Dermatologic outcomes associated with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a large-scale target trial emulation

Background: While dipeptidyl peptidase-4 inhibitors (DPP-4is) are linked to autoimmune skin diseases, comparative data on glucagon-like peptide-1 receptor agonists (GLP-1 RAs) remain limited. Methods: We emulated a randomized active-comparator trial using the TriNetX US Collaborative Network. Adults with type 2 diabetes (T2DM) initiating GLP-1 RAs or DPP-4is between January 1, 2018, and December 31, 2022, were identified, excluding prior users of either class. Balanced cohorts (n=169,630 each) were created using 1:1 propensity score matching. To address protopathic bias, outcomes occurring within 3 months after drug initiation were not considered. Patients were followed for up to 4 years for newly diagnosed autoimmune or inflammatory skin diseases. Cox regression estimated hazard ratios (HRs) and 95% confidence intervals (CIs). Results: Compared with DPP-4i initiation, GLP-1 RA initiation was associated with a higher risk of incident psoriasis (HR 1.19, 95% CI 1.11-1.28) and lower risks of pemphigus (HR 0.32, 95% CI 0.16-0.63) and bullous pemphigoid (HR 0.61, 95% CI 0.43-0.87). No significant differences were observed for other inflammatory or autoimmune skin outcomes after multiple-testing correction. Findings persisted across subgroup and sensitivity analyses. Conclusion: In a large, real-world study designed to emulate a clinical trial, GLP-1 RAs were linked to increased psoriasis and decreased autoimmune blistering diseases compared with DPP-4is over up to 4 years' follow-up. These results provide a dermatologic safety context to guide incretin therapy selection and highlight the importance of ongoing skin monitoring.