Neurocognitive effects associated with proprotein convertase subtilisin-kexin type 9 inhibitor use: a narrative review

Abstract

Neurocognitive adverse events have been observed with the widespread use of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors or “statins,” which reduce low-density lipoprotein cholesterol (LDL-C) levels and subsequently cardiovascular risk. The United States Food and Drug Association directed manufacturers of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors to monitor for neurocognitive adverse events due to their potent effects on LDL-C reduction, which is a proposed mechanism for neuronal cell dysfunction. Other proposed mechanisms for PCSK9 inhibitor-associated neurocognitive adverse events include N-methyl-d-aspartate receptor modulation, dysregulation of lipid and glucose metabolism, and patient-specific risk factors for cognitive impairment. The purpose of this narrative review article is to describe the proposed mechanisms, incidence of neurocognitive adverse events from phase II and III trials for PCSK9 inhibitors, neurocognitive assessments utilized in clinical trials, and clinical implications. Given the increasing prevalence of PCSK9 inhibitor use and the neurocognitive adverse events observed with prior lipid-lowering therapies, clinicians should be aware of the risks associated with PCSK9 inhibitors, especially when therapy is indicated for patients at high risk for cardiovascular events. Overall, the incidence of PCSK9 inhibitor-associated neurocognitive appears to be uncommon. However, additional prospective studies evaluating cognitive impairment may be beneficial to determine the long-term safety of these agents.

Function of proprotein convertase subtilisin/kexin type 9 and its role in central nervous system diseases: An update on clinical evidence

“…Neurocognitive adverse events have been observed in the use of LDL‐C lowering HMG‐CoA reductase inhibitors, which has been recognized that lowering LDL‐C is a key incentive in neuronal cell dysfunction (Shahid et al, 2022; Yuet et al, 2021). The main objective of this review article is to describe the effect of different PCSK9 levels (PCSK9 gene mutations and PCSK9 inhibitors) on neurocognitive adverse events through population samples.…”

Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors Induced Neurocognitive Disorder: A Pharmacovigilance Study by Analyzing the Data from the U.S. FDA Adverse Event Reporting System

“…Recent research proposed the mechanism that the neurocognitive adverse event may pose by sustained low LDL-C levels. While the treatment effect of PCSK9 inhibitor can promote the above process, thus neurocognitive dysfunction becomes the potential adverse event [12,20]. Based on this mechanism and the disproportional analysis, it is necessary to keep vigilant for the usage of PCSK9 inhibitors in the clinic and record the effect.…”

Neurocognitive Impairment in Cardiovascular Disease Patients Taking Statins Versus Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors: A Systematic Review

“…These monoclonal antibodies due to their larger size cannot cross the blood-brain barrier; therefore, the cognitive damage is due to the effect of lowered LDL-C in the body from their use. There are four proposed mechanisms: dysregulation of lipid and glucose metabolism, N-methyl-D-aspartate (NMDA) receptor modulation, alteration in neuronal cell membrane integrity, and predisposing risk factors like genetic variance [26].…”