurred in a placebo-treated subject.
Assessment of laboratory results for clinically significant trends showed few differences. In the ETC-1002 groups, mean uric acid was increased by 7% to 16%. Increases in mean homocysteine (ULN: 15 μmol/l) appeared to have been dose related (absolute mean changes ± SD with ETC-1002 40, 80, and 120 mg and placebo: +1.3 ± 2.1, +1.9 ± 1.8, +2.4 ± 2.2, and +0.2 ± 1.3 μmol/l, respectively) (data not shown). Mean hemoglobin was also decreased (absolute mean changes ± SD: –0.3 ± 0.5, –0.5 ± 0.6, –0.6 ± 0.6, and –0.1 ± 0.7 g/dl), with no corresponding changes in white blood cells or platelets (data not shown). Other safety measures (electrocardiography, vital signs, weight, ankle circumference, and other parameters measured on physical examination) did not demonstrate any apparent differences between ETC-1002 and placebo (data not shown).
ETC-1002 is an investigational drug that inhibits sterol and fatty acid synthesis and promotes mitochondrial long-chain fatty acid oxidation through modulation of hepatic ACL and AMPK (5). This study was the first Phase II study of ETC-1002 in hypercholesterolemic individuals with or without elevated triglyceride levels. After 12 weeks, ETC-1002 significantly lowered LDL-C levels up to 27% (placebo reduced LDL-C levels 2%), irrespective of normal to elevated baseline plasma triglyceride levels. The reduction in LDL-C with ETC-1002 was accompanied by similar reductions in non–HDL-C, apoB, and LDL particle number. Post-hoc analyses suggested that ETC-1002 may have the potential to reduce hsCRP, blood pressure, and fasting insulin in certain subgroups. ETC-1002 was generally safe and well tolerated in the subject population.
Cardiovascular disease remains the leading cause of death in the United States (15), and its burden is expected to increase as the population ages and medical costs rise (16). It has been projected that although the prevalence of cardiovascular disease is expected to grow approximately 10% by 2030, its direct medical costs (in 2008 dollars) will triple (16). In order to alter the projected course of cardiovascular disease, improved prevention and early intervention to treat established risk factors are needed (16). Statins will remain central to this strategy; however, there is increasing awareness of the limitations and cautions of statin use. In 2011, the U.S. Food and Drug Administration (FDA) mandated safety-labeling changes limiting the use of high-dose (80 mg) simvastatin due to safety concerns of muscle injury or myopathy (17). Although myopathy is rare, a more widespread problem is various muscular side effects, such as pain and weakness, particularly at high doses, resulting in poor tolerability and a lack of persistence with statin therapy (18). Recently, more subtle side effects of statin therapy, including an increased risk for diabetes (19), particularly at higher doses (20), prompted the FDA to mandate additional safety-labeling warnings (21).
Other than statins, few drugs have been approved for lowering LDL-C, and their efficacy is modest. This Phase II study suggests that ETC-1002 may reduce LDL-C levels more than currently approved nonstatin agents. For example, ezetimibe is an intestinal cholesterol absorption inhibitor that has been reported to lower LDL-C by 18% in patients with primary hyperlipidemia (22). Colesevelam is a bile acid sequestrant that has been reported to lower LDL-C by up to 18% (23), whereas extended-release niacin doses up to 2 g have been reported to lower LDL-C by up to 17% (24). Finally, fenofibrate, a peroxisome proliferator-activated receptor alpha activator, was reported to lower LDL-C levels by approximately 20% in patients with hypercholesterolemia (25) but may substantially increase LDL-C levels in patients with hypertriglyceridemia.
The blunting of the LDL-C lowering found with fibrate administration in patients with hypertriglyceridemia (25) is in contrast to the modest changes in triglyceride levels with ETC-1002 in patients with higher triglyceride levels, highlighting distinct differences in the metabolic effects of these lipid-regulating compounds. The median percent changes from baseline in triglycerides were –14.5%, –12.5%, and +1.5% in the ETC-1002 40-, 80-, and 120-mg treatment groups, respectively, versus –5.5% in the placebo group, with no significant differences in efficacy in the subgroup with elevated baseline triglycerides (data not shown). The limited triglyceride lowering with ETC-1002 observed in the current study is different from the data from some preclinical experiments (5); this difference may be due to the relatively minor role of de novo fatty acid synthesis in affecting plasma triglyceride levels in humans (26).
