Metformin: A New Shine on an Old Medication
The story of the popular drug's past, present, and possible future
For many people with diabetes, metformin comes first. The American Diabetes Association (ADA) recommends that doctors prescribe this medication to their newly diagnosed patients with type 2 diabetes before trying other drugs. And yet despite being one of the most prescribed medications worldwide, metformin is not mundane. It continues to intrigue researchers, doctors, and patients, even after more than 15 years on the U.S. market and decades of use in Europe.
In addition to its ability to lower blood glucose—safely and inexpensively—metformin may have some other tricks up its sleeve. Recent studies suggest that it may be an antidote to everything from obesity to cancer. It's not yet clear whether this humble pill will live up to the hype, but researchers are optimistic.
Type 2 diabetes is marked, in part, by insulin resistance, the body's inability to lower blood glucose levels in response to the hormone insulin. Metformin helps restore the body's ability to respond to insulin, particularly in the liver. Of all the type 2 diabetes medications, only metformin and the thiazolidinediones—rosiglitazone (Avandia, the use of which has been severely curtailed by U.S. and European regulators) and pioglitazone (Actos)—are insulin sensitizers; the others increase the amount of insulin the body produces or work in other ways.
Metformin is typically taken twice a day, and its most common side effects are gastrointestinal, including nausea and diarrhea. It's also not recommended for people with kidney disease. While a lot of diabetes medications have the often unwelcome side effects of weight gain and hypoglycemia (low blood glucose), metformin causes neither. Yet metformin may not be enough to control blood glucose in the long term. A study published in March in Diabetes Care found that people who started metformin within three months of their diagnosis didn't need to move on to additional medications as soon as those who initiated the treatment later. But most people with type 2 require additional medication as the disease progresses.
Metformin's effect on the liver, which stores and distributes excess glucose from the blood, is of particular importance in diabetes. Insulin not only signals the body to absorb glucose from the blood, but it also tells the liver to stop doling out glucose. "When people have diabetes, the liver continues to put sugar, or glucose, back into the circulation even when sugar is around," says Mary Rhee, MD, MS, a diabetes researcher at Emory University. "What metformin does is it helps to increase sensitivity at the liver."
In addition to its influence on blood glucose, metformin seems to be doing other things in the body as well. "You'll often hear people say that we don't know how metformin works," says Clifford Bailey, PhD, FRCP, FRCPath, a professor of clinical science at Aston University in the United Kingdom. "But that's a polite way of saying metformin has a variety of effects."
As suggested by several large, long-term studies, metformin appears to lower the risk of heart disease, a common and sometimes deadly complication of diabetes. "There is lots of animal data and a modest amount of clinical data to support this," says Bailey. "The cardiovascular benefits are probably independent of glucose-lowering effects. That is why we keep patients on metformin even when using insulin." It's these independent effects that have many researchers falling in love with metformin all over again.
While there are all sorts of theories about how metformin tweaks various biochemical pathways to influence human health, the big question now is whether there are other conditions besides type 2 diabetes that metformin can treat. The most obvious candidates are other types of diabetes. Research suggests that metformin may benefit people with prediabetes, gestational diabetes, and even some with type 1 diabetes.
The Diabetes Prevention Program, a major clinical trial whose results were announced in 2001, enrolled adults with prediabetes and found that, over five years, those given metformin had a 31 percent lower risk of developing type 2 than those not given the medication. "Some may say that you could prevent diabetes with other drugs [besides metformin]," says Rhee. "I think the main reason metformin has been accepted is because it has few side effects and it's also very cheap." ADA recommends that people at very high risk for type 2 diabetes be considered for treatment with metformin.
Gestational diabetes, which develops during pregnancy and goes away after giving birth, is typically treated with insulin, the only medication considered safe for the baby. However, a 2008 study published in the New England Journal of Medicine found that metformin wasn't associated with more complications than insulin and was preferred by pregnant women with gestational diabetes. It's not clear whether metformin would be safe for pregnant women with type 2 diabetes.
Since metformin sensitizes the body to insulin, some research has looked into whether people with type 1 stand to benefit from its use in combination with insulin. "It's not very common to use metformin in type 1," says Bailey. "It can be used extremely effectively [in type 1], but it's not for everyone." A study published this year in Diabetes Care analyzed 197 previous reports and found evidence that metformin allowed people with type 1 to maintain the same blood glucose levels on average using less insulin. The authors also found that metformin was well tolerated, though hypoglycemia was a concern.
Already, metformin is being used outside of diabetes. Polycystic ovary syndrome (PCOS) is a hormonal disorder in women that is linked to insulin resistance and type 2 diabetes. PCOS can hinder a woman's ability to become pregnant, but studies have shown that metformin can increase fertility. Other studies have found that, as with diabetes, metformin improves insulin resistance and cardiovascular risk in women with PCOS. Women who are obese are more likely to develop PCOS, and metformin is particularly effective in these situations, helping with PCOS and weight loss. While it is not explicitly approved, doctors sometimes prescribe metformin for PCOS off-label, even for people who do not have type 2.
The obesity epidemic has researchers scrambling to develop new weight-loss medications or, as in the case of metformin, repurpose old medications. A study published in the February issue of Archives of Pediatrics & Adolescent Medicine reported that obese adolescent girls without diabetes who took metformin for 48 weeks lowered their body weight more than those taking a placebo. The weight loss was modest, but it could be enough to impart health benefits.
Further afield, some studies in recent years have come to the enticing conclusion that people with diabetes who take metformin are less likely to get cancer than those who don't. Now, cell and animal studies have taken this association a step further. Kevin Struhl, PhD, who studies cancer at the Harvard School of Medicine, never expected to be investigating metformin. "We were working on a cancer project, far from working with diabetes. We basically found in the course of the cancer work a . . . cancer gene signature that was connected to other diseases." This cancer signature was found to overlap with that of type 2 diabetes, so Struhl decided to test diabetes medications against breast cancer cells.
The most effective drug by far was metformin, says Struhl, adding: "Once we found that metformin had these impressive effects in cancer cells, we did experiments in mice." The evidence suggested that metformin was killing cancer stem cells, which, according to Struhl, are the tumor cells that are most resistant to chemotherapy. "If you treat the tumors with chemotherapy alone," says Struhl, the tumors come back. "But if you treated with chemotherapy and metformin, the combination, the tumors didn't come back." Another study, by a different lab, found that metformin could reduce the number of lung cancer tumors in mice. According to Struhl, clinical trials in Canada, Italy, and New Zealand are in the works to test metformin in people with cancer.
Even if all metformin really does is help with type 2 diabetes, this inexpensive and safe pill has made millions of people worldwide healthier. Of course, for people already taking metformin, these exciting and provocative findings about its benefits beyond diabetes may make the medicine go down just a little easier.