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More on Metformin and Statins: Drugs Approved by the FDA for Other Purposes That May Prevent Liver Cancer

From HBF’s expert Guest Blogger, Dr. Thomas London

In an earlier blog, I pointed out that the available drugs to treat or prevent primary liver cancer (hepatocellular carcinoma, HCC) have been disappointing.  I noted that there may be drugs used for other purposes that may work against HCC.  The most promising of these was an old drug called metformin that has been used to treat type II diabetes for 17 years.  Now a new study on metformin provides the most intriguing results yet.

At the 2012 Digestive Disease Week meeting in San Diego, an enormous study from Taiwan was reported that encompassed almost all of Taiwan’s 23 million people. (I am indebted to Christine Frangou for her excellent report in Gastroenterology and Endoscopy News and have quoted from it extensively.) The investigators used the Taiwan National Insurance Database to identify all cases of HCC diagnosed from 1997 to 2008. There were 97,430 patients with HCC (most of whom would have had chronic hepatitis B). They were compared with 200,000 controls matched to the HCC cases by age, gender, and date of first physician visit.  Using the same database they linked all patients with diabetes and their treatment methods to patients with and without HCC.

From this they were able to show that patients with diabetes had a 2.3-fold increased risk of developing HCC.  In those patients who were taking metformin, however, HCC occurred about 20% less often than in those who were not treated with metformin. Furthermore, the longer patients took metformin, the lower their risk of HCC; about 7% lower for each year that they took the drug.

This study is not the final answer.  We don’t know why some diabetic patients were treated with metformin and some were not.  It is possible that the patients who did not take metformin had some unknown liver abnormality and were deliberately not treated with metformin.  Nevertheless, anti-tumor effects of metformin in experimental animals and in cell culture systems continue to be reported.  I will keep my eye out for more research on metformin and HCC and report it as it hits the medical press.

Statins are another group of drugs that are in common use. They were first approved by the FDA in 1987 to lower serum cholesterol levels and thereby prevent heart disease.  Statins inhibit an enzyme in the liver used to make cholesterol.  Several isolated reports suggested that statins might also help prevent HCC.  This month investigators at the Mayo Clinic in Rochester, Minnesota reported a meta-analysis (a statistical method to combine results from different studies) of all the reports in the medical literature of new cases (incidence) of HCC and exposure to statin therapy.  Ten studies reporting a total of 4,928 HCC cases in 1,459,417 patients were analyzed.  Overall, patients who were treated with statins had a 40% lower risk of developing HCC than those who were untreated.  The results varied from population to population. Asian populations which were more likely to also have chronic hepatitis B, had a 50% lower risk of developing HCC, while western populations had about a 30% lower risk.

At this time we do not know what the mechanism of a preventative effect of statins on HCC might be.  Nor do we know whether statins might have been withheld from patients with high cholesterol levels because they had a liver abnormality. It is likely, however, that more information on these issues will become available in the near future.  When that happens I will report it to you.

 

Dr. Tom London – Hepatitis B and Liver Cancer

Hep B Talk is pleased to introduce Guest Blogger W.Thomas London, MD. Dr. London is internationally renowned for his many decades of work on hepatitis B and liver cancer, which started with his joining the research team  that discovered the hepatitis B virus. Dr. London has been at the forefront of liver cancer prevention and has written extensively about hepatitis B from the perspective of an epidemiologist, a clinician and a virologist. As founder and director of the Liver Cancer Disease Prevention Division at Fox Chase Cancer Center in Philadelphia, PA, he  developed one of the first successful community-based strategies to help people reduce their cancer risk through the early detection of chronic HBV infection. Dr. London has received the Distinguished Interdisciplinary Research Award  from the American Cancer Society and the Distinguished Scientist Award from the Hepatitis B Foundation where he currently serves as Vice-Chair of the Board and as the Senior Medical Advisor.  

Liver cancer, hepatocellular carcinoma (HCC), is the 3rd most common cause of death in the world.  Little attention was paid to HCC in the United States until recently because it was thought to be rare, but now it is one of the few cancer types that is rising in incidence (number of new cases per year). It is now the most rapidly increasing cancer in men in the US. The prognosis of HCC is poor; one year survival in the United States from the time of diagnosis is only 50%.  Detection of tumors when they are very small, less than 2 cm in diameter, and can be removed surgically is the best chance for cure.  Liver transplantation is often done if there is more than 1 tumor and the cancers are less than 3 cm in diameter.  Unfortunately, most HCCs are diagnosed when they are too large for successful surgical resection or transplantation.

Chemotherapy for HCC has been disappointing. Recently, the drug, Sorafenib (Nexavar), has been shown to be active against HCC, but it only extended survival time by a few months.  Thousands of drugs have been developed by the pharmaceutical industry for a great variety of conditions.  Of these, 983 have approved by the FDA.  That is they were tested in clinical trials, found to be safe and were beneficial for the purposes that they were approved

Scientists at the Hepatitis B Foundation and elsewhere have raised the question, are there drugs on the currently approved FDA list that are used for other purposes that might have a role in the treatment or prevention of HCC?  Recent publications suggest 2 candidates.  One is metformin (Glucophage), which is derived from the French lilac, and has been used in Europe since 1958 to treat Type 2 diabetes and in the United States since 1995. The other is propranalol, which is used to treat patients with cirrhosis who have varicose veins in the lower end of their esophagus (esophageal varices).

Diabetes is a recognized risk factor for HCC, particularly in persons who are obese and have a fatty liver. (Diabetics are also at increased risk of acquiring hepatitis B). Because patients with diabetes are often treated with metformin, investigators in China and France have looked at whether treatment with metformin lowers the risk of developing HCC.  By examining the records of diabetic patients who were treated with metformin or not, they observed that the risk of HCC was lower in the treated patients.  Furthermore, an experimental study of liver cancer in mice showed that metformin reduced the number and size of liver tumors.

Propranolol is used to lower the pressure in the portal vein and thereby in esophageal varices.  A group of physicians in France looked at the occurrence of HCC in patients with hepatitis C and esophageal varices who received propranolol treatment and those who did not.  There was about a 75% reduction in the incidence of HCCs in the propranolol treated patients.  Propranolol blocks receptors for epinephrine (adrenalin) and nor-epinephrine on cells in the body.  Such receptors are particularly rich on the surface of tumor cells, including HCCs. Experimentally propranolol has been effective in reducing the size and number of  several different kinds of tumors.

The studies that have been done so far are intriguing, but they are not conclusive.  Neither drug has been studied in a clinical trial to either treat established HCCs or to prevent HCC from occurring in the first place.  Such studies are in the planning stages.  Keep watching for progress on this front.