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Eur Heart J. 2018 Feb 1;39(5):374-381. doi: 10.1093/eurheartj/ehx661.

No evidence of neurocognitive adverse events associated with alirocumab treatment in 3340 patients from 14 randomized Phase 2 and 3 controlled trials: a meta-analysis of individual patient data.

Author information

Department of Psychiatry, University of Miami Miller School of Medicine, 1120 NW 14th Street, Suite 1450, Miami, FL, USA.
Barrow Neurological Institute, 350 W Thomas Rd, Phoenix, AZ 85013, USA.
Alzheimer Center, VUmc, De Boelelaan 1118, 1081 HZ Amsterdam, The Netherlands.
IoPPN, Kings's College, 16 De Crespigny Park, London SE5 8AF, UK.
Columbia University, 622 West 168 Street, New York, NY 10032, USA.
University of Pierre and Marie Curie, 47-83 Boulevard de l'Hôpital, 75013 Paris, France.
Regeneron Pharmaceuticals, 777 Old Saw River Road, Tarrytown, NY 10591, USA.
Sanofi, 55 Corporate Drive, Bridgewater, NJ 08807, USA.
Sanofi, 1 Avenue Pierre Brossolette, 91380 Chilly-Mazarin, France, and IviData Stats, 79 Baudin Street, 92300 Levallois-Perret, France.
Point Médical, Rond Point de la Nation, 21000 Dijon, France, and Department of Cardiology, CHU Dijon Bourgogne, 2 Bd Maréchal de Lattre of Tassigny, 21000 Dijon, France.



Despite patient reports of neurocognitive disorders with lipid-lowering treatments (LLTs), large clinical trials have found no significant association between neurocognitive disorders and LLTs. We assessed incidence of neurocognitive treatment-emergent adverse events (TEAEs) from 14 Phase 2 and 3 trials of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab.

Methods and results:

Patients (most on background maximally tolerated statin) received alirocumab 75/150 mg every 2 weeks (n = 3340; 4029 patient-years of exposure), placebo (n = 1276), or ezetimibe (n = 618). Data were pooled by the control used. Neurocognitive TEAEs were reported by 22 (0.9%) alirocumab-treated patients vs. 9 (0.7%) with placebo in placebo-controlled trials [hazard ratio (HR) 1.24, 95% confidence interval (CI) 0.57-2.68] and 10 (1.2%) with alirocumab vs. 8 (1.3%) with ezetimibe in ezetimibe-controlled trials (HR 0.81, 95% CI 0.32-2.08). Rates of neurocognitive TEAEs were similar in patients receiving alirocumab with LDL cholesterol (LDL-C) levels <25 mg/dL (<0.65 mmol/L; n = 5/839; 0.6%; 0.5/100 patient-years) vs. ≥25 mg/dL (n = 26/2501; 1.0%; 0.8/100 patient-years). One patient (0.1%; ezetimibe-controlled pool) receiving alirocumab had a neurocognitive TEAE leading to discontinuation vs. two (0.2%) patients receiving placebo and three (0.4%) patients receiving ezetimibe. Neurocognitive TEAE incidence was also similar between alirocumab and controls when stratified by age.


Neurocognitive TEAE incidences were low (≤1.2%), with no significant differences between alirocumab vs. controls up to 104 weeks. No association was found between neurocognitive TEAEs and LDL-C <25 mg/dL based on the completed Phase 2 and 3 trials examined, although long-term effects of very low LDL-C levels induced by PCSK9 inhibitors are currently unknown.


Cholesterol-lowering drugs; Cognitive function ; LDL; PCSK9; Patient safety

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