Effect of diabetes mellitus and metformin use on oncologic outcomes of patients treated with radical cystectomy for urothelial carcinoma

Objectives: Evidence suggests a positive effect of metformin on cancer incidence and outcome. To date, the effect of metformin use on prognosis in urothelial carcinoma of the bladder (UCB) remains uninvestigated. We tested the hypothesis that metformin use affects oncologic outcomes of patients treated with radical cystectomy for UCB. Methods and materials: We retrospectively evaluated 1,502 patients treated at 4 institutions with radical cystectomy and pelvic lymphadenectomy without neoadjuvant therapy. Cox regression models addressed the association of diabetes mellitus (DM) and metformin use with disease recurrence, cancer-specific mortality, and any-cause mortality. Results: A total of 200 patients (13.3%) had DM, 80 patients (5.3%) used metformin. Within a median follow-up of 34 months, 509 patients (33.9%) experienced disease recurrence, 402 patients (26.8%) died of UCB, and 551 patients (36.7%) died from any cause. In univariable Cox regression analyses, DM without metformin use was associated with increased risk of disease recurrence (hazard ratio [HR]: 1.40, 95% confidence interval [CI] 1.05-1.87, P = 0.02), cancer-specific mortality (HR: 1.60, 95% CI 1.17-2.17, P = 0.003), and any-cause mortality (HR: 1.55, 95% CI 1.18-2.03, P = 0.002), whereas metformin use was associated with decreased risk of disease recurrence (HR: 0.61, 95% CI 0.37-0.98, P = 0.04), cancer-specific mortality (HR: 0.56, 95% CI 0.33-0.97, P = 0.04), and any-cause mortality (HR: 0.54, 95% CI 0.33-0.88, P = 0.01). In multivariable Cox regression analyses, DM treated without metformin use remained associated with worse cancer-specific mortality (HR: 1.53, 95% CI 1.12-2.09, P = 0.007) and any-cause mortality (HR: 1.52, 95% CI 1.16-2.00, P = 0.003) but not disease recurrence. Conclusions: Diabetic patients who do not use metformin appear to be at higher risk of cancer-specific and any-cause mortality than patients without DM. It remains unclear, whether the severity of DM in this group of patients or the use of metformin itself affects outcomes of UCB. The mechanisms behind the effect of DM on patients with UCB and the potential protective effect of metformin need further elucidation.