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0.36 (0.25 to 0.53) for incident suicidal ideation and 0.51 (0.31 to 0.86) for recurrent suicidal ideation among patients with type 2 diabetes).9 A third study found protective effects of GLP-1 receptor agonists compared with DPP-4 inhibitorson the risk of suicide attempts among patients with type 2 diabetes (odds ratio 0.46, 95% CI 0.37 to 0.58),10 and a fourth study found no effect of GLP-1 receptor agonists compared with SGLT-2 inhibitors or DPP-4 inhibitors on the risk of suicidal ideation (hazard ratios 1.05 (95% CI 0.77 to 1.43) and 0.96 (0.72 to 1.27), respectively) or suicidal behaviours (0.82 (0.41 to 1.67) and 0.92 (0.42 to 2.01), respectively) among older adults with type 2 diabetes.11 Another study conducted among patients with both type 2 diabetes and obesity observed no association between GLP-1 receptor agonist use and a composite of suicidal ideation and self-injury (hazard ratio 1.04, 95% CI 0.35 to 3.14),12 and a final study observed a reduced risk of self-harm (hazard ratio 0.77, 0.65 to 0.91) but a non-significant increase in the risk of suicide (1.25, 0.83 to 1.88) among a diverse group of patients on GLP-1 receptor agonists compared with SGLT-2 inhibitors.13 Overall, some of these observational studies had methodological shortcomings, including prevalent user bias,9 immortal time bias,9 important confounding,9101113 limited generalisability,11 exclusion of patients at high risk (such as those with a history of psychiatric conditions),811 and limited sample sizes generating imprecise estimates.812 Biological mechanisms The absence of an independent association between GLP-1 receptor agonists and suicidality suggests that the effects of these drugs on the hypothalamic-pituitary-adrenal axis, sudden weight loss, or brain derived neurotrophic factor dysregulation are not sufficient to induce suicidal ideation, self-harm, or suicide.1415161718 Although these biological mechanisms may contribute to the complex interplay of factors influencing suicidality, they do not seem to act independently in causing such outcomes in GLP-1 receptor agonist users

doi: 10.1016/j.bcp.2022.115108 91

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