Evaluation of Proprotein Convertase Subtilisin/Kexin Type 9: Focus on Potential Clinical and Therapeutic Implications for Low‐Density Lipoprotein Cholesterol Lowering

Lose, Jennifer M.; Dorsch, Michael P.; Bleske, Barry E.

doi:10.1002/phar.1222

Cited by 7 publications

(5 citation statements)

References 73 publications

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“…Further investigation with animal models revealed that overexpression of the PCSK9 gene results in a dropout in the LDLR and an increase in LDL-C levels [8]. Researchers hypothesized that a gain-of-function mutation leads to an increase in LDL-C and a loss-of-function mutation leads to a decrease in LDL-C [9].…”

Section: History Of Pcsk9mentioning

confidence: 99%

“…The LDLR is produced within the endoplasmic reticulum and 8excreted to the surface of the hepatocyte where it binds LDL-C ( Figure 1a). The LDL-C/LDLR complex is then endocytosed into an endosome, which fuses with the lysosome [8][9][10][11][12]. A variety of lipases are involved in breaking down the content of LDL-C and the LDLR can be recirculated to the surface of the hepatocyte.…”

Section: Role Of the Ldl Receptormentioning

confidence: 99%

“…Normal function of PCSK9 is to promote degradation of LDL receptors. Adapted from reference[8]. LDL-C, low-density lipoprotein cholesterol; LDLR, low-density lipoprotein receptor; mRNA, messenger ribonucleic acid; PCSK9, proprotein convertase subtilisin/kexin type 9.…”

mentioning

confidence: 99%

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Focus on PCSK9 Inhibitors: From Genetics to Clinical Practice

Sabatine

Underberg

Koren

et al. 2016

Postgraduate Medicine

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Elevation of low-density lipoprotein cholesterol (LDL-C) is an important cause of atherosclerotic cardiovascular disease (ASCVD). Over the years, clinical outcome studies with LDL-C lowering agents have revealed that reducing LCL-C levels is effective in reducing rates of major ASCVD events. Although secondary factors play a role in clinical expression, severe lipid disorders often have a strong genetic component. Genetic revelations have provided novel targets for improving LDL-C management in high-risk individuals. Most recently, researchers have explored how the inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) alters LDL metabolism and lowers LDL-C levels to achieve lipid goals and potentially reduce ASCVD risk in patients with severe lipid disorders, including familial hypercholesterolemia (FH). This CMHC Spotlight article summarizes the clinical evidence demonstrating the safety, tolerability, and efficacy of PCSK9 inhibitors in lowering LDL-C levels. Reductions in LDL-C levels by PCSK9 inhibitors alone in patients who are statin intolerant or combined with maximally tolerated statins in patients with severe lipid disorders demonstrate the potential for reduced morbidity and mortality associated with ASCVD.

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Section: History Of Pcsk9mentioning

confidence: 99%

Section: Role Of the Ldl Receptormentioning

confidence: 99%

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Focus on PCSK9 Inhibitors: From Genetics to Clinical Practice

Sabatine

Underberg

Koren

et al. 2016

Postgraduate Medicine

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“…23 In the Atherosclerosis Risk in Communities (ARIC) trial, a retrospective trial involving over 12,000 patients, the loss of function mutation of the PCSK9 gene was found to be associated with a 28% reduction of LDL-C and 88% reduction in the risk of heart disease among African Americans, and a 15% and a 47% reduction, respectively, among whites. 24 A similar reduction in LDL-C levels was observed even among children with the mutations in the Bogalusa Heart Study.…”

Section: Pcsk9mentioning

confidence: 99%

Incorporating biomarkers into clinical trials in cardiovascular medicine

Lee¹,

Ota²

2014

CBF

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Developing novel therapies and establishing clinical benefits over conventional therapies has become a highly competitive and a costly endeavor. In this regard, biomarkers have become increasingly important in accurately assessing both efficacy and safety of these novel therapies. While the use of biomarkers has proved vital in cardiovascular research and disease management, current established biomarkers are inadequate in capturing and accounting for the entire cardiovascular disease process and responses to therapeutic interventions. Substantial effort has been made in exploring and clinically evaluating novel biomarkers. The present review aims to shed light on some of the novel cardiovascular biomarkers being investigated, including high sensitivity C-reactive protein, proprotein convertase subtilisin/kexin type 9, P-selectin, secretory phospholipase A 2 , lipoprotein-associated phospholipase A 2 , and growth differentiation factor 15, and illustrate their relevance to clinical research.

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“…It has been observed that lacking PCSK9 in mice causes an increase in LDLRs reserving for LDL-C (14). Mutations, leading to gain of function in PCSK9, give rise to elevation in LDL-C and subsequently increase the cardiovascular events, while loss of function mutations cause diminution in LDL-C, leading to a reduction in coronary heart disease (15). The expression of PCSK9 gene is controlled by intracellular cholesterol content (16).…”

Section: Introductionmentioning

confidence: 99%

Does Evolocumab, as a PCSK9 Inhibitor, Ameliorate the Lipid Profile in Familial Hypercholesterolemia Patients? A Meta-Analysis of Randomized Controlled Trials

et al. 2017

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-Proprotein convertase subtilisin-kexin type 9 (PCSK9) is a member of regulatory serine proteases which is mostly expressed in liver. In the physiological condition, LDL-C binds to LDL receptors (LDLRs) and via endocytosis, LDLRs are degraded. PCSK9 binds to the epidermal growth factor-like repeat A (EGFA) domain of extracellular LDLRs, and then physiological recycling of LDLRs from surface of liver is cancelled, resulting in elevation of circulating LDL-C in plasma. To evaluate whether evolucomab, as PCSK9 inhibitor monoclonal antibody, ameliorates lipid profile in familial hypercholesterolemia (FH) patients, this meta-analysis has been conducted. PubMed, Web of Science (ISI) and Scopus databases were searched for studies which had investigated the efficacy of evolucomab. Types of outcome investigated were percentage changes from baseline of the lipid profile. Our meta-analysis shows that evolucomab at the dosage of 420 mg monthly could decrease LDL-C by 54.71%, TC by 35.08%, VLDL-C by 28.37 %, ratio of TC to HDL-C by 39.14 %, triglycerides by 12.11 %, and increased HDL-C by 6.06% from baseline compared to placebo at the end of study in FH patients. Our findings indicate that evolocumab could be a hopeful agent for challenging patients, such as statin intolerance or patients who fail to attain the target goal of LDL-C despite consumption of maximum doses of statins.

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Evaluation of Proprotein Convertase Subtilisin/Kexin Type 9: Focus on Potential Clinical and Therapeutic Implications for Low‐Density Lipoprotein Cholesterol Lowering

Cited by 7 publications

References 73 publications

Focus on PCSK9 Inhibitors: From Genetics to Clinical Practice

Focus on PCSK9 Inhibitors: From Genetics to Clinical Practice

Incorporating biomarkers into clinical trials in cardiovascular medicine

Does Evolocumab, as a PCSK9 Inhibitor, Ameliorate the Lipid Profile in Familial Hypercholesterolemia Patients? A Meta-Analysis of Randomized Controlled Trials

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