二甲双胍可降低肝癌风险

圣迭戈(EGMN)——美国2012消化疾病周(DDW)上报告的两项研究显示，糖尿病患者服用二甲双胍或许能够一举两得，既降低血糖又预防肝癌。

其中一项研究表明，二甲双胍能使糖尿病患者罹患肝内胆管癌(ICC)的风险降低80%以上。另一项研究则显示，二甲双胍可以剂量依赖性地使肝细胞癌(HCC)年发病风险降低约7%。

美国梅奥医院的Roongruedee Chaiteerakij博士及其同事回顾分析了2000~2010年期间在该院就诊的612例ICC患者和594名年龄、性别、种族和居住地相匹配的对照者的资料。根据多变量分析，ICC的相关危险因素包括胆管疾病、肝硬化、糖尿病和吸烟。

有趣的是，接受二甲双胍治疗的糖尿病患者罹患ICC的校正比值比(OR)为1.4，与非糖尿病患者相当，而未使用二甲双胍的糖尿病患者的校正OR值则高达8.8。Chaiteerakij博士指出：“二甲双胍对ICC的预防作用与该药对其他类型癌症的预防作用在同一数量级上。”

在第二项研究中，台北国立阳明大学的吴俊颖博士及其同事利用台湾健康保险研究数据库，分析了1997~2008年期间97,430例确证为HCC的患者和194,860名年龄、性别、就诊时间匹配的对照者的资料。

结果显示，在校正年龄、性别和肝病等因素之后，与非糖尿病患者相比，HCC风险最高的是未服用二甲双胍的糖尿病患者(OR，1.95)，之后依次是很少服用二甲双胍者、经常服用二甲双胍者和定期服用二甲双胍者，OR值分别为1.74、1.67和1.56。“糖尿病患者服用二甲双胍的时间每增加1年，发生HCC的风险就降低近7%。”

除了发现二甲双胍与HCC风险呈剂量依赖的负相关性之外，研究者还分析了二甲双胍在体外条件下对HepG2和HepB3肝细胞癌细胞系增殖和周期的影响。研究者将HepG2和Hep3B细胞暴露于不同浓度的二甲双胍中48 h，继而采用MTT检测细胞的生存力。实验结果与上述观察结果一致：二甲双胍对这2个细胞系的增殖有抑制作用，能诱导细胞周期停止于G0~G1期，并且也呈剂量依赖关系。

尽管二甲双胍可预防肝癌的机制尚不完全明确，但可能与该药可激活AMP活化蛋白激酶有关。“二甲双胍可减少循环中的葡萄糖和胰岛素，限制其全身效应，还能减少肝脏脂质堆积，从而干扰可能有助于肝癌细胞形成的分子水平事件。”

Chaiteerakij博士和吴俊颖博士均报告称无相关利益冲突。

爱思唯尔  版权所有

BY DIANA MAHONEY
Elsevier Global Medical News
Breaking News

SAN DIEGO (EGMN)–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, Minnesota, 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.