title: Metformin efficacy and safety for colorectal polyps: a double-blind randomized controlled trial.
abstract: BACKGROUND
  Colorectal cancer is one of the major neoplasms and a leading cause of cancer death worldwide, and new preventive strategies are needed to lower the burden of this disease. Metformin, a biguanide, which is widely used for treating diabetes mellitus, has recently been suggestive to have a suppressive effect on tumorigenesis and cancer cell growth. In a previous study conducted in non-diabetic subjects, we showed that oral short-term low-dose metformin suppressed the development of colorectal aberrant crypt foci (ACF). ACF have been considered as a useful surrogate biomarker of CRC, although the biological significance of these lesions remains controversial. We devised a prospective randomized controlled trial to evaluate the chemopreventive effect of metformin against metachronous colorectal polyps and the safety of this drug in non-diabetic post-polypectomy patients.
  
  
  METHODS
  This study is a multi-center, double-blind, placebo-controlled, randomized controlled trial to be conducted in non-diabetic patients with a recent history of undergoing colorectal polypectomy. All adult patients visiting the Yokohama City University hospital or affiliated hospitals for polypectomy shall be recruited for the study. Eligible patients will then be allocated randomly into either one of two groups: the metformin group and the placebo group. Patients in the metformin group shall receive oral metformin at 250 mg per day, and those in the placebo group shall receive an oral placebo tablet. At the end of 1 year of administration of metformin/placebo, colonoscopy will be performed to evaluate the polyp formation.
  
  
  CONCLUSIONS
  This is the first study proposed to explore the effect of metformin against colorectal polyp formation. Metformin activates AMPK, which inhibits the mammalian target of rapamycin (mTOR) pathway. The mTOR pathway plays an important role in the cellular protein translational machinery and cell proliferation. Patients with type 2 diabetes taking under treatment with metformin have been reported to be at a lower risk of cancer development than those not taking under treatment with metformin. We showed in a previous study that metformin suppressed the formation of human colorectal ACF. We therefore decided to conduct a study to determine whether metformin might suppress the formation of human colorectal polyps.
  
  
  BACKGROUND
  This trial has been registered in the University hospital Medical Information Network (UMIN) Clinical Trials Registry as UMIN000006254.
authors.affiliation: Division of Gastroenterology, Yokohama City University School of Medicine, Yokohama, Japan.
authors.forename: Takuma
authors.initials: T
authors.lastname: Higurashi
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Takahashi
authors.forename: Hiroki
authors.initials: H
authors.lastname: Endo
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Hosono
authors.forename: Eiji
authors.initials: E
authors.lastname: Yamada
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ohkubo
authors.forename: Eiji
authors.initials: E
authors.lastname: Sakai
authors.forename: Takashi
authors.initials: T
authors.lastname: Uchiyama
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Hata
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Fujisawa
authors.forename: Shiori
authors.initials: S
authors.lastname: Uchiyama
authors.forename: Akiko
authors.initials: A
authors.lastname: Ezuka
authors.forename: Hajime
authors.initials: H
authors.lastname: Nagase
authors.forename: Takaomi
authors.initials: T
authors.lastname: Kessoku
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Matsuhashi
authors.forename: Shoji
authors.initials: S
authors.lastname: Yamanaka
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Inayama
authors.forename: Satoshi
authors.initials: S
authors.lastname: Morita
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakajima
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016588:Anticarcinogenic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D003111:Colonic Polyps / Q000517:prevention & control*; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008687:Metformin / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D011446:Prospective Studies
chemical_list: D016588:Anticarcinogenic Agents; D008687:Metformin