The findings from a large cohort study have suggested no link between glucagon-like peptide-1 (GLP-1) receptor agonists and suicide, according to the researchers.
Use of the drugs has surged in recent years, driven by their benefits in glucose control in type 2 diabetes, weight reduction, and cardiovascular and renal outcomes. Given the increasing number of patients being treated with them, timely assessment of potential safety signals is important.
In July 2023, the European Medicines Agency launched an investigation into thoughts of suicide and self-harm potentially linked to GLP-1 receptor agonists.
Although meta-analyses of randomised controlled trials have not indicated that they increase suicidality, depression, anxiety, and other adverse mental health outcomes, the clinical trials were not designed to assess those outcomes, and the statistical power of the analyses have been limited by the low number of events.
In addition, reports The BMJ, most clinical trials have excluded patients at high risk of suicidality. In this situation, adequately designed observational studies are warranted.
In the latest paper, Shapiro and colleagues report a cohort study of more than 30 000 users of GLP-1 receptor agonists with type 2 diabetes in the UK, using data from the Clinical Practice Research Datalink (CPRD).
The primary study outcome was suicidality, a composite of suicidal ideation, self-harm and death from suicide.
In separate analyses using dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose cotransporter-2 (SGLT-2) inhibitors as comparators, they found no indication of an increased risk associated with GLP-1 receptor agonists, with upper limits of the 95% confidence intervals for the hazard ratio at 1.23 (versus DPP-4 inhibitors) and 1.12 (versus SGLT-2 inhibitors).
In this broad study population, event rates were low and the analyses ruled out moderate magnitudes of increases in risk on both the relative and the absolute scale.
In contrast to some of the previous analyses of data from routine clinical practice, the study by Shapiro and colleagues used appropriate comparator drugs and an active comparator new user design, which is not affected by time related biases such as immortal time bias.
Their findings were largely consistent across several analyses using both comparator drugs. Although potentially small increased risks in the broader study populations are unlikely to affect treatment decisions, people at high risk of suicidality owing to previous or existing psychiatric conditions comprise a subgroup of specific interest.
The analyses by Shapiro and colleagues found no signs of a higher risk linked to GLP-1 receptor agonists in this subgroup.
The study, however, has important limitations, according to the editorial in The BMJ. Around two-thirds of the composite outcome events comprised suicidal ideation.
This outcome is inconsistently and incompletely captured in routinely collected databases. The study does not describe the content and definition of this outcome that was recorded in the CPRD, and uncertainty remains about its completeness and validity, especially as the reliability of other related diagnoses is limited in this database.
The remaining third of the outcome events in the study mostly comprised self-harm events, which are also incompletely captured in databases from routine clinical practice.
Meanwhile, death from suicide, the most reliable and clinically relevant study outcome, could not be assessed in detail: in the GLP-1 receptor agonist group, only six events were captured in analyses versus DPP-4 inhibitors and fewer than five events in analyses versus SGLT-2 inhibitors, yielding imprecise and inconclusive estimates.
Moreover, the proportion of GLP-1 receptor agonist users who used drugs that are rarely prescribed in contemporary clinical practice (exenatide and lixisenatide) was around 40% in analyses versus DPP-4 inhibitors and 23% in analyses versus SGLT-2 inhibitors.
Semaglutide, the most used GLP-1 receptor agonist today, was used by less than 10% of the patients who were treated with GLP-1 receptor agonists. Future studies may specifically assess the safety of semaglutide and tirzepatide, which have surpassed other GLP-1 receptor agonists in popularity because of their larger effects on weight reduction and glucose control.
The carefully conducted and adequately designed study by Shapiro and colleagues adds to the existing literature on the safety of GLP-1 receptor agonists.
At this point, data from clinical trials and observational studies in broad populations do not indicate that GLP-1 receptor agonists increase the risk of suicidality.
Study details
Glucagon-like peptide-1 receptor agonists and risk of suicidality among patients with type 2 diabetes: active comparator, new user cohort study
Samantha B Shapiro, Hui Yin, Laurent Azoulay et al.
Published in The BMJ on 26 February 2025
Abstract
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 3.9 v 1.8 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 4.3 v 2.7 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.
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.
The BMJ article – GLP-1 receptor agonists and suicidality (open access)
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Questions remain on weight loss drugs’ suicide risk – US study
No link between suicide and weight loss drugs – EMA