Sex-Specific Associations of Glycemic Status and Smoking with Bladder Cancer Risk: A Nationwide Cohort Study

Background: Sex differences in the effects of hyperglycemia and smoking on bladder cancer risk remain poorly understood, despite their known roles as modifiable risk factors. We investigated the sex-specific associations of prediabetes, diabetes, and smoking with bladder cancer risk. Methods: We analyzed data from 9,492,331 cancer-free adults (54.8% men) who underwent the 2009 Korean national health screening. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for bladder cancer incidence were calculated using Cox proportional hazards models. Results: Over a median follow-up of 8.3 years, 12,095 men and 2467 women were diagnosed with bladder cancer. The male-to-female incidence ratio was 4.1:1 among never-smokers with normoglycemia and 2.7:1 among ever-smokers with diabetes. In women, both prediabetes and diabetes were associated with elevated bladder cancer risk (aHRs, 95% CIs: 1.12, 1.02-1.24; and 1.27, 1.13-1.43). In men, only diabetes showed an increased risk (aHR: 1.22, 1.12-1.32). Combined diabetes and smoking increased the risk synergistically in women (aHR: 2.75, 1.95-3.87; synergy index = 2.38, p < 0.01), while the effect was additive in men (aHR: 1.82, 1.70-1.95). Conclusions: The typical male predominance in bladder cancer incidence appeared attenuated in the presence of hyperglycemia and smoking, suggesting that these risk factors may have a relatively greater impact on bladder cancer risk among women. These findings underscore the importance of targeted bladder cancer prevention strategies, with particular attention to women with hyperglycemia who smoke, given their disproportionately elevated risk.