Modelling of Glucose and Insulin profiles in Patients with Type 2 Diabetes Mellitus treated with a GLP-1 analogue
Rikke M Røge1,2, Søren Klim1, Steen H Ingwersen1, Maria C Kjellsson2, Niels R Kristensen1
1 Novo Nordisk A/S, Søborg, Denmark. 2 Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
Objectives: In recent years several Glucagon-like peptide-1 (GLP-1) based therapies for the treatment of type 2 diabetes mellitus (T2DM) have been developed. GLP-1 analogues stimulate insulin secretion in a glucose-dependent manner, slow gastric emptying and decrease appetite, which leads to an improved glycaemic control. The aim of this work was to extend the previously developed semi-mechanistic integrated glucose-insulin (IGI) model  to include the effects of a GLP-1 analogue on glucose and insulin homeostasis in T2DM patients.
Methods: The data used for model development were from a single-center, randomized, placebo-controlled, double-blind, two-period, crossover trial, comparing the effect of steady-state liraglutide at three dose levels (0.6, 1.2, and 1.8 mg/day) versus placebo on the responses of fasting plasma glucose and post-prandial glucose, insulin, and gastric emptying in T2DM patients . After one week of treatment at each dose level, an energy fixed meal tolerance test (MTT) was performed during which serum insulin and glucose profiles were obtained.
The IGI model, used in the analysis, consists of glucose and endogenous insulin compartments and control mechanisms in the form of effect compartments . The model was extended to allow incorporation of the effect of liraglutide on glucose homeostasis. The data were analysed using NONMEM7.
Results: The IGI model was extended to describe the glucose profiles for T2DM patients treated with a GLP-1 analogue. The effect of the GLP-1 analogue on glucose homeostasis was incorporated in the model by including: 1) a stimulatory effect on insulin secretion, and 2) an inhibitory effect on glucose absorption, which was included to account for a delay in gastric emptying during the early phase after the MTT.
The predictive performance of the model was graphically evaluated by a visual predictive check (VPC). The VPC showed that the main trend of glucose and insulin was well captured by the model at all dose levels.
Conclusions: The IGI model was successfully extended to describe glucose homeostasis in T2DM patients treated with the GLP-1 analogue liraglutide. As other GLP-1 analogues have similar mode of action it is believed that the model can also be used to describe the effect of other analogues on glucose homeostasis.
Acknowledgement: This work was supported by the DDMoRe project.
 Jauslin PM, Silber HE, Frey N, Gieschke R, Simonsson USH, Jorga K, Karlsson MO. An integrated glucose-insulin model to describe oral glucose tolerance test data in type 2 diabetics. J Clin Pharmacol. 2007;47:1244-1255.
 Flint A, Kapitza C, Hindsberger C, Zdravkovic M. The Once-Daily Human Glucagon-Like Peptide-1 (GLP-1) Analog Liraglutide Improves Postprandial Glucose Levels in Type 2 Diabetes Patients. Adv Ther. 2011; 28: 213-226.