Dapagliflozin is a new molecular entity in the antidiabetic class known as SGLT2 inhibitors. Through selective and reversible inhibition of SGLT2, dapagliflozin causes renal elimination of glucose. The magnitude of HbA1c reduction observed in the dapagliflozin clinical program is
relatively consistent across trials and similar to that of other recently approved antidiabetic drugs, including the SGLT2 inhibitor, canagliflozin. In addition to improvement in glycemic control, dapagliflozin produces modest reductions in body weight and systolic blood pressure. Consistent with the results of previous meta-analyses, the updated meta-analysis of major cardiovascular events in the pool of 21 Phase 2b and Phase 3 clinical trials included in this NDA resubmission
continues to meet the December 2008 Guidance, ruling out the unacceptable increase in CV risk of greater than 80% above comparator groups. Furthermore, divergence in the Kaplan-Meier curves, in favor of dapagliflozin, were observed for the primary CV composite endpoint after approximately eight months, suggesting potential benefit with prolonged use. However, there appears to be a numeric imbalance in early MACE events not favoring dapagliflozin. A similar
observation of an early imbalance in cardiovascular events was seen with canagliflozin, also not favoring canagliflozin. For dapagliflozin, discordant with the results of the updated meta­ analysis, a pool of two large, well-designed clinical trials enriched with individuals at high risks
for CV events—and in whom statistically significant reductions in HbA1c, systolic blood pressure, and body weight were observed—achieved a point estimate and upper bound 95% confidence interval for the hazard ratio of the composite MACE endpoint which exceeded 1 and
1.8, respectively. When considering efficacy of dapagliflozin, potential benefits should be balanced against credible safety concerns identified during clinical development. There continues to be a numeric
imbalance in cases of bladder cancer, not favoring dapagliflozin. An imbalance in bladder cancer events was not seen with canagliflozin. Additionally, a potential case of drug-induced liver
injury was observed during the first review cycle for which an association with dapagliflozin remains plausible. The Applicant has provided more than three years of follow-up data for this case to support a possible reclassification of the diagnosis. Overall, the occurrence of marked
liver laboratory test abnormalities remains relatively balanced between dapagliflozin and the comparator treatment arms.