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 Sep 24;62(13):1154-62. doi: 10.1016/j.jacc.2013.05.050. Epub 2013 Jun 13.


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).

Keywords: ACL; AMPK; HDL-C; LDL-C; ULN; adenosine monophosphate-activated protein kinase; adenosine triphosphate-citrate lyase; apo; apolipoprotein; cardiovascular disease; high-density lipoprotein cholesterol; high-sensitivity C-reactive protein; hsCRP; low-density lipoprotein cholesterol; mITT; modified intent-to-treat; prevention; risk factors; upper limit of normal.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • AMP-Activated Protein Kinases / drug effects
  • ATP Citrate (pro-S)-Lyase / antagonists & inhibitors
  • Aged
  • Dicarboxylic Acids / administration & dosage*
  • Dicarboxylic Acids / adverse effects
  • Double-Blind Method
  • Fatty Acids / administration & dosage*
  • Fatty Acids / adverse effects
  • Female
  • Humans
  • Hypercholesterolemia / drug therapy*
  • Hypolipidemic Agents / administration & dosage*
  • Hypolipidemic Agents / adverse effects
  • Male
  • Middle Aged
  • Risk Factors


  • Dicarboxylic Acids
  • Fatty Acids
  • Hypolipidemic Agents
  • 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid
  • ATP Citrate (pro-S)-Lyase
  • AMP-Activated Protein Kinases

Associated data

  • ClinicalTrials.gov/NCT01262638