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 β-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, HbA_1C 8.1±1.1% (± SD) randomized to 5 μg exenatide or placebo twice daily for 4 weeks. Subsequently, one arm remained at 5 μg twice daily, one arm escalated to 10 μg 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 β-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 β-cell dose-response. Model-predicted insulin secretion rate at a reference glucose concentration increased 72% (10 μg), increased 40% (5 μg), or decreased 21% (placebo) at week 30 p=0.015 (10 μg); p=0.045 (5 μg); vs. placebo. At week 30, the 2-hour post-meal to basal potentiation factor ratio was increased to 1.53±0.10 (10 μg; p=0.0142 vs. placebo) or 1.40±0.08 (5 μg; p=0.0402 vs. placebo) compared with 1.15±0.06 (placebo). Exenatide caused an upward shift of the β-cell dose-response and enhanced potentiation of insulin secretion. This model suggests exenatide improved β-cell function in patients with type 2 diabetes treated with metformin±a sulfonylurea.