Cognitive Function in a Randomized Trial of Evolocumab

Study Questions:

Is there evidence that proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors plus statins that lower low-density lipoprotein cholesterol (LDL-C) to very low levels are associated with cognitive deficits?


In a subgroup of patients from a randomized, placebo-controlled trial of evolocumab added to statin therapy (FOURIER), cognitive function was assessed using the Cambridge Neuropsychological Test Automated Battery. The primary endpoint was the score on the spatial working memory strategy index of executive function, with lower scores indicating a more efficient use of strategy and planning. Secondary endpoints were the scores for working memory, with lower scores indicating fewer errors, episodic memory with lower scores indicating fewer errors, and psychomotor speed 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.


A total of 1,204 patients were followed for a median of 19 months; at baseline, mean age was 63 years, 6% had a previous myocardial infarction (MI), about 20% had a previous stroke, and median LDL-C was 92 mg/dl; >70% were on high- and 30% on moderate-intensity statins, 90% were on platelet inhibitors, and 74% were on beta-blockers and angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, or aldosterone antagonists. The mean change from baseline over time in the raw score for the spatial working memory strategy index of executive function (primary endpoint) 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 endpoints of scores for working memory, episodic memory, or psychomotor speed. In an exploratory analysis, there were no associations between LDL-C levels and cognitive changes.


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.


The signal that statins or very low levels of LDL-C may cause cognitive impairment is one of the reasons for poor statin compliance. This study helps to refute that concern. However, as the authors summarized, the follow-up was short and patients with mild cognitive impairment were excluded. There is a 5-year extension trial of FOURIER that includes 500 patients in the EBBINGHAUS trial.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Sleep Apnea

Keywords: Adrenergic beta-Antagonists, Angiotensin Receptor Antagonists, Cholesterol, LDL, Cognition, Cognition Disorders, Dyslipidemias, Executive Function, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Memory Disorders, Myocardial Infarction, Neuropsychological Tests, Platelet Aggregation Inhibitors, Primary Prevention, Proprotein Convertases, Stroke, Subtilisins

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