Comparison of Power, Prognosis, and Extrapolation Properties of Four Population Pharmacodynamic Models of HbA1c for Type 2 Diabetes

Reusing published models saves time; time to be used for informing decisions in drug development. In antihyperglycemic drug development, several published HbA1c models are available but selecting the appropriate model for a particular purpose is challenging. This study aims at helping selection by investigating four HbA1c models, specifically the ability to identify drug effects (shape, site of action, and power) and simulation properties. All models could identify glucose effect nonlinearities, although for detecting the site of action, a mechanistic glucose model was needed. Power was highest for models using mean plasma glucose to drive HbA1c formation. Insulin contribution to power varied greatly depending on the drug target; it was beneficial only if the drug target was insulin secretion. All investigated models showed good simulation properties. However, extrapolation with the mechanistic model beyond 12 weeks resulted in drug effect overprediction. This investigation aids drug development in decisions regarding model choice if reusing published HbA1c models.