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Peer-reviewedCC BY 4.0British Journal of Clinical Pharmacology

Cardiovascular and neuropsychiatric outcomes with PCSK9 inhibitors in atherosclerotic cardiovascular disease: A retrospective cohort study

  • Tianshu Gu1,2
  • Yang Chen1
  • Nan Zhang2
  • Uazman Alam3,4,5
  • Riccardo Proietti1
  • Tong Liu2
  • Kang‐Yin Chen2
  • Gregory Y. H. Lip1,2,6,7
7 affiliations
  1. 1Liverpool Centre for Cardiovascular Science at University of Liverpool Liverpool John Moores University and Liverpool Heart and Chest Hospital Liverpool UK
  2. 2Tianjin Key Laboratory of Ionic‐Molecular Function of Cardiovascular disease, Department of Cardiology, Tianjin Institute of Cardiology The Second Hospital of Tianjin Medical University Tianjin China
  3. 3Department of Cardiovascular and Metabolic Medicine University of Liverpool Liverpool UK
  4. 4Liverpool Centre for Cardiovascular Sciences University of Liverpool and Liverpool University Hospitals NHS Foundation Trust Liverpool UK
  5. 5Centre for Biomechanics and Rehabilitation Technologies Staffordshire University Stoke‐on‐Trent UK
  6. 6Department of Clinical Medicine Aalborg University Aalborg Denmark
  7. 7Department of Cardiology, Lipidology and Internal Medicine with Intensive Coronary Care Unit Medical University of Bialystok Bialystok Poland
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Abstract

Aims: PCSK9 inhibitors reduce major cardiovascular events in randomized trials of atherosclerotic cardiovascular disease (ASCVD), but real‐world neuropsychiatric safety remains uncertain.

Methods: In a propensity score–matched retrospective cohort study using the TriNetX U.S. Federated Research Network, adults with established ASCVD initiating alirocumab or evolocumab between 2017 and 2024 were matched 1:1 to statin‐monotherapy initiators. The 12‐month primary analysis assessed major adverse cardiovascular events (MACE: myocardial infarction, heart failure [HF], ischaemic stroke, all‐cause death), neurodegenerative disease (dementia, Parkinson's disease) and psychiatric disorders (psychosis, bipolar disorder, depression, anxiety), with Bonferroni correction and negative control. Secondary analyses examined individual agents, ASCVD subtypes, statin use, an intensified lipid‐lowering comparator and extended follow‐up.

Results: Among 60 885 matched pairs (mean age 70 years; 61% male), PCSK9 inhibitor therapy was associated with lower 12‐month risks of MACE (HR 0.84, 95% CI 0.80–0.88), myocardial infarction (HR 0.82, 0.79–0.86), HF (HR 0.87, 0.83–0.92) and all‐cause mortality (HR 0.40, 0.37–0.43); ischaemic stroke did not differ. After Bonferroni correction, no neurodegenerative association remained significant. PCSK9 inhibitor use was associated with higher risks of any psychiatric diagnosis (HR 1.33, 1.25–1.42), depression (HR 1.44, 1.28–1.61) and anxiety (HR 1.39, 1.28–1.50), persisting in secondary analyses; negative control outcomes did not differ.

Conclusions: PCSK9 inhibitor use was associated with favourable cardiovascular outcomes and no clear neurodegenerative harm, but higher rates of depression and anxiety. Given the observational design and potential residual confounding, statin‐intolerance‐related treatment selection and surveillance bias, these findings should be interpreted as hypothesis‐generating and warrant further prospective evaluation.

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Cite

BibTeXRIS
BibTeX
@article{gu2026cardiovascular,
  title = {{Cardiovascular and neuropsychiatric outcomes with PCSK9 inhibitors in atherosclerotic cardiovascular disease: A retrospective cohort study}},
  author = {Tianshu Gu and Yang Chen and Nan Zhang and Uazman Alam and Riccardo Proietti and Tong Liu and Kang‐Yin Chen and Gregory Y. H. Lip},
  journal = {British Journal of Clinical Pharmacology},
  year = {2026},
  month = jul,
  doi = {10.1002/bcp.70687},
  url = {https://doi.org/10.1002/bcp.70687},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Cardiovascular and neuropsychiatric outcomes with PCSK9 inhibitors in atherosclerotic cardiovascular disease: A retrospective cohort study
AU  - Tianshu Gu
AU  - Yang Chen
AU  - Nan Zhang
AU  - Uazman Alam
AU  - Riccardo Proietti
AU  - Tong Liu
AU  - Kang‐Yin Chen
AU  - Gregory Y. H. Lip
PY  - 2026
DA  - 2026/07/07
JO  - British Journal of Clinical Pharmacology
DO  - 10.1002/bcp.70687
UR  - https://doi.org/10.1002/bcp.70687
AB  - Aims: PCSK9 inhibitors reduce major cardiovascular events in randomized trials of atherosclerotic cardiovascular disease (ASCVD), but real‐world neuropsychiatric safety remains uncertain.  Methods: In a propensity score–matched retrospective cohort study using the TriNetX U.S. Federated Research Network, adults with established ASCVD initiating alirocumab or evolocumab between 2017 and 2024 were matched 1:1 to statin‐monotherapy initiators. The 12‐month primary analysis assessed major adverse cardiovascular events (MACE: myocardial infarction, heart failure [HF], ischaemic stroke, all‐cause death), neurodegenerative disease (dementia, Parkinson's disease) and psychiatric disorders (psychosis, bipolar disorder, depression, anxiety), with Bonferroni correction and negative control. Secondary analyses examined individual agents, ASCVD subtypes, statin use, an intensified lipid‐lowering comparator and extended follow‐up.  Results: Among 60 885 matched pairs (mean age 70 years; 61% male), PCSK9 inhibitor therapy was associated with lower 12‐month risks of MACE (HR 0.84, 95% CI 0.80–0.88), myocardial infarction (HR 0.82, 0.79–0.86), HF (HR 0.87, 0.83–0.92) and all‐cause mortality (HR 0.40, 0.37–0.43); ischaemic stroke did not differ. After Bonferroni correction, no neurodegenerative association remained significant. PCSK9 inhibitor use was associated with higher risks of any psychiatric diagnosis (HR 1.33, 1.25–1.42), depression (HR 1.44, 1.28–1.61) and anxiety (HR 1.39, 1.28–1.50), persisting in secondary analyses; negative control outcomes did not differ.  Conclusions: PCSK9 inhibitor use was associated with favourable cardiovascular outcomes and no clear neurodegenerative harm, but higher rates of depression and anxiety. Given the observational design and potential residual confounding, statin‐intolerance‐related treatment selection and surveillance bias, these findings should be interpreted as hypothesis‐generating and warrant further prospective evaluation.
SN  - 0306-5251
SN  - 1365-2125
ER  -