GLP-1 RAs and mortality or CV outcomes in adults with serious mental illness

Bipolar disorder, major depressive disorder and schizophrenia are associated with considerable excess mortality, largely due to cardiovascular disease, the leading cause of death among individuals living with these serious mental illnesses. Identifying strategies to reduce this burden is an important public health priority. The mortality-lowering effects and reduction in cardiovascular morbidity observed with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in persons with type 2 diabetes raise the hypothesis that these agents may also reduce mortality and cardiovascular morbidity in persons living with serious mental illness.To examine this issue, a group of Canadian and US researchers evaluated associations between initiation of GLP-1 RAs versus sodium-glucose cotransporter-2 (SGLT2) inhibitors and all-cause mortality and major adverse cardiovascular events (MACEs) among adults with and without serious mental illness.The large-scale, retrospective target trial used data from the TriNetX Analytics Network, a multinational electronic health record network. Adults starting a GLP-1 RA or SGLT2 inhibitor were included using a new-user, active-comparator design with propensity score matching and separate psychiatric and nonpsychiatric cohorts. Data were analyzed at pre-specified follow-up intervals of one, four and 10 years. GLP-1 RAs included semaglutide, tirzepatide, dulaglutide, liraglutide, exenatide (no longer marketed in Canada), lixisenatide (only marketed in combination with insulin glargine in Canada) and albiglutide (not marketed in Canada). SGLT2 inhibitors included empagliflozin, dapagliflozin, canagliflozin and ertugliflozin (no longer marketed in Canada).The primary outcome was four-year all-cause mortality. The key secondary outcome was one-year mortality. Additional outcomes included three- and five-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 serious mental illness subgroups, agent-specific effects and combination therapy.Key results:For the primary four-year analysis, 1,528,230 adults were propensity score matched (764,115 total pairs; 195,184 pairs with serious mental illness and 568,931 pairs without serious mental illness).Among participants with serious mental illness, mortality was lower with GLP-1 RA initiation (4.91%) than with SGLT2 inhibitor initiation (6.45%); hazard ratio [HR], 0.76; 95% CI, 0.74–0.78; absolute risk difference, −1.54 percentage points; 95% CI, −1.68 to −1.39; P < .001). Among participants with serious mental illness and type 2 diabetes, semaglutide initiation, compared with SGLT2 inhibitor initiation, was associated with lower risks of three-point MACE (HR, 0.77; 95% CI, 0.76–0.79), five-point MACE, myocardial infarction, stroke, heart failure and coronary artery bypass grafting. In a separately matched one-year serious mental illness cohort, mortality was lower with GLP-1 RA initiation (1.46%) than with SGLT2 inhibitor initiation (2.84%); RR, 0.52; 95% CI, 0.49–0.54; absolute risk difference, −1.38 percentage points; 95% CI, −1.47 to −1.29; P < .001). At one year, GLP-1 RA initiation was associated with a 48% lower relative risk of death in the serious mental illness cohort (RR, 0.52; absolute risk difference, −1.38 percentage points) compared with a 41% lower relative risk in the nonpsychiatric cohort (RR, 0.59; absolute risk difference, −0.74 percentage points).Semaglutide and tirzepatide demonstrated robust mortality reductions, with tirzepatide yielding the largest observed effect (RR, 0.27; HR, 0.49), while older agents showed no consistent survival benefit.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 group (RR, 0.55; 95% CI, 0.53–0.56), the bipolar disorder group (RR, 0.57; 95% CI, 0.51–0.63), and the schizophrenia group (RR, 0.67; 95% CI, 0.59–-0.75) (all P < .001). The primary mortality association persisted across prespecified sensitivity analyses.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 adults with serious mental illness. Benefits were evident within one year, consistent across serious mental illness subgroups, and driven by semaglutide and tirzepatide. The authors point out that this cohort study represents one of the largest population-based investigations examining the association between GLP-1 RAs and cardiovascular outcomes and mortality among individuals with serious mental illness. Their study findings support the integration of GLP-1 RAs within care models aimed at preventing premature cardiovascular morbidity in patients with serious mental illness, although prospective randomized trials to further examine this issue are warranted.ReferenceMcIntyre RS, Zhang-James Y, Kwan ATH, et al. Glucagon-like peptide 1 receptor agonists, mortality, and cardiovascular outcomes in serious mental illness. JAMA Psychiatry 2026; published online: August 26, 2026. (accessed September 1, 2026).

GLP-1 RAs and mortality or CV outcomes in adults with serious mental illness

Register for free access or login.

Related Topics