LDL-c lowering with PCSK9i not associated with changes in cognitive functions

Cognition After Lowering LDL-Cholesterol With Evolocumab

Literature - Gencer B, Mach F, Guo J et al., - J Am Coll Cardiol. 2020. doi: 10.1016/j.jacc.2020.03.039.

Introduction and methods

Addition of evolocumab to a statin reduced stroke, without affecting neurocognitive adverse events in the FOURIER trial (1,2). The neurocognitive function of 1204 patients from the FOURIER trial has been studied in the EBBINGHAUS trial (Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects) [3]. The EBBINGHAUS trial used formal serial objective cognitive testing in the domains of executive and memory functions and did not show any changes in cognitive performance between evolocumab and placebo during an average treatment period of 19 months. This study investigated patient-reported outcomes for cognitive function in 22,655 participants from the FOURIER cohort using a patient self-survey.

The FOURIER trial was a randomized, double-blind, placebo-controlled trial that enrolled 27,564 patients with atherosclerotic CV disease at increased CV risk and a LDL-c ≥70mg/dl or non-high-density lipoprotein cholesterol ≥100 mg/dl while being on optimal statin therapy, with or without ezetimibe. Patients were randomized in a 1:1 ratio to receive either evolocumab (140 mg every 2 weeks or 420 mg every month, subcutaneous) or matching placebo. The primary endpoint of the current analysis was patient-reported cognition, measured at the final visit using an abbreviated 23-item questionnaire with executive and memory domain subscales of the Everyday Cognition (ECog) scale. 22,655 Patients (11,292 randomized to placebo and 11,363 randomized to evolocumab, 82.3% of the overall FOURIER trial) rated their ability to perform tasks in the memory domain or executive function at the end of the study in comparison with the start of the study. The executive function was divided into planning, organization, and divided attention. Median follow-up period was 2.2 years.

Reported scores in cognitive function were compared in the evolocumab vs. placebo group and between pre-specified subgroups of achieved LDL-c values at week 4, irrespective of treatment assignment (<20, 20 to 50, 50 to<70, 70 to <100, and ≥100 mg/dl).

Main results

  • There were no significant differences in reported scores in cognitive function between treatment groups.
  • Percentages of patients reporting a decline in cognition (average ECog score≥2) were similar between the placebo vs. evolocumab group for the total score (3.6% vs. 3.7%, P=0.62), memory function (5.8% vs. 6.0%, P=0.53), executive total score (3.6% vs. 3.7%, P=0.83), executive planning (4.3% vs. 4.4%, P=0.47), executive organization (3.7% vs. 4.1%, P=0.088), and executive divided attention (6.4% vs. 6.5%, P=0.86).
  • No significant trend across subgroups of achieved LDL-c at week 4 was observed after multivariate adjustment for total score (P-trend=0.33), memory score (P-trend=0.12), and executive score (P-trend=0.38).
  • Percentages of patients reporting a decrease in cognition (average ECog score≥2) were similar between the lowest category of achieved LDL-c (<20 mg/dl, n=2,338) vs the highest category of achieved LDL-c (≥100 mg/dl, n=3.613) for total score (3.8% vs. 4.5%, P=0.57), memory function (5.8% vs. 6.9%, P=0.92), and executive function (3.9% vs. 4.6%, P=0.48).


This study showed that the addition of evolocumab to maximally tolerated statin therapy had no significant impact on patient-reported cognition, compared to placebo. Moreover, no association was found between achieved LDL-c at 4 weeks and cognitive function after an average treatment period of 2.2 years.


1. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713–22.

2. Giugliano RP, Pedersen TR, Park JG, et al. Clinical efficacy and safety of achieving very low LDLcholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet 2017;390:1962–71.

3. Giugliano RP, Mach F, Zavitz K, et al. Cognitive function in a randomized trial of evolocumab. N Engl J Med 2017;377:633–43.

Find this article online at J Am Coll Cardiol.

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