title: Metformin does not reduce markers of cell proliferation in esophageal tissues of patients with Barrett's esophagus.
abstract: OBJECTIVE
  Obesity is associated with neoplasia, possibly via insulin-mediated cell pathways that affect cell proliferation. Metformin has been proposed to protect against obesity-associated cancers by decreasing serum insulin. We conducted a randomized, double-blind, placebo-controlled, phase 2 study of patients with Barrett's esophagus (BE) to assess the effect of metformin on phosphorylated S6 kinase (pS6K1), a biomarker of insulin pathway activation.
  
  
  METHODS
  Seventy-four subjects with BE (mean age, 58.7 years; 58 men [78%; 52 with BE >2 cm [70%]) were recruited through 8 participating organizations of the Cancer Prevention Network. Participants were randomly assigned to groups given metformin daily (increasing to 2000 mg/day by week 4, n = 38) or placebo (n = 36) for 12 weeks. Biopsy specimens were collected at baseline and at week 12 via esophagogastroduodenoscopy. We calculated and compared percent changes in median levels of pS6K1 between subjects given metformin vs placebo as the primary end point.
  
  
  RESULTS
  The percent change in median level of pS6K1 did not differ significantly between groups (1.4% among subjects given metformin vs -14.7% among subjects given placebo; 1-sided P = .80). Metformin was associated with an almost significant reduction in serum levels of insulin (median -4.7% among subjects given metformin vs 23.6% increase among those given placebo, P = .08) as well as in homeostatic model assessments of insulin resistance (median -7.2% among subjects given metformin vs 38% increase among those given placebo, P = .06). Metformin had no effects on cell proliferation (on the basis of assays for KI67) or apoptosis (on the basis of levels of caspase 3).
  
  
  CONCLUSIONS
  In a chemoprevention trial of patients with BE, daily administration of metformin for 12 weeks, compared with placebo, did not cause major reductions in esophageal levels of pS6K1. Although metformin reduced serum levels of insulin and insulin resistance, it did not discernibly alter epithelial proliferation or apoptosis in esophageal tissues. These findings do not support metformin as a chemopreventive agent for BE-associated carcinogenesis. ClinicalTrials.gov number, NCT01447927.
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospitals Case Medical Center, Cleveland, Ohio. Electronic address: amitabh.chak@UHhospitals.org.
authors.forename: Amitabh
authors.initials: A
authors.lastname: Chak
authors.affiliation: Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Navtej S
authors.initials: NS
authors.lastname: Buttar
authors.affiliation: Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota.
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Foster
authors.affiliation: Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota.
authors.forename: Drew K
authors.initials: DK
authors.lastname: Seisler
authors.affiliation: Department of Medicine, Gastroenterology, St Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Norman E
authors.initials: NE
authors.lastname: Marcon
authors.affiliation: Department of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Robert
authors.initials: R
authors.lastname: Schoen
authors.affiliation: Department of Gastroenterology Oncology at UPR Cancer Center, University of Puerto Rico, San Juan, Puerto Rico.
authors.forename: Marcia R
authors.initials: MR
authors.lastname: Cruz-Correa
authors.affiliation: Department of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Gary W
authors.initials: GW
authors.lastname: Falk
authors.affiliation: Department of Gastroenterology, Hepatology and Motility, Kansas City VA, Kansas City, Missouri.
authors.forename: Prateek
authors.initials: P
authors.lastname: Sharma
authors.affiliation: Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Chin
authors.initials: C
authors.lastname: Hur
authors.affiliation: Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
authors.forename: David A
authors.initials: DA
authors.lastname: Katzka
authors.affiliation: Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Luz M
authors.initials: LM
authors.lastname: Rodriguez
authors.affiliation: Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Ellen
authors.initials: E
authors.lastname: Richmond
authors.affiliation: Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Anamay N
authors.initials: AN
authors.lastname: Sharma
authors.affiliation: Department of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Smyrk
authors.affiliation: Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota.
authors.forename: Sumithra J
authors.initials: SJ
authors.lastname: Mandrekar
authors.affiliation: Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Limburg
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001471:Barrett Esophagus / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D004311:Double-Blind Method; D016145:Endoscopy, Digestive System; D004938:Esophageal Neoplasms / Q000517:prevention & control*; D005260:Female; D006801:Humans; D007328:Insulin / Q000097:blood; D008297:Male; D008687:Metformin / Q000008:administration & dosage*; D008875:Middle Aged; D010919:Placebos / Q000008:administration & dosage; D011446:Prospective Studies; D019893:Ribosomal Protein S6 Kinases / Q000032:analysis; D055815:Young Adult
chemical_list: D007328:Insulin; D010919:Placebos; D008687:Metformin; D019893:Ribosomal Protein S6 Kinases
keywords: Cancer Development; Diabetes Drug; HOMA-IR; Tumorigenesis