Long-term exposure to very low LDL-c with evolocumab does not affect cognition in patients with ASCVD

In the EBBINGHAUS-OLE study among patients with stable ASCVD and LDL-c ≥70 mg/dL, exposure to even very low LDL-c levels, achieved with PCSK9 inhibition and statin therapy, was not associated with cognitive impairment during follow-up (up to 7.2 years).

This summary is based on the publication of Zimerman A, O’Donoghue ML, Ran X, et al. - Long-Term Cognitive Safety of Achieving Very Low LDL Cholesterol with Evolocumab. NEJM Evid. 2025 Jan;4(1):EVIDoa2400112. doi: 10.1056/EVIDoa2400112

Introduction and methods

Background

Lipid-lowering therapies are the cornerstone of MACE prevention in high-risk populations [1-3], but there are concerns about the effect of very low LDL-c levels on cognitive function [4]. Although systematic reviews and meta-analyses have not shown any significant adverse effects of this treatment on cognition in the short term [5-7], the long-term cognitive effect of sustained exposure to very low LDL-c levels are unknown.

The EBBINGHAUS (Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects) study demonstrated no differences in cognitive function of high-risk patients with ASCVD who were treated with evolocumab versus placebo, in addition to statin therapy, during a median follow-up time of 1.6 years [8].

Aim of the study

In the EBBINGHAUS-OLE (open-label extension) study, the authors assessed the long-term effect of evolocumab on cognitive function of high-risk patients with ASCVD.

Methods

The EBBINGHAUS study was a prespecified neurocognitive study embedded in the FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial, which was an international, multicenter, double-blind, placebo-controlled, phase 3 RCT that enrolled 27,564 patients with established ASCVD and LDL-c ≥70 mg/dL (≥1.8 mmol/L) or non–HDL-c ≥100 mg/dL (≥2.6 mmol/L) despite optimized statin therapy. Participants were randomized to subcutaneous evolocumab (140 mg every 2 weeks or 420 mg every 4 weeks) or placebo. Patients with no cognitive impairment from selected sites were eligible for the EBBINGHAUS study (n=1974). Cognitive function was assessed with the Cambridge Neuropsychological Test Automated Battery (CANTAB).

At the end of the FOURIER trial, patients who completed the trial at participating sites in North America and Europe were eligible for enrollment in the observational FOURIER-OLE study, where they all received evolocumab [9]. Patients from the EBBINGHAUS study also underwent cognitive assessments during the OLE period, and 473 of them were included in the current analysis. In the EBBINGHAUS-OLE study, median follow-up duration was 5.1 years (IQR: 5.0–5.1; maximum: 5.5), with a median total follow-up time from randomization of 6.7 years (IQR: 6.6–6.9; maximum: 7.2). At week 12 of the OLE period, the median LDL-c level was 35 mg/dL (IQR: 21–55) and 159 patients achieved very low LDL-c levels (<25 mg/dL).

Outcomes

The primary endpoint was the change from baseline in executive function, as measured with score on the spatial working memory strategy index (SWMI), a principal component of the CANTAB. The SWMI score ranges from 4 to 28, with lower scores indicating better performance.

Secondary safety endpoints included 3 additional CANTAB measures: (1) spatial working memory between-errors score, to assess working memory; (2) paired associates learning score, to assess episodic memory; and (3) median 5-choice reaction time, to assess psychomotor speed. In all these tests, lower scores indicate better performance.

Main results

Cognitive endpoints

• During the OLE period, treatment with evolocumab was not associated with a change in executive function from baseline in patients who were originally randomized to and continued with evolocumab (n=235) (mean ± SD difference in SWMI score: 0.1 ± 2.8; P=0.49) and those originally randomized to placebo who were then switched to evolocumab (n=238) (mean ± SD difference in SWMI score: –0.1 ± 2.5; P=0.64).
• In addition, there was no apparent difference in the change in executive function between the treatment groups over time.
• With regard to the secondary safety endpoints, there were no apparent changes over time in working memory, either in each group individually or between groups. • On the episodic memory test, patients originally randomized to evolocumab showed a trivial improvement (Cohen’s d=0.14), whereas a small improvement was seen in patients originally randomized to placebo (Cohen’s d=0.23).
• For the psychomotor speed test, there was no apparent change over time in patients originally randomized to evolocumab and a trivial worsening in patients originally randomized to placebo (Cohen’s d=0.19), with no apparent between-group difference.
• At the final study visit, there were no apparent differences between the treatment groups in any of the 4 cognitive scores, and all differences in effect size were considered to be trivial (all Cohen’s d≤0.18).

Association between change in cognitive function and achieved LDL-c levels

• In the total study population, stratification of patients based on LDL-c levels at week 12 of the OLE period indicated similar changes in the primary and secondary safety endpoints between the subgroups.
• Among patients who were originally randomized to placebo and later switched to evolocumab, achieving very low LDL-c levels (<25 mg/dL) was also not associated with subsequent changes in any of the cognitive scores.

Conclusion

In the EBBINGHAUS-OLE study among high-risk patients with stable ASCVD, exposure to even very low LDL-c levels, achieved with PCSK9 inhibition and statin therapy, was not associated with cognitive impairment through long-term follow-up (up to 7.2 years). The authors conclude: “Our findings in this rigorous cognitive assessment study provide reassurance that, irrespective of achieved LDL-c, PCSK9 inhibition is unlikely to lead to long-term cognitive deterioration.”

Find this article online at NEJM Evid.

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