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

John B. Buse; Ralph A. DeFronzo; Julio Rosenstock; Terri Kim; Colleen Burns; Sharon Skare; Alain Baron; Mark Fineman

Disclosures

Diabetes Care. 2016;39(2):198-205. 

In This Article

Abstract and Introduction

Abstract

Objective Delayed-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 immediate-release 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 Methods Study 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).

Results The 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 HbA1c 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.

Conclusions Dissociation 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.

Introduction

Although metformin was introduced as a treatment for type 2 diabetes (T2DM) >50 years ago, the mechanism of metformin action is still debated.[1] Historically, the glucose-lowering actions of metformin have been attributed to its effects on mitochondrial function, AMPK, and glucagon receptor–stimulated adenylate cyclase in the liver and skeletal muscle, albeit at suprapharmacological doses.[2,3] A recent study[4] in rodents suggests that intravenous metformin inhibits the redox shuttle enzyme mitochondrial glycerophosphate dehydrogenase, resulting in an altered hepatocellular redox state, reduced conversion of lactate and glycerol to glucose, and decreased hepatic gluconeogenesis at lower doses than are required to affect AMPK. However, reports[5,6] that short-term intravenous metformin administration is less effective than oral administration in rats and humans have suggested that the gut may be important for the glucose-lowering action of metformin. Gut effects include secretion of the enteroendocrine L-cell products glucagon-like peptide 1 (GLP-1) and peptide YY, bile acid metabolism, and the gut microbiome.[7,8]

When currently available metformin formulations (immediate-release metformin [Met IR] and extended-release metformin [Met XR]) are orally administered, the absolute bioavailability is ~50% of the total dose with the majority of absorption occurring in the duodenum and jejunum.[9–11] Importantly, as metformin is not metabolized in the gut,[11] ~50% of a typical therapeutic dose is delivered to the distal small intestine where it accumulates in the gut mucosa at concentrations up to 300 times greater than concentrations in plasma.[12] After a single dose of orally administered Met IR, ~30% of the dose is recovered in the feces.[10] Given that metformin absorption is transporter rate limited, lower doses (<1,000 mg) have higher bioavailability[11] but are less effective.[13] Thus, we speculated that higher doses of metformin (≥1,500 mg) are necessary to "overwhelm" the transporters in the proximal small intestine and deliver optimally effective doses of metformin to the lower bowel. The fact that there is a clear dose response for metformin while the pharmacokinetic (PK)/pharmacodynamic relationship is weak[14] also supports the concept that presystemic mechanisms may be important to its glucose-lowering effect.

We tested the hypothesis that gut exposure to metformin predominantly accounts for its glucose-lowering effect by using a delayed-release metformin (Met DR) formulation that targets the ileum, a region of the gut where the absorption of metformin is low.[9,11] Met DR targets the ileum through pH-dependent dissolution of the tablet without modifying the structure of the metformin molecule. In this report, we describe two studies demonstrating that Met DR has lower bioavailability compared with Met IR and Met XR in otherwise healthy subjects (study 1) and that the delivery of low doses of metformin (600–1,000 mg) to the lower bowel is at least as effective as similar doses of Met XR in lowering plasma glucose levels over 12 weeks in subjects with T2DM (study 2).

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