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Dapagliflozin Provides Additional Benefit as Add-On to Sitagliptin

In earlier clinical trials dapagliflozin consistently reduced HbA1c in treatment-naive patients….

In this 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 study, researchers found that adding dapagliflozin to sitagliptin reduces hemoglobin (Hb)A1c levels in patients with type 2 diabetes, but is associated with more genital infections. Many patients with type 2 diabetes eventually require multiple agents to achieve their HbA1c targets. Unlike other oral antidiabetic agents, dapagliflozin, a selective inhibitor of sodium glucose cotransporter 2 (SGLT2 Inhibitor), reduces hyperglycemia independently of insulin secretion or action. In earlier clinical trials dapagliflozin consistently reduced HbA1c in treatment-naive patients, as add-on therapy to metformin, sulfonylurea, or pioglitazone, and in patients requiring insulin.

The authors of this study assessed the efficacy and safety of dapagliflozin in 451 patients whose HbA1c levels were not adequately controlled with sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor. Of the 225 patients randomized to dapagliflozin, 208 (92%) completed the 24-week double-blind period, and 202 (90%) completed an additional 24-week blinded extension. Two hundred twenty-six patients were assigned to placebo: 203 (90%) completed the first 24 weeks, and 185 (82%) completed the 24-week extension. By 24 weeks, HbA1c decreased by 0.6% more with dapagliflozin than with sitagliptin alone (p<0.0001) and by 0.4% more with dapagliflozin than with sitagliptin plus metformin (p=0.0001). Glycemic and weight benefits observed at week 24 were maintained through week 48. Adverse events were balanced between groups and discontinuation rates were low. At week 48, signs and symptoms suggestive of genital infection were more frequent with dapagliflozin (9.8%) than with placebo (0.4%). Signs and symptoms suggestive of urinary tract infection were balanced between dapagliflozin (6.7%) and placebo (6.2%).

Based on the results of this study, the researchers conclude that dapagliflozin may be an appropriate choice for a wide range of patients at different stages of type 2 diabetes, including those in the advanced stages of the disease with significantly compromised beta-cell function who are already receiving one or more (oral antidiabetic agents). Dapagliflozin is currently approved in Europe, but its initial new drug application (NDA) was rejected by the U.S. Food and Drug Administration because of concerns about its risk-benefit profile. The NDA was resubmitted in July 2013, and the FDA has until January 2014 to make a decision regarding its approval.

Practice Pearls:
  • Adding dapagliflozin to sitagliptin reduces HbA1c levels in patients with type 2 diabetes, but is associated with more genital infections.
  • By 24 weeks, HbA1c decreased by 0.6% more with dapagliflozin than with sitagliptin alone (p<0.0001) and by 0.4% more with dapagliflozin than with sitagliptin plus metformin (p=0.0001).
  • At week 48, signs and symptoms suggestive of genital infection were more frequent with dapagliflozin (9.8%) than with placebo (0.4%).

Diabetes Care, October, 2013