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

Abstract

Objective: Metformin 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 methods: Participants (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.

Results: 571 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%).

Conclusion: Metformin 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 registration: Clinicaltrials.gov NCT02526524.

Fig 1. Study flow diagram.

Fig 2. Systemic exposure and glycemic efficacy of metformin DR and metformin IR.

Upper Panel: Metformin systemic (plasma) exposure (A) observed at trough (median) and (B) steady state AUC0-24h (geometric mean [95%CI]) estimated from trough and post-dose sampling. Middle Panel: Efficacy presented as (C) HbA1c change at Week 16 (LS mean + SE) and (D) Caverage Week 4–16 change in fasting glucose from baseline (LS mean + SE). Lower Panel: The efficacy/exposure relationship of 1500 mg Metformin DR and 2000 mg Metformin IR represents HbA1c (E) and fasting glucose improvement (F) per unit of systemic metformin exposure. Efficacy/exposure data are HbA1c (LS mean reduction from baseline at Week 16) or reduction in fasting glucose (Caverage Week 4–16) divided by calculated metformin exposure (AUC0-24h); data are normalized to Metformin IR 2000 mg. Data are from the mITT Population (n = 542), with the exception of modeled steady-stated metformin AUC0-24h (ITT population; n = 571). * p<0.05 vs. Placebo.

Fig 3. Time to occurrence of gastrointestinal treatment-emergent adverse events.

Probability of any gastrointestinal treatment-emergent adverse event (top figure) or nausea/diarrhea events (bottom figures). Abbreviations: CI = Confidence interval; DR = Delayed-release; HR = Hazard ratio; IR = Immediate-release; Met = Metformin; TEAE = Treatment-emergent adverse event. Data are from the ITT Population (n = 571).