Increased Risk of Adverse Neurocognitive Outcomes with Proprotein Convertase Subtilisin-Kexin Type 9 Inhibitors

Abdur Rahman Khan, Chirag Bavishi, Haris Riaz, Talha A. Farid, Sobia Khan, Michel Atlas, Glenn Hirsch, Sohail Ikram, Roberto Bolli

Research output: Contribution to journalArticle


Background - There is encouraging evidence of the efficacy of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors; however, their long-term safety remains unclear. We performed a meta-analysis of studies to evaluate the long-term safety of PCSK9 inhibitors. Methods and Results - Our search strategy yielded 11 studies (9 smaller early-phase and 2 larger outcome trials). The outcomes assessed were cumulative serious adverse events, musculoskeletal adverse events, neurocognitive adverse events, and stroke. Odds ratio (OR) was calculated using the Mantel-Haenszel method. Subgroup analysis was done to assess the difference in safety between the smaller early-phase studies and the larger outcome studies. Our meta-analysis suggested no difference in the incidence of serious adverse events (OR, 1.00; 95% confidence interval [CI], 0.88-1.15), musculoskeletal adverse events (OR, 1.01; 95% CI, 0.87-1.13), neurocognitive adverse events (OR, 1.29; 95% CI, 0.64-2.59), or stroke (OR, 1.44; 95% CI, 0.57-3.65) with the use of PCSK9 inhibitors. Subgroup analysis of the 2 large outcome studies did suggest an increased incidence of neurocognitive adverse events (OR, 2.85; 95% CI, 1.34-6.06) with the use of PCSK9 inhibitors. However, the overall incidence of neurocognitive adverse events and stroke was <1%, whereas the cumulative incidence of serious adverse events and musculoskeletal events was >10% in both the groups. Conclusions - Our analysis suggests that PCSK9 inhibitors are not associated with an increased risk of cumulative severe adverse effects, musculoskeletal effects, or stroke. There is a signal toward adverse neurocognitive effects, seen in the outcome studies with a larger sample size and longer follow-up. There should be close monitoring, for the increased risk of neurocognitive events in the ongoing outcome studies and post-marketing surveillance.

Original languageEnglish (US)
Article numbere003153
JournalCirculation: Cardiovascular Quality and Outcomes
Issue number1
Publication statusPublished - Jan 1 2017
Externally publishedYes



  • cognitive impairment
  • meta-analysis
  • proprotein convertases
  • stroke
  • subtilisins

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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