Once-daily delayed-release metformin lowers plasma glucose and enhances fasting and postprandial GLP-1 and PYY: results from two randomised trials

Abstract

Aims/hypothesis: Delayed-release metformin (Metformin DR) was developed to maximise gut-based mechanisms of metformin action by targeting the drug to the ileum. Metformin DR was evaluated in two studies. Study 1 compared the bioavailability and effects on circulating glucose and gut hormones (glucagon-like peptide-1, peptide YY) of Metformin DR dosed twice-daily to twice-daily immediate-release metformin (Metformin IR). Study 2 compared the bioavailability and glycaemic effects of Metformin DR dosages of 1,000 mg once-daily in the morning, 1,000 mg once-daily in the evening, and 500 mg twice-daily.

Methods: Study 1 was a blinded, randomised, crossover study (three × 5 day treatment periods) of twice-daily 500 mg or 1,000 mg Metformin DR vs twice-daily 1,000 mg Metformin IR in 24 participants with type 2 diabetes conducted at two study sites (Celerion Inc.; Tempe, AZ, and Lincoln, NE, USA). Plasma glucose and gut hormones were assessed over 10.25 h at the start and end of each treatment period; plasma metformin was measured over 11 h at the end of each treatment period. Study 2 was a non-blinded, randomised, crossover study (three × 7 day treatment periods) of 1,000 mg Metformin DR once-daily in the morning, 1,000 mg Metformin DR once-daily in the evening, or 500 mg Metformin DR twice-daily in 26 participants with type 2 diabetes performed at a single study site (Celerion, Tempe, AZ). Plasma glucose was assessed over 24 h at the start and end of each treatment period, and plasma metformin was measured over 30 h at the end of each treatment period. Both studies implemented centrally generated computer-based randomisation using a 1:1:1 allocation ratio.

Results: A total of 24 randomised participants were included in study 1; of these, 19 completed the study and were included in the evaluable population. In the evaluable population, all treatments produced similar significant reductions in fasting glucose (median reduction range, -0.67 to -0.81 mmol/l across treatments) and postprandial glucose (Day 5 to baseline AUC0-t ratio = 0.9 for all three treatments) and increases in gut hormones (Day 5 to baseline AUC0-t ratio range: 1.6-1.9 for GLP-1 and 1.4-1.5 for PYY) despite an almost 60% reduction in systemic metformin exposure for 500 mg Metformin DR compared with Metformin IR. A total of 26 randomised participants were included in study 2: 24 had at least one dose of study medication and at least one post-dose pharmacokinetic/pharmacodynamic assessment and were included in the pharmacokinetic/pharmacodynamic intent-to-treat analysis; and 12 completed all treatment periods and were included in the evaluable population. In the evaluable population, Metformin DR administered once-daily in the morning had 28% (90% CI -16%, -39%) lower bioavailability (least squares mean ratio of metformin AUC0-24) compared with either once-daily in the evening or twice-daily, although the glucose-lowering effects were maintained. In both studies, adverse events were primarily gastrointestinal in nature, and indicated similar or improved tolerability for Metformin DR vs Metformin IR; there were no clinically meaningful differences in vital signs, physical examinations or laboratory values.

Conclusions/interpretation: Dissociation of gut hormone release and glucose lowering from plasma metformin exposure provides strong supportive evidence for a distal small intestine-mediated mechanism of action. Directly targeting the ileum with Metformin DR once-daily in the morning may provide maximal metformin efficacy with lower doses and substantially reduce plasma exposure. Metformin DR may minimise the risk of lactic acidosis in those at increased risk from metformin therapy, such as individuals with renal impairment.

Trial registration: Clinicaltrials.gov NCT01677299, NCT01804842 FUNDING: : This study was funded by Elcelyx Therapeutics Inc.

Keywords: Clinical care; Clinical study; Lactate; Mechanisms; Metformin.

Figures

Fig. 1

Study 1: plasma metformin concentrations and bioavailability. (a) Steady state plasma metformin concentrations (mean ± SD) by treatment. White circles, 1,000 mg Metformin IR twice-daily; black squares, 1,000 mg Metformin DR twice-daily; black triangles, 500 mg Metformin DR twice-daily. All treatments were administered at t = −1 min (arrow) relative to the standardised breakfast (t = 0 h) and lunch (t = 5 h) (dotted vertical lines). (b, c) Plasma metformin relative bioavailability and exposure at steady state (data are the geometric LS mean and 90% CI for the ratios of twice-daily 1,000 mg Metformin DR [Met DR] and 500 mg Metformin DR to twice-daily 1,000 mg Metformin IR). Evaluable population, n = 19. ****p < 0.0001 vs twice-daily 1,000 mg Metformin IR

Fig. 2

Study 1: change in plasma glucose and gut hormone levels. (a) Individual (median) changes from baseline to day 5 in FPG concentrations by treatment. (b–d) Mean and SEM for plasma glucose at baseline and day 5. (e–g) Mean and SEM for plasma GLP-1 active at baseline and day 5. (h–j) Mean and SEM for PYY total at baseline and day 5. White symbols, values at baseline; black symbols, values at day 5. Evaluable population, n = 19. All treatments were administered at t = −1 min relative to the standardised breakfast (t = 0 h) and lunch (t = 5 h; dotted vertical lines). Met, metformin

Fig. 3

Study 2: change in metformin concentrations and bioavailability. (a) Steady state plasma metformin concentrations (mean ± SD) by treatment. Inset: mean plasma metformin concentration from the time of dose administration (t = 0). Black squares, 1,000 mg Metformin DR once-daily am; white squares, 1,000 mg Metformin DR once-daily pm; grey triangles, 500 mg Metformin DR twice-daily. (b, c) Plasma metformin (mean and 90% CI) relative bioavailability and exposure at steady state. (d) 24 h urine excretion (Ae) of metformin (mean and %CV) by treatment at steady state. Evaluable population, n = 12. Meals were administered at t = 0, 3, 12 and 18 h. **p < 0.01, *p < 0.05

Fig. 4

Study 2: change in plasma glucose. (a, b) Overall plasma glucose and peak exposure at baseline and steady state. White bars, baseline; black bars, treatment. (c) FPG change from baseline at steady state. Data are the geometric LS mean and SEM (a, b) or LS mean and SEM (c) for the evaluable population (n = 12). *p < 0.05, **p < 0.01, ***p < 0.001