{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T23:24:40Z","timestamp":1788305080341,"version":"build-2803163510"},"reference-count":18,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T00:00:00Z","timestamp":1753660800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004699","name":"Chung Shan Medical University Hospital","doi-asserted-by":"publisher","award":["CSH-2022-A-022"],"award-info":[{"award-number":["CSH-2022-A-022"]}],"id":[{"id":"10.13039\/501100004699","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Individuals with schizophrenia have substantially elevated cardiovascular morbidity and mortality, a disparity further exacerbated by coexisting type 2 diabetes mellitus (T2DM). The impact of specific antipsychotics on long-term cardiovascular outcomes in patients with T2DM remains unclear. We aimed to compare major adverse cardiovascular events (MACEs) in patients with co-occurring T2DM and schizophrenia treated with aripiprazole versus risperidone.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We conducted a multi-center retrospective cohort study within the TriNetX US Collaborative Network (2014\u20132024). Adults (\u226518\u00a0years) with diagnoses of T2DM and schizophrenia who were new users of aripiprazole or risperidone were identified. Aripiprazole and risperidone cohorts were propensity score\u2013matched 1:1 (n = 5,691 each) on demographics (age, sex, race\/ethnicity, body mass index), healthcare utilization, socioeconomic and lifestyle factors, comorbidities, and baseline medications. The primary outcome was time to first major adverse cardiovascular events, defined as a composite of myocardial infarction, ischemic or hemorrhagic stroke, heart failure, ventricular arrhythmia, sudden cardiac death, or all-cause mortality. Kaplan-Meier estimation and Cox proportional hazards models were used to compare outcomes over up to 10\u00a0years of follow-up. Subgroup analyses by sex, age, and race and a time-stratified analysis (\u22641\u00a0year vs. &amp;gt;1\u00a0year follow-up) were performed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>After matching, baseline characteristics were well balanced (mean age 51.1\u00a0years, 45% female, median HbA1c \u223c7.3% in both groups). Aripiprazole was associated with a significantly elevated hazard of MACE compared to risperidone (hazard ratio [HR] 1.10, 95% confidence interval 1.02\u20131.18). This risk difference emerged primarily beyond the first year of treatment. The excess risk with aripiprazole was driven largely by higher rates of heart failure and ventricular arrhythmias, whereas risks of myocardial infarction and ischemic stroke were similar between groups. No significant heterogeneity in the treatment effect was observed across sex, age, or racial subgroups.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In this large real-world cohort of patients with T2DM and schizophrenia, aripiprazole use was associated with a modest but significant increase in the risk of MACEs compared to risperidone. Clinicians should remain vigilant about cardiovascular risk management in this population regardless of antipsychotic choice. Further research is needed to elucidate mechanisms and to confirm these observations in prospective studies.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1617534","type":"journal-article","created":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T09:10:37Z","timestamp":1753693837000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Comparative cardiovascular outcomes of aripiprazole vs. risperidone in patients with type 2 diabetes and schizophrenia: a retrospective cohort study"],"prefix":"10.3389","volume":"16","author":[{"given":"Yi-Ting","family":"Yeh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Chang","family":"Lo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chien-Ning","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Sun","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei-Lun","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edy","family":"Kornelius","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1291\/hypres.18.99","article-title":"The role of the autonomic nervous system in hypertension","volume":"18","author":"Amerena","year":"1995","journal-title":"Hypertens. Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"596","DOI":"10.2337\/diacare.27.2.596","article-title":"Consensus development conference on antipsychotic drugs and obesity and diabetes","volume":"27","year":"2004","journal-title":"Diabetes Care"},{"key":"B3","doi-asserted-by":"publisher","first-page":"96","DOI":"10.3389\/fphys.2012.00096","article-title":"The role of inhibitory G proteins and regulators of G protein signaling in the in vivo control of heart rate and predisposition to cardiac arrhythmias","volume":"3","author":"Ang","year":"2012","journal-title":"Front. Physio"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1199","DOI":"10.4088\/JCP.13m08642","article-title":"Incidence of cardiovascular outcomes and diabetes mellitus among users of second-generation antipsychotics","volume":"74","author":"Citrome","year":"2013","journal-title":"J. Clin. Psychiatry"},{"key":"B5","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1002\/wps.20994","article-title":"Mortality in people with schizophrenia: a systematic review and meta\u2010analysis of relative risk and aggravating or attenuating factors","volume":"21","author":"Correll","year":"2022","journal-title":"World Psychiatry"},{"key":"B6","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1038\/nrendo.2011.156","article-title":"Metabolic and cardiovascular adverse effects associated with antipsychotic drugs","volume":"8","author":"De Hert","year":"2012","journal-title":"Nat. Rev. Endocrinol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1395771","DOI":"10.3389\/fendo.2024.1395771","article-title":"Schizophrenia and type 2 diabetes risk: a systematic review and meta-analysis","volume":"15","author":"Dong","year":"2024","journal-title":"Front. Endocrinol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1037\/pha0000219","article-title":"Aripiprazole-induced atrial fibrillation in a patient with concomitant risk factors","volume":"26","author":"D\u2019Urso","year":"2018","journal-title":"Exp. Clin. Psychopharmacol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1038\/s41537-021-00158-z","article-title":"Efficacy and tolerability of aripiprazole versus D2 antagonists in the early course of schizophrenia: a systematic review and meta-analysis","volume":"7","author":"Kim","year":"2021","journal-title":"NPJ Schizophr."},{"key":"B10","doi-asserted-by":"publisher","first-page":"672","DOI":"10.1093\/aje\/kwj289","article-title":"Diabetes risk associated with use of olanzapine, quetiapine, and risperidone in veterans health administration patients with schizophrenia","volume":"164","author":"Lambert","year":"2006","journal-title":"Am. J. Epidemiol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.schres.2011.06.008","article-title":"Life expectancy among persons with schizophrenia or bipolar affective disorder","volume":"131","author":"Laursen","year":"2011","journal-title":"Schizophr. Res."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1516126","DOI":"10.3389\/fphar.2025.1516126","article-title":"A comprehensive review of methodologies and application to use the real-world data and analytics platform TriNetX","volume":"16","author":"Ludwig","year":"2025","journal-title":"Front. Pharmacol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"963","DOI":"10.1007\/s40263-014-0176-0","article-title":"Atypical antipsychotics olanzapine, quetiapine, and risperidone and risk of acute major cardiovascular events in young and middle-aged adults: a nationwide register-based cohort study in Denmark","volume":"28","author":"Pasternak","year":"2014","journal-title":"CNS Drugs"},{"key":"B14","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1007\/s40263-013-0054-1","article-title":"Antipsychotic-induced metabolic and cardiovascular side effects in schizophrenia: a novel mechanistic hypothesis","volume":"27","author":"Scigliano","year":"2013","journal-title":"CNS Drugs"},{"key":"B15","doi-asserted-by":"publisher","first-page":"3019","DOI":"10.2147\/NDT.S91771","article-title":"Severe arrhythmia induced by orally disintegrating aripiprazole tablets (Bosiqing\u00ae): a case report","volume":"11","author":"Shao","year":"2015","journal-title":"NDT"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1715","DOI":"10.2165\/00003495-200464150-00010","article-title":"Aripiprazole: a review of its use in schizophrenia and schizoaffective disorder","volume":"64","author":"Swainston Harrison","year":"2004","journal-title":"Drugs"},{"key":"B17","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1093\/ijnp\/pyac033","article-title":"Aripiprazole and risperidone present comparable long-term metabolic profiles: data from a pragmatic randomized controlled trial in drug-na\u00efve first-episode psychosis","volume":"25","author":"V\u00e1zquez-Bourgon","year":"2022","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1427","DOI":"10.1016\/j.hlc.2020.07.003","article-title":"Sudden cardiac death in schizophrenia: a review","volume":"29","author":"Vohra","year":"2020","journal-title":"Heart, Lung Circulation"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1617534\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T09:10:38Z","timestamp":1753693838000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1617534\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,28]]},"references-count":18,"alternative-id":["10.3389\/fphar.2025.1617534"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1617534","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,28]]},"article-number":"1617534"}}