No dementia, cognitive risk with PCSK9 inhibition; statin findings mixed
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Data from a genetics-based study show PCSK9 inhibition does not affect cognition function or dementia risk; however, statin use may be associated with some impaired cognitive performance that is outweighed by any CV benefits.
“PCSK9 inhibition, as modeled via genetic Mendelian randomization methods, has a neutral cognitive profile,” Falk W. Lohoff, MD, chief of the section on clinical genomics and experimental therapeutics and Lasker Clinical Research Scholar at the National Institute on Alcohol Abuse and Alcoholism at the NIH, told Healio. “While we observed some possible adverse neurocognitive effects with statins, the effect size was small and might not outweigh their well-known clinical cardiovascular benefits.”
PCSK9 inhibition safe
Using publicly available genome-wide association summary-level statistics of LDL, Lohoff and colleagues extracted single nucleotide polymorphisms in 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and PCSK9. The researchers performed drug-target Mendelian randomization, proxying the potential neurocognitive impact of drug-based PCSK9 and HMGCR inhibition using seven cognitive function outcomes (including cognitive performance and fluid intelligence using verbal-numerical reasoning scores) and four dementia-related outcomes (including Alzheimer’s disease progression score and cerebral amyloid deposition).
The findings were reported in the Journal of the American College of Cardiology.
Using data from a combined sample of 740,000 participants, researchers found effect estimates for PCSK9 inhibition were null for every cognitive-related outcome.
“Our data suggest that long-term PCSK9 inhibition is safe from a neurocognitive and dementia risk standpoint,” Lohoff told Healio. “Ultimately, clinical studies are needed to confirm our observations.”
The researchers wrote that the findings are important to alleviate ongoing concern regarding the neurocognitive safety of PCSK9 inhibition that may be contributing to their underuse.
‘Continued pharmacovigilance’ with statins
In contract with the PCSK9 findings, researchers observed several adverse associations between HMGCR inhibition and cognitive outcomes, including lowered cognitive performance (beta = –0.082; 95% CI, –0.16 to –0.008; P = .03), reaction time (beta = 0.00064; 95% CI, 0.0003-0.00098; P = .0002), and cortical surface area (beta = –0.18; 95% CI, –0.35 to –0.014; P = .03).
“We identified potential relationships between sustained HMGCR inhibition and cognitive outcomes (reduced cortical surface area, worsened reaction time and impaired cognitive performance) in line with some post-marketing surveillance, case reports and patient survey-based analyses identifying cognitive impairment with statin use,” the researchers wrote. “Prior studies have also reported that cognitive side effects associated with statin use were reversed upon their discontinuation. Given that statins are among the most commonly prescribed classes of medication, our findings, taken together with these observations, suggest continued pharmacovigilance by clinicians and public health officials.”
There were no associations between PCSK9 or HMGCR inhibition and biomarkers of Alzheimer’s disease progression or Lewy body dementia risk.
Additionally, the researchers cautioned that the adverse effect estimates for HMGCR inhibition suggest additional studies are warranted, but the findings do not outweigh the CV benefits of statin use.
“Together, these findings should help alleviate ongoing fears of cognitive decline and other adverse neurocognitive effects that may be contributing to the underuse of these cardiovascular therapeutic classes,” the researchers wrote.
‘Carefully, deliberately and cautiously’ interpret results
In a related editorial, Brian A. Ference, MD, MPhil, MSc, FACC, FESC, executive director of the Centre for Naturally Randomized Trials at the University of Cambridge, wrote that the CV community should be reassured that the data do not provide compelling evidence that treatment with a statin can potentially cause cognitive impairment.
“As a result, persons taking a statin should not discontinue their therapy for fear that statins cause cognitive impairment,” Ference wrote. “Instead, this study serves as an important example of why it is necessary to carefully, deliberately and cautiously interpret the clinical implications of drug-target Mendelian randomization studies to avoid potentially ‘causing’ harm to patients.”
Reference:
Ference BA. J Am Coll Cardiol. 2022;doi:10.1016/j.jacc.2022.06.007.
For more information:
Falk W. Lohoff, MD, can be reached at falk.lohoff@nih.gov.
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