PCSK9 inhibitor use was associated with a lower 12-month risk of MACE (HR 0.84; 95% CI 0.80-0.88) but a higher risk of any psychiatric diagnosis (HR 1.33; 95% CI 1.25-1.42).
Cohort (n=121,770)
Yes
Does PCSK9 inhibitor therapy reduce MACE and affect neuropsychiatric outcomes compared to statin monotherapy in adults with established ASCVD?
In a real-world ASCVD cohort, PCSK9 inhibitors were associated with reduced MACE but an increased risk of depression and anxiety compared to statin monotherapy, warranting further prospective evaluation.
Hazard Ratio: 0.84 (95% CI 0.8–0.88)
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.
Gu et al. (Tue,) conducted a cohort in Atherosclerotic cardiovascular disease (ASCVD) (n=121,770). PCSK9 inhibitors (alirocumab or evolocumab) vs. Statin monotherapy was evaluated on Major adverse cardiovascular events (MACE: myocardial infarction, heart failure, ischaemic stroke, all-cause death), neurodegenerative disease, and psychiatric disorders (HR 0.84, 95% CI 0.80-0.88). PCSK9 inhibitor use was associated with a lower 12-month risk of MACE (HR 0.84; 95% CI 0.80-0.88) but a higher risk of any psychiatric diagnosis (HR 1.33; 95% CI 1.25-1.42).