title: 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.
abstract: OBJECTIVE
  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).
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas; Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart and Vascular Center, Houston, Texas. Electronic address: cmb@bcm.edu.
authors.forename: Christie M
authors.initials: CM
authors.lastname: Ballantyne
authors.forename: Michael H
authors.initials: MH
authors.lastname: Davidson
authors.forename: Diane E
authors.initials: DE
authors.lastname: Macdougall
authors.forename: Harold E
authors.initials: HE
authors.lastname: Bays
authors.forename: Lorenzo A
authors.initials: LA
authors.lastname: Dicarlo
authors.forename: Noah L
authors.initials: NL
authors.lastname: Rosenberg
authors.forename: Janice
authors.initials: J
authors.lastname: Margulies
authors.forename: Roger S
authors.initials: RS
authors.lastname: Newton
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000187:drug effects; D001275:ATP Citrate (pro-S)-Lyase / Q000037:antagonists & inhibitors; D000368:Aged; D003998:Dicarboxylic Acids / Q000008:administration & dosage* / Q000009:adverse effects; D004311:Double-Blind Method; D005227:Fatty Acids / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy*; D000960:Hypolipidemic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D012307:Risk Factors
chemical_list: D003998:Dicarboxylic Acids; D005227:Fatty Acids; D000960:Hypolipidemic Agents; C581236:8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid; D001275:ATP Citrate (pro-S)-Lyase; D055372:AMP-Activated Protein Kinases
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