Glucagon-Like Peptide 1 Receptor Agonists, Mortality, and Cardiovascular Outcomes in Serious Mental Illness

Importance: Bipolar disorder, major depressive disorder, and schizophrenia are associated with substantial excess mortality, principally from cardiovascular disease. Identifying strategies to reduce this burden is a critical psychiatric priority. Objective: To evaluate associations between initiation of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) vs sodium-glucose cotransporter-2 (SGLT2) inhibitors and all-cause mortality and major adverse cardiovascular events (MACEs) among adults with and without serious mental illness (SMI). Design, Setting, and Participants: This was a retrospective target trial emulation within the TriNetX Analytics Network, a multinational federated electronic health record network. Adults initiating GLP-1 RAs or SGLT2 inhibitors were included using a new-user, active-comparator design with propensity score matching and separate psychiatric and nonpsychiatric cohorts. The study included all available data in the TriNetX network through the most recent database refresh. Data were queried and analyzed in March 2026, with prespecified follow-up intervals of 1, 4, and 10 years. Additional subgroup analyses were conducted following peer review in May 2026. Exposure: First-recorded GLP-1 RA vs SGLT2 inhibitor prescription. Main Outcomes and Measures: The primary outcome was 4-year all-cause mortality; the key secondary outcome, 1-year mortality. Additional outcomes included 3- and 5-point MACEs and individual cardiovascular end points. Sensitivity analyses included diabetes stratification, exclusion of baseline heart failure and chronic kidney disease, and censoring at crossover. Exploratory analyses examined SMI subgroups, agent-specific effects, and combination therapy. Results: For the primary 4-year analysis, 1 528 230 adults were propensity score matched (764 115 pairs; 195 184 pairs with serious mental illness [SMI] and 568 931 pairs without SMI). The mean [SD] age in the GLP-1RA and SGLT2 inhibitor groups was 60.5 [12.0] and 60.2 [13.3] years, respectively, in the SMI cohort and 60.9 [12.2] and 60.6 [13.0] years, respectively, in the non-SMI cohort; 112 911 [57.8%], 113 488 [58.1%], 251 679 [44.2%], and 260 480 [45.8%] were female, respectively. Among participants with SMI, mortality was lower with GLP-1RA initiation than with SGLT2 inhibitor initiation (9585 of 195 184 [4.91%] vs 12 584 of 195 184 [6.45%]; hazard ratio [HR], 0.76; 95% CI, 0.74-0.78; absolute risk difference [ARD], -1.54 percentage points; 95% CI, -1.68 to -1.39; P < .001). Among participants with SMI and type 2 diabetes, semaglutide initiation, compared with SGLT2 inhibitor initiation, was associated with lower risks of 3-point MACE (HR, 0.77; 95% CI, 0.76-0.79), 5-point MACE, myocardial infarction, stroke, heart failure, and coronary artery bypass grafting. In a separately matched 1-year SMI cohort, mortality was lower with GLP-1RA initiation than with SGLT2 inhibitor initiation (2898 of 198 065; 1.46% vs 5624 of 198 065; 2.84%; RR, 0.52; 95% CI, 0.49-0.54; ARD, -1.38 percentage points; 95% CI, -1.47 to -1.29; P < .001). In 10-year exploratory analyses among participants with type 2 diabetes, semaglutide initiation, compared with SGLT2 inhibitor initiation, was associated with lower mortality in the major depressive disorder (RR, 0.55; 95% CI, 0.53-0.56), bipolar disorder (RR, 0.57; 95% CI, 0.51-0.63), and schizophrenia (RR, 0.67; 95% CI, 0.59-0.75) groups (all P < .001). The primary mortality association persisted across prespecified sensitivity analyses. Conclusions and Relevance: In this study, GLP-1 RA initiation was associated with lower mortality and cardiovascular events compared to SGLT2 inhibitor initiation, with greater absolute reductions in SMI. Benefits were evident within 1 year, consistent across SMI subgroups, and driven by semaglutide and tirzepatide. Prospective randomized trials are warranted.