Very Low LDL-C Achieved With Evolocumab Not Associated With Long-Term Cognitive Impairment

According to results from a prospective trial conducted by investigators and published in the New England Journal of Medicine Evidence, exposure to very low levels of low-density lipoprotein cholesterol (LDL-C) through treatment with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition and statin therapy was not associated with cognitive impairment during a long-term follow-up. However, investigators note the need for further investigations to assess the generalizability to adults at a higher risk of dementia.¹

Very low LDL cholesterol levels have been suspected to cause varying degrees of cognitive impairment. | Image Credit: © Superrider - stock.adobe.com

Evolocumab is a type of PCSK9 inhibitor indicated to reduce the risk of myocardial infarction, coronary revascularization, and stroke in adults with cardiovascular disease. Additionally, and of most interest to the present investigators, the medicine can treat patients with primary hyperlipidemia, help reduce lipoprotein cholesterol levels when used in combination with a healthy diet, and treat homozygous familial hypercholesterolemia.^1,2

Studies have found that evolocumab can reduce median LDL-C to 30 mg/dL and reduce patient cardiovascular risk. However, concerns among clinicians and treatment providers have remained regarding the cognitive safety of achieving very low levels of LDL-C. Results from short-term studies provide some reassurance; one trial, conducted by Hua et al with a 2-year follow-up, found that low LDL-C levels were associated with significantly slower cognitive decline in a population-based setting. Despite these promising results, it has remained unknown what the long-term cognitive effects of sustained exposure to very low LDL-C levels are, especially through combined PCSK9 inhibition and statin therapy.^1,3

Enrollees in this trial included a subset of adults with atherosclerotic cardiovascular disease who had completed a neurocognitive substudy—EBBINGHAUS—of a placebo-controlled randomized trial of evolocumab—FOURIER—and were eligible for participation in a long-term open-label extension. In the trial, investigators sought to assess the long-term effects of evolocumab on cognitive function; cognitive function was assessed annually, with a primary end point of change from baseline in executive function in each group. This was measured using a spatial working memory strategy index score—lower scores indicate better cognitive performance.^1,4,5

From the parent EBBINGHAUS trial’s population of 1974 patients, a total of 473 were enrolled and followed for a median of 5.1 years. Basic patient demographic information includes a median age of 62 years, 70% of the population being male, and 91% being White. Median LDL-C among the entirety of the overall population was 35 mg/dL (IQR: 21-55 mg/dL) 12 weeks into the open-label extension period, according to the study authors.¹

Investigators found that treatment with evolocumab was not associated with a change in executive function during the open-label extension in both patients who were originally randomly assigned to and continued evolocumab (mean ± SD; 0.1 ± 2.8, P = .49) and patients originally randomly assigned to placebo and then started on evolocumab (0.1 ± 2.5, P = .64). Upon the final study visit for patients, executive function scores were found to be similar between the randomly assigned groups (17.5 ± 3.7 and 17.3 ± 3.7, respectively).¹

“Exposure to very low levels of LDL-C, achieved via PCSK9 inhibition and statin therapy, was not associated with cognitive impairment through long-term follow-up,” the investigators asserted. “Further studies are needed to assess the generalizability to adults at higher risk of dementia.”¹

REFERENCES

1. Zimerman A, O’Donoghue ML, Ran X, et al. Long-term cognitive safety of achieving very low LDL cholesterol with evolocumab. NEJM Evid. 2025;4(1). doi:10.1056/EVIDoa2400112

2. Arakelians S. Pharmacists’ guide to evolocumab for lowering LDL-C. Pharmacy Times. Published August 28, 2024. Accessed March 27, 2025. https://www.pharmacytimes.com/view/pharmacists-guide-to-evolocumab-for-lowering-ldl-c

3. Gua R, Ma Y, Li C, et al. Low levels of low-density lipoprotein cholesterol and cognitive decline. Science Bulletin. 2021;66(16):1684-1690. doi:10.1016/j.scib.2021.02.018

4. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713-1722. doi:10.1056/NEJMoa1615664

5. Giugliano RP, Mach F, Zavitz K, et al. Cognitive function in a randomized trial of evolocumab. N Engl J Med. 2017;377(7):633-643. doi:10.1056/NEJMoa1701131