GLP-1 Receptor Agonists Linked to Higher Depression Risk Than SGLT2 Inhibitors in T2D: Study
USA: Adults with type 2 diabetes who begin treatment with certain glucose-lowering medications may face differing risks for developing depression, a large real-world study published in Diabetes, Obesity and Metabolism has revealed.
The research, led by Stephanie A. Hooker of HealthPartners Institute in Minneapolis, Minnesota, evaluated the comparative safety of four commonly prescribed drug classes and found that sustained use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) was associated with a modestly higher risk of new-onset depression over 2.5 years compared with some alternatives.
To investigate the relationship, researchers conducted a retrospective cohort study using electronic health record data from six integrated health systems between January 2014 and December 2022. The team emulated six comparative “target trials,” each examining a pairwise comparison between medication classes: GLP-1 RAs, sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors), dipeptidyl peptidase-4 inhibitors (DPP4 inhibitors), and sulfonylureas (SU).
Cohort sizes ranged from 54,773 to 227,414 adults aged 18 years and older. Eligible participants were new users of one of the medications and had no evidence of depression or prior use of the comparator drug in the two years before starting therapy. Medication exposure was determined through pharmacy dispensing and claims records, with treatment periods defined as twice the days supplied.
The primary outcome was time to a new diagnosis of depression within 2.5 years of drug initiation, identified using diagnostic codes from inpatient, outpatient, or emergency department visits.
The analysis revealed the following findings:
- Continuous GLP-1 receptor agonist (RA) use was associated with a higher cumulative risk of incident depression compared with sustained SGLT2 inhibitor use (risk difference [RD] 1.0%).
- GLP-1 RA use was also linked to a higher risk of depression compared with sulfonylurea use (RD 1.8%).
- No significant difference in depression risk was observed between GLP-1 RAs and DPP4 inhibitors.
- SGLT2 inhibitor use was associated with a lower risk of depression compared with DPP4 inhibitor use (RD −0.7%).
- No meaningful difference in depression risk was found between SGLT2 inhibitors and sulfonylureas.
- GLP-1 RAs and DPP4 inhibitors showed the highest relative risks for new-onset depression overall.
- Sulfonylureas demonstrated an intermediate risk profile.
- SGLT2 inhibitors were associated with the lowest risk of incident depression.
- After adjusting for time-varying demographic and clinical factors, only the difference between GLP-1 RAs and SGLT2 inhibitors remained statistically significant.
The findings suggest that while the absolute differences in risk were small, they may still be clinically relevant in long-term diabetes management. The authors note that decisions regarding glucose-lowering therapy should incorporate these mental health considerations alongside established benefits such as glycemic control, cardiovascular protection, and weight effects. For patients with type 2 diabetes, particularly those with a history of mood vulnerability, individualized treatment discussions may be warranted.
Reference:
Hooker SA, Neugebauer RS, Schmittdiel JA, An J, Cassidy-Bushrow AE, Dombrowski SK, Oshiro CES, Bergenstal R, Gilliam LK, Nolan MB, Thomas T, Rossom RC, Kaur J, Finertie H, Yassin M, Lin S, Izadian K, O'Connor PJ. Comparative safety of glucose-lowering medications on depression in adults with type 2 diabetes. Diabetes Obes Metab. 2026 Mar;28(3):2215-2226. doi: 10.1111/dom.70415. Epub 2026 Jan 2. PMID: 41479367.
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