No Short-Term Cognitive Harm From Low LDL-C Levels Achieved With Evolocumab


A new study found that the use of PCSK9 inhibitors with maximally tolerated statins does not negatively affect the mental cognition of patients.


A new study suggests that the use of PCSK9 inhibitors in addition to maximally tolerated statins does not negatively affect the mental cognition of patients.

The findings, which were reported in the Journal of the American College of Cardiology, evaluated patient-reported cognition in the entire Further Cardiovascular Outcomes Research With PCSK9 Inhibitors In Subjects With Elevated Risk (FOURIER) clinical trial using self-survey.1

Previously, the Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects (EBBINGHAUS) trial demonstrated that evolocumab (Repatha) added to a background statin did not affect cognitive performance based on a subset of 1204 patients in the FOURIER study.1

For the current analysis, the investigators used 2-year follow up data from the entire FOURIER trial. Patients in the FOURIER study had atherosclerotic cardiovascular disease and low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dl or non-high-density cholesterol ≥100 mg/d despite statin therapy.1

At their final visit, patients completed a 23-item survey on memory and executive domains from the Everyday Cognition (ECog) scale, comparing their levels of everyday function at the end of their trial with their levels at the beginning. A total of 22,655 patients completed ECog after a median duration of 2.2 years, according to the study.1

The analysis showed that ECog scores of 2 or greater occurred in 3.6% of patients receiving placebo versus 3.7% of patients receiving evolocumab. Additionally, 5.8% of patients receiving placebo and 6% of patients receiving evolocumab reported memory decline, and 3.6% of placebo patients and 3.7% of evolocumab patients reported declines in total executive function.1

Overall, the findings indicated that cognitive decline was similar among patients with LDL-C levels less than 20 mg/dl compared with those with levels of 100 mg/dl (3.8% and 4.5%, respectively).1

“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,” corresponding study author Robert P. Giugliano, MD, SM, senior investigator of the TIMI Study Group at Brigham, Women’s Hospital, and professor of medicine at Harvard Medical School, said in a statement.2

However, in an accompanying editorial, Jennifer G. Robinson, MD, MPH, professor of epidemiology and medicine at the University of Iowa suggested that longer follow-up and more diverse trial populations are needed.3

“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,” she said.3

Study limitations included the healthy volunteer bias in the cognitive survey responders, the relatively younger age of participants, and the low proportion of patients with a history of stroke.2


1. Gencer B, Mach F, Guo J, et al. Cognition after lowering LDL-cholesterol with evolocumab. Journal of the American College of Cardiology. May 2020. 10.1016/j.jacc.2020.03.039
2. PCSK9 Inhibitors with Statin Does Not Cause Memory Loss or Impaired Mental Skills in High-Risk Heart Disease Patients. News Release. American College of Cardiology; May 4, 2020. Accessed May 7, 2020.
3. Robinson JG. Low LDL-C Levels Likely No Short-Term Cognitive Harm. Editorial Comment. Journal of the American College of Cardiology. May 2020. DOI: 10.1016/j.jacc.2020.03.040

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