Key result
PCSK9 inhibitors linked to ~16% lower 12-month MACE vs. statins, alongside higher depression and anxiety.
Why the study?
PCSK9 inhibitors reduce major cardiovascular events in randomized trials of ASCVD, but their real-world neuropsychiatric safety remains uncertain.
Is PCSK9 inhibitor therapy (alirocumab or evolocumab) associated with reduced major adverse cardiovascular events and altered risks of neurodegenerative or psychiatric disorders compared with statin monotherapy in adults with established atherosclerotic cardiovascular disease?
Cohort (n=121,770)
Yes
Is PCSK9 inhibitor therapy (alirocumab or evolocumab) associated with reduced major adverse cardiovascular events and altered risks of neurodegenerative or psychiatric disorders compared with statin monotherapy in adults with established atherosclerotic cardiovascular disease?
In a large real-world ASCVD cohort, PCSK9 inhibitors were associated with reduced cardiovascular events and neutral neurocognitive risk compared with statins, but higher rates of depression and anxiety that warrant clinical vigilance and further prospective evaluation.
Answers are grounded in this paper and cite their sources.
Associated lower MACE risk with PCSK9 inhibitors versus statins warrants psychiatric monitoring; leaves open causality and long-term effects.
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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Gu et al. (2026) conducted a cohort in Atherosclerotic cardiovascular disease (ASCVD) (n=121,770). PCSK9 inhibitor therapy (alirocumab or evolocumab, as monotherapy or in combination with a statin) vs. Statin monotherapy was evaluated on 12-month major adverse cardiovascular events (MACE: composite of ischaemic stroke, acute myocardial infarction, heart failure, and all-cause death) (HR 0.84, 95% CI 0.80–0.88, p=<.001). PCSK9 inhibitor therapy was associated with a 16% lower 12-month risk of MACE (HR 0.84, 95% CI 0.80-0.88) compared with statins, alongside higher risks of depression and anxiety.
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