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/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

Metformin, Diabetes, and Survival among U.S. Veterans with Colorectal Cancer

“…These effects are particularly intriguing for CRC because Peutz-Jeghers polyposis involves loss of LKB1, a tumor suppressor that also regulates AMPK. Metformin also appears to inhibit polyp formation and aberrant crypt foci (40–42). …”

Metformin in Cancer Treatment and Prevention

“…Other high-risk groups include patients with premalignant conditions such as colorectal polyps or Barrett's esophagus. Indeed, a multicenter double-blind placebo-controlled randomized trial of metformin in the prevention of colorectal polyps in nondiabetic patients is currently under way (72). If proven effective, metformin will be an attractive anticancer agent because of its safety, tolerability, and widespread availability, but further investigation into the effects of metformin are required to properly assess its potential in oncology.…”

Combined Use of Vitamin D3 and Metformin Exhibits Synergistic Chemopreventive Effects on Colorectal Neoplasia in Rats and Mice

“…In vitro study has also demonstrated growth inhibitory effects of metformin in colon cancer cells via activating AMP-activated protein kinase (AMPK) pathway (12). Furthermore, in clinical trials, metformin suppressed colonic epithelial proliferation and rectal ACF formation in humans (13, 14). It is hypothesized that metformin has both direct and indirect anti-neoplastic actions.…”