Dapagliflozin is an inhibitor of the human renal sodium glucose co-transporter type 2 (SGLT2), which lowers plasma glucose by promoting urinary glucose excretion. Dapagliflozin is approved for the treatment of type 2 diabetes mellitus in adults. The effect of dapagliflozin in type 1 diabetes mellitus (T1DM) has been evaluated in 2 clinical trials: DEPICT 1 and DEPICT 2 (NCT02268214 and NCT02460978). The aim of this analysis was to use pooled data from both studies and assess the dose-response (DR) and exposure-response (ER) relationship for dapagliflozin on HbA1c reduction in T1DM patients. In both studies, T1DM patients underwent double-blinded 24-week treatment with either placebo, 5 or 10 mg dapagliflozin doses—plus adjustable insulin. Mixed-Effect Model Repeated Measures including DR/ER functions was used to describe the longitudinal HbA1c data. The DR and ER models described the data from T1DM patients well. DR model predicted HbA1c mean (95% CI) reductions at week 24 (placebo-corrected change from baseline) in T1DM patients to: -0.38% (-0.46, -0.3) and -0.43% (-0.52, -0.35) for 5 mg and 10 mg doses, respectively, which was in good agreement with the actual observations (-0.42% and -0.37% for 5 mg and -0.45% and -0.42% for 10 mg in DEPICT 1 and DEPICT 2 studies, respectively). The estimated ED50 was 1.39 mg and AUC50 (exposure resulting in half maximal effect) was 35.56 ng/ml*h. The effect of several covariates was assessed and the method of insulin administration was found to have an impact on dapagliflozin efficacy in T1DM patients. According to the model, patients who were using insulin pump were predicted to have somewhat larger HbA1c reductions compared to patients who used multiple daily injections. For example, following 10 mg dapagliflozin treatment, patients using pump were predicted to have mean HbA1c reduction of -0.47%, compared to -0.39% in patients without the pump. The difference in the maximum HbA1c reductions was however only approximately 20% and was not deemed to be clinically relevant.
J.R. Parkinson: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. J. Melin: Employee; Self; AstraZeneca. M. Åstrand: Employee; Self; AstraZeneca. B. Hamren: Employee; Self; AstraZeneca. Employee; Spouse/Partner; AstraZeneca. D.W. Boulton: Employee; Self; AstraZeneca. Stock/Shareholder; Self; Bristol-Myers Squibb Company. W. Tang: Employee; Self; AstraZeneca.
