Delayed response to hypoglycaemic agents and effect on progression of type 2 diabetes
Nick Holford (1), Jenny Chien (2), Vikram Sinha (2), David Manner (2), Michael Heathman (2), Jeanne Geiser (2)
(1) Dept of Pharmacology & Clinical Pharmacology, University of Auckland, Auckland, New Zealand; (2) Lilly Research Laboratories, Indianapolis, USA
Objectives: The modeling of time course of glucose and insulin changes during prolonged treatment with oral hypoglycaemic drugs has to consider disease progression mechanisms as well as drug action. De Winter et al. (1) proposed a mechanism-based model for changes in beta cell function and insulin potency during treatment with gliclazide (GLZ), metformin (MET) and pioglitazone (PIO). We have extended this model using up to 2 years of glucose and insulin observations from placebo, GLZ, MET and PIO treated patients.
Methods: The steady state solution to the modified HOMA (2) model for glucose-insulin regulation was used to describe glucose and insulin responses to changes in beta cell function (BF) and insulin potency (IP). The time course of BF and IP was described by an exponential decrease. Offset effects of GLZ, MET and PIO on BF and IP were estimated with an effect compartment model for the delay in onset of drug action. Slope effects on BF and IP progression were estimated assuming an immediate effect of each treatment. Parameter estimation used NONMEM VI level 1.3.
Results: Overall, baseline BF was 28% and baseline IP was 23% of HOMA values in normal subjects. BF decreased with a half-life ~ 17.6 years and IP ~ 6.2 years. All 3 drugs assumed both actions on offset and slope change for BF and IP. Offset effects on BF were delayed with effect half-lives of 3 (GLZ), 6 (MET) and 14 (PIO) weeks. Offset effect half lives for IP were 0.1 (GLZ), 21 (MET) and 14 (PIO) weeks. In comparison to PIO, GLZ and MET had marked effects on increasing loss of BF progression (at least 2 fold) (3). The 3 treatments had similar effects on IP progression.
Conclusions: Commonly used oral hypoglycaemic drugs have a slow onset of action explained by increasing beta cell function and enhancing insulin potency. There are marked differences in the speed of action with GLZ being most rapid. This model adequately described the time course of insulin and glucose for these treatments. In addition, the model distinguishes effects of these three drugs on BF and IP and changes in BF and IP. While additional work with this model is needed, disease progression models advance our understanding of progression of diabetes and the effects of pharmaceutical intervention.
 de Winter W, DeJongh J, Post T, Ploeger B, Urquhart R, Moules I, 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. 2006;33(3):313-43.
 Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28(7):412-9.
 Tan MH, Baksi, A, Krahulec B, Kubalski P, Stankiewicz A, Urquhart R, Edwards G and Johns D for the GLAL Study Group. Comparison of Pioglitazone and Gliclazide in Sustaining Glycemic Control Over 2 Years in Patients With Type 2 Diabetes. DiabetesCare. 2005;28(3):544-550.