The New Face of Hyperlipidemia Management: Proprotein Convertase Subtilisin/Kexin Inhibitors (PCSK-9) and Their Emergent Role As An Alternative To Statin Therapy

Abstract

This review analyzes Proprotein Convertase Subtilisin/Kexin 9 inhibitors (PCSK-9), a new medication class that has arisen in the last year to combat hypercholesterolemia. They are targeted towards patients who are unable to achieve acceptable low density lipoprotein (LDL) levels despite maximum statin therapy, as well as those who are unable to tolerate maximum statin therapy due to side effects such as myopathy or myalgia. Two of these medications have been released in the last year: alirocumab (Praluent) and evolocumab (Repatha). This article will overview this medication class, describe their pathophysiology, and analyze the clinical data from the numerous studies and trials done on both of these medications for their efficacy and safety outcomes. Data compiled on this new class of medications support the research that PCSK-9 inhibitors are both a safe and effective means of lowering the LDL levels of resistant or otherwise currently unmanaged hypercholesterolemia patients.

Selection of DNA aptamers with two modified bases

“…PCSK9 binds to LDL-R and promotes its degradation in lysosomes preventing recycling of LDL-R to the surface of hepatocytes, which results in increased plasma LDL cholesterol (37). The US Food and Drug Administration (FDA) has recently approved two drugs targeting PCSK9 (Alirocumab and Evolocumab) for the treatment of high-risk individuals with hypercholesterolemia (38). In addition, the quantification of PCSK9 in plasma by immunoaffinity (IA) enrichment LC-MS with a SOMAmer containing a single modified nucleotide was recently reported (39).…”

“…It is now well-established that PCSK9 antagonism is an effective therapeutic option for lowering plasma cholesterol levels (38). Aside from antibodies that have received approval (38), there is considerable interest in identifying other types of PCSK9 antagonists as potential therapeutics (42–44).…”

“…Aside from antibodies that have received approval (38), there is considerable interest in identifying other types of PCSK9 antagonists as potential therapeutics (42–44). To identify a SOMAmer inhibitor of PCSK9, 41 SOMAmers (30-mers, K d < 1 nM) were screened in a plate-based sandwich assay where biotinylated PCSK9 was incubated with or without SOMAmer, added to an LDL-R–coated plate, and detected using streptavidin-HRP conjugate in a chemiluminescent readout ( SI Appendix , Fig.…”

LJ-1888, a selective antagonist for the A3 adenosine receptor, ameliorates the development of atherosclerosis and hypercholesterolemia in apolipoprotein E knock-out mice

“…Controlling lipoprotein and cholesterol levels is important for reducing the risk of atherosclerosis ( 1 , 21 , 22 ). Hypercholesterolemia may be ameliorated by lowering LDL-chol and TG concentrations and by increasing HDL-chol concentrations, using agents such as HMG-CoA reductase inhibitors, cholesterol absorption inhibitors, bile acid sequestrants, and proprotein convertase subtilisin/kexin type-9 (PCSK-9) inhibitors ( 7 – 9 , 23 , 24 ). We therefore assessed the mechanism by which LJ-1888 improves hypercholesterolemia in WD fed ApoE −/− mice.…”

“…Statins, which act as 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors, are representative lipid-lowering medications that have shown protective effects in cardiovascular diseases by inhibiting cholesterol synthesis, enhancing the expression of LDL receptors on the surface of hepatocytes, and increasing anti-inflammatory responses ( 7 ). Other medications used to lower LDL-chol levels include cholesterol absorption inhibitors, bile acid sequestrants, and protein convertase subtilisin/kexin type-9 (PCSK-9) inhibitors ( 8 , 9 ). Moreover, elevated plasma levels of HDL-chol have been closely associated with clinical benefits in patients with cardiovascular diseases ( 10 ).…”