New study uncovers connection between long-term metformin use and risk of colorectal cancer

Long-term use of metformin in diabetes patients—particularly men—is significantly linked to lower colorectal cancer risk, according to a new study published in Cancer Epidemiology, Biomarkers & Prevention.

“Several epidemiologic studies have reported strong inverse associations between metformin use and risk of colorectal cancer, although time-related biases, such as immortal time bias, may in part explain these findings,” wrote authors led by Laurel A. Habel, PhD, Division of Research, Kaiser Permanente Northern California (KPNC), Oakland, CA.

Previous in vitro and animal studies have indicated that metformin attenuates the growth of colorectal cancer by activating AMP-activated protein kinase (AMPK). However, many epidemiological studies on the association have yielded mixed results. Importantly, time-related biases have been implicated in explaining inverse associations between metformin use and cancer risk. These time-related biases include immortal time bias, which happens when unexposed time is wrongly categorized as exposed time in cohort studies.

In this study, Dr. Habel and colleagues examined the correlation between metformin and colorectal cancer, adjusting for various measures of metformin exposure—such as duration and recency—to minimize time-related biases. “To reduce methodologic biases encountered in previous studies,” the team wrote, “we evaluated the incidence of colorectal cancer in new users of metformin, accounting for time varying exposure to metformin and other diabetes medications, and adjusting for diabetes duration, history of lower endoscopy, and other potential confounding factors.”

The researchers mined data representing 47,351 patients with diabetes from the KPNC Diabetes Registry. Patients in the registry completed a health survey between 1994 and 1996 and were aged 40 years or older with no previous history of cancer or metformin use. In total, 21,524 of the patients received metformin during follow-up.

The researchers traced patient histories between January 1997 and June 2012 searching for colorectal cancer incidence and metformin use. After adjusting for covariates, Dr. Habel and colleagues found a decreased risk of colorectal cancer in the following long-term (≥5 years) metformin users:

• full population (HR = 0.78, 95% CI = 0.60–1.02)
• men (HR = 0.65, 95% CI = 0.45–0.94)
• current users (HR = 0.78, 95% CI = 0.59–1.04)

Two additional associations were also significantly linked to lower colorectal cancer risk: higher cumulative metformin doses and metformin use among initial sulfonylurea users.

On the other hand, the researchers discovered no significant inverse associations between metformin use and colorectal cancer with respect to ever using metformin, increasing total duration of metformin, recency of metformin utilization, or long-term metformin use in women.

The authors suggest that data from their subgroup analyses showing an inverse correlation between metformin use and colorectal cancer among long-term users and those taking high cumulative doses could be due to chemopreventive properties of metformin. The reason why long-term metformin use was associated with reduced colorectal cancer risk in men but not in women “remains unexplained and may merit further investigation,” the authors wrote.

One potential limitation of this study is that health records reflected metformin prescription, not patient adherence. In other words, the researchers were unsure whether subjects actually took the drug. Consequently, the team included only subjects who filled two or more metformin prescriptions during a 6-month period.

“Our findings showed an inverse association between long-term use of metformin and colorectal cancer risk,” the authors concluded. “Findings, especially the risk reduction among men, need to be confirmed in large, well-conducted studies. If our findings are confirmed, metformin may have a role in the chemoprevention of colorectal cancer.”