New Phase III data showed Dapagliflozin significantly reduced HbA1c compared to placebo

AstraZeneca (NYSE: AZN) and Bristol-Myers Squibb Company (NYSE: BMY) today announced results from a Phase III study evaluating dapagliflozin in adult patients with type 2 diabetes who were inadequately controlled on combination treatment with metformin plus sulfonylurea. Patients treated with dapagliflozin 10 mg as an add-on therapy to metformin plus sulfonylurea demonstrated significant improvements in glycosylated hemoglobin levels (HbA1c) and, among key secondary endpoints, significant reductions in fasting plasma glucose (FPG) and in body weight compared to placebo at 24 weeks. Significant improvements were also observed in seated systolic blood pressure (SBP) at eight weeks in patients treated with dapagliflozin compared to placebo. The results were presented today at the 49th Annual Meeting of the European Association for the Study of Diabetes (EASD) in Barcelona, Spain.

In this study, overall rates of adverse events were similar between the two treatment groups, and most were reported as mild or moderate in intensity. More patients in the dapagliflozin group reported hypoglycemia, genital infection and renal adverse events compared to the placebo group. Rates of urinary tract infection were the same for both groups.

“The improvements in glycemic control combined with the significant reduction in body weight observed in this study add to the clinical profile of dapagliflozin, specifically when used as part of a triple oral therapy regimen with metformin and sulfonylurea,” said Stephan Matthaei, M.D., primary study investigator and director of the Diabetes and Metabolism Center, Quakenbrück Hospital, Quakenbrück, Germany.

Dapagliflozin is a selective and reversible inhibitor of sodium-glucose cotransporter 2 (SGLT2), which works independently of insulin. It is currently approved for the treatment of type 2 diabetes in the European Union, Australia, Brazil, Mexico and New Zealand. A resubmission of the New Drug Application (NDA) for dapagliflozin was accepted for review by the U.S. Food and Drug Administration (FDA) in July 2013 with a new Prescription Drug User Fee Act (PDUFA) goal date of January 11, 2014.

Study Results

At the end of 24 weeks, patients treated with dapagliflozin 10 mg added to metformin plus sulfonylurea demonstrated significantly greater improvements in glycemic control compared to those who received placebo, with a mean change from baseline in HbA1c of -0.86% (95% Confidence Interval [CI]: -1.00, -0.72) in the dapagliflozin group versus -0.17% (95% CI: -0.31, -0.02) in the placebo group (p-value < 0.0001). Additional results of the key secondary endpoints included the following:

• More patients treated with dapagliflozin (31.8%) achieved an HbA1c < 7.0% compared to patients who received placebo (11.1%) at week 24 (p-value < 0.0001).
• At week 24, patients treated with dapagliflozin showed significant improvements in adjusted mean FPG (-34.23 mg/dL; 95% CI: -40.98, -27.48) compared to patients who received placebo (-0.78 mg/dL; 95% CI: -7.56, 6.01; p-value < 0.0001).
• Patients treated with dapagliflozin experienced significant reductions in mean body weight (-2.65 kg; 95% CI: -3.16, -2.14) at week 24 compared to patients who received placebo (-0.58 kg; 95% CI: -1.09, -0.07; p-value < 0.0001).
• At week eight, patients treated with dapagliflozin had significant reductions in mean SBP (-4.04 mmHg) compared to patients who received placebo (-0.27 mmHg; p-value = 0.025).

Overall, 48.6% of patients in the dapagliflozin group and 51.4% of patients in the placebo group experienced ≥ 1 adverse events, most of which were reported as mild or moderate in intensity. Adverse events of special interest occurring during the 24 weeks included hypoglycemia (12.8% for dapagliflozin vs. 3.7% for placebo; no major episodes observed), urinary tract infection (6.4% for dapagliflozin vs. 6.4% for placebo), genital infection (5.5% for dapagliflozin vs. 0% for placebo) and renal adverse events (1.8% for dapagliflozin vs. 0% for placebo). One event of pyelonephritis was observed in the dapagliflozin group. One or more serious adverse events occurred in 0.9% of patients in the dapagliflozin group and 5.5% of patients in the placebo group. The overall profile of dapagliflozin in this trial is consistent with those seen in Phase II and III clinical trials for dapagliflozin.

Study Design

This 24-week Phase III, randomized, double-blind, placebo-controlled study with an ongoing 28-week extension is designed to evaluate the efficacy and safety of dapagliflozin in patients with type 2 diabetes with inadequate glycemic control on combination therapy with metformin plus sulfonylurea. The primary endpoint is mean change in HbA1c from baseline to week 24. Secondary endpoints include mean change from baseline to week 24 in FPG and total body weight, proportion of patients achieving HbA1c levels of < 7.0% at week 24 and change in SBP from baseline to week 8.

The study includes 216 adult patients with type 2 diabetes (aged ≥ 18 years) with inadequate glycemic control (HbA1c ≥ 7.0% and ≤ 10.5%) receiving metformin (≥ 1500 mg QD) and a maximum tolerated dose of sulfonylurea (at least half the maximum label dose for ≥ 8 weeks). Patients were randomized to receive dapagliflozin 10 mg (n = 108) or placebo (n = 108) for 24 weeks.

About SGLT2 Inhibition

The kidney plays an important role in maintaining normal glucose balance by filtering and reabsorbing glucose from circulation. SGLT2, a sodium-glucose cotransporter found predominantly in the kidney, is responsible for the majority of glucose reabsorption. In patients with type 2 diabetes, the capacity of the kidney to reabsorb glucose is increased by approximately 20%, further exacerbating the hyperglycemia associated with the disease. Selective inhibition of SGLT2 reduces the reabsorption of excess glucose and enables its removal via the urine.