Most of the 20 million people diagnosed with type 2 diabetes in the U.S. take metformin to help control their blood glucose. The drug is ultrasafe: millions of diabetics have taken it for decades with few side effects beyond gastrointestinal discomfort. And it is ultracheap: a month's supply costs $4 at Walmart. And now new studies hint that metformin might help protect the brain from developing diseases of aging, even in nondiabetics.
Diabetes is a risk factor for neurodegenerative diseases, but using metformin is associated with a dramatic reduction in their incidence. In the most comprehensive study yet of metformin's cognitive effects, Qian Shi and her colleagues at Tulane University followed 6,000 diabetic veterans and showed that the longer a patient used metformin, the lower the individual's chances of developing Alzheimer's disease, Parkinson's disease, and other types of dementia and cognitive impairment. In line with some of the previous, smaller studies of long-term metformin use, patients in the new study who used the drug longer than four years had one quarter the rate of disease as compared with patients who used only insulin or insulin plus other antidiabetic drugs—bringing diabetics' risk level to that of the general population. The findings were presented in June at the American Diabetes Association's Scientific Sessions meeting.
Even in the absence of diabetes, Alzheimer's patients often have decreased insulin sensitivity in the brain, says Suzanne Craft, a neuroscientist who studies insulin resistance in neurodegenerative disease at the Wake Forest School of Medicine. The association has led some people to call Alzheimer's “type 3 diabetes.” Insulin plays many roles in the brain—it is involved in memory formation, and it helps to keep synapses free of protein debris, including the tau tangles and amyloid plaques that build up in Alzheimer's, Craft says.
Metformin, then, may help correct insulin issues in the aging brain. Research in animals shows that the drug's effect on neural stem cells might be key. Neuroscientists Jing Wang and Freda Miller, both then at Toronto's Hospital for Sick Children, showed that when nondiabetic mice are given metformin, their memory improves, thanks to an increase in the neural stem cell population and in the number of these cells that develop into healthy neurons in the hippocampus, the brain's memory center.
Human clinical trials also show promise in treating early Alzheimer's. Steven E. Arnold, a neurologist at Massachusetts General Hospital showed that early Alzheimer's patients had small but significant improvements in their memory and cognitive functioning after taking metformin for eight weeks as compared with a placebo. Brain imaging also revealed some improvements in neural metabolism. Such small effects are the norm when it comes to Alzheimer's; even established drugs are only modestly effective and only for a limited period. “That is one of the great motivations to find new therapies,” Craft says.
Arnold hopes to run a larger trial that can better evaluate metformin's efficacy, but funding has been an issue. Because metformin is generic and cheap, drug companies have little profit motive to test it, according to Arnold. “This is a simple, common, cheap medicine that may affect an important aspect of cognitive impairment in older adults, and there's a compelling scientific reason to look at it. Now we just need to really study it in a way that will give us a clear answer as to whether it really helps,” Arnold says. If the funding were in place, he believes a definitive study could be completed in two years.
Craft's and Arnold's research groups are also working to find Alzheimer's biomarkers, measurable biological signals of the disease, so that patients at high risk of developing neurodegenerative disorders could be identified early. Those patients could potentially use metformin and other insulin sensitizers to prevent its onset.