title: Effects of currently prescribed LDL-C-lowering drugs on PCSK9 and implications for the next generation of LDL-C-lowering agents.
abstract: BACKGROUND
  During the past decade, proprotein convertase subtilisin kexin type 9 (PCSK9) has been identified as a key regulator of serum LDL-cholesterol (LDL-C) levels. PCSK9 is secreted by the liver into the plasma and binds the hepatic LDL receptor, causing its subsequent degradation. In humans, gain-of-function mutations in PCSK9 cause a form of familial hypercholesterolemia that manifests with dramatically increased serum levels of LDL-C, while loss-of-function mutations in PCSK9 are associated with significantly decreased LDL-C and cardiovascular risk.
  
  
  RESULTS
  Initial studies in animals and cultured cells demonstrated that statins increased PCSK9 mRNA expression, resulting in many research groups exploring the effect of statins on PCSK9 levels in humans. We first reported that statins increased human PCSK9 circulating protein levels. Additional researchers subsequently confirmed these observations, further prompting many laboratories including our own to examine the effect of other lipid lowering medications on PCSK9 levels. Our observation that fenofibrate (200 mg/day) significantly increased PCSK9 levels was confirmed by another laboratory, and an additional group demonstrated that ezetimibe also increased PCSK9 levels.
  
  
  CONCLUSIONS
  It has become clear that the major classes of commonly prescribed lipid-lowering medications increase serum PCSK9 levels. These observations almost certainly explain why these agents are not more effective in lowering LDL-C and suggest that efforts should be made toward the development of new LDL-C lowering medications that either do not increase circulating PCSK9 levels or work through decreasing or inhibiting PCSK9.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. konrad_robert@lilly.com
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Konrad
authors.forename: Jason S
authors.initials: JS
authors.lastname: Troutt
authors.forename: Guoqing
authors.initials: G
authors.lastname: Cao
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D001384:Azetidines / Q000494:pharmacology; D008078:Cholesterol, LDL / Q000097:blood*; D000069438:Ezetimibe; D011345:Fenofibrate / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000235:genetics; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases / Q000097:blood / Q000187:drug effects* / Q000235:genetics
chemical_list: D000924:Anticholesteremic Agents; D001384:Azetidines; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D000069438:Ezetimibe; D011345:Fenofibrate