Statins are used to reduce low-density lipoprotein cholesterol (LDL-C), or bad cholesterol, and prevent heart disease and stroke. However, some high-risk patients need to take PCSK9 inhibitors combined with a maximally tolerated statin or other lipid-lowering therapies to reduce their LDL-C even more. While prior research has shown that heart disease patients do not experience adverse neurocognitive effects when taking PCSK9 inhibitors with statin to treat bad cholesterol, until now there has not been a large-scale trial to investigate the impact of using evolocumab and statin to achieve very low LDL-C levels on patient-reported cognition.

Researchers in this study looked at the self-reported Everyday Cognition study results from 22,655 patients in the original FOURIER trial, which was completed after a median duration of 2.2 years. The percentage of patients who reported cognitive decline at the end of the study was similar for placebo vs. those taking evolocumab, both for total score 3.6% vs. 3.7%, respectively, and for subdomains (memory 5.8% vs. 6% and total executive function 3.6% vs. 3.7%, respectively). The proportion reporting cognitive decline was similar in patients who achieved very low LDL-C levels (<20 mg/dL) vs. those with LDL-C ≥100 mg/dL, with scores of 3.8% vs. 4.5%, respectively.

"These data confirm the neurocognitive safety of intensive LDL-C reduction with evolocumab, while simultaneously reducing recurrent cardiovascular events in high-risk patients, and suggest that very low achieved LDL-C levels may be safely targeted for high-risk patients," said Robert P. Giugliano, MD, SM, corresponding author of the study and senior investigator of the TIMI Study Group at Brigham, Women's Hospital and Professor of Medicine at Harvard Medical School in Boston.

The patient-reported outcomes of this comprehensive study in over 22,000 patients build upon the results of the EBBINGHAUS trial, which demonstrated evolocumab added to background statin did not affect cognitive performances using a validated battery of neurocognitive tests performed serially in a subset of 1,204 patients enrolled in the FOURIER trial.

FOURIER was a randomized, double-blind, placebo-controlled trial involving patients with atherosclerotic cardiovascular disease and LDL-C levels ≥70 mg/dL despite statin. At the final visit, patients completed a 23-item survey on memory and executive domains from the Everyday Cognition scale.

This study has several limitations, including a healthy volunteer bias in the cognitive survey responders, the relatively younger age of the participants, and the low proportion of patients with a history of stroke.

"It is unclear if this expectation of safety can be extrapolated to periods of greater than 3 years, or to patients who are older than 75 years, are at very high ASCVD risk, or with a history of ischemic or hemorrhagic stroke," said Jennifer G. Robinson, MD, MPH, professor of epidemiology and medicine at the University of Iowa, in an accompanying editorial. "An altered safety profile may influence the potential for a net cardiovascular risk reduction benefit from the addition of PCSK9 mAbs. Longer follow-up and more diverse trial populations are needed."