New Phase III Data Showed Dapagliflozin Significantly Reduced HbA1c Compared to Placebo at 24 Weeks
September 24, 2013
New Phase III Data Showed Dapagliflozin Significantly Reduced HbA1c Compared to Placebo at 24 Weeks in Patients with Type 2 Diabetes Inadequately Controlled with the Combination of Metformin Plus Sulfonylurea
- Dapagliflozin added to metformin plus sulfonylurea demonstrated significantly greater improvements in HbA1c from baseline compared to placebo
- Significantly more patients treated with dapagliflozin achieved goal HbA1c levels of less than 7%, a key secondary endpoint
- Among other key secondary endpoints, dapagliflozin showed significant reductions in fasting plasma glucose and body weight at 24 weeks, and systolic blood pressure at 8 weeks
- Overall rates of adverse events were similar between the two treatment groups, and most were reported as mild or moderate in intensity
WILMINGTON, Del. & PRINCETON, N.J.--(BUSINESS WIRE)-- AstraZeneca (NYS: AZN) and Bristol-Myers Squibb Company (NYS: 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.
About Diabetes
In 2012, diabetes was estimated to affect more than 370 million people worldwide. The prevalence of diabetes is projected to reach more than 550 million by 2030. Type 2 diabetes accounts for approximately 90% to 95% of all cases of diagnosed diabetes in adults. Type 2 diabetes is a chronic disease characterized by insulin resistance and dysfunction of beta cells in the pancreas, leading to elevated glucose levels. Over time, this sustained hyperglycemia contributes to further progression of the disease. Significant unmet needs still exist, as many patients remain inadequately controlled on their current glucose-lowering regimen.
About the AstraZeneca/Bristol-Myers Squibb Diabetes Alliance
Dedicated to addressing the global burden of diabetes by advancing individualized patient care, AstraZeneca and Bristol-Myers Squibb are working in collaboration to research, develop and commercialize a versatile portfolio of innovative treatment options for diabetes and related metabolic disorders that aim to provide treatment effects beyond glucose control. Find out more about the Alliance and our commitment to meeting the needs of health care professionals and people with diabetes at www.astrazeneca.com or www.bms.com.
About AstraZeneca
AstraZeneca is a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of cardiovascular, metabolic, respiratory, inflammation, autoimmune, oncology, infection and neuroscience diseases. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information please visit: www.astrazeneca.com.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol-Myers Squibb, visit www.bms.com or follow us on Twitter at http://twitter.com/bmsnews.
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