Type 2 Diabetes Patients Treated With Dapagliflozin Show Dose-Dependent Glycaemic Changes: Presented at ACCP

To print: Select File and then Print from your browser's menu
---------------------------------------------------------------------------------------
Title: Type 2 Diabetes Patients Treated With Dapagliflozin Show Dose-Dependent Glycaemic Changes: Presented at ACCP
URL: http://www.pslgroup.com/dg/22C7EA.htm
Doctor's Guide
September 16, 2008

By Crina Frincu-Mallos, PhD

PHILADELPHIA -- September 16, 2008 -- Use of dapagliflozin in patients with type 2 diabetes appears to have a dose-dependent effect on levels of glycosylated haemoglobin (Hb A1C) and fasting plasma glucose (FPG) levels, researchers reported here at the American College of Clinical Pharmacology (ACCP) 37th Annual Meeting

Dapagliflozin, a highly selective inhibitor of sodium glucose co-transporter 2 (SGLT2), is currently being investigated in clinical trials on diabetic patients.

Yan Feng, PhD, Strategic Modeling & Simulation, Pharmaceutical Research Institute, Bristol-Myers Squibb, Princeton, New Jersey, and colleagues studied the relationships between exposure of these patients with type 2 diabetes to dapagliflozin and efficacy outcomes.

The SGLT2 is located almost exclusively in the kidney and is thought to be responsible for approximately 90% of renal glucose reabsorption in the proximal tubule.(1)

Dr. Feng and colleagues sought to characterise the relationship between patients' exposure to dapagliflozin and glycaemic efficacy outcomes.

A secondary objective of the study was to evaluate the covariate effects on exposure-efficacy outcome modelling parameters, that is, FPG and Hb A1C levels, as well as the patient's age, body mass index, and gender, explained Dr. Feng in a presentation on September 14.

An exposure model was developed using dapagliflozin plasma concentration data from 1,823 blood samples collected from 270 patients participating in 2 studies. The dose regimen was 2.5 to 50 mg daily administered orally, for a total of 12 weeks.

At baseline, patients were a mean of 54.8 years old (range, 18-79 years) and the male-to-female ratio of the cohort was 1:1. Hb A1C level was between 7% and 10% prior to exposure to the drug.

Patients were randomised to dapagliflozin (2.5, 5, 10, 20, or 50 mg/day), placebo, or metformin XR 750 mg/day. After 12 weeks of treatment, the study medication was discontinued and patients were followed up for 4 weeks.

Change in Hb A1C and FPG from baseline to the end of the 12-week treatment period was used as efficacy data for exposure-efficacy outcome analysis. Individual estimated area under the concentration curve (AUC) at steady state was taken as exposure measurement, said Dr. Feng. Linear and dose-response models were used to assess the exposure-outcome relationships.

A total of 270 observations of Hb A1C changes from baseline and 244 observations of FPG changes from baseline were available for analysis.

Median steady-state AUC values by dose of dapagliflozin administered were: 124 ng.hr/mL in the arm treated with dapagliflozin 2.5 mg; 261 ng.hr/mL at dapagliflozin 5 mg; 466 ng.hr/mL at 10 mg of the drug; 967 ng.hr/mL at 20 mg; and 2,447 ng.hr/mL at 50 mg.

The impact of baseline Hb A1C on the Hb A1C response was more pronounced in all 5 arms of dapagliflozin administration relative to the placebo arm. "The higher the baseline, the greater the Hb A1C response," said Dr. Feng.

In addition, the predicted maximal Hb A1C changes from baseline at week 12 were -0.69% and -1.2% in patients with baseline Hb A1C values of 8.0% and 9.0%.

Looking at glucose levels, the researchers said that the predicted maximal FPG changes from baseline at week 12 were -21.5 mg/dL and -48.5 mg/dL in patients with baseline FPG values of 150 mg/dL and 200 mg/dL, respectively.

Based on these data, the investigators concluded that Hb A1C and FPG levels at baseline are significant covariates for the modelled efficacy outcomes, according to Dr. Feng and colleagues.

Funding for this study was provided by Bristol-Myers Squibb.

1. Kanai Y et al. J Clin Invest. 1994;93:397-404.

[Presentation title: Dapagliflozin, a Novel, Selective Inhibitor of SGLT2, Exhibits Exposure-Dependent Changes in Glycemic Parameters in Patients With Type 2 Diabetes Mellitus. Abstract 69]

http://www.docguide.com

Return to News Story Page

webmaster@pslgroup.com