Autoimmune Disease Risk With GLP-1RA, DPP-4i, and SGLT2i Treatment in Patients With Diabetes

OBJECTIVE: Dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1RA), and sodium-glucose cotransporter-2 inhibitors (SGLT2i) are widely used for type 2 diabetes, yet their comparative immunologic safety is uncertain. To address this gap, we evaluated autoimmune disease incidence among patients treated with these agents. METHODS: We conducted emulated target trials using electronic health record data from 152 health care organizations in the TriNetX network (2016-2023). Adults with type 2 diabetes initiating DPP-4i, GLP-1RA, or SGLT2i monotherapy and no prior autoimmune disease were included. Propensity score matching balanced demographics, comorbidities, laboratory data, and medications. Cohorts comprised 118,419 matched DPP-4i versus GLP-1RA pairs, 102,810 DPP-4i versus SGLT2i pairs, and 105,869 GLP-1RA versus SGLT2i pairs. Primary outcomes included three-year risks of incident autoimmune diseases such as psoriasis, rheumatoid arthritis, systemic sclerosis, dermatomyositis, and multiple sclerosis. RESULTS: Compared with GLP-1RA, DPP-4i was associated with lower risk of psoriasis (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.70-0.85), psoriatic arthritis (HR 0.65, 95% CI 0.53-0.79), and autoimmune thyroiditis (HR 0.68, 95% CI 0.59-0.76), but higher risk of dermatomyositis (HR 2.18, 95% CI 1.24-3.53) and bullous pemphigoid (HR 1.78, 95% CI 1.24-2.46). CONCLUSION: Compared with GLP-1RA, DPP-4i use decreased psoriasis and thyroiditis risk but increased dermatomyositis, bullous pemphigoid, and giant cell arteritis risk. No significant differences were observed between GLP-1RA and SGLT2i treatments. These findings provide novel safety signals and may inform antidiabetic drug selection while guiding future mechanistic and prospective research.