title: The effect of metformin on cancer-specific survival outcomes in diabetic patients undergoing radical cystectomy for urothelial carcinoma of the bladder.
abstract: OBJECTIVE
  Metformin, a first-line oral therapy for diabetes, has anticancer properties. Our objective was to evaluate the association between metformin use and oncologic outcomes in diabetic patients undergoing radical cystectomy (RC) for bladder cancer (BC).
  
  
  METHODS
  A single-institution retrospective cohort (January 1997-June 2013) of diabetic patients undergoing RC was assembled. Medication use was assessed at time of surgery. Outcome measures were recurrence-free survival (RFS), BC-specific survival (BCSS), and overall survival (OS). Multivariable Cox proportional hazards models were used. To create parsimonious models, the change of estimate approach (10% threshold) was used as a variable selection strategy for final model inclusion separately for each outcome measure.
  
  
  RESULTS
  Of 421 patients, 85 (20%) had diabetes. There were 39 (46%) patients on metformin therapy. Among diabetic patients, there were 21 patients with BC recurrence, 16 who died of BC, and 30 who died overall. In univariate analyses, metformin use among diabetic patients was associated with improved RFS (hazard ratio = 0.54, 95% CI: 0.33-0.88, P = 0.013) and trended toward improved BCSS (hazard ratio = 0.65, 95% CI: 0.40-1.07, P = 0.087), but not with OS (P = 0.87). In multivariable models, metformin use among diabetic patients was associated with significantly improved RFS (adjusted hazard ratio = 0.38, 95% CI: 0.20-0.72, P = 0.003) and BCSS (adjusted hazard ratio = 0.57, 95% CI: 0.35-0.91, P = 0.019), but not with OS (P = 0.89). Use of other oral hypoglycemic agents or insulin was not associated with oncologic outcomes.
  
  
  CONCLUSIONS
  Our study is among the first to report an association between metformin use and improved RFS and BCSS in diabetic patients undergoing RC. Given its low cost and demonstrated safety among nondiabetic patients, further studies are warranted to evaluate potential therapeutic and preventive roles of metformin in BC.
authors.affiliation: Department of Surgery, Princess Margaret Cancer Centre, University Health Network and the University of Toronto, Toronto, Canada; Department of Surgical Oncology, Princess Margaret Cancer Centre, University Health Network and the University of Toronto, Toronto, Canada. Electronic address: madhur.nayan@mail.utoronto.ca.
authors.forename: Madhur
authors.initials: M
authors.lastname: Nayan
authors.affiliation: Department of Surgery, Princess Margaret Cancer Centre, University Health Network and the University of Toronto, Toronto, Canada; Department of Surgical Oncology, Princess Margaret Cancer Centre, University Health Network and the University of Toronto, Toronto, Canada.
authors.forename: Bimal
authors.initials: B
authors.lastname: Bhindi
authors.affiliation: Faculty of Medicine, University of Toronto, Toronto, Canada.
authors.forename: Julie L
authors.initials: JL
authors.lastname: Yu
authors.affiliation: Department of Surgery, Princess Margaret Cancer Centre, University Health Network and the University of Toronto, Toronto, Canada; Department of Surgical Oncology, Princess Margaret Cancer Centre, University Health Network and the University of Toronto, Toronto, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hermanns
authors.affiliation: Department of Surgery, Princess Margaret Cancer Centre, University Health Network and the University of Toronto, Toronto, Canada; Department of Surgical Oncology, Princess Margaret Cancer Centre, University Health Network and the University of Toronto, Toronto, Canada.
authors.forename: Aza
authors.initials: A
authors.lastname: Mohammed
authors.affiliation: Department of Surgery, Princess Margaret Cancer Centre, University Health Network and the University of Toronto, Toronto, Canada; Department of Surgical Oncology, Princess Margaret Cancer Centre, University Health Network and the University of Toronto, Toronto, Canada.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Hamilton
authors.affiliation: Department of Surgery, Princess Margaret Cancer Centre, University Health Network and the University of Toronto, Toronto, Canada; Department of Surgical Oncology, Princess Margaret Cancer Centre, University Health Network and the University of Toronto, Toronto, Canada.
authors.forename: Antonio
authors.initials: A
authors.lastname: Finelli
authors.affiliation: Department of Surgery, Princess Margaret Cancer Centre, University Health Network and the University of Toronto, Toronto, Canada; Department of Surgical Oncology, Princess Margaret Cancer Centre, University Health Network and the University of Toronto, Toronto, Canada.
authors.forename: Michael A S
authors.initials: MA
authors.lastname: Jewett
authors.affiliation: Department of Surgery, Mount Sinai Hospital, University of Toronto, Toronto, Canada.
authors.forename: Alexandre R
authors.initials: AR
authors.lastname: Zlotta
authors.affiliation: Department of Surgery, Princess Margaret Cancer Centre, University Health Network and the University of Toronto, Toronto, Canada; Department of Surgical Oncology, Princess Margaret Cancer Centre, University Health Network and the University of Toronto, Toronto, Canada.
authors.forename: Neil E
authors.initials: NE
authors.lastname: Fleshner
authors.affiliation: Department of Surgery, Princess Margaret Cancer Centre, University Health Network and the University of Toronto, Toronto, Canada; Department of Surgical Oncology, Princess Margaret Cancer Centre, University Health Network and the University of Toronto, Toronto, Canada.
authors.forename: Girish S
authors.initials: GS
authors.lastname: Kulkarni
mesh_terms: D000368:Aged; D002295:Carcinoma, Transitional Cell / Q000401:mortality* / Q000601:surgery; D015331:Cohort Studies; D015653:Cystectomy; D003920:Diabetes Mellitus / Q000188:drug therapy*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D001749:Urinary Bladder Neoplasms / Q000401:mortality* / Q000601:surgery
chemical_list: D007004:Hypoglycemic Agents; D008687:Metformin
keywords: Cystectomy; Metformin; Mortality; Patient outcome assessment; Urinary bladder neoplasms