Differential effects of imeglimin and metformin on insulin and incretin secretion-An exploratory randomized controlled trial

Abstract

Aims: Imeglimin is a new oral anti-diabetic drug with a similar structure to that of metformin; however, unlike metformin, clinical trials indicate that imeglimin elicits its glucose-lowering effect mainly by enhancement of insulin secretion. The comparative effects of the two drugs on incretin secretion remains to be elucidated.

Materials and methods: A single-center, open-label, randomized controlled trial was conducted in patients with type 2 diabetes who were drug-naïve or were on a single oral hypoglycaemic agent (OHA). For patients taking a single OHA, an 8-week washout period was employed before randomization. Participants were randomized to the imeglimin group (IME, 2000 mg/day) or the metformin group (MET, 1000 mg/day), and OGTT was performed before treatment and after 12 and 24 weeks of treatment.

Results: The reduction in HbA1c at 24 weeks was similar in IME and MET. OGTT revealed a comparable decrease in post-challenge blood glucose excursion in both groups, but insulin levels were increased only in IME. Total and active glucagon-like peptide-1 (GLP-1) levels were increased in both IME and MET; however, total and active glucose-dependent insulinotropic peptide (GIP) levels were increased only in IME. Interestingly, while an increase in insulin levels in IME was positively correlated with an increase in GLP-1 at 12 weeks, it was correlated only with an increase in GIP at 24 weeks.

Conclusions: Unlike metformin, imeglimin enhances GIP secretion as well as GLP-1 secretion, in addition to its direct insulinotropic mechanism of glucose control, emphasizing its potential as a therapeutic option in the treatment of patients with diabetes.

Keywords: imeglimin; incretin; metformin; randomized controlled trial.

FIGURE 1

Changes during 24‐week observation period in HbA1c (A) and body weight (B). Black circle or black bar (imeglimin) and black triangle or hatched bar (metformin). Each value represents the mean ± standard error of the mean. *p < 0.05 (0 week and 12 weeks), ^# p < 0.05 (0 week and 24 weeks), ^✟ p < 0.05 (12 weeks and 24 weeks) in by paired t test or Wilcoxon signed‐rank test with Bonferroni correction.

FIGURE 2

Time course curves for glucose (A), insulin (C), and CPR (F) during oral glucose tolerance test before and after initiation of imeglimin or metformin. Left panel shows changes in the imeglimin group and right panel shows changes in the metformin group. p Values for differences at week (X), time (Y), and the interaction of week and time (Z) were calculated by mixed effects models. Glucose, imeglimin X0.000, Y0.000, and Z0.046; metformin, X0.000, Y0.000, and Z0.031. Insulin, imeglimin X0.000, Y0.000, and Z0.912; metformin, X0.417, Y0.000, and Z0.884. CPR, imeglimin X0.000, Y0.000, and Z0.920; metformin, X0.040, Y0.000, and Z0.962 (0 week, black circle (imeglimin) or triangle (metformin); 12 weeks, blue circle (imeglimin) or triangle (metformin); and 24 weeks, red circle (imeglimin) or triangle (metformin)). Area under the curves (AUC)_0–240min of glucose (B), insulin (D), insulin/glucose (E), CPR (G), and CPR/glucose (H) are indicated (0 week, black bar; 12 weeks, blue bar; and 24 weeks, red bar). AUCs were analysed by paired t test or Wilcoxon signed‐rank test Bonferroni correction, *p < 0.05 (0 week and 12 weeks), ^# p < 0.05 (0 week and 24 weeks), ^✟ p < 0.05 (12 weeks and 24 weeks).

FIGURE 3

Time course curves for glucagon (A), total GLP‐1 (C), total GIP (E), active GLP‐1 (G), and active GIP (I) during oral glucose tolerance test before and after initiation of imeglimin or metformin. Left panel shows changes in the imeglimin group and right panel shows changes in the metformin group. p Values for differences at week (X), time (Y), and the interaction of week and time (Z) were calculated by mixed effects models. Glucagon, imeglimin X0.024, Y0.000, and Z0.878; metformin, X0.809, Y0.000, and Z0.236. Total GIP‐1, imeglimin X0.000, Y0.000, and Z0.891; metformin, X0.000, Y0.000, and Z0.305. Total GIP, imeglimin X0.000, Y0.000, and Z0.773; metformin, X0.364, Y0.000, and Z0.950. Active GLP‐1, imeglimin X0.016, Y0.000, and Z0.799; metformin, X0.000, Y0.000, and Z0.168. Active GIP, imeglimin X0.000, Y0.000, and Z0.632; metformin, X0.283, Y0.000, and Z0.961 (0 week, black circle (imeglimin) or triangle (metformin); 12 weeks, blue circle (imeglimin) or triangle (metformin); and 24 weeks, red circle (imeglimin) or triangle (metformin)). Area under the curves (AUC)_0–240min of glucagon (B), total GLP‐1 (D), total GIP (F), active GLP‐1 (H), active GIP (J) are indicated (0 week, black bar; 12 weeks, blue bar; and 24 weeks, red bar). AUCs were analysed by paired t test or Wilcoxon signed‐rank test with Bonferroni correction, *p < 0.05 (0 week and 12 weeks), ^# p < 0.05 (0 week and 24 weeks), ^✟ p < 0.05 (12 weeks and 24 weeks).

FIGURE 4

Changes during 24‐week observation period for liver enzymes and other parameters. DPP‐4 activity (A), AST (B), ALT (C), γ‐GTP (D), lactate (E), and VitB12 (F) were assessed at weeks 0, 12, and 24 weeks respectively (0 week, black; 12 weeks, blue; and 24 weeks, red). Left panel shows changes in the imeglimin group and right panel shows changes in the metformin group. Each value represents the mean ± standard error of the mean. *p < 0.05 (0 week and 12 weeks), ^# p < 0.05 (0 week and 24 weeks), ^✟ p < 0.05 (12 weeks and 24 weeks) in Wilcoxon signed‐rank test with Bonferroni correction.