Sodium-Glucose Cotransporter 2 Inhibitors for Patients With Prostate Cancer Undergoing Hormone Therapy

Abstract

<p><strong>Importance</strong> While preliminary evidence suggests that sodium-glucose cotransporter 2 (SGLT2) inhibitors for diabetes may have antitumorigenic effects, their potential benefits in prostate cancer remain unexplored. Understanding their association with outcomes among patients undergoing hormone therapy could inform future adjunct treatment strategies.</p><p><strong>Objective</strong> To evaluate whether the use of SGLT2 inhibitors is associated with clinical outcomes in patients with prostate cancer receiving hormone therapy.</p><p><strong>Design, Setting, and Participants</strong> This population-based, sequential target trial emulation of monthly cohorts used territory-wide electronic health records (January 1, 1993, to April 30, 2025) from the Hong Kong Hospital Authority, covering a population of approximately 7.5 million. Adult men diagnosed with prostate cancer who initiated androgen deprivation therapy (ADT) were included. Follow-up extended through April 2025, and data were analyzed from June to October 2025.</p><p><strong>Exposures</strong> Use of SGLT2 inhibitors (primarily dapagliflozin and empagliflozin) initiated during hormone therapy and maintained for at least 1 month. Comparator groups included nonusers of SGLT2 inhibitors.</p><p><strong>Main Outcomes and Measures</strong> The primary outcome was time to ADT failure. Secondary outcomes include time to next-generation hormonal agent failure, disease-specific survival, and overall survival. Both intention-to-treat and per-protocol analyses were conducted using complementary log-log model regression to provide the hazard ratio (HR) estimate.</p><p><strong>Results</strong> Among 14 223 eligible patients (median [IQR] age at enrollment, 74 [68-80] years) with a median follow-up of 66 months (95% CI, 65-67 months), intention-to-treat SGLT2 inhibitor use was associated with reduced risk of ADT failure (HR, 0.63; 95% CI, 0.41-0.95; <em>P</em> = .03) and next-generation hormonal agent failure (HR, 0.44; 95% CI, 0.20-0.97; <em>P</em> = .04). Sensitivity analyses confirmed robustness of these findings across different comparator subgroups. Metformin monotherapy was not associated with disease progression but was associated with improved overall survival (HR, 0.59; 95% CI, 0.42-0.83; <em>P</em> = .002). No statistically significant outcome differences were observed between dapagliflozin and empagliflozin.</p><p><strong>Conclusions and Relevance</strong> In this cohort study with a target trial emulation design, SGLT2 inhibitor use was associated with delayed hormone therapy failure in patients with prostate cancer, suggesting a potential oncologic benefit beyond glucose lowering. These findings support the potential of SGLT2 inhibitors in treatment for prostate cancer.</p>