Emerging PCSK9 inhibitors for treating dyslipidaemia: buttressing the gaps in coronary prevention

Page, Michael M.; Watts, Gerald F.

doi:10.1517/14728214.2015.1035709

Cited by 8 publications

(6 citation statements)

References 87 publications

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“…Instead, evolocumab is indicated in adults with hypercholesterolaemia (heterozygous familial and non-familial) and mixed dyslipidaemia (alone or in combination with other lipid-lowering therapies) and in adults and adolescents with homozygous familial hypercholesterolaemia (in combination with other lipid-lowering therapies). Based on data from epidemiological studies demonstrating a correlation between the reduction of plasma LDL-C levels and a reduction of cardiovascular risk [8], both drugs have obtained the indication for the reduction of cardiovascular risk in adults with established atherosclerotic cardiovascular disease.…”

Section: Data Sourcementioning

confidence: 99%

PCSK9 Inhibitors and Neurocognitive Adverse Drug Reactions: Analysis of Individual Case Safety Reports from the Eudravigilance Database

et al. 2020

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Introduction Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9Is) were associated with a risk of neurocognitive adverse drug reactions (ADRs). Objective We aimed to investigate the occurrence of neuropsychiatric ADRs related to PCSK9Is. Methods We analyzed Individual Case Safety Reports (ICSRs) sent through the European pharmacovigilance database that reported alirocumab or evolocumab as the suspected drug and at least one neurological or psychiatric ADR. The reporting odds ratio (ROR) was computed to compare the probability of reporting ICSRs with neuropsychiatric ADRs between alirocumab, evolocumab and statins. Results Overall, 2041 ICSRs with alirocumab and/or evolocumab as the suspected drug described the occurrence of neuropsychiatric ADRs. The most reported preferred terms for both drugs were headache, insomnia and depression. No difference between alirocumab and evolocumab was observed for the RORs of ICSRs with ADRs belonging to the System Organ Classes (SOCs) ‘Nervous system disorders’ or ‘Psychiatric disorders’ (ROR 1.02, 95% confidence interval 0.91–1.14; and 1.12, 95% CI 0.94–1.34, respectively), while evolocumab and alirocumab had a higher reporting probability of ICSRs with ADRs belonging to the SOC ‘Nervous system disorders’ compared with atorvastatin and fluvastatin. A lower reporting probability was instead found for ICSRs with ADRs belonging to the SOC ‘Psychiatric disorders’ for evolocumab and alirocumab versus simvastatin, pravastatin and rosuvastatin. Conclusion Our results demonstrated that 22.7% of all ICSRs reporting alirocumab or evolocumab as suspect drugs described the occurrence of neuropsychiatric ADRs. The ROR showed that evolocumab and alirocumab had a higher reporting probability of neurological ADRs compared with statins. Further data from real-life contexts are needed. Electronic supplementary material The online version of this article (10.1007/s40264-020-01021-3) contains supplementary material, which is available to authorized users.

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Section: Data Sourcementioning

confidence: 99%

PCSK9 Inhibitors and Neurocognitive Adverse Drug Reactions: Analysis of Individual Case Safety Reports from the Eudravigilance Database

et al. 2020

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“…The hypocholesterolemic effect of anti-PCSK9 drugs in humans has been widely demonstrated in clinical trials (Page & Watts 2015). Despite the success, there are uncertainties about the metabolic consequences of long-term drastic reduction of plasma cholesterol.…”

Section: From Proenzymes (Pcsk1-8) To Pcsk9 As An Escort Proteinmentioning

confidence: 99%

60 YEARS OF POMC: From the prohormone theory to pro-opiomelanocortin and to proprotein convertases (PCSK1 to PCSK9)

Chrétien

Mbikay

2016

Journal of Molecular Endocrinology

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Pro-opiomelanocortin (POMC), is a polyprotein expressed in the pituitary and the brain where it is proteolytically processed into peptide hormones and neuropeptides with distinct biological activities. It is the prototype of multipotent prohormones. The prohormone theory was first suggested in 1967 when Chrétien and Li discovered γ-lipotropin and observed that (i) it was part of β-lipotropin (β-LPH), a larger polypeptide characterized 2 years earlier and (ii) its C-terminus was β-melanocyte-stimulating hormone (β-MSH). This discovery led them to propose that the lipotropins might be related biosynthetically to the biologically active β-MSH in a precursor to end product relationship. The theory was widely confirmed in subsequent years. As we celebrate the 50th anniversary of the sequencing of β-LPH, we reflect over the lessons learned from the sequencing of those proteins; we explain their extension to the larger POMC precursor; we examine how the theory of precursor endoproteolysis they inspired became relevant for vast fields in biology; and how it led, after a long and arduous search, to the novel proteolytic enzymes called proprotein convertases. This family of nine enzymes plays multifaceted functions in growth, development, metabolism, endocrine, and brain functions. Their genetics has provided many insights into health and disease. Their therapeutic targeting is foreseeable in the near future. Thus, what started five decades ago as a theory based on POMC fragments, has opened up novel and productive avenues of biological and medical research, including, for our own current interest, a highly intriguing hypocholesterolemic Gln152His PCSK9 mutation in French-Canadian families.

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“…The clinical trials of PCSK9 inhibitors have not included cardiovascular endpoints as primary clinical outcomes and, although LDL-C reduction is considered an established surrogate marker for cardiovascular risk reduction, this has mainly been established for statin therapy and not for newer treatments 9,10. In addition, the majority of studies have lasted for 12 (evolocumab) or 24 weeks (alirocumab).…”

Section: Evolocumab and Alirocumabmentioning

confidence: 99%

“…Although statins have become standard lipid-modification therapy for primary and secondary prevention of CVD,7 not all patients are able to tolerate them. As a result, there has been interest in producing lipid-lowering drugs with different modes of action and a range of molecules are being developed 8,9. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein that regulates the recycling of LDL-receptors on the surface of liver cells and decreases the ability of the liver to clear LDL-C from the blood.…”

Section: Introductionmentioning

confidence: 99%

Two new lipid-regulating drugs

2016

DTB

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▼Evolocumab (Repatha-Amgen Ltd) and ▼alirocumab (Praluent-Sanofi) are the first in a novel class of lipid-regulating drugs, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, to be licensed in the UK. Both drugs have marketing authorisation for the treatment of primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia and are administered by subcutaneous injection. Here we consider the evidence for evolocumab and alirocumab in the management of primary hypercholesterolaemia and dyslipidaemias.

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Emerging PCSK9 inhibitors for treating dyslipidaemia: buttressing the gaps in coronary prevention

Cited by 8 publications

References 87 publications

PCSK9 Inhibitors and Neurocognitive Adverse Drug Reactions: Analysis of Individual Case Safety Reports from the Eudravigilance Database

PCSK9 Inhibitors and Neurocognitive Adverse Drug Reactions: Analysis of Individual Case Safety Reports from the Eudravigilance Database

60 YEARS OF POMC: From the prohormone theory to pro-opiomelanocortin and to proprotein convertases (PCSK1 to PCSK9)

Two new lipid-regulating drugs

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