PCSK9 inhibitor initiation associated with lower depression risk versus statins in hyperlipidemia

Background Hyperlipidemia is a major risk factor for cardiovascular disease and is increasingly linked to depression, which is associated with adverse cardiovascular prognosis. As proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are increasingly used for lipid lowering, their neuropsychiatric safety profile compared with established therapies remains uncertain. Objectives This study aimed to compare the risk of incident depression associated with initiation of PCSK9 inhibitor therapy vs statin therapy among adults with hyperlipidemia. Methods In this population-based cohort study, we emulated a target trial using a new-user active-comparator design and real-world data from the TriNetX research network from July 1, 2020, to June 30, 2025. Adults with hyperlipidemia who newly initiated PCSK9 inhibitors or statins were included. The exposure was initiation of PCSK9 inhibitor therapy versus statin therapy. Propensity score matching was performed, yielding 17,805 patients in each group. The primary outcome was incident depression. Cumulative incidence was estimated using the Kaplan-Meier method, and hazard ratios (HRs) with 95% confidence intervals (Cis) were estimated using Cox proportional hazards models. Results Among 35 610 propensity score-matched patients, the mean age was 65.4 (10.6) years and 46.7% were female. During a mean follow-up of 35.0 (21.2) months, incident depression occurred in 546 patients (3.1%) initiating PCSK9 inhibitors and 981 patients (5.5%) initiating statins. The 5-year cumulative incidence of depression was 5.84% for PCSK9 inhibitor initiators and 7.91% for statin initiators. PCSK9 inhibitor initiation was associated with a lower risk of incident depression (HR, 0.74; 95% CI, 0.67-0.82), corresponding to a 5-year number needed to treat of 46. The association was observed for major depressive disorder (HR, 0.71; 95% CI, 0.63-0.80) but not for dysthymic disorder or adjustment disorder. Consistent associations were observed across prespecified subgroups and sensitivity analyses, and the lower depression risk associated with PCSK9 inhibitor initiation remained regardless of comparator statin intensity or lipophilicity. Conclusions In this real-world target trial emulation, initiation of PCSK9 inhibitor therapy was associated with a lower risk of incident depression compared with statin therapy among adults with hyperlipidemia. Further prospective studies are warranted to confirm these findings and clarify underlying mechanisms.