Patient Characteristics are not Associated with Clinically Important Differential Response to Dapagliflozin: a Staged Analysis of Phase 3 Data

Introduction: This study aimed to determine if data mining methodologies could identify reproducible predictors of dapagliflozin-specific treatment response in the phase 3 clinical program dataset. Methods: Baseline and early treatment response variables were selected and data mining used to identify/rank all variables associated with reduction in glycated hemoglobin (HbA(1c)) at week 26. Generalized linear modeling was then employed using an independent dataset to identify which (if any) variables were predictive of dapagliflozin-specific treatment response as compared with treatment response in the study's control arm. The most parsimonious (i.e., simplest) model was validated by meta-analysis of nine other trials. This staged approach was used to minimize risk of type I errors. Results: From the large dataset, 22 variables were selected for model generation as potentially predictive for dapagliflozin-specific reduction in HbA(1c). Although baseline HbA(1c) was the variable most strongly associated with reduction in HbA(1c) at study end (i.e., the best prognostic variable), baseline fasting plasma glucose (FPG) was the only predictive dapagliflozin-specific variable in the model. Placebo-adjusted treatment effect of dapagliflozin plus metformin vs. metformin alone for change in HbA(1c) from baseline was -0.65% at the average baseline FPG of 192.3 mg/dL (10.7 mmol/L). This response changed by -0.32% for every SD [57.2 mg/dL (3.2 mmol/L)] increase in baseline FPG. Effect of baseline FPG was confirmed in the meta-analysis of ninestudies, but the magnitude was smaller. No other variable was independently predictive of a dapagliflozin-specific reduction in HbA(1c). Conclusions: This methodology successfully identified a reproducible baseline predictor of differential response to dapagliflozin. Although baseline FPG was shown to be a predictor, the effect size was not of sufficient magnitude to suggest clinical usefulness in identifying patients who would uniquely benefit from dapagliflozin treatment. The findings do support potential benefit for dapagliflozin treatment that is consistent with current recommended use.