Ellen Evbjer, Steve Choy, Mats O. Karlsson, Maria C. Kjellsson
Department of Pharmaceutical Biosciences, Uppsala University, Sweden
Background: Change in weight (WT) as a result of diet changes is closely associated with change in fasting plasma glucose (FPG) in type 2 diabetes mellitus (T2DM) patients. Exactly what this relationship depends on is unknown but two hypotheses are 1) weight loss induces a change in an intermediary effector that reduces FPG, or 2) an underlying change of the system that affects weight as well as FPG; the latter being driven by the intermediary effector. The intermediary effector in both hypotheses is presumed to be insulin sensitivity (IS) [1], and the underlying change of the system is thought to be the concentration of free fatty acids (FFA), which is known to affect IS [2]. The aim of this study was to implement and test these hypotheses using non-linear mixed effects modelling on summary level data from publications of weight loss and FPG with very low calorie diets (VLCD).
Methods: Summary level data was gathered from 8 clinical studies of diabetic patients treated with VLCD where weight as well as FPG was measured [3-10]. The studies consisted of 13 number of arms with varying number of subjects per arm (median = 8; range = 6-62), varying baseline weight (median = 106 kg; range = 93-118 kg), baseline FPG (median = 253 mg/dL; range = 91-321 mg/dL) with varying disease duration (median = 8.9 yrs; range = 0.8-13.3 yrs), treated with diets ranging from 330 to 909 kcal/day for a period of up to 224 days. Measurements of WT and FPG were taken regularly throughout the course of the studies. Non-linear mixed-effects modelling was performed using NONMEM 7.2 with the FOCEI method.
Results: Both weight and FPG was modelled using indirect response models. For hypothesis 1, the diet was implemented as an instantaneous inhibitory effect on the input of the weight model. The change in weight was then used to influence a mediator which was allowed to affect FPG by a stimulatory effect on the output. For hypothesis 2, the diet was implemented as a step model inhibiting the weight input and the mediator output. The same linear model was applied on both weight and FPG, as there were no evidence to suggest that the effect was non-linear. The objective function value for hypothesis 2 was significantly lower than for hypothesis 1 and the goodness-of-fit diagnostics also supported the model for hypothesis 2. The diet was estimated to reduce 32% of the Kin of weight and the Kout of IS,and the estimated Kout for WT and IS was 0.0147 and 0.216 day-1, respectively.
Conclusions: The model with an underlying mechanism that affects both weight and FPG was found to better describe the data than using weight loss as an effector on a mediator through which FPG is reduced.
References:
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Reference: PAGE 22 () Abstr 2937 [www.page-meeting.org/?abstract=2937]
Poster: Endocrine