title: LDL-cholesterol reduction in patients with hypercholesterolemia by modulation of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase.
abstract: OBJECTIVE
  To review the profile of ETC-1002, as shown in preclinical and clinical studies, including LDL-cholesterol (LDL-C)-lowering activity and beneficial effects on other cardiometabolic risk markers as they relate to the inhibition of adenosine triphosphate-citrate lyase and the activation of adenosine monophosphate-activated protein kinase.
  
  
  RESULTS
  ETC-1002 is an adenosine triphosphate-citrate lyase inhibitor/adenosine monophosphate-activated protein kinase activator currently in Phase 2b clinical development. In seven Phase 1 and Phase 2a clinical studies, ETC-1002 dosed once daily for 2-12 weeks has lowered LDL-C and reduced high-sensitivity C-reactive protein by up to 40%, with neutral to positive effects on glucose levels, blood pressure, and body weight. Importantly, use of ETC-1002 in statin-intolerant patients has shown statin-like lowering of LDL-C without the muscle pain and weakness responsible for discontinuation of statin use by many patients. ETC-1002 has also been shown to produce an incremental benefit, lowering LDL-C as an add-on therapy to a low-dose statin. In over 300 individuals in studies of up to 12 weeks, ETC-1002 has been well tolerated with no serious adverse effects.
  
  
  CONCLUSIONS
  Because adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase play central roles in regulating lipid and glucose metabolism, pharmacological modulation of these two enzymes could provide an important therapeutic alternative for statin-intolerant patients with hypercholesterolemia.
authors: Esperion Therapeutics Inc., Ann Arbor, Michigan, USA.
authors: Sergey
authors: S
authors: Filippov
authors: Stephen L
authors: SL
authors: Pinkosky
authors: Roger S
authors: RS
authors: Newton
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001275:ATP Citrate (pro-S)-Lyase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000924:Anticholesteremic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008078:Cholesterol, LDL / Q000378:metabolism*; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D058990:Molecular Targeted Therapy / Q000379:methods*
chemical_list: D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D001275:ATP Citrate (pro-S)-Lyase; D055372:AMP-Activated Protein Kinases