title: Effect of diabetes mellitus and metformin use on oncologic outcomes of patients treated with radical cystectomy for urothelial carcinoma.
abstract: OBJECTIVE
  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
  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.
authors.affiliation: Department of Urology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY; Department of Urology, University Hospital Basel, Basel, Switzerland.
authors.forename: Malte
authors.initials: M
authors.lastname: Rieken
authors.affiliation: Department of Urology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY; Department of Urology Cochin Hospital, APHP, Paris Descartes University, Paris, France.
authors.forename: Evanguelos
authors.initials: E
authors.lastname: Xylinas
authors.affiliation: Department of Urology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY; Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Luis
authors.initials: L
authors.lastname: Kluth
authors.affiliation: Department of Urology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Crivelli
authors.affiliation: Department of Urology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY.
authors.forename: James
authors.initials: J
authors.lastname: Chrystal
authors.affiliation: Department of Urology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY.
authors.forename: Talia
authors.initials: T
authors.lastname: Faison
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Yair
authors.initials: Y
authors.lastname: Lotan
authors.affiliation: Department of Urology, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Pierre I
authors.initials: PI
authors.lastname: Karakiewicz
authors.affiliation: Department of Urology, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Maxine
authors.initials: M
authors.lastname: Sun
authors.affiliation: Department of Urology, Medical University of Vienna, Vienna, Austria.
authors.forename: Harun
authors.initials: H
authors.lastname: Fajkovic
authors.affiliation: Department of Urology, Hospital Motol, Second Faculty of Medicine, Charles University, Praha, Czech Republic.
authors.forename: Marek
authors.initials: M
authors.lastname: Babjuk
authors.affiliation: Department of Urology, University Hospital Basel, Basel, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Bachmann
authors.affiliation: Department of Urology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY.
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Scherr
authors.affiliation: Department of Urology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY; Division of Medical Oncology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY; Department of Urology, Medical University of Vienna, Vienna, Austria. Electronic address: sfshariat@gmail.com.
authors.forename: Shahrokh F
authors.initials: SF
authors.lastname: Shariat
mesh_terms: D000368:Aged; D002295:Carcinoma, Transitional Cell / Q000401:mortality / Q000601:surgery*; D002423:Cause of Death; D015653:Cystectomy / Q000379:methods*; D003920:Diabetes Mellitus / Q000188:drug therapy*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D053208:Kaplan-Meier Estimate; D008197:Lymph Node Excision; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D017063:Outcome Assessment, Health Care / Q000379:methods / Q000706:statistics & numerical data; D010388:Pelvis; D016016:Proportional Hazards Models; D012044:Regression Analysis; D012307:Risk Factors; D015996:Survival Rate; D001749:Urinary Bladder Neoplasms / Q000401:mortality / Q000601:surgery*
chemical_list: D007004:Hypoglycemic Agents; D008687:Metformin
keywords: Bladder cancer; Diabetes mellitus; Metformin; Outcomes; Radical cystectomy