Treatment Efficacy of Combination-Therapy based on a Mechanistic Characterisation of Disease Processes in Type 2 Diabetes Mellitus over a two-year period
T.M. Post(1), W. de Winter(1), J. DeJongh(1, 2), I. Moules(3), R. Urquhart(3), D. Eckland(3) and M. Danhof(1, 2)
(1)LAP&P Consultants BV, Leiden, The Netherlands; (2)Leiden University, Leiden / Amsterdam Center for Drugs Research, Leiden, The Netherlands; (3)Takeda Europe Research and Development Centre, London, UK
Objective Type 2 Diabetes Mellitus (T2DM) is a chronic progressive disease in which specific disease processes (i.e. progressive decline in b-cell function and insulin sensitivity) result in loss of glycaemic control. Information regarding these processes facilitates differentiation between drug efficacies on a mechanistic basis. By modelling the homeostatic feedback relationship between insulin and fasting plasma glucose such process-information on the time-course of the b-cell function and insulin sensitivity can be derived. Recently, a mechanistic disease progression model was established which jointly characterizes the trajectories of insulin, fasting plasma glucose and HbA1c in relation to these specific disease processes. Treatments are incorporated into this comprehensive system at their corresponding target-site. In the current analysis this model was applied to evaluate the treatment effects on their ability to modify the disease processes in a new patient population of 1269 T2DM patients receiving combination-therapy during a period of two-years.
Methods and Results Two Phase III studies were analysed, with one study comparing the efficacy of pioglitazone to metformin in combination-therapy of patients inadequately controlled by sulphonylurea. The other study compared pioglitazone to gliclazide in combination-therapy of patients inadequately controlled by metformin. The T2DM mechanistic disease progression model was able to adequately capture the characteristics of these newly acquired results. To evaluate drug effects on disease progression, the specific disease processes under influence of combination therapy were analysed. It was found that the treatment groups involving pioglitazone and the treatment group concerning sulphonylurea with metformin as add-on showed an improvement in b-cell function throughout the two-year trial period. In contrast, the combination of gliclazide added to metformin showed a continuing decline in b-cell function after a largely symptomatic effect on this disease process. All treatment groups, except for that with gliclazide, showed a symptomatic effect on insulin sensitivity and pioglitazone added to metformin showed a significant protective effect to loss of insulin sensitivity as compared to the other treatment combinations.
Conclusions In conclusion, the mechanistic disease progression model enabled the charaterisation of the specific disease processes and the resulting biomarker dynamics in T2DM patients on combination-therapy over a period of two-years. Specifically, the model allowed the evaluation of combination-therapy efficacies on the time-course of the b-cell function and insulin sensitivity.