title: PCSK9 inhibition to reduce cardiovascular disease risk: recent findings from the biology of PCSK9.
abstract: OBJECTIVE
  Review novel insights into the biology of proprotein convertase subtilisin/kexin 9 (PCSK9) that may explain the extreme efficiency of PCSK9 inhibition and the unexpected metabolic effects resulting from PCSK9 monoclonal antibody therapy, and may identify additional patients as target of therapy.
  
  
  RESULTS
  For over 20 years, the practical knowledge of cholesterol metabolism has centered around cellular mechanisms, and around the idea that statin therapy is the essential step to control metabolic abnormalities for cardiovascular risk management. This view has been embraced by the recent AHA/ACC guidelines, but is being challenged by recent studies including nonstatin medications and by the development of a new class of cholesterol-lowering agents that seems destined to early US Food and Drug Administration approval. The discovery of PCSK9 - a circulating protein that regulates hepatic low-density lipoprotein (LDL) receptor and serum LDL cholesterol levels - has led to a race for its therapeutic inhibition. Recent findings on PCSK9 regulation and pleiotropic effects will help identify additional patient groups likely to benefit from the inhibitory therapy and unravel the full potential of PCSK9 inhibition therapy.
  
  
  CONCLUSIONS
  Injectable human monoclonal antibodies to block the interaction between PCSK9 and LDL receptor are demonstrating extraordinary efficacy (LDL reductions of up to 70%) and almost the absence of any side-effects. A more moderate effect is seen on other lipoprotein parameters, with the exception of lipoprotein(a) levels. We describe mechanisms that can explain the effect on lipoprotein(a), predict a potential effect on postprandial triglyderides, and suggest a new category of patients for anti-PCSK9 therapy.
authors.affiliation: The Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health and Sciences University, Portland, Oregon, USA.
authors.forename: Hagai
authors.initials: H
authors.lastname: Tavori
authors.forename: Ilaria
authors.initials: I
authors.lastname: Giunzioni
authors.forename: Sergio
authors.initials: S
authors.lastname: Fazio
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000201:enzymology / Q000453:epidemiology / Q000517:prevention & control*; D050171:Dyslipidemias / Q000188:drug therapy* / Q000201:enzymology / Q000453:epidemiology; D006801:Humans; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D050356:Lipid Metabolism / Q000187:drug effects; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D012697:Serine Endopeptidases / Q000276:immunology / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D000960:Hypolipidemic Agents; C573412:LDLR protein, human; D011973:Receptors, LDL; D015842:Serine Proteinase Inhibitors; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases