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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
- Source :
- Journal of pharmacokinetics and pharmacodynamics. 33(3)
- Publication Year :
- 2005
-
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 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.
- Subjects :
- 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
Subjects
Details
- ISSN :
- 1567567X
- Volume :
- 33
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Journal of pharmacokinetics and pharmacodynamics
- Accession number :
- edsair.doi.dedup.....85fb0dd0cadd5a848b35bafd1863dac3