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.