Glucagon-Like Peptide-1 Receptor Agonists and Incident Cardiovascular Events and Death in Treated Serious Mental Illness, Type 2 Diabetes, and Obesity
- Design
- Retrospective cohort · 218043 participants · Hard outcome
- Match to healthy normal-weight adults aged 55–75
- Different populationINDIRECT: all participants had serious mental illness, type 2 diabetes and obesity and were taking antipsychotics or antidepressants; age and BMI are not reported.
- Could weight loss explain it?
- PossiblyAll participants had obesity and type 2 diabetes, and the abstract reports no weight or HbA1c change and no mediation analysis; accounting for SGLT2 and DPP-4 inhibitor use addresses co-medication, not weight mediation.
- Study tier
- Study tier 3LOW: single retrospective propensity-matched TriNetX cohort; the observational design caps the tier, and no confidence intervals are given in the abstract.
- Assessment
- Version 4 · Two reviewers differed; settled by a recorded ruling · Oct 19, 2026
Study facts come from the paper. Population match, weight-loss explanation and study tier are our judgments, made against the reference group of healthy normal-weight adults aged 55–75.
This study used TriNetX health records of 218,043 adults with serious mental illness, type 2 diabetes and obesity who were taking antipsychotics or antidepressants. GLP-1 receptor agonist use was linked to lower risks of heart attack, heart failure and death at 1 and 3 years (for death, risk differences of -0.039 and -0.065; all P<0.001), and semaglutide or tirzepatide showed the same pattern; no outcome was reported as null. The study is observational, so these are associations, not proof that the drugs lowered the risk.
01Findings
What the study reported
- Drugs
- Glp-1 receptor agonists, Semaglutide, Tirzepatide
- Comparator
- nonuse of GLP-1RAs
- Dose
- various
- Primary outcome
- incident myocardial infarction, heart failure and all-cause death at 1 and 3 years
- Effect
- Risk differences at 1 and 3 years: MI -0.007 and -0.010; HF -0.011 and -0.018; death -0.039 and -0.065 (all P<0.001); semaglutide or tirzepatide also associated with lower risks; no null outcome reported
- 95% confidence interval
- Not extracted
- P value
- all P<0.001
- Follow-up
- 1 and 3 years
- Adverse events
- not reported in abstract
- Limitations
- Retrospective observational study in administrative records with no confidence intervals in the abstract; the authors note the clinical heterogeneity of serious mental illness and the limits of administrative case ascertainment.
Who was studied
- Obesity status
- obesity required (criterion not stated)
- Diabetes status
- type 2 diabetes required
- Cvd status
- not reported in abstract
- Ckd status
- not reported in abstract
- Baseline condition
- serious mental illness treated with antipsychotics or antidepressants, with type 2 diabetes and obesity
- Sample size
- 218043
- Inclusion exclusion
- adults with serious mental illness, type 2 diabetes, obesity and active antipsychotic or antidepressant medication (TriNetX)
Study quality details
- Study design
- Retrospective cohort
- Sample size
- 218043
- Randomization
- no
- Blinding
- n/a
- Comparator
- nonuse of GLP-1RAs
- Follow up duration
- 1 and 3 years
- Outcome type
- hard
- Replication
- not assessed
- Consistency with other evidence
- not assessed
- Population applicability
- INDIRECT
- Statistical precision
- no CI reported; risk differences with P values; event counts not stated
- Risk of bias
- not assessed
- Funding conflicts
- unclear
- Peer review status
- yes
02Funding
Funding and conflicts
- Funding
- not reported in abstract
- Industry funded
- Unclear
- Manufacturer
- not stated in source
- Sponsor role
- not reported in abstract
- Author conflicts
- not reported in abstract
- Independent replication
- unknown
Funding is shown on every study and never used to score it.
04Source
The source, as retrieved
Abstract
[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.