The Journal of the American College of Cardiology has recently published a study showing that the addition of a proprotein convertase subtilisin kexin 9 (PCSK9) inhibitor evolocumab to a maximally tolerated dose of statin medication has no adverse impact on patient-reported cognitive performance.1 Patients with atherosclerotic cardiovascular disease (ASCVD) that were treated with evolocumab also showed no significant divergence in cognitive performance when compared to placebo.1,2 These results confirmed that evolocumab is an effective treatment option for reducing low-density lipoprotein cholesterol (LDL-C) while maintaining patient’s neurocognitive function.1
To manage patients at high ASCVD risk, the 2019 European Society of Cardiology/European Atherosclerosis Society Guidelines for the Management of Dyslipidemias recommends treatment to lower LDL-C level to below 70mg/dL.3 PCSK9 inhibitors such as evolocumab, a human monoclonal antibody (mAb), is one such treatment option that can reduce LDL-C levels by approximately 60%.2 However, there is evidence that LDL-C level is inversely related to the incidence of dementia and cognitive impairment.4
To support its widespread use, the neurocognitive safety of evolocumab was studied in two randomized trials: The FOURIER (Further Cardiovascular Outcomes Research With PCSK9 inhibitors in Subjects With Elevated Risk) and EBBINGHAUS (Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects) trials. In the FOURIER trial, 27,564 patients with ASCVD and LDL-C levels of 70mg/dL or higher even after receiving statin therapy were recruited.1 In this randomized, double-blind trial, patients were given statin regimens augmented by either evolocumab or placebo, and the incidence of CV events were evaluated. Results from FOURIER showed that the inhibition of PCSK9 with evolocumab on a background of statin therapy lowered the LDL-C levels to 30mg/dL and reduced the risks of CV events.2
Following the FOURIER trial, the EBBINGHAUS trial investigated the neurocognitive functions of a subset of 1,204 patients who underwent objective cognitive testing in the domains of executive and memory functions using the Cambridge Neuropsychological Test Automated Battery (CANTAB). The trial demonstrated that the evolocumab-statin combo did not impact cognitive performance.5
To further evaluate the safety of evolocumab, a new trial expanded on the premise of the EBBINGHAUS trial and utilized the 2-year follow up data from the entirety of the FOURIER trial. The primary endpoint was the total score of a questionnaire of 23 items abbreviated from the full 39-item Everyday Cognition (ECog) survey. The questionnaire allowed patients to evaluate their own cognitive performance in the subdomains of memory and total executive cognitive function on a four-point scale.1
The outcome showed that there were no statistically significant differences in cognitive ability between patients who received evolocumab and placebo. Declines in cognition (average ECog score ≥2) were similar between evolocumab and placebo group for total score (3.7% vs. 3.6%; p=0.62), memory subdomain (6.0% vs. 5.8%; p=0.53), and total executive subdomain (3.7% vs. 3.6%; p=0.83). Similar patterns were observed between patients with low LDL-C level (<20mg/dL) and high LDL-C amounts (≥100mg/dL) with total score (4.5% vs. 3.8%; p=0.57), memory subdomain (6.9% vs. 5.8%; p=0.92) and total executive subdomain (4.6 vs. 3.9%; p=0.48) when treated with evolocumab.1
The new trial confirmed the neurocognitive safety of the evolocumab-statin regimen in reducing the LDL-C level and the risk of developing ASCVD. In patients with high risk of recurrent CV events, evolocumab can provide intensive LDL-C reduction while maintaining the patient’s neurocognitive function.1
1. Gencer B et al. Cognition After Lowering LDL-Cholesterol With Evolocumab. J Am Coll Cardiol. 2020;75(18):2283-2293.
2. Sabatine MS et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017;376(18):1713-1722.
3. Mach F et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41(1):111-188.
4. Zhou F et al. High Low-Density Lipoprotein Cholesterol Inversely Relates to Dementia in Community-Dwelling Older Adults: The Shanghai Aging Study. Front Neurol. 2018;9:952. Published 2018 Nov 12.
5. Giugliano RP et al. Cognitive Function in a Randomized Trial of Evolocumab. N Engl J Med. 2017;377(7):633-643.