Does using GLP-1 RAs induce suicide in T2D patients?

Patients with type 2 diabetes (T2D) who use glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) appear to have no increased risk of suicidality when compared with the use of dipeptidyl peptidase-4 inhibitors (DPP-4is) or sodium-glucose cotransporter-2 inhibitors (SGLT-2is), a study has found.

Researchers conducted this active comparator, new user cohort study in primary care practices that contributed data to the UK Clinical Practice Research Datalink linked to the Hospital Episodes Statistics Admitted Patient Care and Office for National Statistics Death Registration databases. Patients with T2D were identified and grouped into two cohorts.

The first cohort consisted of patients who initiated and continued using GLP-1 RAs or DPP-4is between 1 January 2007 and 31 December 2020. The other cohort included those who initiated and maintained the use of GLP-1 RAs or SGLT-2is between 1 January 2013 and 31 December 2020. Researchers followed both cohort until 29 March 2021.

Among patients in the first cohort, 36,082 were GLP-1 RA users (median follow-up 1.3 years) and 234,028 were DPP-4i users (median follow-up 1.7 years). [BMJ 2025;388:e080679]

Crude analyses revealed the association of GLP-1 RA use with an increased incidence of suicidality compared with DPP-4is (crude incidence rates, 3.9 vs 1.8 per 1,000 person-years; hazard ratio [HR], 2.08, 95 percent confidence interval [CI], 1.83‒2.36). This association weakened to a null value after accounting for confounding factors (HR, 1.02, 95 percent CI, 0.85‒1.23).

In the second cohort, there were 32,336 GLP-1 RA users (median follow-up 1.2 years) and 96,212 SGLT-2i users (median follow-up 1.2 years).

In crude analysis, the use of GLP-1 RA in this group also correlated with an elevated risk of suicidality compared with SGLT-2is (crude incidence rates, 4.3 vs 2.7 per 1,000 person-years; HR, 1.60, 95 percent CI, 1.37‒1.87) but not after accounting for confounders (HR, 0.91, 95 percent CI, 0.73‒1.12).

Similar findings were seen when suicidal ideation, self-harm, and suicide were analysed separately in the two cohorts.

“[T]he results of this large active comparator, new user cohort study indicate that GLP-1 RAs are not associated with an increased risk of suicidal ideation, self-harm, and suicide when compared with DPP-4is or SGLT-2is among patients with T2D,” the researchers said. “These findings should provide some reassurance with respect to the psychiatric safety of these drugs.”

Mechanism

The lack of an independent relationship between GLP-1 RAs and suicidality indicates the insufficient effects of these drugs on the hypothalamic-pituitary-adrenal axis, sudden weight loss, or brain derived neurotrophic factor dysregulation to cause suicidal ideation, self-harm, or suicide. [Pharmaceuticals (Basel) 2024;17:147; J Affect Disord 2009;116:218-221; Psychiatr Serv 2021;72:920-925]

These biological mechanisms may influence the interplay of factors that affect suicidality, but they do not appear to act independently in inducing such outcomes among GLP-1 RA users, according to the researchers.

“We did not observe associations even among patients with a history of psychiatric disorders, such as self-harm, suicidal ideation, and depression,” they added.