Assessment of the effect of ETC-1002 on nonlipid cardiometabolic risk factors in this study was limited because entry criteria required well-controlled blood pressure and an absence of diabetes mellitus. ETC-1002 lowered insulin levels in a subgroup with baseline levels ≥12 μIU/ml (a cut point for identifying insulin resistance in patients without diabetes mellitus) (27). Similarly, ETC-1002 lowered hsCRP among subjects with baseline hsCRP levels ≥2 mg/l (a cut point for identifying increased cardiovascular-disease risk (28). Finally, ETC-1002 demonstrated a trend toward blood pressure reduction among those with higher blood pressure readings at baseline. The efficacy and safety of ETC-1002 in combination with statins and other lipid-regulating drugs were not tested in this trial and are currently unknown; these will be assessed in future clinical trials.
ETC-1002 treatment was not associated with serious side effects and had a profile that was similar to placebo in terms of the number of subjects with any AE, serious AEs, AEs that were considered related to treatment, and withdrawals due to AEs. Many common AEs were also similarly distributed across all treatment groups, including placebo. Although an increase in homocysteine was observed, the magnitude of change with ETC-1002 appears to be about half (29) of that seen with fenofibrate, and the increase was not accompanied by a corresponding increase in creatinine or reduction in triglycerides, as would be expected with the use of a fibrate.
This study included relatively few subjects, who were treated for only 3 months with ETC-1002. Subjects with severe diseases were excluded. Comprehensive characterization of the safety and efficacy of ETC-1002 will require additional studies.
These results suggest that ETC-1002 monotherapy may be a novel therapeutic approach for LDL-C lowering that may provide efficacy in lowering atherogenic lipoproteins greater than that of currently available nonstatin therapies. The effects of ETC-1002 on other cardiometabolic risk factors merit investigation in future studies.
The authors thank all ETC-1002 Investigators, their staff, and all patient volunteers. The authors also appreciate the statistical and technical contributions of Scott McBride from United BioSource Corp. and Mark Milad from Milad Pharmaceutical Consulting.
This trial was funded by Esperion Therapeutics, Inc. Dr. Ballantyne has received grant/research support (all paid to institution, not individual) from Abbott, Amarin, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Genentech, Merck, Novartis, Roche, Sanofi-Synthelabo, Takeda, NIH, ADA, and AHA; has served as a consultant for Abbott, Adnexus, Amarin, Amgen, Bristol-Myers Squibb, Cerenis, Esperion, Genentech, GlaxoSmithKline, Idera, Kowa, Merck, Novartis, Omthera, Pfizer, Resverlogix, Roche, Sanofi-Synthelabo, and Takeda; has served on the Speakers' Bureau for Abbott and GlaxoSmithKline; and has received honoraria from Abbott, Adnexus, Amarin, AstraZeneca, Bristol-Myers Squibb, Cerenis, Esperion, Genentech, GlaxoSmithKline, Idera, Kowa, Merck, Novartis, Omthera, Resverlogix, Roche, Sanofi-Synthelabo, and Takeda. Dr. Davidson has received a research grant support from Abbott; has served as a consultant for Amgen, AstraZeneca, Merck, and The sanofi-aventis Group; and holds stock options in Omthera. Dr. Bays has received research grant support from Amarin, Amgen, Ardea, Arena, Boehringer-Ingelheim, Cargill, California Raisin Board, Esperion, Essentialis, Forest, Gilead, Given, GlaxoSmithKline, High Point, Hoffman-La Roche, Home Access, Johnson & Johnson, Merck, Micropharma, Novartis, Novo Nordisk, Omthera, Orexigen, Pfizer, Pozen, Proctor and Gamble, Shionogi, Stratun Nutrition, Takeda, TransTech, Trygg, TWI Bio, Vivus, WPU, and Xoma; and has served as a consultant and/or speaker for Amgen, Amarin, Bristol-Myers Squibb, Daiichi-Sankyo, Eisai, Merck, Novo Nordisk, and Vivus. Drs. Newton and Rosenberg, Ms. MacDougall, and Ms. Margulies are employees of Esperion. Dr. DiCarlo has served as a consultant for Esperion.
- Abbreviations and Acronyms
- adenosine triphosphate-citrate lyase
- adenosine monophosphate-activated protein kinase
- high-density lipoprotein cholesterol
- high-sensitivity C-reactive protein
- low-density lipoprotein cholesterol
- modified intent-to-treat
- upper limit of normal
- Received February 20, 2013.
- Revision received April 23, 2013.
- Accepted May 14, 2013.
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