<scp>GLP</scp> ‐1 Receptor Agonists and Risk of Skin Cancer in Adults With Type 2 Diabetes: A Target Trial Emulation

ABSTRACT Aims Existing evidence regarding the association between glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) and risk of melanoma and non‐melanoma skin cancer (NMSC) is inconclusive. This study aimed to assess the association between GLP‐1RA initiation and risks of melanoma and NMSC versus sodium–glucose cotransporter 2 inhibitors (SGLT2is) and dipeptidyl peptidase 4 inhibitors (DPP4is) in adults with type 2 diabetes (T2D). Materials and Methods Target trial emulation using TriNetX electronic health records (2014–2025). Adults with T2D initiating GLP‐1RAs, SGLT2is or DPP4is were included. Outcomes were incident melanoma and NMSC over 3 years. Propensity score matching and Cox models estimated hazard ratios (HRs). Sensitivity analyses included negative control outcome (NCO) calibration, a lag‐period analysis and restriction to patients with obesity. Results After matching, the GLP‐1RA versus SGLT2i cohort included 235 797 pairs; the GLP‐1RA versus DPP4i cohort included 153 873 pairs. Mean follow‐up ranged from 1.8 to 2.2 years. GLP‐1RA use was not associated with melanoma compared with either SGLT2i (HR, 1.04; 95% CI, 0.93–1.17) or DPP4i (HR, 1.09; 95% CI, 0.95–1.25). A borderline increase in NMSC risk was observed in the comparison with SGLT2is (HR, 1.06; 95% CI, 1.00–1.11); no such association was identified in the comparison with DPP4is (HR, 1.03; 95% CI, 0.97–1.09). Findings were generally consistent across sensitivity analyses; however, the association with NMSC was attenuated after NCO calibration. Conclusions GLP‐1RA therapy was not associated with an increased risk of melanoma. A borderline increase in NMSC risk was observed compared with SGLT2is but was not evident after NCO calibration.