A Mechanistic Disease Progression Model for Type 2 Diabetes Mellitus and Pioglitazone Treatment Effects
Willem de Winter (1), Teun Post (1), Joost DeJongh (1,2), Richard Urquhardt(3), Ian Moules (3), David Eckland (3) and Meindert Danhof (1,2)
(1) LAP&P Consultants BV, Archimedesweg 31, 233 CM Leiden, The Netherlands. (2) Leiden University, Leiden / Amsterdam Center for Drugs Research, Division of Pharmacology, P.O. Box 9502, 2300 RA Leiden, The Netherlands. (3) Takeda Europe Research and Development Centre, Savanah House, 11-12
Objectives: Type 2 Diabetes Mellitus (T2DM) is characterized by the progressive failure of pancreatic b-cells to compensate declining insulin sensitivity with increased insulin secretion. Traditional treatment options provide short-term relief, but the UK Prospective Diabetes Study has demonstrated that they typically fail to prevent the relentless progression of T2DM over the long term. Whereas T2DM progression continues over periods of years to decades, clinical trials of antidiabetic agents are usually restricted to timescales of weeks or months. This study aims to develop a population-based mechanistic model of T2DM disease progression that allows a more accurate and precise extrapolation of the results of clinical trials over periods pertinent to T2DM progression.
Methods: A population pharmacodynamic model was developed on the results of two Phase III, one-year efficacy studies comparing pioglitazone to metformin or sulphonylurea in mono-therapy in a total of 2408 newly diagnosed T2DM patients. Change in fasting plasma glucose and glycosylated hemoglobin was modelled as a cascading sequence. Data on insulin in the same subjects were used to model the homeostatic feedback relationships between fasting plasma glucose and insulin. This allowed a mechanistic description of T2DM progression and treatment efficacy in terms of insulin sensitivity and b-cell function, and a physiologically appropriate differentiation of the treatment effects of the various agents.
Results: The model yielded a satisfactory fit to the study data. It was found that sulphonylurea treatment resulted in an acute and pronounced reduction of glycemic levels that was counteracted immediately by a rapid deterioration of glycemic control due to on-going disease progression. In contrast, pioglitazone therapy showed a more gradual lowering of glycemic levels but subsequently maintained glycemic control at a constant level throughout the duration of the trial, reflecting the absence of disease progression. This was also reflected in lowered fasting insulin levels throughout the duration of the trial. Metformin also had a gradual onset of action but showed evidence of continuing disease progression.
Conclusions: This study shows that T2DM disease progression can be modelled more accurately with a mechanistic model approach based on the fasting plasma glucose - insulin homeostasis. It suggests that pioglitazone has a protective effect against T2DM progression in newly diagnosed T2DM patients, and may be better than currently available monotherapies in maintaining glycemic control over the long term.