Metformin – what we didn’t know

A new study has turned conventional wisdom about metformin on its head, and suggested that the drug’s main glucose-lowering effect lies in the gut, not the blood. The results could be a boon to millions of people who cannot take metformin because of kidney disease.

The study compared metformin delayed release (Met DR) to metformin immediate release (Met IR) and metformin extended release (Met XR). Results showed that, even though Met DR was found at much lower levels in the blood than Met IR and Met XR, Met DR was about 40% more potent than Met XR.

“The observation that low doses of Met DR appear to be more effective than similar doses of the more bioavailable Met XR suggests that the gut contribution to glucose lowering may be more important than systemic mechanisms,” wrote first author John Buse, of the University of North Carolina School of Medicine in Chapel Hill, North Carolina, and colleagues.

Metformin has been used for treating type 2 diabetes (T2DM) for over fifty years, yet its mechanism of action has remained elusive. For long, metformin was thought to exert its effects systemically, with major sites of action being the liver and skeletal muscle.

Met IR and Met XR are mostly absorbed in the duodenum and jejunum. Met DR undergoes pH-dependent dissolution in the ileum, delivering active drug to the lower intestine where there is low absorption of metformin, resulting in lower plasma levels of the drug.

The results stem from two studies. The first was a phase 1, randomized, crossover study in 20 healthy participants that looked at the bioavailability of various formulations of metformin. Healthy participants were randomized to Met DR (500 mg twice daily, or 1000 mg twice daily), Met IR (1000 mg twice daily) and Met XR (2000 mg once daily). Participants were mostly male (70%), and white (65%), with a mean age of 32.2 years and mean BMI of 29.6 kg/m².

Results showed:

• Bioavailability was about 50% lower for Met DR compared to Met IR and Met XR.

The second study was a phase 2, multicenter, placebo-controlled study in 240 patients with T2DM. Participants were randomized to 12 weeks of Met DR 600, 800, or 1000 mg once daily; blinded placebo; or unblinded Met XR 1000 or 2000 mg once daily.

Results showed:

• 50% lower median fasting glucose levels for 1000 mg Met DR compared to the same dose of Met XR (1000 mg).

• 40% increased potency for Met DR compared to Met XR.

• Increased plasma lactate concentrations with Met XR but not with Met DR, compared to placebo.

• Treatments were well tolerated, with adverse effects similar to known side effects.

Because high plasma concentrations of metformin can increase plasma lactate levels and the risk for metformin-associated lactic acidosis, Met DR may be better tolerated in patients with renal impairment, the authors suggested. 

“[T]he delivery of metformin to the lower bowel with Met DR resulted in a glucose-lowering efficacy comparable to that with Met XR, but with lower doses and significantly lower systemic exposure. These data provide substantial evidence that currently prescribed metformin doses work predominantly in the gut and that the contribution of systemic metformin is small,” the authors concluded. “Based on its gut-restricted properties, Met DR may allow for the metformin treatment of patients with renal impairment without the risk of lactic acidosis associated with metformin accumulation.”

Take Home Points

• Met DR has about 50% lower bioavailability than Met IR and Met XR.

• Met DR 1000 mg lowers fasting glucose levels by about 50% more than the same dose of Met XR.

• Met DR has about 40% increased potency compared to Met XR.

• Metformin’s main site of action lies in the gut.

• Patients with renal impairment may tolerate Met DR better than other formulations of metformin.

Reference: Buse JB, et al. The primary glucose-lowering effect of metformin resides in the gut, not the circulation. Results from short-term pharmacokinetic and 12-week dose-ranging studies. Diabetes Care. 2015 Aug 18. [Epub ahead of print]