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
| Autor: | Teun M. Post, Willem de Winter, Joost DeJongh, Meindert Danhof, David Eckland, Ian K. Moules, Bart A. Ploeger, Richard Urquhart |
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| Rok vydání: | 2005 |
| Předmět: |
Oncology
Adult Blood Glucose Male medicine.medical_specialty endocrine system diseases Population Type 2 diabetes Models Biological Double-Blind Method Internal medicine Insulin-Secreting Cells medicine Glucose homeostasis Humans Hypoglycemic Agents Insulin Multicenter Studies as Topic Gliclazide education Pioglitazone/Metformin Aged Randomized Controlled Trials as Topic Pharmacology Glycated Hemoglobin education.field_of_study Pioglitazone business.industry nutritional and metabolic diseases Type 2 Diabetes Mellitus Middle Aged medicine.disease Metformin Endocrinology Treatment Outcome Clinical Trials Phase III as Topic Diabetes Mellitus Type 2 Disease Progression Female Thiazolidinediones Insulin Resistance business Algorithms medicine.drug |
| Zdroj: | Journal of pharmacokinetics and pharmacodynamics. 33(3) |
| ISSN: | 1567-567X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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