GLP-1 Receptor Agonists Linked to Lower Mortality, Cardiovascular Events in Serious Mental Illness

Adults with serious mental illness (SMI) who initiated a glucagon-like peptide-1 receptor agonist (GLP-1 RA) had significantly lower all-cause mortality and fewer major adverse cardiovascular events than those who initiated a sodium-glucose cotransporter-2 (SGLT2) inhibitor, according to a large retrospective target trial emulation using electronic health record data from the TriNetX Analytics Network.¹

The study, approved by the State University of New York Upstate Medical University institutional review board, included more than 1.5 million propensity score-matched participants and is among the largest population-based analyses to examine cardiometabolic therapies in individuals with bipolar disorder, major depressive disorder (MDD), and schizophrenia.

Cardiovascular disease is the leading cause of death among individuals living with SMI.^2,3

Study Design

Investigators used a new-user, active-comparator design, matching adults who initiated a GLP-1 RA (semaglutide, tirzepatide, dulaglutide, liraglutide, exenatide, lixisenatide, or albiglutide) 1:1 with adults who initiated an SGLT2 inhibitor (empagliflozin, dapagliflozin, canagliflozin, or ertugliflozin), with separate propensity score matching for cohorts with and without SMI. Data were queried and analyzed in March 2026, with prespecified follow-up windows of 1, 4, and 10 years; additional subgroup analyses were conducted following peer review in May 2026. The query snapshot spanned 127,035,455 patients across 114 health care organizations. The primary outcome was 4-year all-cause mortality; the key secondary outcome was 1-year mortality, with 3-point and 5-point MACEs and individual cardiovascular end points as additional outcomes.

Mortality and Cardiovascular Findings

For the primary 4-year analysis, 1,528,230 adults were matched (764,115 pairs), including 195,184 pairs with SMI and 568,931 pairs without SMI. Among participants with SMI, death occurred in 9585 of 195,184 GLP-1 RA initiators (4.91%) vs 12,584 of 195,184 SGLT2 inhibitor initiators (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). The mortality reduction was numerically larger in the SMI cohort than in the non-SMI cohort (HR, 0.85; 95% CI, 0.83-0.86; ARD, −0.60 percentage points; 95% CI, −0.66 to −0.53).

The mortality curves separated early. At 1 year, death occurred in 2898 of 198,065 GLP-1 RA initiators with SMI (1.46%) vs 5624 of 198,065 SGLT2 inhibitor initiators (2.84%; risk ratio [RR], 0.52; 95% CI, 0.49-0.54; HR, 0.51; 95% CI, 0.49-0.53; P<.001), a 48% lower relative risk of death.

Among participants with SMI and type 2 diabetes, semaglutide initiation was associated with lower risk of 3-point MACE (HR, 0.77; 95% CI, 0.76-0.79), 5-point MACE (HR, 0.76; 95% CI, 0.75-0.77), myocardial infarction (HR, 0.71; 95% CI, 0.69-0.73), stroke (HR, 0.89; 95% CI, 0.86-0.92), heart failure (HR, 0.73; 95% CI, 0.72-0.74), and coronary artery bypass grafting (HR, 0.77; 95% CI, 0.70-0.85), compared with SGLT2 inhibitor initiation (all P<.001).

Agent-Specific and Exploratory Findings

Not all GLP-1 RAs performed equally. Semaglutide and tirzepatide drove the mortality reductions; tirzepatide showed the largest effect (RR, 0.27; 95% CI, 0.25-0.29; HR, 0.49; 95% CI, 0.45-0.52), though its shorter median follow-up (424 days) warrants cautious interpretation. Older agents—dulaglutide, liraglutide, exenatide, lixisenatide, and albiglutide—showed no consistent survival advantage. In 10-year exploratory analyses among participants with type 2 diabetes, semaglutide was associated with lower mortality across all 3 SMI diagnostic subgroups: MDD (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; all P<.001). Combination therapy—an SGLT2 inhibitor plus semaglutide initiated within 30 days—was associated with incremental mortality benefit over SGLT2 inhibitor monotherapy, with the largest relative risk reduction at 10 years in the psychiatric cohort (RR, 0.66; 95% CI, 0.59-0.74).

Findings held across prespecified sensitivity analyses, including diabetes stratification, exclusion of baseline heart failure and chronic kidney disease, and censoring at treatment crossover; the no-crossover analysis produced a larger effect size (HR, 0.70; 95% CI, 0.68-0.72), suggesting that treatment switching in the primary intention-to-treat analysis conservatively attenuated the estimate.

Currently, only lithium, clozapine, and select second-generation long-acting injectable antipsychotics have demonstrated mortality reduction in SMI. The authors say the consistency of benefit across MDD, bipolar disorder, and schizophrenia—including in schizophrenia, a population with substantial barriers to health care engagement—suggests the association does not depend on optimal adherence or health system access.

Study Limitations

The authors note several limitations. As an observational target trial emulation, the study cannot fully exclude unmeasured confounding from medication adherence, lifestyle factors, socioeconomic determinants, and psychiatric illness severity. Cost barriers and structural inequities in access to incretin-based therapies may limit generalizability to the broader SMI population. Residual imbalance in continuous body mass index and type 2 diabetes prevalence persisted after matching, though supplementary double-adjusted analyses yielded concordant findings. The authors call for prospective randomized clinical trials to confirm the associations and to evaluate combination strategies with SGLT2 inhibitors.

References

1. McIntyre 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. Online ahead of print.

2. Yuan M, Xiao ZL, Zhou HY, et al. Bipolar disorder and the risk for stroke incidence and mortality: a meta-analysis. Neurol Sci. 2022;43(1):467-476.

3. Hayes JF, Miles J, Walters K, King M, Osborn DPJ. A systematic review and meta-analysis of premature mortality in bipolar affective disorder. Acta Psychiatr Scand. 2015;131(6):417-425.