Improved glycemic control with minimal systemic metformin exposure: Effects of Metformin Delayed-Release (Metformin DR) targeting the lower bowel over 16 weeks in a randomized trial in subjects with type 2 diabetes.

Robert R Henry,Thomas A Bicsak,Colleen Burns,Mark Fineman,Alain Baron,Brandon Walsh,Juan P Frias,Sharon Skare,John Hemming,Dorit Samocha-Bonet

doi:10.1371/journal.pone.0203946

Robert R Henry, Thomas A Bicsak + Show 8 more

Open Access

https://doi.org/10.1371/journal.pone.0203946

Copy DOI

Abstract

ObjectiveMetformin use is restricted in patients with renal impairment due to potential excess systemic accumulation. This study evaluated the glycemic effects and safety of metformin delayed-release (Metformin DR), which targets metformin delivery to the ileum to leverage its gut-based mechanisms of action while minimizing systemic exposure.Research designs and methodsParticipants (T2DM [HbA1c 7–10.5%], eGFR ≥60 mL/min/1.73m2, not taking metformin for ≥2 months) were randomized to QD placebo (PBO); QD Metformin DR 600, 900, 1200, or 1500 mg; or to single-blind BID Metformin immediate-release (IR) 1000 mg. The primary endpoint was change in HbA1c for Metformin DR vs. PBO at 16 weeks in the modified intent-to-treat (mITT) population (≥ 1 post-baseline HbA1c while on study drug), using a mixed-effects repeated measures model.Results571 subjects were randomized (56 years, 53% male, 80% white; BMI 32.2±5.5 kg/m2; HbA1c 8.6±0.9%; 51% metformin naive); 542 were in the mITT population. Metformin DR 1200 and 1500 mg significantly reduced HbA1c (-0.49±0.13% and -0.62±0.12%, respectively, vs. PBO -0.06±0.13%; p<0.05) and FPG (Caverage Weeks 4–16: -22.3±4.2 mg/dL and -25.1±4.1 mg/dL, respectively vs. -2.5±4.2 mg/dL p<0.05). Metformin IR elicited greater HbA1c improvement (-1.10±0.13%; p<0.01 vs. Placebo and all doses of Metformin DR) but with ~3-fold greater plasma metformin exposure. Normalizing efficacy to systemic exposure, glycemic improvements with Metformin DR were 1.5-fold (HbA1c) and 2.1-fold (FPG) greater than Metformin IR. Adverse events were primarily gastrointestinal but these were less frequent with Metformin DR (<16% incidence) vs. Metformin IR (28%), particularly nausea (1–3% vs 10%).ConclusionMetformin DR exhibited greater efficacy per unit plasma exposure than Metformin IR. Future studies will evaluate the effects of Metformin DR in patients with type 2 diabetes and advanced renal disease.Trial registrationClinicaltrials.gov NCT02526524.

Highlights

Metformin is a first-line treatment for T2DM that has been used for over 60 years
Future studies will evaluate the effects of Metformin DR in patients with type 2 diabetes and advanced renal disease
In instances of overdose [7] or when metformin is not adequately cleared, excessive metformin accumulation in the plasma and liver increases the risk of metformin-associated lactic acidosis (MALA), a rare (

Summary

Introduction

Metformin is a first-line treatment for T2DM that has been used for over 60 years. Upon ingestion, approximately 50% of metformin is absorbed primarily from the duodenum and jejunum [1,2,3,4], and systemically-available metformin is renally excreted unchanged [1]. Most cases of metformin accumulation are insufficient to cause MALA on their own, but its direct and independent effects on oxidative metabolism renders patients more susceptible to lactic acidosis in the event of an intercurrent illness or injury that increases lactate production and/or disrupts lactate clearance (e.g., dehydration, sepsis, cirrhosis, hypoperfusion, acute kidney injury)[10,11,12,13,14] As these intercurrent events are typically not predictable, metformin accumulation in moderate to severe renal impairment should be avoided and concerns over metformin accumulation have led to contraindication in patients with chronic kidney disease (CKD) Stage 4, and recommendation/labeling to use with caution and at reduced dose in CKD Stage 3B [8, 15, 16]

Methods

Results

Conclusion