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DDMODEL00000004: DeWinter_2006_diabetes

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A mechanism-based disease progression model for comparison of long-term effects of pioglitazone, metformin and gliclazide on disease processes underlying Type 2 Diabetes Mellitus
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  • A mechanism-based disease progression model for comparison of long-term effects of pioglitazone, metformin and gliclazide on disease processes underlying Type 2 Diabetes Mellitus.
  • de Winter W, DeJongh J, Post T, Ploeger B, Urquhart R, Moules I, Eckland D, Danhof M
  • Journal of pharmacokinetics and pharmacodynamics, 6/2006, Volume 33, Issue 3, pages: 313-343
  • LAP&P Consultants BV, Leiden, The Netherlands.
  • Effective long-term treatment of Type 2 Diabetes Mellitus (T2DM) implies modification of the disease processes that cause this progressive disorder. This paper proposes a mechanism-based approach to disease progression modeling of T2DM that aims to provide the ability to describe and quantify the effects of treatment on the time-course of the progressive loss of beta-cell function and insulin-sensitivity underlying T2DM. It develops a population pharmacodynamic model that incorporates mechanism-based representations of the homeostatic feedback relationships between fasting levels of plasma glucose (FPG) and fasting serum insulin (FSI), and the physiological feed-forward relationship between FPG and glycosylated hemoglobin A1c (HbA1c). This model was developed on data from two parallel one-year studies comparing the effects of pioglitazone relative to metformin or sulfonylurea treatment in 2,408 treatment-naïve T2DM patients. It was found that the model provided accurate descriptions of the time-courses of FPG and HbA1c for different treatment arms. It allowed the identification of the long-term effects of different treatments on loss of beta-cell function and insulin-sensitivity, independently from their immediate anti-hyperglycemic effects modeled at their specific sites of action. Hence it avoided the confounding of these effects that is inherent in point estimates of beta-cell function and insulin-sensitivity such as the widely used HOMA-%B and HOMA-%S. It was also found that metformin therapy did not result in a reduction in FSI levels in conjunction with reduced FPG levels, as expected for an insulin-sensitizer, whereas pioglitazone therapy did. It is concluded that, although its current implementation leaves room for further improvement, the mechanism-based approach presented here constitutes a promising conceptual advance in the study of T2DM disease progression and disease modification.
Paolo Magni
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  • Model owner: Paolo Magni
  • Submitted: Sep 25, 2014 5:20:22 PM
  • Last Modified: Oct 10, 2016 9:56:13 PM
Revisions
  • Version: 7 public model Download this version
    • Submitted on: Oct 10, 2016 9:56:13 PM
    • Submitted by: Paolo Magni
    • With comment: Update MDL syntax to the version 1.0 and R script to SEE version 2.0.0. Code automatically generated for NONMEM and MONOLIX
  • Version: 6 public model Download this version
    • Submitted on: Jul 16, 2016 4:24:05 PM
    • Submitted by: Paolo Magni
    • With comment: Updated model annotations.
  • Version: 3 public model Download this version
    • Submitted on: Dec 11, 2015 3:32:36 PM
    • Submitted by: Paolo Magni
    • With comment: Edited model metadata online.
  • Version: 1 public model Download this version
    • Submitted on: Sep 25, 2014 5:20:22 PM
    • Submitted by: Paolo Magni
    • With comment: Import of DeWinter_2006_diabetes
 
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