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本帖最后由 StephenW 于 2012-10-20 16:33 编辑
http://www.generalsurgerynews.com/ViewArticle.aspx?d=In%2Bthe%2BNews&d_id=69&i=October+2012&i_id=891&a_id=21959
Drug a ‘Potential Breakthrough’ for Preventing Liver Cancer
 By Christina Frangou
San Diego—One of the most widely used diabetes drugs in the world appears to have an unexpected secondary benefit: reducing the risk for hepatocellular carcinoma (HCC) by more than 50%, according to two new studies.
At the 2012 Digestive Disease Week (DDW) meeting, results from an American case–control study and a nationwide study from Taiwan showed HCC incidence plummeted in patients with diabetes who were taking metformin compared with diabetic patients who were not receiving the therapy.
The reports represent a major step in prevention of liver cancer.
“The results are astonishing. If you put it together these two papers, we have potentially a breakthrough in the prevention of liver cancer,” said Jacques Devière, MD, PhD, professor of medicine at Erasme University Hospital in Brussels, Belgium, after hearing the studies presented.
Previous epidemiologic studies have suggested that metformin may be protective against many cancers, and a recent study published in Cancer Prevention Research showed that metformin slowed tumor activity in mice given chemically-induced liver tumors (2012;5:544-552).
But the two studies presented at the DDW meeting mark an important step in understanding a relationship between metformin and HCC. The studies are unique in size and scope, and the results leave little doubt that metformin has a statistically significant and clinically significant protective effect.
The Taiwanese study was conducted in two parts: a population-based study that started with almost all of the country’s 23 million people and an in vitro study that looked at metformin’s effects in humans and mice (abstract 596). In the first part, investigators used the Taiwanese national health insurance database to identify patients diagnosed with HCC. Between 1997 and 2008, investigators recruited all the newly diagnosed HCC cases, totaling nearly 97,430 patients, and compared them with nearly 200,000 age-, gender- and first-visit-to-physician–matched controls.
As expected, people diagnosed with diabetes had much higher risk for developing HCC—an increase of nearly 2.5-fold (odds ratio [OR], 2.29) compared with people without diabetes, a rate similar to that in previous large epidemiologic studies.
But for the first time, the study showed that in patients with diabetes taking metformin, HCC occurred significantly less often compared with other individuals with diabetes. HCC occurred most often in patients with diabetes who were not using metformin (OR, 1.95; 95% confidence interval [CI], 1.88-2.03), followed by patients with diabetes who rarely used metformin (OR, 1.74; 95% CI, 1.67-1.82) and least often in patients with diabetes who regularly used metformin (OR, 1.56; 95% CI, 1.49-1.64). Moreover, metformin’s effect was shown to be dose-dependent: For every year of metformin use, patients with diabetes had a 7% decrease in HCC risk, after controlling for other factors.
The investigators then performed cell line studies to look at the in vitro effects of metformin on cell proliferation and cell cycle. Studies of HepG2 and Hep3B hepatoma cell lines showed that metformin inhibited hepatocyte proliferation and induced cell cycle arrest at G0/G1 in two ways: by upregulating p21/Cip1 and p27/Kip1 and by downregulating cyclin D1 in a dose-dependent manner. The effect was independent of p53, a protein strongly associated with tumor suppression.
“I think this is an exceptional piece of information because it shows that the decrease in HCC may not only be due to prevention but also by a therapeutic action of some sort,” said Mario Chojkier, MD, professor of medicine at the University of California, San Diego, in summarizing the paper during a “Best of DDW” session at the DDW meeting.
Dr. Chojkier said the findings have significant clinical implications. Although no experts called for patients to receive metformin prophylactically, investigators said more studies might lead to different prescribing patterns. Dr. Chojkier said that for now, physicians should “be stringent” in assessing insulin resistance according to the guidelines from the American Diabetes Association.
The second study on metformin compared 612 patients with histologically proven intrahepatic carcinoma who were seen at Mayo Clinic with 594 patients without a history of cancer matched for age, gender, ethnicity and residential area (abstract 597). Sensitivity analysis showed that metformin use was associated with a 60% reduced risk for intrahepatic carcinoma in diabetics compared with diabetic patients who did not take metformin.
The finding is novel but will require further investigation and validation in another cohort, said lead author Roongruedee Chaiteerakij, MD, of Mayo Clinic, Rochester, Minn.
The same study also showed no significant association between statin use and decreased risk for intrahepatic carcinoma.
Experts say more work on this subject is needed. Hashem B. El-Serag, MD, MPH, chief of gastroenterology and hepatology, Baylor College of Medicine, Houston, said the Mayo study involved too few patients to be conclusive, and the findings may reflect a bias on the part of treating physicians.
“Physicians don’t like to give statin or metformin to people with cirrhosis, so it looks like those who develop cancer are using them less, not because of a biological phenomenon but because of an avoidance phenomenon,” said Dr. El-Serag.
But Chun-Ying Wu, MD, PhD, MPH, of the faculty of medicine at National Yang-Ming University in Taipei, Taiwan, and lead author of the Taiwanese study, believes that metformin should be recommended in patients with diabetes.
“We can say metformin is actually chemopreventive for HCC development.”
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发表于 2012-10-20 16:25
