The next new treatment for breast, colon and prostate cancers, among others, may be a diabetes drug first approved in 1958.
Metformin, the most commonly used medicine to lower blood-sugar, is the subject of about 50 cancer studies globally, according to U.S. government clinical trial information compiled by Bloomberg. The research began after scientists found metformin prevented tumors in mice and that diabetics were less likely to develop a malignancy if they were taking the 5 cents-a-day pill than other diabetes medications.
The medicine is dispensed about 120 million times annually, according to a 2010 report in the journal Molecular Cancer Therapeutics. If the latest trials on breast and other tumors are successful, the drug could become a cheap weapon in the fight against a myriad of diseases including pancreatic and ovarian cancers. All told, cancer kills one in eight people and is the second-leading cause of death in most developed nations.
“The hope is that if it does show safety and efficacy, it would be available in a cost-effective way,” said Chandini Portteus, vice president of research, evaluation and scientific programs at Susan G. Komen for the Cure, a Dallas-based breast cancer advocacy group. “It would be wonderful for patients if we had something that we knew worked and was safe and low-cost.”
The organization has spent about $10 million investigating metformin for breast cancer, Portteus said. “We have to turn over every single rock to determine what the options are for patients who need them.”
Millions of Deaths
Global cancer deaths will climb to 13.1 million by 2030 from 7.6 million in 2008, the Geneva-based World Health Organization said in February. Cancer costs totaled $124.6 billion in the U.S. alone in 2010, according to the National Cancer Institute. Newer, more targeted drug therapies, such as Dendreon Corp.’s $93,000-a-year Provenge for prostate cancer, may add only a few months of life.
Metformin was the seventh most-dispensed medicine in the U.S. in 2011, according to a list published by IMS Institute for Healthcare Informatics in April that ranked a group of painkillers that includes Vicodin as the most-prescribed. A pack of 84 500-milligram tablets of the diabetes pill, taken twice daily, costs the U.K.’s National Health Service 1.37 pounds, or the equivalent of about 3 pence (5 U.S. cents) a day.
The MD Anderson Cancer Center in Houston is studying metformin in at least eight trials, according to a National Institutes of Health online database.
‘Safe and Cheap’
“It is safe and it is cheap,” said Donghui Li, an epidemiologist and professor of medicine at the center. “It reduces the risk and has better survival” in studies she’s done in pancreatic cancer patients.
Patients who had taken metformin had a 60 percent lower risk of developing pancreatic cancer, according to a case-control study Li published in 2009 in which she compared cancer patients taking metformin against people not on metformin.
Metformin didn’t benefit patients whose pancreatic cancer had already spread to other tissues, Li reported this year in the journal Clinical Cancer Research. Those patients whose malignancies were confined to the pancreas survived longer if they were on metformin -- an average of 15 months, or four months more than patients not taking the drug, she found.
More research is needed to confirm those benefits in patients as their disease is developing, Li said.
“I got a lot of calls from patients and other clinicians, but I told them I cannot give them a recommendation,” she said.
Lewis Cantley, director of the Cancer Center at Beth Israel Deaconess Medical Center in Boston, a hospital affiliated with Harvard Medical School, does have a suggestion for doctors who diagnose and treat diabetics: Test patients’ insulin levels in addition to blood sugar.
People whose insulin levels are high should either take metformin or increase their exercise and control their diets by reducing the amount of carbohydrates eaten, Cantley said.
“That will have a huge impact in preventing you from getting cancer,” said Cantley, who trained as a biochemist and biophysicist, in an interview. “It may even slow down the growth of the cancer you already have.”
Lack of Funding
Further studies of metformin in cancer have been hampered by a lack of funding, Li said. Large-scale trials can cost tens of millions of dollars. Metformin, which Bristol-Myers Squibb Co. sold in the U.S. as Glucophage, lost patent protection years ago, meaning that manufacturers no longer reap significant profits from its sale.
Pamela Goodwin, an oncologist at Toronto’s Mount Sinai Hospital, is leading a trial in 3,582 breast-cancer patients at 300 locations. Data analysis from the five-year study may start in 2016 or 2017, according to Goodwin, who said she was ready to start on the research a decade ago, but lacked financial support from companies, including one that still had a patented version. She declined to identify the company.
“When they realized the results wouldn’t be available until they lost their patent, they pulled out,” said Goodwin, whose $25 million study is supported by the Canadian and U.S. governments as well as not-for-profit groups including the Canadian Cancer Society, the Breast Cancer Research Foundation and Cancer Research UK. Apotex Inc., a Toronto-based maker of generic medicines, is supplying metformin and a placebo used in the trial.
“All of the evidence has just become stronger while we waited,” said Goodwin, who is also a professor of medicine at the University of Toronto.
Metformin is a synthetic form of a compound found in French lilac, used as an herbal remedy for frequent urination in the Middle Ages. The drug can produce a life-threatening side effect known as lactic acidosis, in which the body produces lactic acid faster than it breaks it down, which can lead to kidney failure. The complication is rare and the medicine isn’t recommended for people with conditions such as kidney or liver disease and reduced blood-oxygen levels.
Inside cells, metformin acts like a weak poison. Mitochondria, the power source in cells, are tricked into thinking the body is exercising and needs to draw more nutrients and energy from the blood, according to Dario Alessi, a biochemist at the University of Dundee who studies how messages are transmitted within cells.
Registering low energy levels, cells turn off the inappropriate division that is a hallmark of cancer, he said. By lowering blood-glucose levels and sensitizing cells to the effects of insulin, metformin may help control levels of the hormone, which is implicated in cell division and cancer.
Alessi and colleagues suspected that if cancer cells were treated with metformin, they would be tricked into thinking they don’t have enough energy to divide and grow. He petitioned diabetes epidemiologist Andrew Morris to search a database of users of metformin and other diabetes drugs for their cancer incidence to test the theory.
“Me, being very open-minded, said, ‘but we’ve been using it for diabetes for 50 years and that’s all it does,” said Morris, now the University of Dundee’s dean of medicine and Scotland’s chief scientist. He and colleagues conducted two epidemiological studies based on observational data.
“We showed that those who hadn’t developed cancer had a greater tendency to have been prescribed metformin,” Morris said in an interview.
The results showed 20 percent fewer cases of cancer among diabetics taking metformin, Alessi said. “The nice thing is that this has been replicated by at least 10 other studies now with larger patient numbers in other parts of the world.”
Researchers are pooling the data to discern the cancer types metformin may be most protective against, Morris said.
When Alessi and colleagues gave metformin to tumor-prone mice, they found the drug delayed the emergence of growths by 30 percent to 40 percent, he said. In that way, metformin could be used to stop cancer cells before they develop into tumors.
Cantley of Beth Israel Deaconess said if he were diagnosed with cancer, he’d want to know whether his tumor cells had receptors for insulin. If so, he’d want to keep his insulin level under control to inhibit the cancer process, he said.
“I have a lot of colleagues who have early-stage prostate cancer who have gone on metformin,” Cantley said. “They’ve called me up. They want to keep their insulin levels down even though they’re not diabetic yet.
‘‘It’s possible that it’s only going to be useful at this early stage.”