Glucagon-Like Peptide-1 Receptor Agonists and Incident Cardiovascular Events and Death in Treated Serious Mental Illness, Type 2 Diabetes, and Obesity

BACKGROUND: Adults with serious mental illness (SMI), type 2 diabetes, and obesity have elevated cardiovascular risk. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have established cardiometabolic benefits in the general population, but their effects in SMI are unclear. We evaluated whether GLP-1RA use was associated with lower risks of incident myocardial infarction (MI), heart failure (HF), and all-cause death. METHODS: This was a retrospective propensity score-matched cohort study of 218 043 adults with SMI, type 2 diabetes, obesity, and active antipsychotic or antidepressant medications in the TriNetX database (73 health care organizations). Outcomes were incident MI, HF, and all-cause death at 1 and 3 years. The primary exposure was GLP-1RA use versus nonuse; secondary analyses examined semaglutide or tirzepatide. Exploratory analyses evaluated sex, race, and sodium-glucose cotransporter-2 inhibitor and dipeptidyl peptidase-4 inhibitor use. RESULTS: GLP-1RA use was associated with lower risks of incident MI, HF, and all-cause death. Risk differences at 1 and 3 years were -0.007 and -0.010 for MI, -0.011 and -0.018 for HF, and -0.039 and -0.065 for death (all P<0.001). Semaglutide or tirzepatide use was also associated with lower risks of MI, HF, and death (all P<0.001). Findings were directionally consistent after accounting for sodium-glucose cotransporter-2 inhibitor and dipeptidyl peptidase-4 inhibitor use. CONCLUSIONS: Adults with treated SMI, type 2 diabetes, and obesity using GLP-1RAs, particularly semaglutide or tirzepatide, had significantly reduced 1- and 3-year risks of incident MI, HF, and all-cause death versus nonusers. These pooled associations should be interpreted in the context of SMI's clinical heterogeneity and the limitations of administrative case ascertainment.