Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9): Lessons Learned from Patients with Hypercholesterolemia

Awan, Zuhier; Baass, Alexis; Genest, Jacques

doi:10.1373/clinchem.2014.225946

Cited by 36 publications

(21 citation statements)

References 71 publications

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“…It was also observed that some hepatic furins cleave and inactivate plasma PCSK9 [40]. Overall, plasma PCSK9 concentrations do not directly reflect PCSK9 biological activity [41]. That could explain the absence of correlation between PCSK9 and apoB-48 concentrations observed in the present study.…”

Section: Discussionmentioning

confidence: 60%

The elevation of plasma concentrations of apoB-48-containing lipoproteins in familial hypercholesterolemia is independent of PCSK9 levels

Drouin‐Chartier¹,

Hogue

Tremblay³

et al. 2017

Lipids Health Dis

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BackgroundPrevious studies have reported high plasma concentrations of both intestinal apolipoprotein (apo) B-48-containing lipoproteins and PCSK9 in subjects with familial hypercholesterolemia (FH). However, the extent to which LDL receptor deficiency and PCSK9 levels influence plasma apoB-48 concentrations in humans remains to be fully characterized. The objective of the study was to assess the independent association between FH, PCSK9 concentrations and plasma apoB-48 levels in a large cohort of genetically defined FH heterozygotes (HeFH) and homozygotes (HoFH).MethodsA total of 118 HeFH, 6 HoFH, and 117 controls were included in the study. Plasma PCSK9 and apoB-48 concentrations were measured in the fasting state.ResultsPlasma PCSK9 and apoB-48 levels were higher in FH subjects compared with controls (PCSK9: HoFH: 642.6 ± 246.9 vs. HeFH: 324.9 ± 119.8 vs. controls: 194.5 ± 65.9 ng/mL, P < 0.0001; apoB-48: HoFH: 14.71 ± 4.36 vs. HeFH: 6.55 ± 4.24 vs. controls: 3.03 ± 2.07 μg/mL; P < 0.0001). There were no correlations between apoB-48 and PCSK9 plasma levels in both controls (ρ = 0.06, P = 0.5) and HeFH subjects (ρ = 0.07, P = 0.4). Multiple linear regression analysis showed that the FH status was the only independent factor associated with apoB-48 levels, contributing to 28.7% of the variance (P < 0.0001).ConclusionsThese data indicate that the elevation in plasma apoB-48 levels associated with FH is independent of PCSK9 levels.Trial registration NCT02225340.

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Section: Discussionmentioning

confidence: 60%

The elevation of plasma concentrations of apoB-48-containing lipoproteins in familial hypercholesterolemia is independent of PCSK9 levels

Drouin‐Chartier¹,

Hogue

Tremblay³

et al. 2017

Lipids Health Dis

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“…3). PCSK9 is known to modify LDL receptor processing [31]. Its expression in the EGF domain of the LDLR locus is regulated by sterol regulatory element-binding proteins 1a and 2, and it binds to the EGF domain of the cell surface LDL receptor.…”

Section: Critical Interpretation Of the Statement Based On Mendelian mentioning

confidence: 99%

A Critical Review of the Consensus Statement from the European Atherosclerosis Society Consensus Panel 2017

Okuyama

Hamazaki²,

Hama³

et al. 2018

Pharmacology

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Background: The Consensus Statement from the European Atherosclerosis Society (EAS) Consensus Panel 2017 concludes on the basis of 3 different types of clinical studies that low-density lipoprotein (LDL) causes atherosclerotic cardiovascular disease (ASCVD). In Mendelian randomization studies, rare genetic mutations affecting LDL receptor function were found to cause higher or lower LDL-C levels, which are associated with correspondingly altered ASCVD risk. In prospective cohort studies and randomized controlled trials (RCTs) of statins, a remarkably consistent log-linear association was demonstrated between the absolute magnitude of LDL-C exposure and ASCVD risk. The EAS Statement proposes that any mechanism of lowering plasma LDL concentration should reduce the risk of ASCVD events proportional to the absolute reduction in LDL-C and the cumulative duration of exposure to lower LDL-C. However, as we explain, we do not find this conclusion acceptable. Summary: Our review points out that different interpretations are possible for the results of Mendelian randomization studies. As for prospective cohort studies, many inconsistent reports on the association of LDL-C and ASCVD were disregarded when drafting the Statement, reports with and without genetic factors related to LDL receptor function should be analyzed separately, and the term ASCVD in the Statement is used inappropriately because myocardial infarction and cerebral infarction differ in their association with LDL-C. As for RCTs, clinical reports on statins published before and after the implementation of new regulations affecting clinical trials (2004/2005) should not both be included in meta-analyses because the evaluated efficacy of statins changed markedly, and the irreversible adverse effects of statins need to be evaluated more rigorously now that their mechanisms have been elucidated. Key Messages: Apart from the EAS hypothesis that LDL causes ASCVD, recent pharmacological/biochemical studies, as summarized in this review and elsewhere, have revealed that atherosclerosis is caused by statins taken to lower LDL-C, as well as by warfarin and some types of vegetable fats and oils, in the absence of significantly elevated LDL-C levels. Thus, the promotion of statin treatment by the Statement is rather risky and we do not feel that the conclusions are justified for the prevention of ASCVD.

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“…The theoretical induction of intestinal tumors by an excessive production of bile acid was not confirmed in practice. Due to the lack of safety evidence during pregnancy, PCSK9 inhibitors are contraindicated in this state [97]. Nevertheless, bococizumab did not affect the embryo-fetal development in an animal study [98].…”

Section: Safety Concernsmentioning

confidence: 99%

PCSK9 inhibitors – from discovery of a single mutation to a groundbreaking therapy of lipid disorders in one decade

Jaworski¹,

Jankowski²,

Kosior³

2017

aoms

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Hypercholesterolemia is one of the main risk factors for coronary heart disease and significantly contributes to the high mortality associated with cardiovascular diseases. Statin therapy represents the gold standard in the reduction of low-density lipoprotein cholesterol concentration. Nevertheless, many patients still cannot achieve the recommended target levels, due to either inadequate effectiveness or intolerance of these drugs. Monoclonal antibodies that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9) have emerged as a promising option in lipid-lowering treatment. After confirmation of their efficacy and safety in clinical trials, evolocumab and alirocumab received approval from the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for introduction into clinical practice. In this review, we present a history of the development and mechanisms of action, as well as the results of the most important studies concerning PCSK9 inhibitors.

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Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9): Lessons Learned from Patients with Hypercholesterolemia

Cited by 36 publications

References 71 publications

The elevation of plasma concentrations of apoB-48-containing lipoproteins in familial hypercholesterolemia is independent of PCSK9 levels

The elevation of plasma concentrations of apoB-48-containing lipoproteins in familial hypercholesterolemia is independent of PCSK9 levels

A Critical Review of the Consensus Statement from the European Atherosclerosis Society Consensus Panel 2017

PCSK9 inhibitors – from discovery of a single mutation to a groundbreaking therapy of lipid disorders in one decade

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