GLP-1RAs Not Linked to Increased Risk for Suicidal Thoughts

Huilin Tang, MSc

Credit: UF Health

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) do not increase the risk for suicidal thoughts or behaviors, a recent study found.¹

People have raised concerns about GLP-1Ras increasing suicidal thoughts. At the start of the year, the US Food and Drug Administration (FDA) evaluated reports of suicidal thoughts or actions in patients taking GLP-1RAs.

On January 11, 2024, the FDA announced the preliminary evaluation did not reveal evidence that these medications lead to suicidal thoughts or actions.² After a review of the clinical trials, the FDA did not find an association between the use of GLP-1RAs and the occurrence of suicidal thoughts or actions.

In fact, in an interview with HCPLive during the American Psychiatric Association (APA) 2024 Annual Meeting in New York, NY, Roger S. McIntyre, MD, professor of psychiatry and pharmacology at the University of Toronto, discussed the prospect of GLP-1RAs in the treatment of psychiatric disorders. The dynamic drug class could bring a potential 3-fold benefit.³

“We now have reasons to believe that mechanistic steps that lead to symptom relief in many mental disorders includes activating molecular and cellular systems in the brain relevant to neuroplasticity, neuroprotection, and so-called anti-apoptosis—keeping cells alive,” McIntyre said. “This is a mechanism shared by antidepressants, shared by neurostimulation—like transcranial magnetic stimulation—as well as by psychotherapy. What's interesting about GLPs and GIPs, is…they also activate molecular and cellular systems relevant to neuroplasticity, neuroprotection, anti-apoptosis.”

GLP-1RAs are used to treat type 2 diabetes and obesity. The agonists reduce appetite by altering reward effects in the brain, and the mechanism of action has left people concerned the medication may increase suicidal thoughts and risk. FDA-approved GLP-1RAs for type 2 diabetes include exenatide, dulaglutide, liraglutide, lixisenatide, liraglutide + insulin, lixisenatide + insulin glargine, exenatide, semaglutide, and tirzepatide.⁴ GLP-1RAs approved for obesity include liraglutide, semaglutide, and tirzepatide.

Investigators, led by Huilin Tang, MSc, from the Department of Pharmaceutical Outcomes and Policy at the University of Florida College of Pharmacy in Gainesville, Florida, aimed to examine the risk of suicidal ideation and behaviors in older adults with type 2 diabetes taking GLP-1Ras, compared with sodium-glucose cotransporter-2 (SGLT2) inhibitors or dipeptidyl peptidase-4 (DPP4) inhibitors.¹ The primary endpoint was suicidal ideation and behaviors.

The team conducted 2 target trial emulation studies comparing propensity score-matched cohorts for GLP-1RA vs SGLT2 inhibitors and GLP-1RA vs DPP4 inhibitors. They leveraged US national Medicare administrative data from January 2017 to December 2020. At baseline, participants (≥ 66 years) had type 2 diabetes, no record of suicidal ideation or behaviors, and a first prescription for GLP-1RA, SGLT2 inhibitors, and DPP4 inhibitors.

Patients who were new users of GLP-1 RA were matched 1:1 on propensity score to new users of an SGLT2 inhibitor or DPP4 inhibitor The study included 21807 pairs of patients treated with a GLP-1RA compared to those treated with an SGLT2 inhibitor, and 21402 pairs of patients treated with a GLP-1RA compared to those treated with a DPP4 inhibitor.

The hazard risk of suicidal ideation and behaviors on GLP1RAs, relative to SGLT2 inhibitors was 1.07 (95% confidence interval [CI], 0.80 to 1.45; rate difference, 0.16 (95% CI, - 0.53 to 0.86) per 1000 person-years. The hazard ratio of GLP1RAs when compared to DPP4 inhibitors was 0.94 (95% CI, -0.92 to 0.57 per 1000 person-years).¹

“Among Medicare beneficiaries with [type 2 diabetes], this study found no clear increased risk for suicidal ideation and behaviors with GLP-1 RAs, although estimates were imprecise and a modest adverse risk could not be ruled out,” investigators concluded.

References

1. ^{Huilin Tang, Ying Lu, William T. Donahoo, et al. Glucagon-Like Peptide-1 Receptor Agonists and Risk for Suicidal Ideation and Behaviors in U.S. Older Adults With Type 2 Diabetes: A Target Trial Emulation Study. Ann Intern Med. [Epub 16 July 2024]. doi:10.7326/M24-0329}
2. ^{Update On FDA’s Ongoing Evaluation of Reports of Suicidal Thoughts or Actions in Patients Taking a Certain Type of Medicines Approved for Type 2 Diabetes and Obesity. US Food and Drug Administration. March 8, 2024. https://www.fda.gov/drugs/fda-drug-safety-podcasts/update-fdas-ongoing-evaluation-reports-suicidal-thoughts-or-actions-patients-taking-certain-type#:~:text=Similarly%2C%20our%20reviews%20of%20the,of%20suicidal%20thoughts%20or%20actions. Accessed July 15, 2024.}
3. ^{Kunzmann, K. Roger S. McIntyre, MD: GLP-1 Agonists for Psychiatry? HCPLive. May 5, 2024. https://www.hcplive.com/view/roger-mcintyre-md-glp-1-agonists-for-psychiatry. Accessed July 15, 2024.}
4. ^{Update On FDA’s Ongoing Evaluation of Reports of Suicidal Thoughts or Actions in Patients Taking a Certain Type of Medicines Approved for Type 2 Diabetes and Obesity. US Food and Drug Administration. January 30, 2024. https://www.fda.gov/drugs/drug-safety-and-availability/update-fdas-ongoing-evaluation-reports-suicidal-thoughts-or-actions-patients-taking-certain-type. Accessed July 15, 2024.}