PCSK9 inhibitors and cognition back in the news
Two recent reports have again raised the question of a possible link between the long-term effects of PCSK9 inhibition and cognitive adverse effects.
In the first report from the UK BioBank (1), the association of genetic variants in PCSK9 with continuous measures of cognitive ability were evaluated using a Mendelian randomization design. The following cognitive measures were used: two from baseline (2006-2010) involving fluid reasoning and reaction time which showed good intra-participant longitudinal reliability, and two from 2014–2015 via the internet: trail making test (TMT), which assessed processing speed plus executive function, and digit symbol coding, which assessed executive function. Six independent single nucleotide polymorphisms associated with a lower LDL cholesterol level were used as proxy for therapeutic inhibition of PCSK9.
The association of the six variants in PCSK9 scaled to 50 mg/dL lower LDL cholesterol was assessed in 109,870 individuals with measures of fluid reasoning, 337,348 with reaction time, 73,044 with processing speed (TMT A), 73,063 with processing speed plus executive function (TMT B), and 82,012 with digit symbol coding (executive function). The investigators were not able to provide definitive evidence for any association between PCSK9 genetic variants and cognition. The possibility that this finding may have been due to lack of power, is contradicted by demonstration of an association of the PCSK9 allele score with the risk of prevalent self-reported coronary heat disease, as well as associations of conventional risk factors (such as age and smoking) and genetic variants (e.g., APOE e4) with the studied cognitive traits. These observations reinforce 1) the validity of the PCSK9 genetic score and 2) sufficient statistical power for detecting association with relevant traits.
The authors concluded that based on their findings, life-long lower LDL cholesterol levels due to the carriage of PCSK9 genetic variants does not appear to be associated with meaningful adverse effects on cognition. However, they also reaffirm the need for continued pharmacovigilance of patients receiving PCSK9 inhibitors.
The second report focused on information from individual case safety reports from the Eudravigilance Database, a European pharmacovigilance database (2). In total, 2041 case safety reports (22.7% of the total) were available with alirocumab and/or evolocumab as the suspected drug with neuropsychiatric adverse drug reactions. In most cases, the preferred reporting terms were headache, insomnia and depression. While there was no difference between alirocumab and evolocumab for the system organ classes ‘Nervous system disorders’ or 'Psychiatric disorders', both had a higher reporting probability of 'Nervous system disorders' compared with atorvastatin and fluvastatin. In contrast, both PCSK9 inhibitors had a lower reporting probability for 'Psychiatric disorders' than simvastatin, pravastatin and rosuvastatin. The authors concluded that further long-term data from real-life prescribing was needed.
According to PCSK9 Forum Editor, Professor Derick Raal (University of the Witwatersrand, Johannesburg, South Africa) the possibility that very low LDL cholesterol levels attained with PCSK9 inhibitors adversely affect cognitive function is a common clinical concern. There are, however, accumulating data that suggest a lack of any association between PCSK9 inhibition and adverse effects on cognitive function. The EBBINGHAUS (Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in high Cardiovascular Risk Subjects) study, a sub study of FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), which specifically evaluated this question using a battery of validated cognitive tests, failed to show any association with the addition of evolocumab to statin therapy over the trial period (3). Cognitive function was also evaluated on completion of the total FOURIER study population using a 23-item survey on memory and executive domains from the Everyday Cognition scale and this also failed to show any adverse effect on cognitive function (4). These findings are supported by genetic data which show no evidence of adverse effects on cognitive function in individuals with lifelong very low LDL cholesterol levels due to genetic causes (5).
The accumulating data are reassuring for the clinician. However, as investigators from both studies acknowledge, continued pharmacovigilance of the effects of long-term treatment with PCSK9 inhibitors is needed.
- Lyall DM, Ward J, Banach M, et al. PCSK9 genetic variants and cognitive abilities: a large-scale Mendelian randomization study. Arch Med Sci. 2021;17:241-4. PUBMED https://pubmed.ncbi.nlm.nih.gov/33488877/
- di Mauro G, Zinzi A, Scavone C, et al. PCSK9 inhibitors and neurocognitive adverse drug reactions: analysis of individual case safety reports from the Eudravigilance Database. Drug Saf 2020; doi: 10.1007/s40264-020-01021-3. PUBMED https://pubmed.ncbi.nlm.nih.gov/33351170/
- Giugliano RP, Mach F, Zavitz K, et al. Cognitive function in a randomized trial of evolocumab. N Engl J Med 2017;377:633-43. PUBMED https://www.ncbi.nlm.nih.gov/pubmed/28813214
- Gencer B, Mach F, Guo J et al. Cognition after lowering LDL-cholesterol with evolocumab. J Am Coll Cardiol 2020;75:2283-93. PUBMED https://www.ncbi.nlm.nih.gov/pubmed/32381158
- Benn M, Nordestgaard BG, Frikke-Schmidt R, Tybjaerg-Hansen A. Low LDL cholesterol, PCSK9 and HMGCR genetic variation, and risk of Alzheimer's disease and Parkinson's disease: Mendelian randomisation study. BMJ 2017;357:j1648. PUBMED https://www.ncbi.nlm.nih.gov/pubmed/28438747