The blood-sugar-lowering effects of the diabetes medicine metformin take place in the gut, and not in the bloodstream as previously thought, according to a new study led by the University of North Carolina School of Medicine at Chapel Hill. This discovery opens up the possibility that an experimental form of the drug may be able to help the 40% of people with Type 2 diabetes who cannot currently use metformin, say the researchers.
Metformin is the most commonly prescribed diabetes drug in the world, with over 61 million prescriptions filled in 2012 in the United States alone. It lowers blood glucose levels by increasing insulin sensitivity and lowering the amount of glucose that is released into the bloodstream by the liver. The medicine is not recommended in people with kidney disease because too much of the drug can accumulate in the blood, resulting in a potentially life-threatening condition known as lactic acidosis (the buildup of lactic acid in the bloodstream).
Despite metformin’s nearly 60-year history in treating diabetes, researchers still debate exactly how it works. To evaluate whether the drug is active primarily in the gut or the bloodstream, researchers compared immediate-release metformin (IR), extended-release metformin (XR), and placebo (inactive treatment) to an investigational medicine known as metformin delayed release (DR), which is designed to work primarily in the lower intestine with limited absorption into the bloodstream.
In the phase 1 study, researchers compared single doses of metformin IR and metformin XR to metformin DR in 20 volunteers without diabetes. Roughly half the amount of the medicine was found in the blood of those taking metformin DR compared to the blood of those taking the other two versions of the drug.
In the 12-week phase 2 trial, the researchers compared various doses of metformin DR to metformin XR or placebo in 240 people with Type 2 diabetes. Once a day, the participants received either 600 milligrams, 800 milligrams, or 1,000 milligrams of metformin DR, 1,000 milligrams or 2,000 milligrams of metformin XR, or placebo. Metformin DR was found to have a 40% increase in strength compared to metformin XR and produced statistically significant and sustained reductions in fasting blood sugar compared to placebo. The medicine was well tolerated with side effects similar to those of currently available versions of metformin.
“Our clinical trials show that metformin works largely in the lower intestine, reversing half a century of conventional thinking. These findings create an opportunity to develop a new metformin treatment option for the 40% of patients that currently can’t take this first-line drug of choice,” noted first author John Buse, MD, PhD. “These studies provide evidence that delivering metformin DR to the lower bowel significantly reduces the amount of metformin in the blood, while maintaining its glucose-lowering effect.”
For more information, read the article “Diabetes drug metformin’s primary effect in the gut, not the bloodstream” or see the study’s abstract in the journal Diabetes Care. And for more information about metformin, see the primer on the medicine by certified diabetes educator Amy Campbell.