PCSK9 Inhibitors and Statins for lowering LDL Cholesterol Levels exhibit Long-Term Cognitive Safety: Study

Concerns have been raised about the cognitive safety of obtaining extremely low levels of low-density lipoprotein (LDL) cholesterol through PCSK9 inhibition and statin therapy. Although short-term studies are reassuring, the long-term effects of sustained exposure to very low LDL cholesterol levels through combined PCSK9 inhibition and statin therapy are uncertain. Hence, researchers conducted a prospective study to assess the long-term effect of evolocumab on cognitive function.

The study included adults with atherosclerotic cardiovascular disease who had completed a neurocognitive sub-study (EBBINGHAUS) of a placebo-controlled evolocumab (FOURIER) trial and were eligible for a long-term open-label extension. Cognitive function was assessed every year. The primary endpoint was a change from baseline in executive function within each group. A spatial working memory strategy index score was used to measure the change in the scores. A range of 4-28 was given to the scores, and lower scores indicated better performance.

Findings:

• About 473 of the 1974 patients in the parent EBBINGHAUS study were enrolled and followed for a median of 5.1 years (maximum follow-up since original random assignment 7.2 years).
• The median age was 62; 70% were male, and 91% were White.
• At 12 weeks into the open-label extension period, median LDL cholesterol across the overall population was 35 mg/dl (interquartile range, 21–55 mg/dl).
• There was no change in executive function in patients treated with evolocumab during the open-label extension, either patients who were initially randomly assigned to and continued evolocumab or patients initially randomly assigned to placebo and then started on evolocumab.
• The executive function scores were similar between randomly assigned groups in the final study visit.

Thus, the study concluded that exposure to low LDL cholesterol levels was not associated with cognitive impairment in patients requiring aggressive lipid therapy. The study underscores the importance of cognitive safety reassurance from long-term statin therapy. As the condition is not compromised, rapid lipid-lowering agents can be used for long-term adherence in needed individuals. However, researchers suggest further research in diverse populations to explore the potential effects of these drugs.

Further reading: 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):EVIDoa2400112. doi:10.1056/EVIDoa2400112.