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

Abstract

OBJECTIVEDelayed-release metformin (Met DR) is formulated to deliver the drug to the lower bowel to leverage the gut-based mechanisms of metformin action with lower plasma exposure. Met DR was assessed in two studies. Study 1 compared the bioavailability of single daily doses of Met DR to currently available immediaterelease metformin (Met IR) and extended-release metformin (Met XR) in otherwise healthy volunteers. Study 2 assessed glycemic control in subjects with type 2 diabetes (T2DM) over 12 weeks. RESEARCH DESIGN AND METHODSStudy 1 was a phase 1, randomized, four-period crossover study in 20 subjects. Study 2 was a 12-week, phase 2, multicenter, placebo-controlled, dose-ranging study in 240 subjects with T2DM randomized to receive Met DR 600, 800, or 1,000 mg administered once daily; blinded placebo; or unblinded Met XR 1,000 or 2,000 mg (reference). RESULTSThe bioavailability of 1,000 mg Met DR b.i.d. was ∼50% that of Met IR and Met XR (study 1). In study 2, 600, 800, and 1,000 mg Met DR q.d. produced statistically significant, clinically relevant, and sustained reductions in fasting plasma glucose (FPG) levels over 12 weeks compared with placebo, with an ∼40% increase in potency compared with Met XR. The placebo-subtracted changes from baseline in HbA 1c level at 12 weeks were consistent with changes in FPG levels. All treatments were generally well tolerated, and adverse events were consistent with Glucophage/Glucophage XR prescribing information. CONCLUSIONSDissociation of the glycemic effect from plasma exposure with gut-restricted Met DR provides strong evidence for a predominantly lower bowel-mediated mechanism of metformin action.

Calcium alginate microspheres containing metformin hydrochloride niosomes and chitosomes aimed for oral therapy of type 2 diabetes mellitus

“…The data were analyzed for significant differences by ANOVA followed by a Bonferroni's post hoc comparison procedure (*p < 0.05 vs pure MTF at the same time; ^P < 0.05vs pre-test of the same group, ^^P < 0.05 vs alginate bead with plain MTF at the same time; **P < 0.05 vs MTF chitosomal alginate beads at the same time). more intense and longer effect of chitosomal and even more of niosomal-alginate beads seems to be due to a better control of the drug release rate from such formulations, and/or an increased residence time at intestinal level which could allow MTF to better exploit its lower bowel-mediated mechanism of action (Buse et al, 2016). The reduced solubility of MTF in such formulations, due to interactions with DCP (present in both kinds of colloidal dispersions) could also concur to this effect.…”

“…Alginate beads have been successfully used as a vehicle for liposomes (Xing et al, 2003;Bansal et al, 2016) to protect the entrapped hydrophilic drugs and release them to the lower bowel, after specific local biodegradation of the polymer. Such an effect could be particularly beneficial in the case of metformin, since it has been recently proved the important role of the lowel bowel-mediated mechanism in the primary glucoselowering effect of the drug (Buse et al, 2016).…”

The effects of metformin on gut microbiota and the immune system as research frontiers

“…Evidence (reviewed in [16,29]) that blood glucose-lowering effects of a poorly absorbed metformin formulation can be demonstrated suggests that at least a portion of the therapeutic benefit of metformin is attributable to effects within the gastrointestinal system. How can a drug acting only within the gut affect systemic carbohydrate metabolism?…”

Metformin: clinical topics and new mechanisms of action

“…Clinical studies using metformin DR highlights the ileum as a site of uptake and as an important site of action in lowering blood glucose. Compared with metformin IR or metformin XR, the bioavailability of metformin DR is lower, yet its glucose-lowering efficacy is similar despite the lower systemic metformin exposure [19]. After a single daily doseof DR 1000 mg, plasma concentrations and bioavailability were *50% compared with those using XR; however, clinical effects after 4 weeks were similar.…”