Elsevier

The Lancet Oncology

Volume 17, Issue 4, April 2016, Pages 475-483
The Lancet Oncology

Articles
Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: a multicentre double-blind, placebo-controlled, randomised phase 3 trial

https://doi.org/10.1016/S1470-2045(15)00565-3Get rights and content

Summary

Background

The prevalence of, and mortality from, colorectal cancer is increasing worldwide, and new strategies for prevention are needed to reduce the burden of this disease. The oral diabetes medicine metformin might have chemopreventive effects against cancer, including colorectal cancer. However, no clinical trial data exist for the use of metformin for colorectal cancer chemoprevention. Therefore, we devised a 1-year clinical trial to assess the safety and chemopreventive effects of metformin on sporadic colorectal cancer (assessed by adenoma and polyp recurrence) in patients with a high risk of adenoma recurrence.

Methods

This trial was a multicentre, double-blind, placebo-controlled, randomised phase 3 trial. Non-diabetic adult patients who had previously had single or multiple colorectal adenomas or polyps resected by endoscopy were enrolled into the study from five hospitals in Japan. Eligible patients were randomly assigned (1:1) to receive oral metformin (250 mg daily) or identical placebo tablets by a stratified computer-based randomisation method, with stratification by institute, age, sex, and body-mass index. All patients, endoscopists, doctors, and investigators were masked to drug allocation until the end of the trial. After 1 year of administration of metformin or placebo, colonoscopies were done to assess the co-primary endpoints: the number and prevalence of adenomas or polyps. Our analysis included all participants who underwent random allocation, according to the intention-to-treat principle. This trial is registered with University Hospital Medical Information Network (UMIN), number UMIN000006254.

Findings

Between Sept 1, 2011, and Dec 30, 2014, 498 patients who had had single or multiple colorectal adenomas resected by endoscopy were enrolled into the study. After exclusions for ineligibility, 151 patients underwent randomisation: 79 were assigned to the metformin group and 72 to the placebo group. 71 patients in the metformin group and 62 in the placebo group underwent 1-year follow-up colonoscopy. The prevalence of total polyps (hyperplastic polyps plus adenomas) and of adenomas in the metformin group was significantly lower than that in the placebo group (total polyps: metformin group 27 [38·0%; 95% CI 26·7–49·3] of 71 patients, placebo group 35 [56·5%; 95% CI 44·1–68·8] of 62; p=0·034, risk ratio [RR] 0·67 [95% CI 0·47–0·97]; adenomas: metformin group 22 [30·6%; 95% CI 19·9–41·2] of 71 patients, placebo group 32 [51·6%; 95% CI 39·2–64·1] of 62; p=0·016, RR 0·60 [95% CI 0·39–0·92]). The median number of polyps was zero (IQR 0–1) in the metformin group and one (0–1) in the placebo group (p=0·041). The median number of adenomas was zero (0–1) in the metformin group and zero (0–1) in the placebo group (p=0·037). 15 (11%) of patients had adverse events, all of which were grade 1. We recorded no serious adverse events during the 1-year trial.

Interpretation

The administration of low-dose metformin for 1 year to patients without diabetes was safe. Low-dose metformin reduced the prevalence and number of metachronous adenomas or polyps after polypectomy. Metformin has a potential role in the chemoprevention of colorectal cancer. However, further large, long-term trials are needed to provide definitive conclusions.

Funding

Ministry of Health, Labour and Welfare, Japan.

Introduction

Colorectal cancer is a common neoplasm worldwide,1 and both its prevalence and associated mortality are increasing. The removal of colorectal polyps reduces the risk of future development of colorectal cancer and advanced adenoma.2 However, patients with polyps (adenomas or hyperplastic polyps) constitute a high-risk group for the development of metachronous colorectal polyps, colorectal cancer, or both.3 Therefore, a change in approach from surveillance for early detection of cancer and adenomas (the latter often being treated by polypectomy) to new strategies for prevention, including chemoprevention, is needed to reduce the burden of this disease. Several large epidemiological and clinical studies have assessed the possible preventive effects against colorectal cancer development of more than 200 agents, including fibre, calcium, and non-steroidal anti-inflammatory drugs, such as aspirin and selective COX-2 inhibitors.4 Non-steroidal anti-inflammatory drugs, especially COX-2 inhibitors, administered either alone or in combination with other agents, have shown the most promise for reducing colorectal cancer risk. However, an increased risk of serious cardiovascular events is associated with the use of COX-2 inhibitors.5, 6 Because of the adverse cardiovascular effects of COX-2 inhibitors and the absence of demonstrable efficacy of other agents that had initially showed promise in this setting, new drugs are needed that are both safe and effective for colorectal cancer prevention. Colorectal cancer is associated with lifestyle-related diseases, such as diabetes mellitus and obesity.7, 8 Therefore, we postulated that these disorders might represent potential new targets for colorectal cancer chemoprevention.

