Metformin’s Effect Primarily Occurs in Gut, Not Bloodstream

Contrary to conventional belief, the diabetes drug works primarily in the lower intestine.

Despite popular belief, metformin — a recommended first-line treatment for type 2 diabetes —appears to work primarily in the gut as opposed to the bloodstream, according to new data.

Researchers discussed these findings in their paper, published in Diabetes Care, on phase 1 and phase 2 studies of investigational delayed-release metformin, which is designed to target the lower bowel and limit absorption into the blood.

“Our clinical trials show that metformin works largely in the lower intestine, reversing half a century of conventional thinking,” John B. Buse, MD, PhD, study researcher and professor of medicine and director of the Diabetes Care Center at the University of North Carolina School of Medicine, said in a press release.

“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.”

In the phase 1 study, Buse and colleagues compared single daily doses of delayed-release metformin with immediate-release metformin and extended-release metformin in 20 healthy participants.

After treatment with delayed-release metformin, participants had about half the amount of metformin in the bloodstream when compared with those treated with immediate-release or extended-release metformin, study results indicated.

In the phase 2 randomized study, the researchers compared 600-mg, 800-mg or 1,000-mg doses of once daily delayed-release metformin with blinded placebo or unblinded 1,000-mg or 2,000-mg doses of extended-release metformin daily. Those previously treated with metformin went without therapy for 2 weeks before randomization.

Delayed-release metformin was linked to a 40% increase in potency, as compared with extended-release metformin, according to the data. Moreover, significant and sustained decreases in fasting plasma glucose were observed with delayed-release metformin vs. placebo over 12 weeks.

The researchers also reported that delayed-release metformin was well tolerated.

“One of the top reasons metformin isn’t used for all people with type 2 diabetes is that patients with impaired kidneys accumulate too much drug in the blood, and this can result in life-threatening lactic acidosis,” Buse said.

“These studies provide evidence that delivering delayed-release metformin to the lower bowel significantly reduces the amount of metformin in the blood while maintaining its glucose-lowering effect.”


  1. Buse JB et al. Diabetes Care. 2015;doi:10.2337/dc15-0488.