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

🎖️ Top 10% JournalJun 17, 2025Psychiatry research

Effectiveness and safety of GLP-1 receptor agonists versus SGLT2 inhibitors and DPP-4 inhibitors in people with schizophrenia and diabetes in Denmark

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Abstract

Among 354 individuals with schizophrenia and type-2 diabetes, treatment with GLP1-receptor agonists did not show different outcomes in psychiatric hospital admissions or all-cause mortality compared to other diabetes medications.

No significant difference in the risk of psychiatric admissions was found between those treated with GLP1-receptor agonists, DPP-4 inhibitors, and SGLT2 inhibitors.
The hazard rate ratio for psychiatric admission when comparing DPP-4 inhibitors and SGLT2 inhibitors to GLP1-receptor agonists was 0.78, indicating no significant risk reduction.
Only 5 deaths were recorded during the follow-up period, making a comparison of all-cause mortality across treatment groups unfeasible.
The study included participants with a mean age of 43.8 years, with a gender distribution of 47% female.

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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.

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