Glucagon-like peptide-1 receptor agonists and risk of suicidality among patients with type 2 diabetes: active comparator, new user cohort study

Feb 26, 2025BMJ (Clinical research ed.)

Risk of suicidal thoughts in type 2 diabetes patients starting glucagon-like peptide-1 receptor drugs compared to other treatments

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Abstract

Among 36,082 users of GLP-1 receptor agonists, no increased risk of suicidality was found compared to DPP-4 inhibitors or SGLT-2 inhibitors.

Initial analyses indicated a higher incidence of suicidality among GLP-1 receptor agonist users compared to DPP-4 inhibitor users.
Crude incidence rates were 3.9 and 1.8 per 1000 person-years for GLP-1 receptor agonists and DPP-4 inhibitors, respectively.
After adjusting for confounding factors, the association between GLP-1 receptor agonist use and suicidality diminished to a hazard ratio of 1.02.
In comparisons with SGLT-2 inhibitors, GLP-1 receptor agonists showed an increased risk in crude analyses, with incidence rates of 4.3 and 2.7 per 1000 person-years.
However, after accounting for confounding factors, the hazard ratio for suicidality with GLP-1 receptor agonists fell to 0.91.

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OBJECTIVE: To determine whether the use of glucagon-like peptide-1 (GLP-1) receptor agonists is associated with an increased risk of suicidal ideation, self-harm, and suicide among patients with type 2 diabetes compared with the use of dipeptidyl peptidase-4 (DPP-4) inhibitors or sodium-glucose cotransporter-2 (SGLT-2) inhibitors.

DESIGN: Active comparator, new user cohort study.

SETTING: Primary care practices contributing 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.

PARTICIPANTS: Patients with type 2 diabetes.

EXPOSURES: Two cohorts were assembled, with the first composed of patients who started and continued on GLP-1 receptor agonists or DPP-4 inhibitors between 1 January 2007 and 31 December 2020 and the second composed of patients who started and continued on GLP-1 receptor agonists or SGLT-2 inhibitors between 1 January 1 2013 and 31 December 2020. Both cohorts were followed until 29 March 2021.

MAIN OUTCOME MEASURES: The primary outcome was suicidality, defined as a composite of suicidal ideation, self-harm, and suicide. Secondary outcomes were each of these events considered separately. Propensity score fine stratification weighted Cox proportional hazards models were fitted to estimate hazard ratios and 95% confidence intervals (CIs) to estimate the average treatment effect among the treated patients.

RESULTS: The first cohort included 36 082 GLP-1 receptor agonist users (median follow-up 1.3 years) and 234 028 DPP-4 inhibitor users (median follow-up 1.7 years). In crude analyses, GLP-1 receptor agonist use was associated with an increased incidence of suicidality compared with DPP-4 inhibitors (crude incidence rates 3.91.8 per 1000 person years, respectively; hazard ratio 2.08, 95% CI 1.83 to 2.36). This estimate decreased to a null value after confounding factors were accounted for (hazard ratio 1.02, 95% CI 0.85 to 1.23). The second cohort included 32 336 GLP-1 receptor agonist users (median follow-up 1.2 years) and 96 212 SGLT-2 inhibitor users (median follow-up 1.2 years). Similarly, GLP-1 receptor agonist use was associated with an increased risk of suicidality compared with SGLT-2 inhibitors in crude analyses (crude incidence rates 4.32.7 per 1000 person years; hazard ratio 1.60, 95% CI 1.37 to 1.87) but not after confounding factors were accounted for (0.91, 0.73 to 1.12). Similar findings were observed when suicidal ideation, self-harm, and suicide were analysed separately in both cohorts. v v

CONCLUSIONS: In this large cohort study, the use of GLP-1 receptor agonists was not associated with an increased risk of suicidality compared with the use of DPP-4 inhibitors or SGLT-2 inhibitors in patients with type 2 diabetes.

Key numbers

3.9 per 1000 person years

Crude Incidence Rate of (GLP-1 vs. DPP-4)

had 301 events over 77 377 person years.

1.02

for (GLP-1 vs. DPP-4)

After weighting, the for compared to was 1.02.

4.3 per 1000 person years

Crude Incidence Rate of (GLP-1 vs. SGLT-2)

had 240 events over 55 620 person years.

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Glucagon-like peptide-1 receptor agonists and risk of suicidality among patients with type 2 diabetes: active comparator, new user cohort study

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