PCSK9 Inhibitors and Neurocognitive Adverse Events: Exploring the FDA Directive and a Proposal for N-of-1 Trials

Swiger, Kristopher J.; Martin, Seth S.

doi:10.1007/s40264-015-0296-6

Cited by 58 publications

(48 citation statements)

References 53 publications

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“…Although it should be noted that these events are uncommon and that adverse event reporting is not part of a systematic evaluation of neurocognitive function, currently available trial evidence suggests that neurocognitive adverse events may occur more frequently in individuals receiving proprotein convertase subtilisin-kexin type 9 inhibitors independently of on-treatment LDL levels. 15 At the same time, high-dose monthly regimens of proprotein convertase subtilisin-kexin type 9 monoclonal antibodies are known to produce substantial fluctuations of LDL-C between doses. 16 On the basis of our results, this increased variability could possibly contribute to the observed higher rate of neurocognitive events and should be examined by currently ongoing proprotein convertase subtilisin-kexin type 9 trials.…”

Section: Discussionmentioning

confidence: 99%

“…Si bien deberá observarse que estos eventos son infrecuentes y que la notificación de eventos adversos no forma parte de una evaluación sistemática de la función neurocognitiva, la evidencia actualmente disponible de los estudios indica que los eventos adversos neurocognitivos pueden presentarse con más frecuencia en individuos que reciben inhibidores de la proproteína-convertasa subtilisina-kexina tipo 9 independientemente de los niveles de LDL durante el tratamiento. 15 Al mismo tiempo, se sabe que los regímenes mensuales de dosis altas de anticuerpos monoclonales anti proproteína-convertasa subtilisina-kexina tipo 9 producen fluctuaciones sustanciales del LDL-C entre las dosis. 16 Sobre la base de nuestros resultados, este aumento de la variabilidad posiblemente podría contribuir a la mayor tasa observada de eventos neurocognitivos y deberá ser investigada por los estudios actualmente en curso de la proproteína-convertasa subtilisina-kexina tipo 9.…”

Section: Discussionunclassified

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Higher Visit-to-Visit Low-Density Lipoprotein Cholesterol Variability Is Associated With Lower Cognitive Performance, Lower Cerebral Blood Flow, and Greater White Matter Hyperintensity Load in Older Subjects

et al. 2016

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Background: Recently, it was shown that intraindividual variation in low-density lipoprotein cholesterol (LDL-C) predicts both cerebrovascular and cardiovascular events. We aimed to examine whether this extends to cognitive function and examined possible pathways using a magnetic resonance imaging substudy. Methods: We investigated the association between LDL-C variability and 4 cognitive domains at month 30 in 4428 participants of PROSPER (PROspective Study of Pravastatin in the Elderly at Risk). Additionally, we assessed the association of LDL-C variability with neuroimaging outcomes in a subset of 535 participants. LDL-C variability was defined as the intraindividual standard deviation over 4 postbaseline LDL-C measurements, and all analyses were adjusted for mean LDL-C levels and cardiovascular risk factors. Results: Higher LDL-C variability was associated with lower cognitive function in both the placebo and pravastatin treatment arms. Associations were present for selective attention ( P =0.017 and P =0.11, respectively), processing speed ( P =0.20 and P =0.029), and memory (immediate recall, P =0.002 and P =0.006; delayed recall, P =0.001 and P ≤0.001). Furthermore, higher LDL-C variability was associated with lower cerebral blood flow in both trial arms ( P =0.031 and P =0.050) and with greater white matter hyperintensity load in the pravastatin arm ( P =0.046). No evidence was found for interaction between LDL-C variability and pravastatin treatment for both cognitive and magnetic resonance imaging outcomes. Conclusions: We found that higher visit-to-visit variability in LDL-C, independently of mean LDL-C levels and statin treatment, is associated with lower cognitive performance, lower cerebral blood flow, and greater white matter hyperintensity load.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionunclassified

