Efficacy and safety of GLP1-ras compared to SGLT2is and DPP-4is in individuals with schizophrenia and diabetes: A Danish nationwide target-trial emulation study

Psychiatry Res. 2025 Jun 9;351:116592. doi: 10.1016/j.psychres.2025.116592. Online ahead of print.

ABSTRACT

OBJECTIVE: Previous studies have suggested that glucagon-like-peptide-1-receptor-agonists (GLP1-ras) may offer neuroprotective and cardiovascular benefits. However, concerns have been raised about potential adverse effects of GLP1-ras including depression and suicidal ideation. This target-trial-emulation study aims to examine the effects of GLP1-ras treatment on psychiatric hospital admission and all-cause mortality in individuals with schizophrenia.

METHODS: We used the Danish nationwide registers to identify all individuals diagnosed with schizophrenia and who were treated with metformin (Glucophage). Among these, we identified those who initiated second-line treatment for type-2-diabetes with one of the following glucose-lowering drugs: GLP1-ras, sodium-glucose-cotransporter-2-inhibitors(SGLT2is), or dipeptidyl-peptidase-4-inhibitors(DPP-4is). We then compared the hazard rate ratios(HRR) for psychiatric admission and all-cause mortality between the different treatment arms using a Cox-proportional-hazards model, adjusting for covariates to minimize confounding.

RESULTS: We included 354 individuals with schizophrenia(47 % female, mean age 43.8 years) and type-2-diabetes who initiated treatment with a second-line GLD. Of these, 71, 197, and 86 initiated treatment with GLP1-ras, DPP-4is, and SGLT2is respectively. We found no difference in the risk of psychiatric admission between the three treatment arms. In the fully adjusted model, treatment with DPP-4is and SGLT2is analysed as a compound exposure, was not associated with a significant reduced risk of psychiatric admission, with a HRR of 0.78(95 %-CI:0.38-1.59), when compared to GLP1-ras. Only 5 deaths occurred during follow-up, making a comparison of all-cause mortality between the treatment arms unfeasible.

CONCLUSION: We observed no difference in the risk of psychiatric admission or all-cause mortality for individuals with schizophrenia treated with GLP1-ras compared to SGLT2is and DPP-4is.

PMID:40526989 | DOI:10.1016/j.psychres.2025.116592