GLP-1 RAs Associated With Lower Mortality in Mental Illness

Initiation of a glucagon-like peptide-1 receptor agonist (GLP-1 RA) was associated with lower all-cause mortality and cardiovascular risks than initiation of a sodium-glucose cotransporter-2 (SGLT2) inhibitor among adults with serious mental illness, according to a target trial emulation published in JAMA Psychiatry.

Investigators used the multinational TriNetX electronic health record network and a new-user, active-comparator design. Propensity-score matching produced 764,115 treatment pairs for the primary 4-year analysis, including 195,184 pairs with serious mental illness—including major depressive disorder, bipolar disorder, or schizophrenia—and 568,931 pairs without serious mental illness.

In the serious mental illness cohort, 4-year mortality occurred in 9,585 GLP-1 RA initiators (4.91%) and 12,584 SGLT2 inhibitor initiators (6.45%). GLP-1 RA initiation was associated with lower mortality (hazard ratio [HR], 0.76; 95% CI, 0.74-0.78), corresponding to an absolute risk difference of −1.54 percentage points.

In a separately matched 1-year cohort, mortality was 1.46% with GLP-1 RAs and 2.84% with SGLT2 inhibitors (risk ratio, 0.52; 95% CI, 0.49-0.54). Among participants with serious mental illness and type 2 diabetes, semaglutide initiation was also associated with lower risks of 3-point and 5-point major adverse cardiovascular events, myocardial infarction, stroke, heart failure, and coronary artery bypass grafting compared with SGLT2 inhibitor initiation.

Because this was a retrospective target trial emulation, the findings are associative and cannot establish that GLP-1 RAs caused the observed differences. Exposure was defined according to the first-recorded GLP-1 RA or SGLT2 inhibitor prescription. The results compare GLP-1 RAs with SGLT2 inhibitors, not with no treatment. The authors said prospective randomized trials are warranted.

Source: McIntyre RS, Zhang-James Y, Kwan ATH. Glucagon-like peptide 1 receptor agonists, mortality, and cardiovascular outcomes in serious mental illness. JAMA Psychiatry. Published online August 26, 2026. doi:10.1001/jamapsychiatry.2026.2574