Evaluation of the Long-term Durability and Glycemic Control of FPG and HbA1c for Pioglitazone in Japanese Patients with Type 2 Diabetes

Aim: Application of a model-based approach to evaluate long term durability and glycemic control of pioglitazone in comparison to other oral glucose-lowering drugs in Japanese type 2 diabetes mellitus (T2DM) patients. Methods: Japanese T2DM patients were enrolled in a prospective, randomized, open-label, blinded-endpoint study and received pioglitazone ± other oral glucose-lowering drugs (excluding another thiazolidinedione (TZD)) (n=293) or oral glucose-lowering drugs excluding TZD (n=294). Treatment was adjusted to achieve HbA1c<6.9% and samples for FPG and HbA1c were collected over 2.5-4 years. A simultaneous cascading indirect response model structure was applied to describe the time course of FPG and HbA1c. HbA1c levels were described using both an FPG-dependent and an FPG-independent function. To account for titration, drug effects for both treatment groups were implemented using a time dependent Emax model. Results: Pioglitazone was superior in both time to maximum effect and the magnitude of reduction achieved in FPG and HbA1c. Greater reduction (2-fold) in FPG was observed with pioglitazone compared to the control group. Maximum drug effect for FPG was predicted to occur earlier (11 months) for pioglitazone than the control group (14 months). The simulated additional reduction in FPG and HbA1c achieved with pioglitazone was predicted to be maintained beyond the currently observed study duration. Conclusion: Pioglitazone was found to result in improved glycemic control and durability compared to control treatment. This model-based approach enabled the quantification of differences in FPG and HbA1c for both treatment groups and simulation to evaluate longer term durability on FPG and HbA1c. Introduction The prevalence of diabetes in Japan has been increasing over the past two decades, primarily driven by lifestyle changes [1,2]. There will be an estimated number of diabetes cases in Japan of 8.9 million by the year 2030, following the same trend as other Asian countries [3]. Epidemiological studies have established that hyperglycemia is a significant risk factor for the development of cardiovascular disease (CVD) [4,5]. Japanese type 2 diabetes mellitus (T2DM) subjects have been shown to have a three-fold higher risk for CVD than non-diabetic subjects and the Ministry of Health, Labour and Welfare in Japan has now identified diabetes as a healthcare priority [1]. Current guidelines in Japan recommend achieving a target HbA1c <7.0% to inhibit the progress of and prevent the onset of macrovascular disease [6]. There are currently seven groups of oral agents currently used in Japan: Sulfonylurea drugs, fast-acting insulin secretion stimulators (glinides), biguanides, thiazolidines (TZD), alpha-glucosidase inhibitors, dipeptidyl peptidase-4 inhibitors, and sodium glucose cotransporter-2 inhibitors [7]. However there are differences in the usage patterns compared to North America and Europe [1]. Furthermore the underling pathology of T2DM was found to be different between Japanese and Caucasian subjects [8,9]. In comparison to Caucasians, Japanese are unable to compensate insulin resistance with increased insulin secretion to the same extent. A recent study identified body composition as the major determinant for these pathophysiological differences between Japanese and Caucasian T2DM subjects [9]. As a result of differences in glycemic targets and in the pathophysiological features of diabetes, treatment guidelines in Japan differ from those in Western countries [7]. T2DM is a slowly progressing disease and glycemic deterioration is predominantly due to insulin resistance and beta-cell failure [10]. Currently there are no available therapies that can completely stop the progressive loss of glycemic control, although different therapies can delay the extent of this loss by different degrees [11]. To evaluate this further, determination of a coefficient of failure (which is the slope obtained by performing regression analysis) was proposed as an approach to assess beta-cell failure from any index of glycaemia [12]. Further extension of this approach can be undertaken using pharmacokinetic-pharmacodynamic Chapter 6