Higher Visit-to-Visit Low-Density Lipoprotein Cholesterol Variability Is Associated With Lower Cognitive Performance, Lower Cerebral Blood Flow, and Greater White Matter Hyperintensity Load in Older Subjects

et al. 2016

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“…More recently, we have noted white adipose tissue anomalies in a PCSK9 Q152H female subject (Wassef et al 2015). It has been recommended that patients treated with anti-PCSK9 drugs be monitored for adverse neurocognitive effects (Swiger & Martin 2015). For our part, we plan to verify whether the remarkable lifelong hypocholesterolemia observed in our PCSK9 Q152H carriers might protect them from cognitive impairment of cerebrovascular origin and/or of Alzheimer's degeneration.…”

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

confidence: 95%

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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“…One study showed increased levels of β-site amyloid precursor protein cleaving enzyme 1 (the rate-limiting enzyme for generation of amyloid β-peptide) and amyloid β-peptide in PCSK9 −/− mice, 64 whereas another study reported no change in either β-site amyloid precursor protein cleaving enzyme 1 or amyloid β-peptide. 65 As recently reviewed elsewhere, 66 there is controversy concerning the potential for PCSK9-based therapies to cause neurocognitive impairment, an effect theoretically ascribed to the recognized ability of PCSK9 inhibitors to dramatically lower LDL-C, which has raised concern that this may affect central nervous system function. On the one hand, the brains of PCSK9 −/− mice showed no gross structural differences compared with wild-type mice, suggesting no adverse effect of PCSK9 deficiency on brain development, 67 although the applicability of this finding to humans is uncertain.…”

Section: Brainmentioning

confidence: 99%

Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition

Bergeron¹,

et al. 2015

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Abstract-Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in the regulation of cholesterol homeostasis. By binding to hepatic low-density lipoprotein (LDL) receptors and promoting their lysosomal degradation, PCSK9 reduces LDL uptake, leading to an increase in LDL cholesterol concentrations. Gain-of-function mutations in PCSK9 associated with high LDL cholesterol and premature cardiovascular disease have been causally implicated in the pathophysiology of autosomal-dominant familial hypercholesterolemia. In contrast, the more commonly expressed loss-of-function mutations in PCSK9 are associated with reduced LDL cholesterol and cardiovascular disease risk. The development of therapeutic approaches that inhibit PCSK9 function has therefore attracted considerable attention from clinicians and the pharmaceutical industry for the management of hypercholesterolemia and its associated cardiovascular disease risk. This review summarizes the effects of PCSK9 on hepatic and intestinal lipid metabolism and the more recently explored functions of PCSK9 in extrahepatic tissues. Therapeutic approaches that prevent interaction of PCSK9 with hepatic LDL receptors (monoclonal antibodies, mimetic peptides), inhibit PCSK9 synthesis in the endoplasmic reticulum (antisense oligonucleotides, siRNAs), and interfere with PCSK9 function (small molecules) are also described. Finally, clinical trials testing the safety and efficacy of monoclonal antibodies to PCSK9 are reviewed. These have shown dose-dependent decreases in LDL cholesterol (44%-65%), apolipoprotein B (48%-59%), and lipoprotein(a) (27%-50%) without major adverse effects in various high-risk patient categories, including those with statin intolerance. Initial reports from 2 of these trials have indicated the expected reduction in cardiovascular events. Hence, inhibition of PCSK9 holds considerable promise as a therapeutic option for decreasing cardiovascular disease risk.

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PCSK9 Inhibitors and Neurocognitive Adverse Events: Exploring the FDA Directive and a Proposal for N-of-1 Trials

Abstract: Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors are a novel class of medications that greatly lower low-density lipoprotein cholesterol (LDL-C) by upregulating LDL receptor availability. In early 2014,

Cited by 58 publications

References 53 publications

Higher Visit-to-Visit Low-Density Lipoprotein Cholesterol Variability Is Associated With Lower Cognitive Performance, Lower Cerebral Blood Flow, and Greater White Matter Hyperintensity Load in Older Subjects

Higher Visit-to-Visit Low-Density Lipoprotein Cholesterol Variability Is Associated With Lower Cognitive Performance, Lower Cerebral Blood Flow, and Greater White Matter Hyperintensity Load in Older Subjects

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

Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition

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