Statin therapy may impact cognitive health, experts say to interpret results very carefully: JACC
USA: Statin use for lowering LDL-cholesterol levels may result in adverse neurocognitive effects related to HMGCR inhibition, which may be outweighed by its cardiovascular benefits but requires pharmacovigilance, states a genetic-based study published in the Journal of the American College of Cardiology.
On the other hand, PCSK9 inhibitors, which also lower LDL-C levels but through a different mechanism may have a neutral cognitive profile. The experts who were not involved in the study, however, urged precaution in the interpretation of the findings.
Lipid-lowering therapy with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition and statins are effective strategies for lowering the risk of cardiovascular disease, however, concerns there are concerns about potential long-term adverse neurocognitive effects. Considering this, Daniel B. Rosoff, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA, and colleagues aimed to evaluate the relationships of long-term PCSK9 inhibition and statin use on neurocognitive outcomes in a genetics-based study.
For this purpose, the researchers extracted single-nucleotide polymorphisms in 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and PCSK9 from predominantly European ancestry-based genome-wide association studies summary-level statistics of LDL-cholesterol and performed drug-target Mendelian randomization. The potential neurocognitive impact of drug-based PCSK9 and HMGCR inhibition was proxied using a range of outcomes to capture the complex facets of cognition and dementia.
The study led to the following findings:
- Using data from a combined sample of ∼740,000 participants, the researchers observed a neutral cognitive profile related to genetic PCSK9 inhibition, with no significant effects on cognitive performance, memory performance, or cortical surface area.
- Several adverse associations were observed for HMGCR inhibition with lowered cognitive performance (beta: –0.082), reaction time (beta = 0.00064), and cortical surface area (beta = –0.18).
- Neither PCSK9 nor HMGCR inhibition impacted biomarkers of Alzheimer's disease progression or Lewy body dementia risk.
- Consistency of findings across Mendelian randomization methods accommodating different assumptions about genetic pleiotropy strengthens causal inference.
"The results of Mendelian randomization studies in general—and drug-target Mendelian randomization studies in particular — must be interpreted carefully and with extreme caution," Brian A. Ference wrote in an accompanying editorial. "This is particularly true for evaluating potential adverse events in drug-target Mendelian randomization studies because drug-related adverse events tend to be uncommon and have unclear causal explanations."
"We failed to find genetic evidence of an adverse PCSK9-related impact, indicating a neutral cognitive profile," the researchers wrote. In contrast, adverse neurocognitive effects related to HMGCR inhibition was observed, which may well be outweighed by the cardiovascular benefits of statin use, but nonetheless may warrant pharmacovigilance."
Reference:
Rosoff DB, Bell AS, Jung J, Wagner J, Mavromatis LA, Lohoff FW. Mendelian Randomization Study of PCSK9 and HMG-CoA Reductase Inhibition and Cognitive Function. J Am Coll Cardiol. 2022 Aug 16;80(7):653-662. doi: 10.1016/j.jacc.2022.05.041. PMID: 35953131.
