Janna K Duong (1,2), Katia M Verhamme (1), Teun Post (3), Willem de Winter (4), Nele Plock (5), Himanshu Naik (5), Walter Krauwinkel (6), Miriam C Sturkenboom (1), Bruno H Stricker (7,8), Meindert Danhof (2).
(1) Department of Medical Informatics, Erasmus Medical Centre, Rotterdam, The Netherlands; (2) Leiden Academic Centre for Drug Research, Division of Pharmacology, Leiden, The Netherlands; (3) Pharmacokinetics, Pharmacodynamics & Drug Metabolism (PPDM), Merck Research Laboratories, Merck Sharp & Dohme, The Netherlands; (4) Janssen Research and Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium; (5) Global Pharmacometrics, Takeda Pharmaceuticals International, Zurich, Switzerland and Deerfield, USA; (6) Global Clinical Pharmacology and Exploratory Development, Astellas Pharma Europe BV, Leiden, The Netherlands; (7) Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands; (8) Drug Safety Unit, The Health Care Inspectorate, The Hague, The Netherlands.
Objectives: Type 2 diabetes mellitus (T2DM) is by insulin resistance and deficient insulin secretion by pancreatic beta cells. Antidiabetic medications are used to restore glucose-insulin homeostasis, but it is unknown whether these medications alter i)the disease progression, and ii)therapeutic outcome (cardiovascular morbidity and mortality). A number of semi-mechanistic models has been proposed to describe disease progression in T2DM, in terms of the change in insulin sensitivity (also in relation to weight change) and the loss of beta cell function with disease progression [1,2]. In theory, these models constitute a scientific basis to differentiate between the symptomatic and the disease modifying effects of antidiabetic medications. These models have been developed solely based on the analysis of data from clinical trials and has not led to firm conclusions with regard to the eventual disease modifying effects of antidiabetic medications. Moreover, these models have not been applied to data from the real life population. Consequently, the effect on therapeutic outcome, in terms of cardiovascular morbidity and mortality, is unknown. The objective of this research is to mechanistically investigate the association between the use of anti-diabetic medications, their effects on glucose-insulin homeostasis and ultimately cardiovascular outcomes in the real-life situation.
Methods & Results: Firstly, an overview of the available glucose-insulin homeostasis and T2DM disease progression models will be prepared to select the most optimal model. Secondly, the effect of treatment on glucose-insulin dynamics will be explored in the clinical trial population using data from drug-naïve patients receiving antidiabetic medications (metformin, gliclazide, pioglitazone). The third step will be the application of this model to longitudinal data from the real life population, the Rotterdam Study [3]. Additionally, using a case-controlled study design, a preliminary analysis on the association of various covariates (including also sex, age, creatinine clearance, total cholesterol/HDL ratio and systolic blood pressure) with the risk of developing cardiovascular morbidity and mortality (incident myocardial infarction) will be performed in subjects treated either with metformin, sulphonylureas and insulin.
Conclusions: The ultimate goal is the interfacing of the mechanism-based disease progression model with the epidemiological model to assess the effect of drug treatment on the therapeutic outcome in the real life population.
References:
[1] Choy S, Kjellsson MC, Karlsson MO, de Winter W. A novel model using weight change to describe the disease progression of type 2 diabetes [abstract #216]. Paper presented at the Proceedings of the Annual Scientific Meeting – Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists (ASCEPT), December 1-4, 2013 (pp. 65), Melbourne, Australia.
[2] de Winter W, De Jongh J, Post T, 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. Journal of pharmacokinetics and pharmacodynamics 2006; 33: 313-43.
[3] Hofman A, van Duijn CM, Franco OH et al. The Rotterdam Study: 2012 objectives and design update. European journal of epidemiology 2011; 26(8):657-86.
Reference: PAGE 23 () Abstr 3080 [www.page-meeting.org/?abstract=3080]
Poster: Drug/Disease modeling - Endocrine