title: Targeting PCSK9 as a promising new mechanism for lowering low-density lipoprotein cholesterol.
abstract: Statins and other lipid-lowering drugs have dominated the market for many years for achievement of recommended levels of low-density lipoprotein cholesterol (LDL-C). However, a substantial number of high-risk patients are unable to achieve the LDL-C goal. Proprotein convertase subtilisin/kexin 9 (PCSK9) has recently emerged as a new, promising key therapeutic target for hypercholesterolemia. PCSK9 is a protease involved in chaperoning the low-density lipoprotein receptor to the process of degradation. PCSK9 inhibitors and statins effectively lower LDL-C. The PCSK9 inhibitors decrease the degradation of the LDL receptors, whereas statins mainly interfere with the synthetic machinery of cholesterol by inhibiting the key rate limiting enzyme, the HMG CoA reductase. PCSK9 inhibitors are currently being developed as monoclonal antibodies for their primary use in lowering LDL-C. They may be especially useful for patients with homozygous familial hypercholesterolemia, who at present receive minimal benefit from traditional statin therapy. The monoclonal antibody PCSK9 inhibitors, recently granted FDA approval, show the most promising safety and efficacy profile compared to other, newer LDL-C lowering therapies. This review will primarily focus on the safety and efficacy of monoclonal antibody PCSK9 inhibitors in comparison to statins. The review will also address new, alternative PCSK9 targeting drug classes such as small molecules, gene silencing agents, apolipoprotein B antisense oligonucleotides, and microsomal triglyceride transfer protein inhibitors.
authors.affiliation: The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, USA.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Della Badia
authors.affiliation: Shifa Biomedical Corporation, Malvern, PA, USA.
authors.forename: Nabil A
authors.initials: NA
authors.lastname: Elshourbagy
authors.affiliation: The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, USA. Electronic address: shaker.mousa@acphs.edu.
authors.forename: Shaker A
authors.initials: SA
authors.lastname: Mousa
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000924:Anticholesteremic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D008078:Cholesterol, LDL / Q000378:metabolism*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D006937:Hypercholesterolemia / Q000188:drug therapy*; D006938:Hyperlipoproteinemia Type II / Q000188:drug therapy; D000091362:PCSK9 Inhibitors; D011973:Receptors, LDL / Q000187:drug effects / Q000378:metabolism; D000071449:Proprotein Convertase 9
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000091362:PCSK9 Inhibitors; D011973:Receptors, LDL; C000598888:bococizumab; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; C577155:evolocumab; C571059:alirocumab
keywords: Alirocumab; Cardiovascular disease; Evolocumab; Hypercholesterolemia; Low-density lipoprotein cholesterol; PCSK9