Linking the 4GI glucose homeostasis and Hall body composition models to quantify weight loss effects of GLP-1R agonists, and body weight effects on insulin sensitivity
Objectives: Our previously published 4GI systems pharmacology model describes drug effects on glucose, glucagon-like peptide-1 (GLP-1), glucagon, glucose-dependent insulinotropic peptide (GIP) and insulin (4GI) dynamics in type 2 diabetes mellitus (T2DM) and healthy volunteers (HV) [1]. However, body weight effects on insulin sensitivity were not captured. This investigation aimed to link the 4GI with the Hall body composition model [2] to quantify the effect of GLP-1 receptor (GLP-1R) agonists on body weight, and body weight effects on glucose homeostasis.
Methods: A selection of [NS1] literature clinical data were collected that included both diet and GLP-1R agonistic effects on body weight. These data were combined with the original 4GI literature data. The Hall body composition model code was translated to NONMEM, extended for GLP-1R agonistic effects using in-vitro EC50 normalized free drug concentration as driver of the effect, and linked with the 4GI model. The GLP-1 and diet effects on Hall energy intake, and the 4GI meal related parameters, such as the glucose absorption rate constant[NS2] , were estimated. All other system specific parameters were kept fixed. To assess the weight loss effect on insulin sensitivity the model-predicted absolute change from baseline body weight was used as a continuous covariate on the insulin dependent glucose clearance, which reflects insulin sensitivity in the 4GI model.
Results: The diet effect on body weight was captured by an initial reduction in food intake that diminishes over time. The GLP-1R agonistic effects of liraglutide and semaglutide on energy intake were best described using an Emax model with a tolerance effect on the EC50, resulting in a reduced effect over time. The developed model was able to adequately describe diet and GLP-1R agonist induced weight loss. Including weight loss effects on insulin sensitivity in the 4GI model resulted in a significantly lower objective function value and an improved description of glucose levels.
Conclusions: The Hall body composition model was successfully extended for GLP-1R agonistic effects on body weight by assuming an inhibiting effect on energy intake.
Combining the Hall model with the 4GI model showed that weight loss has a positive effect on insulin sensitivity.
Citations
[1] Bosch, R., Petrone, M., Arends, R., Vicini, P., Sijbrands, E. J. G., Hoefman, S., & Snelder, N. (2022). A novel integrated QSP model of in vivo human glucose regulation to support the development of a glucagon/GLP-1 dual agonist. CPT: Pharmacometrics and Systems Pharmacology, 11(3), 302–317.
[2] Hall, K. D. (2010). Predicting metabolic adaptation, body weight change, and energy intake in humans. American Journal of Physiology - Endocrinology and Metabolism, 298(3).
Author(s)
- Rolien Bosch, LAP&P Consultants BV, Leiden, The Netherlands (Presenting Author)
- Nelleke Snelder, LAP&P Consultants BV, Leiden, The Netherlands (CoAuthor)