SAT-617 - Incident Suicidality after Initiating Semaglutide vs. Sglt2I in U.S. Veterans with Type 2 Diabetes

Importance: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective medications for type 2 diabetes (T2D). Earlier studies found an increased risk of suicidality with GLP-1RA use, while more recent studies have found no link. For U.S. veterans with T2D, robust research is crucial given that veterans have an increased risk of suicidality.

Objective: To emulate a target trial evaluating the risk of suicidality (ideation and attempts/completion) associated with initiation of semaglutide, a GLP-1RA, compared with a sodium-glucose cotransporter-2 inhibitor (SGLT2i) as second-line therapy for T2D in a nationwide cohort of U.S. Veterans.

Design: Active-comparator, new-user, target trial emulation. Marginal cause-specific hazard ratios (HRs) were estimated using overlap weighting to account for confounding.
Setting: The Veterans Health Administration (VHA) nationwide health care system between March 1, 2018 and March 1, 2025.
Participants: U.S. Veterans with T2D using metformin and no prior exposure to GLP-1RAs or SGLT2is.
Exposure: Initiation of semaglutide or SGLT2is.
Outcomes: 1) incident suicidal ideation, defined as ICD-10 codes, clinician-administered or self-report questionnaires, e.g., CSSRS, PHQ9; and 2) incident suicide attempts/completions.

Results: A total of 102,361 Veterans met inclusion criteria (semaglutide: 11,478; SGLT2i: 90,883). Baseline characteristics were well balanced between treatment groups after overlap weighting (mean [SD] age, 60.1 [11.7] years; BMI, 37.8 [6.8] kg/m2; A1c, 7.0% [1.4]; 85.5% male; 61.9% non-Hispanic White; 20.7% Black; 8.1% Hispanic). Over a median follow-up of 2.1 years, patients who initiated semaglutide were not at a higher risk than patients who initiated SGLT2i for suicidal ideation (HR, 1.02; 95% CI, 0.96–1.08; P=0.6) nor suicide attempts/completions (HR, 1.08; 95% CI, 0.86–1.36; P=0.5). Results were similar when stratified by history of suicidality.

Conclusion: U.S. Veterans with T2D who initiated semaglutide were not observed to have a higher risk of suicidality compared to those who initiated SGLT2i regardless of their history of suicidality.

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