An inexpensive drug taken by millions of people to control diabetes may do more than lower blood sugar, with research suggesting it might have anti-inflammatory effects that could help protect against common age-related diseases including heart disease, cancer and cognitive decline.
To test whether the medication metformin might help prevent these diseases and promote a longer health span in healthy, older adults, scientists who study the biology of ageing have designed a clinical study known as The TAME Trial (Targeting Aging with Metformin).
Metformin costs less than a dollar a day, and depending on insurance, many people pay no out-of-pocket costs for the drug, reports NPR.
“I don’t know if metformin increases lifespan in people, but the evidence that exists suggests that it very well might,” said Steven Austad, a senior scientific adviser at the American Federation for Ageing Research, who studies the biology of ageing.
Old drug with surprising benefits
Metformin was first used to treat diabetes in the 1950s in France. The drug is a derivative of guanidine, a compound found in Goat’s Rue, a herbal medicine long used in Europe.
The FDA approved metformin for the treatment of type 2 diabetes in the US in the 1990s, but since then, researchers have documented several surprises, including a reduced risk of cancer.
“That was a bit of a shock,” Austad said. A meta-analysis that included data from dozens of studies found people who took metformin had a lower risk of several types of cancers, including gastrointestinal, urologic and blood cancers.
A British study found a lower risk of dementia and mild cognitive decline among people with type 2 diabetes taking metformin, and in addition, there’s research pointing to improved cardiovascular outcomes in people who take metformin, including a reduced risk of cardiovascular death.
As promising as this sounds, Austad said most of the evidence was observational, pointing only to an association between metformin and the reduced risk. The evidence stops short of proving cause and effect.
Also, it’s unknown if the benefits documented in people with diabetes will also reduce the risk of age-related diseases in healthy, older adults.
“That’s what we need to figure out,” says Steve Kritchevsky, a professor of gerontology at Wake Forest School of Medicine, who is a lead investigator for the Tame Trial.
The goal is to better understand the mechanisms and pathways by which metformin works in the body. For instance, researchers are looking at how the drug may help improve energy in the cells by stimulating autophagy – the process of clearing out or recycling damaged bits inside cells.
Researchers also want to know more about how metformin can help reduce inflammation and oxidative stress, which may slow biological ageing.
“When there’s an excess of oxidative stress, it will damage the cell. And that accumulation of damage is essentially what ageing is,” said Kritchevsky.
When the forces that are damaging cells are running faster than the forces that are repairing or replacing cells, that’s ageing, he added. And it’s possible that drugs like metformin could slow down this process.
By targeting the biology of ageing, the hope is to prevent or delay multiple diseases, said Dr Nir Barzilai of Albert Einstein College of Medicine, who is leading the effort to get the trial started.
Ultimate in preventative medicine
Austad and a group of colleagues began pushing for a clinical trial back in 2015.
He said when they approached the FDA to ask them to approve a trial for metformin, the agency was receptive. “If you could help prevent multiple problems at the same time, as we think metformin may do, then that’s almost the ultimate in preventative medicine.”
The aim is to enrol 3 000 people between 65 and 79 for a six-year trial. But Barzilai said it has been slow-going to get it funded.
“The main obstacle … is that metformin is a generic drug, so no pharmaceutical company stands to make money,” he said.
Barzilai has turned to philanthropists and foundations, and has some pledges. The National Institute on Ageing, part of the National Institutes of Health, set aside about $5m for the research, but that’s not enough to pay for the study, which is estimated to cost between $45m and $70m.
The frustration over the lack of funding is that if the trial points to protective effects, millions of people could benefit. “It’s something everybody will be able to afford,” Barzilai added.
The FDA doesn’t recognise ageing as a disease to treat, but the researchers hope this study could usher in a paradigm shift – from treating each age-related medical condition separately, to treating these conditions together, by targeting ageing itself.
For now, metformin is approved only to treat type 2 diabetes in the US, but doctors can prescribe it off-label for conditions other than its approved use.
Research shows a small percentage of people who take metformin experience GI distress that makes the drug intolerable. And some people develop a B12 vitamin deficiency. One study found people over 65 who take metformin may have a harder time building new muscle.
“There’s some evidence that people on metformin who exercise have less gain in muscle mass,” said Dr Eric Verdin, president of the Buck Institute for Research on Ageing.
That could be a concern for people who are under-muscled.
But it may be possible to repurpose metformin in other ways, he said. “A number of companies are exploring metformin in combination with other drugs.”
He cites current research to combine metformin with a drug called galantamine for the treatment of sarcopenia, the medical term for age-related muscle loss that affects millions of older people, especially women.
The science of testing drugs to target ageing is rapidly advancing, and metformin isn’t the only medicine that may treat the underlying biology.
“Nobody thinks this is the be all and end all of drugs that target ageing,” Austad said, adding that data from the clinical trial could stimulate investment by the big pharmaceutical companies in this area. “They may come up with much better drugs.”
NPR article – A cheap drug may slow down aging. A study will determine if it works (Open access)
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