Research in context

Evidence before this study

We searched PubMed between Jan 1, 1990, and Sept 1, 2011, using the terms “colorectal cancer”, “chemoprevention”, “metformin”, and “clinical trial”. We searched for articles published in English only. We found no clinical trial data related to the use of metformin for colorectal cancer chemoprevention. As a preliminary study before considering long-term colorectal cancer chemoprevention trials, we devised a 1-year clinical trial to assess the safety and the chemopreventive effect of metformin against the development of metachronous colorectal adenomas or polyps in patients without diabetes post-polypectomy.

Added value of this study

To our knowledge, this is the first comparative randomised trial to assess the chemopreventive effect of metformin for metachronous colorectal adenomas and polyps. Low-dose metformin reduced the incidence and number of metachronous adenomas and polyps after polypectomy. The 1-year administration of low-dose metformin was safe for non-diabetic patients.

Implication of all the available evidence

Recent evidence indicates that metformin has a suppressive effect on tumorigenesis and cancer cell growth by activating AMPK and suppressing the mTOR pathway. Many metformin chemoprevention trials against various types of cancer are in progress. Our findings suggest that metformin has a potential role in the chemoprevention of colorectal cancer.

Metformin is a biguanide derivative that is used widely to treat diabetes mellitus.9 It reduces basal glucose output by suppressing gluconeogenesis and glycogenolysis in the liver and increasing glucose uptake by muscle. Because metformin does not directly stimulate insulin secretion, it is associated with a lower risk of hypoglycaemia than other oral antidiabetic drugs.10 The molecular mechanism involved in the action of metformin is liver kinase B1-dependent activation of AMP-activated protein kinase (AMPK).11, 12 Patients with type 2 diabetes who are treated with metformin seem to be at a lower risk of developing cancer (including colorectal cancer) than those not treated with metformin.13 This evidence suggests that metformin might be a candidate drug for colorectal cancer chemoprevention in patients with diabetes. However, because diabetes itself is a risk factor for cancer, treatment of diabetes might reduce this risk. Therefore, whether the suppressive effect of metformin against colorectal cancer is caused by a direct chemopreventive effect of the drug or is mediated by its antidiabetic effect remains unclear.

We have previously shown the chemopreventive effect of metformin against colorectal cancer in two models of colorectal carcinoma in non-diabetic mice,14, 15 which suggested the direct chemopreventive potential of metformin itself. We also did a trial involving non-diabetic human patients and showed that oral low-dose metformin (250 mg/day) was safe and suppressed the formation of colorectal aberrant crypt foci.16 This clinical trial was the first to show that metformin has chemopreventive potential against colon carcinogenesis. However, the trial was limited by its short duration (1 month) and the use of human aberrant crypt foci as the surrogate biomarker of colorectal cancer; although these are regarded as a useful surrogate biomarker,17 their biological significance remains controversial. Generally, in colorectal cancer chemoprevention trials, the incidence of polyps or cancer is set as the study endpoint. The incidence of colorectal cancer would be the most reliable endpoint but is unsuitable for colorectal cancer chemoprevention trials because of the low incidence of colorectal cancer in the general population and the long-term observation period that it would necessitate. Moreover, serious ethical issues would be involved in withholding endoscopic resection and waiting for polyps detected in annual colonoscopies to potentially develop into cancer.

To the best of our knowledge, no colorectal cancer chemoprevention trials using metformin in non-diabetic patients have been done. Consequently, the safety of the patients needs careful consideration in the design and execution of such a trial. We did a 1-year clinical trial to assess the safety and chemopreventive effect of metformin on sporadic colorectal cancer (assessed by adenoma and polyp recurrence) in patients with a high risk of adenoma recurrence as a preliminary study before considering long-term colorectal cancer chemoprevention trials.

Section snippets

Study design and participants

This study was a multicentre, double-blind, placebo-controlled, randomised trial of patients without diabetes with a recent history of colorectal polypectomy. The study was done at five hospitals in Japan (appendix).

All adult patients (aged ≥20 years) scheduled for polypectomy were recruited for the study. The inclusion criteria were: no colorectal polyps present after polypectomy, age 40–80 years on the date of informed consent, and willingness to provide written informed consent. We set the

Results

Patient enrolment began on Sept 1, 2011, and the trial ended, with the final analysis done, on Dec 30, 2014. 498 patients were screened for eligibility, of whom 347 were excluded (figure 1). We excluded 183 patients because of inadequate colon cleaning, such as an incompletely clean polypectomy, poor preparation, short observation time, or lack of insertion to the caecum (ie, if a patient's endoscopy had any of these characteristics, they were judged to have incomplete polypectomy).

The

Discussion

In this randomised phase 3 trial, metformin prevented both metachronous hyperplastic polyps and adenomas in non-diabetic patients post-polypectomy. Moreover, few adverse events occurred in the trial period. The safety results suggest that low-dose metformin intake for 1 year was safe for non-diabetic patients. This study is the first to our knowledge to assess the chemopreventive effect of low-dose metformin against metachronous colorectal adenoma or polyp formation.

In a colorectal cancer

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