Comparative safety of glucose‐lowering medications on depression in adults with type 2 diabetes

Jan 2, 2026Diabetes, obesity & metabolism

Depression risks of different blood sugar medicines in adults with type 2 diabetes

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Abstract

Sustained GLP-1 receptor agonist use is associated with a 1.0% increased risk of incident depression compared to sodium-glucose cotransporter-2 inhibitors.

Sustained use of GLP-1 receptor agonists (GLP-1RA) is linked to a higher risk of developing depression compared to both sodium-glucose cotransporter-2 inhibitors (SGLT2i) and sulfonylureas (SU).
The cumulative risk difference for GLP-1RA versus SGLT2i is 1.0%, while it is 1.8% compared to SU.
SGLT2 inhibitors are associated with a decreased risk of incident depression when compared to dipeptidyl peptidase 4 inhibitors (DPP4i), with a risk difference of -0.7%.
No significant differences in depression risk were found between sulfonylureas and DPP4 inhibitors.
The findings indicate that medication choice may influence the risk of depression in patients with type 2 diabetes.

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AIMS: To examine the impact of four classes of diabetes medications on incident depression in adults with type 2 diabetes during routine clinical care.

MATERIALS AND METHODS: Six cohort studies (N = 54 773 to 227 414 patients) were used to emulate comparative safety trials using data collected from electronic health records between January 1, 2014, and December 31, 2022, from six integrated health systems. Eligible patients were new users of one glucose-lowering medication: glucagon-like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter-2 inhibitors (SGLT2i), dipeptidyl peptidase 4 inhibitors (DPP4i), or sulfonylureas (SU), with no evidence of depression and no prior dispensing of the comparator medication in the 2 years prior to drug initiation. The primary outcome was incident depression diagnoses in the 2.5 years after drug initiation. Analyses included targeted minimum loss-based estimation with super learning.

RESULTS: Sustained GLP-1RA use was associated with increased risk of incident depression compared with SGLT2i (cumulative risk difference [RD] = 1.0%, 95% confidence interval [CI] = [0.6%, 1.4%]) and SU (RD = 1.8%, 95% CI = [1.3%, 2.4%]), but not DPP4i. SGLT2i were significantly associated with decreased risk of incident depression compared with DPP4i (RD = -0.7%, 95% CI = [-1.2%, -0.2%]) but not SU. There were no differences between SU and DPP4i.

CONCLUSIONS: Sustained use of GLP-1RA or DPP4i was associated with small, increased risks of incident depression compared with SGLT2i. GLP-1RA use was also associated with increased risk of depression compared to SU. Patients and clinicians may consider these risks along with other potential benefits and risks when initiating glucose-lowering medications.

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Comparative safety of glucose‐lowering medications on depression in adults with type 2 diabetes

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