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Metformin may act as a protective agent against colorectal cancer
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One year of low-dose metformin reduced the prevalence and number of metachronous adenomas after polypectomy in nondiabetic adults, according to the results of a phase 3 randomized controlled trial.
These results suggest a potential role for metformin in the chemoprevention of colorectal cancer, according to the researchers.
“Colorectal cancer is a common neoplasm worldwide, and both its prevalence and associated mortality are increasing,” Atsushi Nakajima, MD, PhD, professor of gastroenterology and hepatology at Yokohama City University School of Medicine in Japan, and colleagues wrote. “The removal of colorectal polyps reduces the risk for future development of colorectal cancer and advanced adenoma. However, patients with polyps (adenomas or hyperplastic polyps) constitute a high-risk group for the development of metachronous colorectal polyps, colorectal cancer or both.”
Andrew T. Chan
Epidemiological and animal studies have suggested that the oral diabetes medicine metformin may have chemopreventive effects against several cancer subtypes, including colorectal cancer, according to study background.
Thus, Nakajima and colleagues conducted a double-blind, randomized, controlled phase 3 trial to determine the safety and chemopreventive effects of metformin on sporadic colorectal cancer among nondiabetic individuals considered at high risk for adenoma recurrence.
The researchers randomly assigned 151 nondiabetic adults (median age, 64 years; range, 40-78) who had single or multiple resected colorectal adenomas to oral metformin (250 mg daily; n = 79) or placebo (n = 72) for 1 year.
The number and prevalence of colorectal adenomas or polyps served as the primary endpoints, with colonoscopies performed after 1 year of drug administration.
Seventy-one participants assigned metformin and 62 participants assigned placebo underwent 1-year colonoscopies.
Overall, participants assigned metformin had significant fewer total polyps (27 vs. 35; risk ratio = 0.67; 95% CI, 0.47-0.97) and adenomas (22 vs. 32; risk ratio = 0.6; 95% CI, 0.39-0.92).
Because individuals in the metformin arm had a lower family history of colorectal cancer and a higher family history of hyperlipidemia than those in the placebo arm, researchers conducted sensitivity analyses adjusting for these characteristics (total polyps, risk ratio = 0.64; 95% CI, 0.43-0.96).
The researchers found 110 polyps at the 1-year endoscopy (adenomas, n = 96; hyperplastic polyps, n = 14).
The metformin arm had 44 polyps identified at 1 year (adenomas, n = 37; hyperplastic polyps, n = 7), compared with 66 (adenomas, n = 59; hyperplastic polyps, n = 7) in the placebo arm.
Participants in the metformin arm had a median number of zero polyps (interquartile range [IQR], 0-1), compared with one polyp (IQR, 0-1) in the placebo arm (P = .041). For adenomas, the median number in both arms was zero (IQR, 0-1; P = .037).
Eleven percent of participants (n = 15) experienced adverse events, all of which were grade 1. The most frequently reported adverse events included abdominal pain, diarrhea, rash, constipation and alopecia.
One patient in the placebo arm discontinued treatment due to diarrhea. However, the researchers did not observe any serious adverse events, despite high median patient compliance in both arms (metformin, 91%; placebo, 92%).
Study limitations included the lack of a dose–response analysis of the effect of metformin on colorectal polyp formation, as well as the relatively short follow-up period.
The researchers further noted that participants did not receive a “clean colon confirmed colonoscopy” after initial polypectomy, suggesting that lingering polyps and adenomas may have been missed. They also reported that because the study was conducted in a single geographical region in Japan, their findings may not be generalizable to non-Japanese individuals.
“Low-dose metformin is safe and effective in reducing the prevalence of metachronous adenomas and polyps in nondiabetic patients after polypectomy,” Nakajima and colleagues wrote. “Low-dose metformin might be more effective for patients who are insulin-resistant, even if they do not have diabetes. … Metformin has potential in chemoprevention for colorectal cancer.”
These findings will drive new research in chemoprevention for colorectal cancer despite the study’s limitations, Andrew T. Chan, MD, MPH, associate professor of medicine at Harvard Medical School and program director of the gastroenterology training program at Massachusetts General Hospital, wrote in an accompanying editorial.
“These exciting findings should sustain optimism that metformin might have a role in cancer prevention, thereby encouraging and informing the development of more definitive randomized controlled trials,” Chan wrote. “For colorectal cancer prevention specifically, a large-scale randomized controlled trial of metformin (perhaps in combination with aspirin, an established chemopreventive agent) for adenoma recurrence in a population with a broader risk profile appears warranted. If such a study yielded positive results, the time and expense of larger scale randomized controlled trials of metformin in the prevention of not only other cancers, but also other obesity-associated outcomes, would seem to be justified.” – by Cameron Kelsall
Disclosure: The researchers report no relevant financial disclosures. Chan reports consultant roles with Bayer HealthCare and Pfizer for work unrelated to this study.
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