Very Low LDL-C Levels Do Not Contribute to Declines in Mental Cognition


A new analysis of two-year data from the FOURIER trial is shedding light on the impact of PCSK9 use for lowering LDL-C.

Robert Giugliano, MD, SM

Robert Giugliano, MD, SM

New research is seeking to settle any debate over whether use of PCSK9 inhibitors in addition to maximally-tolerated statins negatively impacts the mental cognition of patients.

An analysis using 2-year follow-up data from the entire FOURIER trial indicated patients taking evolocumab (Repatha) and statins to achieve very low LDL-C levels showed no increase in the incidence of neurocognitive impairments, including memory loss.

"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 study investigator Robert Giugliano, MD, SM, senior investigator of the TIMI Study Group at Brigham and Women's Hospital and Professor of Medicine at Harvard Medical School in Boston, in a statement.

With no information from large-scale trials addressing a potential association between PCSK9 inhibitors and adverse neurocognitive effects, investigators designed the current analysis to fill that gap using the entire FOURIER cohort. Briefly, FOURIER examined use of adjunct evolocumab in atherosclerotic cardiovascular disease versus placebo in more than 27,000 patients.

At the final visit of the FOURIER trial, participants were asked to complete a 23-item survey on memory and executive domains from the Everyday Cognition scale. The survey prompted patients to compare levels of function at the end of the trial with levels at the beginning—scored as 1 (no change or improvement), 2 (occasionally worse), 3 (consistently little worse), or 4 (consistently much worse).

For the purpose of the current analysis, investigators compared the participants’ scores according to the treatment arms and LDL-C levels achieved at week 4. Of the 27,564 patients originally included in FOURIER, 22,655 completed the survey and were included in the analysis—this cohort had a median follow-up of 2.2 years.

Upon analysis, investigators observed Everyday Cognition scores of 2 or greater were present among 3.6% of patients receiving placebo versus 3.7% receiving evolocumab. Investigators also noted 5.8% of patients receiving placebo and 6% receiving evolocumab reported memory decline and 3.6% of placebo patients and 3.7% of evolocumab patients reported declines in total executive function.

Additionally, results indicated cognitive decline was similar among patients with LDL-C levels less than 20 mg/dL compared to those with levels of 100 mg/dL or more with rates of 3.8% and 4.5%, respectively.

The aforementioned release noted multiple limitations within the study. These limitations included a healthy volunteer bias, relatively younger age of participants, and a low proportion of patients with history of stroke.

In an accompanying editorial, Jennifer Robinson, MD, MPH, professor of epidemiology and medicine at the University of Iowa, cautions against overinterpretation of study results due to length of follow-up.

"It is unclear if this expectation of safety can be extrapolated to periods of greater than three 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,” Robinson writes. “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."

This study, “Cognition After Lowering LDL-Cholesterol With Evolocumab,” was published in the Journal of the American College of Cardiology.

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