Patients with prostate cancer (PCa) undergoing androgen deprivation therapy (ADT) frequently develop cardiometabolic complications, particularly those with type 2 diabetes (T2D). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) provide cardiovascular and renal benefits in diabetic populations, but comparative evidence with other glucose-lowering therapies in men receiving ADT remains limited. We conducted a retrospective cohort study using the TriNetX network. Adults with T2D and PCa undergoing ADT who received GLP-1RA, dipeptidyl peptidase-4 inhibitors (DPP-4is), or sodium-glucose cotransporter-2 inhibitors (SGLT2is) between January 2005 and December 2025 were included. Propensity score matching generated balanced cohorts for two comparisons: GLP-1RA versus DPP-4i and GLP-1RA versus SGLT2i. The primary outcome was all-cause mortality; secondary outcomes were major adverse cardiovascular events (MACEs), major adverse kidney events (MAKEs), and thrombotic events. After matching, 659 patients per group were included in the GLP-1RA versus DPP-4i comparison and 1,009 per group in the GLP-1RA versus SGLT2i comparison. Compared with DPP-4i, GLP-1RA use was associated with lower all-cause mortality (HR, 0.60; 95% CI, 0.46-0.79), MAKEs (HR, 0.63; 95% CI, 0.48-0.81), and thrombotic events (HR, 0.53; 95% CI, 0.32-0.89), whereas MACEs were similar (HR, 0.87; 95% CI, 0.63-1.12). Compared with SGLT2i, GLP-1RA use was associated with lower all-cause mortality (HR, 0.76; 95% CI, 0.59-0.99), whereas no significant differences were observed for MACEs, MAKEs, or thrombotic events. These neutral findings should be interpreted cautiously because the limited number of events may have reduced statistical power to detect modest between-group differences. In conclusion, among men with PCa receiving ADT and comorbid T2D, GLP-1RA use was associated with lower all-cause mortality than both DPP-4i and SGLT2i, with additional reductions in kidney and thrombotic events versus DPP-4i. GLP-1RAs may represent a favorable therapeutic option in this metabolically and vascularly vulnerable population. Prospective studies are warranted to confirm these associations and clarify the underlying mechanisms.
