Association between SGLT2 inhibitors and genital cancer: a meta-analysis and mendelian randomization study.

Background: Effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on genital cancer risk remains unclear.

Objective: The objective of this study was to investigate the impact of SGLT2 inhibitors/SGLT2 inhibition on genital cancer risk.

Methods: We systematically searched PubMed, Web of Science, EU Clinical Trials Register, and ClinicalTrials.gov for large randomized controlled trials up to June 4, 2025. The Mantel-Haenszel method was applied, with risk ratios (RRs) and 95% confidence intervals (CIs) used for dichotomous outcomes. In the Mendelian randomization study, genetic variants in SLC5A2 served as instrumental variables to investigate the causal relationship between SGLT2 inhibition and genital cancers.

Results: A total of 15 studies (16 trials) involving 101,430 patients were included. SGLT2 inhibitors did not significantly reduce genital cancer risk compared to placebo (RR 1.10; 95% CI 0.93-1.31; P = 0.28; moderate certainty of evidence), with consistent findings across subgroup analyses. No significant effects of SGLT2 inhibitors were observed for cervical, endometrial, ovarian, prostate, uterine, penile, or vulvar cancers. Dapagliflozin potentially increased the risk of male genital cancers (RR 1.31; 95% CI 0.99-1.74; P = 0.06). SGLT2 inhibition significantly reduced testicular [odds ratio (OR) 0.012; 95% CI 0.001-0.220; P = 0.003] and cervical (OR 0.013; 95% CI 0.001-0.122; P = 1.615 × 10 - 4) cancer risks. Pooled results from both discovery and replication cohorts demonstrated that SGLT2 inhibition reduced cervical cancer risk (OR 0.016; 95% CI 0.002-0.116; P < 0.0001).

Conclusion: SGLT2 inhibitors exhibited a neutral overall risk profile for genital cancers, while genetic evidence demonstrated beneficial effects specifically for cervical cancer.