Background: Luteinizing hormone releasing hormone agonists (LHRHa) are the standard of care treatment for prostate cancer but associated with an increased risk of cardiotoxicity. Recent studies suggest that sodium glucose cotransporter-2 inhibitors (SGLT2i), a class of antidiabetic drugs, reduce the risk of cardiovascular events compared to other glucose-lowering agents. We aim to investigate the potential cardioprotective effect of SGLT2i in prostate cancer patients with T2DM undergoing LHRHa therapy. Methods: We performed a retrospective, propensity score matched study using the TriNetX database, a network comprising deidentified data across more than 120 participating healthcare institutions. We included patients with prostate cancer and T2DM who were treated with LHRHa for prostate cancer and received either SGLT2i or dipeptidyl peptidase 4 inhibitors (DPP4i) for diabetes. The primary outcomes were all-cause mortality, incident hypertension, and incident major cardiovascular adverse events (MACE), which was defined as a composite of heart failure, myocardial infarction, and atrial fibrillation/flutter within 5 years of LHRHa initiation. Results: We matched 932 patients treated with an SGLT2i to patients treated with a DPP4i. The median age was 73 years for both cohorts. A total of 110 and 275 patients died in the SGLT2i and DPP4i cohorts, respectively. In Cox proportional hazard analyses, SGLT2i was associated with a reduction in the risk of all-cause mortality (Hazard ratio (HR), 0.65 [95% CI, 0.52 to 0.81]), hypertension (HR, 0.40 [95% CI: 0.22-0.70]) and major adverse cardiovascular events (HR, 0.70 [95% CI, 0.50 to 0.97]) compared to DPP4i. Similarly, SGLT2i was associated with a statistically significant reduction in heart failure and myocardial infarction. There appeared to be a tendency toward a lower risk of atrial fibrillation/flutter. Conclusions: The use of SGLT2i was associated with a lower risk of mortality, hypertension, and cardiovascular events in patients with prostate cancer and T2DM undergoing LHRHa therapy.

^aAfter propensity score matching by incorporating variables: age, sex, metastatic disease, androgen deprivation therapy, radiation therapy, underlying comorbidities, use of cardiovascular and diabetes medications, smoking status, and hemoglobin A1c.