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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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Abstract

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 β-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 A 1c (HbA 1c). This model was developed on data from two parallel one-year studies comparing the effects of pioglitazone relative to metformin or sulfonylurea treatment in 2408 treatment-naïve T2DM patients. It was found that the model provided accurate descriptions of the time-courses of FPG and HbA 1c for different treatment arms. It allowed the identification of the long-term effects of different treatments on loss of β-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 β-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.

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Correspondence to Meindert Danhof.

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Winter, W.d., DeJongh, J., Post, T. et al. 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. J Pharmacokinet Pharmacodyn 33, 313–343 (2006). https://doi.org/10.1007/s10928-006-9008-2

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  • DOI: https://doi.org/10.1007/s10928-006-9008-2

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