Delayed-release metformin designed to target the lower intestine with reduced absorption into the blood leads to similar glucose-lowering effects, but at a lower dose and reduced systemic exposure.
Delayed-release metformin designed to target the lower intestine with reduced absorption into the blood leads to similar glucose-lowering effects, but at a lower dose and reduced systemic exposure, two new studies show.
This finding may improve treatment for patients with type 2 diabetes while simultaneously revealing a clearer picture of just how the drug works.
Metformin has been used to treat type 2 diabetes for more than 50 years but its mechanism of action is still not clear. It has generally been thought to work primarily in the bloodstream. In patients with impaired kidney function, it can collect in the blood and cause life-threatening lactic acidosis.
Mark Fineman, PhD, Chief Scientific Officer, Elcelyx Therapeutics, San Diego, CA, together with researchers from UNC-Chapel Hill, UTHealth Science Center in San Antonio, and Dallas Diabetes and Endocrine Center conducted two studies to examine the effects of delayed-release metformin (metformin DR) that is delivered to the lower bowel on patients with type 2 diabetes.
In the first study, a phase 1, randomized crossover study of 20 patients, they found that the amount of delayed-release metformin in the bloodstream was about 50 percent that of regular forms of metformin. In the second, a 12-week, phase 2, multi-center trial with 240 patients, taking 600 mg, 800 mg, and 1,000 mg of metformin DR led to statistically significant, clinically relevant reductions in fasting blood glucose levels compared with those taking placebo.
They also saw a 40 percent increase in potency of the medication compared with regular metformin. All treatments were well tolerated and had adverse events similar to those of regular metformin.
“Our clinical trials show that metformin works largely in the lower intestine, reversing half a century of conventional thinking,” said John Buse, MD, PhD, first author of the paper, professor of medicine, and director of the Diabetes Care Center at the University of North Carolina School of Medicine.
“These findings create an opportunity to develop a new metformin treatment option for the 40 percent of patients that currently can’t take this first-line drug of choice.”
By enabling patients to take a lower dose with much less systemic exposure, the 4 million Americans with type 2 diabetes who have impaired kidney function may now be able to benefit from treatment with metformin DR.
“The demonstration is clear and straightforward, and the results may have a great impact not only on our understanding of metformin mechanism in humans but also on future metformin therapy in clinic, for example, using gut-released metformin DR instead of the current formulation (metformin XR),” Ruisheng Song, MD, PhD, from the Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, and Broad Institute of MIT and Harvard, Cambridge, MA, wrote in an accompanying editorial.
The study was published in the February 2016 issue of Diabetes Care.