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Open Access Highly Accessed Study protocol

Metformin efficacy and safety for colorectal polyps: a double-blind randomized controlled trial

Takuma Higurashi1, Hirokazu Takahashi1, Hiroki Endo1, Kunihiro Hosono1, Eiji Yamada1, Hidenori Ohkubo1, Eiji Sakai1, Takashi Uchiyama2, Yasuo Hata2, Nobutaka Fujisawa3, Shiori Uchiyama4, Akiko Ezuka4, Hajime Nagase4, Takaomi Kessoku5, Nobuyuki Matsuhashi6, Shoji Yamanaka7, Yoshiaki Inayama7, Satoshi Morita8 and Atsushi Nakajima19*

Author Affiliations

1 Division of Gastroenterology, Yokohama City University School of Medicine, Yokohama, Japan

2 Department of Gastroenterology, Chigasaki Municipal Hospital, Kanagawa, Japan

3 Gastroenterology Division, Tokyo Metropolitan Hiroo Hospita, Tokyo, Japan

4 Department of Gastroenterology, Yokohama Rosai Hospital, Yokohama, Japan

5 Department of Gastroenterology, Hiratsuka City Hospital, Kanagawa, Japan

6 Department of Gastroenterology, Kanto Medical Center, NTT East, Tokyo, Japan

7 Department of Pathology, Yokohama City University, Yokohama, Japan

8 Department of Biostatistics and Epidemiology, Yokohama City University School of Medicine, Yokohama, Japan

9 Division of Gastroenterology, Yokohama City University School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, Yokohama 236-0004, Japan

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BMC Cancer 2012, 12:118  doi:10.1186/1471-2407-12-118

Published: 26 March 2012

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/Design

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.

Discussion

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.

Trial registration

This trial has been registered in the University hospital Medical Information Network (UMIN) Clinical Trials Registry as UMIN000006254