Metformin May Reduce Liver Cancer Risk



SAN DIEGO – Metformin may do double duty in diabetes patients by decreasing their risk of developing certain types of liver cancers in addition to reducing their blood sugar, studies have shown.

Treatment with the glucose-lowering drug was associated with a nearly 60% reduction in the risk of intrahepatic cholangiocarcinoma (ICC) among diabetes patients in one study presented at Digestive Disease Week 2012, while it was associated with a dose-dependant reduction of hepatocellular carcinoma (HCC) risk of about 7% annually in the second study.

Dr. Roongruedee Chaiteerakij of the Mayo Clinic in Rochester, Minn., and colleagues reviewed the records of 612 patients with ICC and 594 age-, gender-, ethnicity-, and residential area–matched controls who received care at Mayo between January 2000 and May 2010. Risk factors associated with ICC, according to multivariate models, include biliary tract disease, cirrhosis, diabetes, and smoking.

Interestingly, however, "the adjusted odds ratio for [ICC] for diabetic patients treated with metformin was comparable to nondiabetics, at 1.4, but it was significantly increased to 8.8 for diabetic patients not treated with metformin," Dr. Chaiteerakij said, noting that "the magnitude of the metformin-associated risk reduction was comparable to that shown in other cancers."

In the second study, designed to tease out a previously demonstrated relationship between HCC and metformin, Dr. Chun-Ying Wu of the National Yang-Ming University in Taipei, Taiwan, and colleagues identified 97,430 patients diagnosed with HCC between 1997 and 2008 and 194,860 age-, gender-, and physician visit date–matched controls from Taiwan’s National Health Insurance Research Database and evaluated the chemopreventive effects of metformin for different doses and durations of use.

The investigators also studied the in vitro effects of metformin on cell proliferation and cell cycle in HepG2 and HepB3 hepatocellular carcinoma cell lines. HepG2 and Hep3B cells were exposed to various concentrations of metformin for 48 hours and an MTT assay was then used to determine cell viability, calculated as a percentage of the viable vehicle-treated cells, Dr. Wu explained.

Relative to individuals without diabetes, the highest risk of HCC after adjustment for age, gender, and liver disease was observed in diabetic patients who did not take metformin, with an odds ratio of 1.95, followed by those who rarely used it, frequently used it, and regularly used it, with respective odds ratios of 1.74, 1.67, and 1.56, Dr. Wu reported. "In diabetic subjects, each incremental year increase in metformin use was associated with a nearly 7% reduction in the risk of developing [HCC]," he said. The in vitro studies were consistent with this observation. "Cell line studies showed an inhibition of hepatocyte proliferation and induction of cell cycle arrest at the G0-G1 phase associated with metformin in a dose-dependent manner."

Although the mechanism of action has not been fully elucidated, metformin, an activator of AMP-activated protein kinase, "may reduce circulating glucose and insulin levels and limit their systemic effects on the formation and development of tumors," Dr. Wu said in an interview. It also may reduce hepatic lipid accumulation, and by so doing interfere with the molecular events that contribute to the production of cancer cells in the liver, he said. By properly controlling glucose, metformin appears to help avoid or delay diabetes-associated complications, including liver cancer. As such, he concluded, "using metformin in diabetic patients to decrease the risk of hepatocellular carcinoma should be recommended."

Dr. Chaiteerakij and Dr. Wu reported having no relevant financial conflicts of interest.

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