Comparing Metabolic Outcomes Associated with Aripiprazole and Olanzapine in Schizophrenia Spectrum Disorder: Insights from a Large Real-World Cohort Using TriNetX

Background: Second-generation antipsychotics manage schizophrenia spectrum disorders but carry metabolic risks. Olanzapine is associated with greater metabolic liability, while aripiprazole is considered more metabolically neutral. Although multiple randomised controlled trials and meta-analyses have compared these agents, results have varied depending on duration, dosage, and population characteristics. Also, only a few large-scale real-world studies have examined these associations across diverse populations using harmonised electronic health records. Aims: This study compares the risk of developing hyperlipidemia, diabetes mellitus, and pancreatitis among adults prescribed aripiprazole versus olanzapine using electronic health record data. Methods: A retrospective cohort study was performed using the TriNetX Research Network. Adults aged 18-80 years with schizophrenia spectrum disorders (ICD-10: F20-F29) were included. Cohorts consisted of patients prescribed aripiprazole (n=94,759) and patients prescribed olanzapine (n=1,716,356). After 1:1 propensity-score matching by age, sex, race, and ethnicity, each cohort included 94,125 patients. Incidence of the composite metabolic outcome was compared using risk estimates, Kaplan-Meier analysis, log-rank testing, and Cox proportional hazards modelling. Results: The metabolic outcome occurred in 27.7% of aripiprazole patients and 20.1% of olanzapine patients. Aripiprazole was associated with higher metabolic risk: risk difference 0.076 (95% CI:0.073-0.080; p