Cognitive function in a randomized trial of evolocumab
Open accessAbstract
Background Findings from clinical trials of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors have led to concern that these drugs or the low levels of low-density lipoprotein (LDL) cholesterol that result from their use are associated with cognitive deficits. Methods In a subgroup of patients from a randomized, placebo-controlled trial of evolocumab added to statin therapy, we prospectively assessed cognitive function using the Cambridge Neuropsychological Test Automated Battery. The primary end point was the score on the spatial working memory strategy index of executive function (scores range from 4 to 28, with lower scores indicating a more efficient use of strategy and planning). Secondary end points were the scores for working memory (scores range from 0 to 279, with lower scores indicating fewer errors), episodic memory (scores range from 0 to 70, with lower scores indicating fewer errors), and psychomotor speed (scores range from 100 to 5100 msec, with faster times representing better performance). Assessments of cognitive function were performed at baseline, week 24, yearly, and at the end of the trial. The primary analysis was a noninferiority comparison of the mean change from baseline in the score on the spatial working memory strategy index of executive function between the patients who received evolocumab and those who received placebo; the noninferiority margin was set at 20% of the standard deviation of the score in the placebo group. Results A total of 1204 patients were followed for a median of 19 months; the mean (±SD) change from baseline over time in the raw score for the spatial working memory strategy index of executive function (primary end point) was -0.21±2.62 in the evolocumab group and -0.29±2.81 in the placebo group (P<0.001 for noninferiority; P=0.85 for superiority). There were no significant between-group differences in the secondary end points of scores for working memory (change in raw score, -0.52 in the evolocumab group and -0.93 in the placebo group), episodic memory (change in raw score, -1.53 and -1.53, respectively), or psychomotor speed (change in raw score, 5.2 msec and 0.9 msec, respectively). In an exploratory analysis, there were no associations between LDL cholesterol levels and cognitive changes. Conclusions In a randomized trial involving patients who received either evolocumab or placebo in addition to statin therapy, no significant between-group difference in cognitive function was observed over a median of 19 months. (Funded by Amgen; EBBINGHAUS ClinicalTrials.gov number, NCT02207634 .).
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Trials of PCSK9 inhibitors in cardiovascular populations consistently showed substantial reductions in LDL cholesterol without negative cognitive effects.
“Trials of PCSK9 inhibitors in cardiovascular populations consistently showed substantial reductions in LDL cholesterol without negative cognitive effects [11,22].”
From The Roles of PCSK9 in Alzheimer’s Disease: A Systematic Review of Clinical, Genetic, and Preclinical Evidence (2025) · cites this paper as [22]
The Discussion reports no adverse cognitive effect of evolocumab versus placebo over a median of 19 months, even among patients who attained very low LDL cholesterol levels. But this was one evolocumab study, not evidence that PCSK9 inhibitor trials consistently found no negative cognitive effects; the paper also reports that earlier trials and a meta-analysis found an association with cognitive adverse events (Introduction, p. 634; Discussion). (LLM, conf=0.88)
Experimental — accuracy not yet measuredAn anti-PCSK9 antibody study observed no significant between-group difference in cognitive function over a median of 19 months.
“an anti-PCSK9 antibody study observed no significant between-group difference in cognitive function over a median of 19 months [66].”
From PCSK9 acts as a key regulator of Aβ clearance across the blood–brain barrier (2022) · cites this paper as [66]
Large cardiovascular trials of PCSK9 antibodies such as evolocumab have not demonstrated cognitive harm.
“large cardiovascular trials of PCSK9 antibodies such as evolocumab have not demonstrated cognitive harm10,43”
From Small-molecule PCSK9 inhibition enhances BBB amyloid-β clearance and suppresses microglial inflammation in Alzheimer’s disease models (2026) · cites this paper as [43]
No change in cognitive function has been reported in studies with the addition of ezetimibe or PCSK9 inhibitors to statin therapy, including among individuals treated to very low LDL cholesterol levels.
“In addition, no change in cognitive function has been reported in studies with the addition of ezetimibe (119) or PCSK9 inhibitors (121,170) to statin therapy, including among individuals treated to very low LDL cholesterol levels.”
From 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [170]
No change in cognitive function has been reported in studies with the addition of ezetimibe or PCSK9 monoclonal antibodies to statin therapy, including among individuals treated to very low LDL cholesterol levels.
“In addition, no change in cognitive function has been reported in studies with the addition of ezetimibe (112) or PCSK9 monoclonal antibodies (115,164) to statin therapy, including among individuals treated to very low LDL cholesterol levels.”
From 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [164]
Our findings are in line with data from PCSK9 inhibitor clinical trials and from observations that people carrying loss-of-function mutations of PCSK9 gene have no signs of neurological defects.
“Our findings are in line with data from PCSK9 inhibitor clinical trials (Giugliano et al., 2017; Mannarino et al., 2018; Gencer et al., 2020; Ray et al., 2020) and from observations that people carrying loss-of-function mutations of the PCSK9 gene have no signs of neurological defects (Cohen et al., 2005, 2006; Zhao et al., 2006; Hooper et al., 2007; Mefford et al., 2018).”
From PCSK9 deficiency alters brain lipid composition without affecting brain development and function (2023) · cites this paper as Giugliano et al., 2017
The absolute benefit of statin treatment was lower in primary prevention populations, who are typically at lower risk.
“The absolute benefit from statin treatment was lower in people in primary prevention, who are typically at lower risk [36,38,214,215].”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [215]
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- Authors
- Giugliano, R. P., Mach, F., Zavitz, K., Kurtz, C., Im, K., Kanevsky, E., Schneider, J., Wang, H., Keech, A., Pedersen, T. R., Sabatine, M. S., Sever, P. S., Robinson, J. G., Honarpour, N., Wasserman, S. M., & Ott, B. R.
- Affiliations
- Oslo University Hospital (NO)
- University of Iowa (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2017-08-17
- Volume
- 377
- Issue
- 7
- Pages
- 633-643
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2746224452
- Cited by
- 492
- References
- 29
- Citations by year
- 2026: 36 · 2025: 39 · 2024: 35 · 2023: 41 · 2022: 46 · 2021: 63 · 2020: 68 · 2019: 63 · 2018: 75 · 2017: 23
- FWCI
- 64.10
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- NORA - Norwegian Open Research Archives (submittedVersion, other-oa)
- Spiral (Imperial College London) (submittedVersion)
- Funders
- National Institute for Health and Care Research (NF-SI-0513-10059)
- University of California, Davis
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- evolocumab, PCSK9 inhibitors, cognitive function, executive function, spatial working memory, working memory, episodic memory, psychomotor speed, LDL cholesterol, statin therapy, non-inferiority, cognitive safety, hypercholesterolemia, Alzheimer's disease risk, dementia risk, cognitive decline
- MeSH terms
- Proprotein Convertase 9, PCSK9 Inhibitors, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Anticholesteremic Agents, Cognition, Double-Blind Method, Drug Therapy, Combination, Female, Humans, Cholesterol, LDL, Male, Memory, Middle Aged, Prospective Studies, Psychological Tests, Self-Assessment, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Atherosclerosis, Antibodies, Monoclonal, Humanized
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