Model-based characterization of the relationship between dapagliflozin systemic exposure and HbA1c response in patients with type 1 diabetes mellitus

Abstract

Aims: To quantitatively describe the relationship between dapagliflozin systemic exposure and HbA1c response among patients with type 1 diabetes mellitus (T1DM) and assess the potential impact of covariate effects.

Materials and methods: Individual longitudinal HbA1c data from two phase 3 studies in patients with T1DM (24-week treatment with once-daily dapagliflozin 5 or 10 mg or placebo, with adjustable insulin) were analyzed using a non-linear mixed effect modeling approach. Area under the concentration curve was used to measure dapagliflozin systemic exposure. Baseline HbA1c, estimated glomerular filtration rate, reduction in total insulin dose, baseline glucose concentrations, age, sex, race (Asian vs. non-Asian), and insulin administration method (multiple daily injections vs. insulin pump) were assessed as covariates.

Results: A maximum effect (E_max ) model identified a positive exposure-response relationship. Model-predicted placebo-corrected HbA1c reductions after 24 weeks for dapagliflozin 5- and 10-mg doses were - 0.42% [95% confidence interval (CI) -0.47 to -0.36) and - 0.45% (95% CI -0.50 to -0.40), respectively; baseline HbA1c was ~8.4%. This was in good agreement with actual observations from both studies. Baseline HbA1c was a significant covariate: patients with higher baseline HbA1c were predicted to have greater HbA1c reductions.

Conclusions: The relationship between dapagliflozin systemic exposure and HbA1c response was successfully described in patients with T1DM. None of the tested covariates affected the efficacy of dapagliflozin to a clinically relevant extent. Therefore, no dose adjustment of dapagliflozin is required in patients with T1DM based on the tested covariates. ClinicalTrials.gov, NCT02268214; NCT02460978.

Keywords: dapagliflozin; dose-response; exposure-response; type 1 diabetes mellitus.

Figure 1

Mean placebo‐corrected change in HbA1c from baseline over time during treatment with dapagliflozin (A) 5 mg and (B) 10 mg in patients with T1DM or T2DM. The plots show mean last observation carried forward data from the two T1DM studies (NCT02460978 and NCT02268214) and four T2DM studies (NCT00528879, NCT00683878, NCT00680745 and NCT00673231). Details of the T2DM studies, including the type of background medication used and baseline HbA1c for each treatment arm, are presented in Table S3. Abbreviations: T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus

Figure 2

(A) Model‐predicted exposure–response and (B) derived dose–response relationship for HbA1c reduction with dapagliflozin at week 24. Solid lines and shaded areas correspond to the mean model prediction with 95% CI. The prediction was calculated using baseline HbA1c of 8.4%. Density curves on the exposure–response plot (dashed/dotted lines on the bottom of the plot) correspond to the actual distribution of dapagliflozin exposure (steady‐state AUC range used in the analysis) for 5‐ and 10‐mg doses (dashed and dotted lines, respectively), based on individual AUC data from both clinical studies. The actual clinical HbA1c data on the dose–response plot (mean change from baseline, based on a mixed model, with 95% CI) are shown as data points. Abbreviations: AUC, area under the dapagliflozin plasma concentration curve; CI, confidence interval; T1DM, type 1 diabetes mellitus

Figure 3

Forest plot showing covariate effect on model‐predicted dapagliflozin HbA1c efficacy, represented as E_max ratio. The solid vertical line corresponds to the reference individual: T1DM patient with baseline HbA1c of 8.4%. E_max in patients with lower and higher baseline HbA1c was compared with the reference individual with HbA1c baseline of 8.4%; the symbols represent the median model predicted E_max ratio and the whiskers represent the 95% CI