Rethinking Whether Very Low LDL Levels Impair Cognition

Published - Written by Michael Mi, MD


In May 2017, NEJM published the much-awaited results of the FOURIER trial (see also related blog post). In that study, evolocumab, a monoclonal antibody against PCSK9, reduced cardiovascular events when added to lipid-lowering therapy. Finally, clinicians had another tool in their armamentarium to dramatically lower low-density lipoprotein cholesterol (LDL-C) levels and improve outcomes in patients receiving maximally tolerated statin therapy but still at high risk for adverse cardiovascular outcomes. However, lingering in the minds of everyone was the issue of safety, especially with unprecedented low levels of LDL-C; the median LDL-C level of patients randomized to evolocumab in FOURIER was 30 mg per deciliter. 

You may remember that in 2012, the FDA added a warning to the label for statins that they may cause cognitive side effects such as memory loss or confusion. The initial finding was based on post-marketing reports, observational studies, and smaller randomized clinical trials than FOURIER. Subsequent research has not established this association and it remains uncertain whether the cognitive effects, if they exist at all, are from lowering of LDL-C or from some other property unique to statins. Because cholesterol is important for synapse formation and function and for neuronal membrane integrity, it is biologically plausible that exceedingly low concentrations of lipids could be harmful. Previous results from phase 2 and phase 3 studies and open-label continuation studies of PCSK9 inhibitors have shown a small increase (approximately 0.5%) in neurocognitive adverse events in the drug groups.

Recognizing the possibility of similar cognitive impairment with evolocumab and the lack of high-quality evidence, the FOURIER investigators pre-planned a subgroup study, EBBINGHAUS (perhaps aptly named in honor of Hermann Ebbinghaus, the German psychologist and pioneer in the study of memory). This week, NEJM published the results from the EBBINGHAUS study of 1974 patients from FOURIER with no history of dementia, mild cognitive impairment, or other significant mental or neurologic disorders. The investigators prospectively tested the patients’ cognitive function with an FDA-approved and validated tablet-based tool (the Cambridge Neuropsychological Test Automated Battery [CANTAB]).

The primary outcome was the change in spatial working memory strategy index of executive function (index range, 4 to 28; lower scores represent better function) on CANTAB, and secondary outcomes were changes in other components such as episodic memory and psychomotor speed. The primary analysis was a noninferiority comparison of the change from baseline in the spatial working memory strategy index between patients who received evolocumab or placebo (the noninferiority margin was set at 20% of the standard deviation of the score in the placebo group).

Among the 1204 participants who underwent baseline CANTAB assessment before starting the study, baseline scores for the primary outcome were 17.8 in both groups. After a median follow up of 19.4 months, mean (± SD) changes from baseline were -0.21 ± 2.62 in the evolocumab group and -0.29 ± 2.81 in the placebo group (P< 0.001 for noninferiority). Secondary endpoints also did not differ statistically and similar findings were observed in analysis of the original 1974 patients, including those who had their first CANTAB assessment after starting evolocumab or placebo.

One of the most provocative findings was that cognitive outcome did not differ between groups when stratified by lowest-attained LDL-C level. In other words, very low levels of LDL-C did not seem to increase risk of cognitive impairment. If statins prove to be associated with cognitive risk — and this is not certain — the risk presumably would be caused by some quality of the drug class. Also reassuring was that patients in both groups reported virtually identical results at the end of the study on self-assessment with the Everyday Cognition Questionnaire, (1.13 vs. 1.14 for evolocumab and placebo, respectively).

The authors concluded that, “among patients who received either the PCSK9 inhibitor evolocumab or placebo in addition to statin therapy, we did not find an association between adverse cognitive effects and evolocumab, as compared with placebo, over a median of 19 months, even among patients who attained very low levels of LDL cholesterol.” Both the safety results from the complete FOURIER trial and this substudy should reassure clinicians that evolocumab does not lead to cognitive decline in patients who need another option to reduce their risk of recurrent cardiovascular events.

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Dr. Mi is a 2017-2018 NEJM Editorial Fellow and a hospitalist at Beth Israel Deaconess Medical Center. He graduated from Harvard Medical School and completed his internal medicine training at BIDMC.