title: Metformin Use and Survival of Patients With Pancreatic Cancer: A Cautionary Lesson.
abstract: The inclusion of metformin in the treatment arms of cancer clinical trials is based on improved survival that has been demonstrated in retrospective epidemiologic studies; however, unintended biases may exist when analysis is performed by using a conventional Cox proportional hazards regression model with dichotomous ever/never categorization. We examined the impact of metformin exposure definitions, analytical methods, and patient selection on the estimated effect size of metformin exposure on survival in a large cohort of patients with pancreatic ductal adenocarcinoma (PDAC).
  
  
  
  Of newly diagnosed patients with PDAC with diabetes, 980 were retrospectively included, and exposure to metformin documented. Median survival was assessed by using Kaplan-Meier and log-rank methods. Hazard ratios (HR) and 95% CIs were computed to compare time-varying covariate analysis with conventional Cox proportional hazards regression analysis.
  
  
  
  Median survival of metformin users versus nonusers was 9.9 versus 8.9 months, respectively. By the time-varying covariate analysis, metformin use was not statistically significantly associated with improved survival (HR, 0.93; 95% CI, 0.81 to1.07; P = .28). There was no evidence of benefit in the subset of patients who were naïve to metformin at the time of PDAC diagnosis (most representative of patients enrolled in clinical trials; HR, 1.01; 95% CI, 0.80 to 1.30; P = .89); however, when the analysis was performed by using the conventional Cox model, an artificial survival benefit of metformin was detected (HR, 0.88; 95% CI, 0.77 to 1.01; P = .08), which suggested biased results from the conventional Cox analysis.
  
  
  
  Our findings did not suggest the benefit of metformin use after patients are diagnosed with PDAC. We highlight the importance of patient selection and appropriate statistical analytical methods when studying medication exposure and cancer survival.
authors.affiliation: Roongruedee Chaiteerakij and Lewis R. Roberts, Mayo Clinic College of Medicine and Mayo Clinic Cancer Center; Gloria M. Petersen, William R. Bamlet, Kari G. Chaffee, David B. Zhen, Patrick A. Burch, Emma R. Leof, and Ann L. Oberg, Mayo Clinic, Rochester, MN; Roongruedee Chaiteerakij, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand; and David B. Zhen, University of Michigan, Ann Arbor, MI.
authors.forename: Roongruedee
authors.initials: R
authors.lastname: Chaiteerakij
authors.affiliation: Roongruedee Chaiteerakij and Lewis R. Roberts, Mayo Clinic College of Medicine and Mayo Clinic Cancer Center; Gloria M. Petersen, William R. Bamlet, Kari G. Chaffee, David B. Zhen, Patrick A. Burch, Emma R. Leof, and Ann L. Oberg, Mayo Clinic, Rochester, MN; Roongruedee Chaiteerakij, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand; and David B. Zhen, University of Michigan, Ann Arbor, MI.
authors.forename: Gloria M
authors.initials: GM
authors.lastname: Petersen
authors.affiliation: Roongruedee Chaiteerakij and Lewis R. Roberts, Mayo Clinic College of Medicine and Mayo Clinic Cancer Center; Gloria M. Petersen, William R. Bamlet, Kari G. Chaffee, David B. Zhen, Patrick A. Burch, Emma R. Leof, and Ann L. Oberg, Mayo Clinic, Rochester, MN; Roongruedee Chaiteerakij, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand; and David B. Zhen, University of Michigan, Ann Arbor, MI.
authors.forename: William R
authors.initials: WR
authors.lastname: Bamlet
authors.affiliation: Roongruedee Chaiteerakij and Lewis R. Roberts, Mayo Clinic College of Medicine and Mayo Clinic Cancer Center; Gloria M. Petersen, William R. Bamlet, Kari G. Chaffee, David B. Zhen, Patrick A. Burch, Emma R. Leof, and Ann L. Oberg, Mayo Clinic, Rochester, MN; Roongruedee Chaiteerakij, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand; and David B. Zhen, University of Michigan, Ann Arbor, MI.
authors.forename: Kari G
authors.initials: KG
authors.lastname: Chaffee
authors.affiliation: Roongruedee Chaiteerakij and Lewis R. Roberts, Mayo Clinic College of Medicine and Mayo Clinic Cancer Center; Gloria M. Petersen, William R. Bamlet, Kari G. Chaffee, David B. Zhen, Patrick A. Burch, Emma R. Leof, and Ann L. Oberg, Mayo Clinic, Rochester, MN; Roongruedee Chaiteerakij, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand; and David B. Zhen, University of Michigan, Ann Arbor, MI.
authors.forename: David B
authors.initials: DB
authors.lastname: Zhen
authors.affiliation: Roongruedee Chaiteerakij and Lewis R. Roberts, Mayo Clinic College of Medicine and Mayo Clinic Cancer Center; Gloria M. Petersen, William R. Bamlet, Kari G. Chaffee, David B. Zhen, Patrick A. Burch, Emma R. Leof, and Ann L. Oberg, Mayo Clinic, Rochester, MN; Roongruedee Chaiteerakij, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand; and David B. Zhen, University of Michigan, Ann Arbor, MI.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Burch
authors.affiliation: Roongruedee Chaiteerakij and Lewis R. Roberts, Mayo Clinic College of Medicine and Mayo Clinic Cancer Center; Gloria M. Petersen, William R. Bamlet, Kari G. Chaffee, David B. Zhen, Patrick A. Burch, Emma R. Leof, and Ann L. Oberg, Mayo Clinic, Rochester, MN; Roongruedee Chaiteerakij, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand; and David B. Zhen, University of Michigan, Ann Arbor, MI.
authors.forename: Emma R
authors.initials: ER
authors.lastname: Leof
authors.affiliation: Roongruedee Chaiteerakij and Lewis R. Roberts, Mayo Clinic College of Medicine and Mayo Clinic Cancer Center; Gloria M. Petersen, William R. Bamlet, Kari G. Chaffee, David B. Zhen, Patrick A. Burch, Emma R. Leof, and Ann L. Oberg, Mayo Clinic, Rochester, MN; Roongruedee Chaiteerakij, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand; and David B. Zhen, University of Michigan, Ann Arbor, MI.
authors.forename: Lewis R
authors.initials: LR
authors.lastname: Roberts
authors.affiliation: Roongruedee Chaiteerakij and Lewis R. Roberts, Mayo Clinic College of Medicine and Mayo Clinic Cancer Center; Gloria M. Petersen, William R. Bamlet, Kari G. Chaffee, David B. Zhen, Patrick A. Burch, Emma R. Leof, and Ann L. Oberg, Mayo Clinic, Rochester, MN; Roongruedee Chaiteerakij, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand; and David B. Zhen, University of Michigan, Ann Arbor, MI. oberg.ann@mayo.edu.
authors.forename: Ann L
authors.initials: AL
authors.lastname: Oberg
mesh_terms: D000230:Adenocarcinoma / Q000401:mortality*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D021441:Carcinoma, Pancreatic Ductal / Q000401:mortality*; D005260:Female; D006801:Humans; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000401:mortality*; D016016:Proportional Hazards Models; D012189:Retrospective Studies
chemical_list: D008687:Metformin