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.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) prescribed to treat type 2 diabetes (T2D) are believed to also reduce reward effects in the central nervous system, and there is concern about a higher risk for suicidal ideation and behaviors associated with these medications. This observational study examines Medicare data to assess the risk for diagnoses of suicidal behaviors among older adults with T2D after being newly prescribed GLP-1 RAs compared with those who were newly prescribed sodium–glucose cotransporter-2 inhibitors or dipeptidyl peptidase-4 inhibitors. Visual Abstract. Glucagon-Like Peptide-1 Receptor Agonists and Risk for Suicidal Ideation and Behaviors in U.S. Older Adults With Type 2 Diabetes: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) prescribed to treat type 2 diabetes (T2D) are believed to also reduce reward effects in the central nervous system, and there is concern about a higher risk for suicidal ideation and behaviors associated with these medications. This observational study examines Medicare data to assess the risk for diagnoses of suicidal behaviors among older adults with T2D after being newly prescribed GLP-1 RAs compared with those who were newly prescribed sodium–glucose cotransporter-2 inhibitors or dipeptidyl peptidase-4 inhibitors. Background: A major concern has recently emerged about a potential link between glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and increased risk for suicidal ideation and behaviors based on International Classification of Diseases codes. Objective: To investigate the association between GLP-1 RAs, compared with sodium–glucose cotransporter-2 inhibitors (SGLT2is) or dipeptidyl peptidase-4 inhibitors (DPP4is), and risk for suicidal ideation and behaviors in older adults with type 2 diabetes (T2D). Design: Two target trial emulation studies comparing propensity score (PS)–matched cohorts for GLP-1 RAs versus SGLT2is and GLP-1 RAs versus DPP4is. Setting: U.S. national Medicare administrative data from January 2017 to December 2020. Patients: Older adults (≥66 years) with T2D; no record of suicidal ideation or behaviors; and a first prescription for a GLP-1 RA, SGLT2i, or DPP4i. Measurements: The primary end point was a composite of suicidal ideation and behaviors. New GLP-1 RA users were matched 1:1 on PS to new users of an SGLT2i or DPP4i in each pairwise comparison. A Cox proportional hazards regression was used to estimate the hazard ratio (HR) and 95% CIs within matched groups. Results: This study included 21 807 pairs of patients treated with a GLP-1 RA versus an SGLT2i and 21 402 pairs of patients treated with a GLP-1 RA versus a DPP4i. The HR of suicidal ideation and behaviors associated with GLP-1 RAs relative to SGLT2is was 1.07 (95% CI, 0.80 to 1.45; rate difference, 0.16 [CI, −0.53 to 0.86] per 1000 person-years); the HR relative to DPP4is was 0.94 (CI, 0.71 to 1.24; rate difference, −0.18 [CI, −0.92 to 0.57] per 1000 person-years). Limitations: Low event rate; imprecise estimates; unmeasured confounders, such as body mass index; and potential misclassification of outcomes. Conclusion: Among Medicare beneficiaries with T2D, 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. Primary Funding Source: American Foundation for Pharmaceutical Education, Pharmaceutical Research and Manufacturers of America Foundation, National Institute on Aging, and National Institute of Diabetes and Digestive and Kidney Diseases. [ABSTRACT FROM AUTHOR]