Mathematical Modeling Shows Exenatide Improved β-Cell Function in Patients with Type 2 Diabetes Treated with Metformin or Metformin and a Sulfonylurea

Abstract

The incretin mimetic exenatide improved glycemic control and reduced body weight in patients with type 2 diabetes inadequately controlled with metformin+/-a sulfonylurea. We assessed postprandial beta-cell function by mathematical modeling, independent of confounding effects from differing ambient glucose levels among treatments. Subjects were 63% males, 55+/-10 years, BMI 33+/-6 kg/m2, HbA1C 8.1+/-1.1% (+/- SD) randomized to 5 microg exenatide or placebo twice daily for 4 weeks. Subsequently, one arm remained at 5 microg twice daily, one arm escalated to 10 microg twice daily, and one treatment arm remained on placebo for 26 weeks. Subjects continued metformin+/-a sulfonylurea. A subset with meal tests at baseline and week 30 were analyzed (n=73). Outcome measures were the model-based beta-cell function parameters dose-response relating insulin secretion to glucose concentration, rate sensitivity, and potentiation. Exenatide reduced postprandial glucose excursions. Modeling predicted an upward shift of the beta-cell dose-response. Model-predicted insulin secretion rate at a reference glucose concentration increased 72% (10 microg), increased 40% (5 microg), or decreased 21% (placebo) at week 30 [ p=0.015 (10 microg); p=0.045 (5 microg); vs. placebo]. At week 30, the 2-hour post-meal to basal potentiation factor ratio was increased to 1.53+/-0.10 (10 microg; p=0.0142 vs. placebo) or 1.40+/-0.08 (5 microg; p=0.0402 vs. placebo) compared with 1.15+/-0.06 (placebo). Exenatide caused an upward shift of the beta-cell dose-response and enhanced potentiation of insulin secretion. This model suggests exenatide improved beta-cell function in patients with type 2 diabetes treated with metformin+/-a sulfonylurea.

Exenatide improves β-cell function up to 3 years of treatment in patients with type 2 diabetes: a randomised controlled trial

“…However, none of these effects was sustained at year 3, while glycaemic control remained similar. At year 1, EXE improved insulin secretion at 8 mmol/L glucose, glucose sensitivity and potentiation compared with baseline, confirming data from previous short-term studies using GLP1 receptor agonists (18,19). The difference in insulin secretion at 8 mmol/L glucose was significantly different compared with GLAR.…”

“…The significant inverse correlations of insulin secretion at 8 mmol/L glucose and glucose sensitivity after 3 years of EXE treatment with HbA1c demonstrate the importance of β-cell function in glycaemic control with GLP1 receptor agonist treatment. # GLP1 receptor agonists have previously been shown to improve β-cell function in type 2 diabetic patients using both static and dynamic tests; the latter includes hyperglycaemic clamps (5,20) and oral glucose or meal tolerance tests (9,18,19). However, these studies were limited by the relatively short treatment duration (i.e.…”

Ameliorated pancreatic β cell dysfunction in type 2 diabetic patients treated with a sodium-glucose cotransporter 2 inhibitor ipragliflozin

“…To date, it has been reported that some anti-diabetic agents, including dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and thiazolidinediones, can ameliorate the β cell dysfunction [17][18][19][20][21][22][23][24]. Their ameliorating effect is expected to be through a direct signaling in the β cell, e.g., via the incretin receptor and the peroxisome proliferator-activated receptor-γ (PPAR-γ).…”

Targeting Incretins in Type 2 Diabetes: Role of GLP-1 Receptor Agonists and DPP-4 Inhibitors

“…After 4 weeks, one arm of the exenatide group was uptitrated to 10 µg twice daily. After 30 weeks of therapy, insulin secretion rates increased 40% and 72% in the 5-and 10-µg groups, respectively, compared with a 21% reduction in placebo patients; moreover, exenatide at both dosages enhanced potentiation of insulin secretion [59].…”