Dapagliflozin Study Demonstrated Improved Glycemic Control In Type 2 Diabetes Patients Treated With High Doses of Insulin and Common Oral Anti-Diabetic Medicines

Update: Farxiga (dapagliflozin) Now FDA Approved - January 8, 2014

PRINCETON, N.J. & WILMINGTON, Del.--(BUSINESS WIRE)--Jun 6, 2009 - Results from a 12-week study demonstrated that the investigational drug dapagliflozin, a novel, selective, sodium glucose co-transporter 2 (SGLT2) inhibitor, produced greater improvements across all key glycemic measures studied [glycosylated hemoglobin level (HbA1c), fasting plasma glucose (FPG) and post-prandial glucose (PPG)] in type 2 diabetes patients who were treated with high doses of insulin and commonly used oral anti-diabetes medications (OADs), compared to placebo (placebo plus OADs plus insulin). Overall adverse events across the dapagliflozin treatment arms were reported at a similar rate to placebo. The study also showed that individuals receiving dapagliflozin had greater reductions in body weight compared to individuals taking placebo, and support the findings from a previous 12-week, Phase 2b study. Results from the 12-week study were presented at the 69th American Diabetes Association Annual Scientific Sessions.

Dapagliflozin is an investigational SGLT2 inhibitor currently in Phase 3 trials under joint development by Bristol-Myers Squibb Company (NYSE: BMY) and AstraZeneca (NYSE: AZN) as a once-daily therapy for the treatment of type 2 diabetes. SGLT2 facilitates the reabsorption of glucose in the kidney, thereby returning filtered glucose to the circulation.

“Currently, more than 20 percent of individuals with type 2 diabetes are treated with insulin, and significant proportions of patients are unable to adequately control their blood sugar despite high doses of insulin,” said John Wilding, DM, FRCP, Professor of Medicine & Honorary Consultant Physician, Head of Diabetes and Endocrinology Clinical Research Unit, University Hospital Aintree (UK). “The results presented today on glycemic and weight parameters suggest that further study of dapagliflozin in this patient population is warranted.”

About the Study

The study was designed to assess the efficacy and safety of dapagliflozin in patients with inadequately controlled type 2 diabetes, despite treatment with at least 50 units of U100 insulin per day plus one or two baseline OADs (at least 1000 mg of metformin and/or at least 30 mg of pioglitazone or 4 mg of rosiglitazone). The data represent findings from a randomized, double-blind, placebo-controlled study of 71 individuals with type 2 diabetes (ages 18 –75) whose HbA1c was greater than or equal to 7.5 percent and less than or equal to 10 percent. Individuals were randomized to one of three separate treatment arms: dapagliflozin 10 mg (n= 24), dapagliflozin 20 mg (n= 24) or placebo (n= 23), given once daily. Baseline OAD doses were maintained during the study but initial insulin doses in all study participants were reduced to 50 percent of each individual's daily baseline dose to reduce the risk of hypoglycemia. The primary endpoint of the study compared mean HbA1c change from baseline for each dapagliflozin treatment arm compared to placebo. The secondary endpoints included proportion of individuals achieving the American Diabetes Association recommended HbA1c target of less than 7 percent, proportion of patients achieving HbA1c decrease from baseline of at least 0.5 percent and FPG change from baseline as compared to placebo. Changes in body weight were also assessed.

Study Results

After 12 weeks, individuals receiving dapagliflozin demonstrated an adjusted mean decrease in HbA1c from baseline of 0.61 percent for dapagliflozin 10 mg and 0.69 percent for dapagliflozin 20 mg, compared to an increase of 0.09 percent for placebo.

The percentage of individuals treated with dapagliflozin that achieved HbA1c of less than 7 percent after the 12-week treatment period was 13 percent for dapagliflozin 10 mg and 4.3 percent for dapagliflozin 20 mg, compared to 5.3 percent for placebo. The percentage of individuals that achieved HbA1c decrease from baseline of at least 0.5 percent was 65.2 percent for dapagliflozin 10 mg and 65.2 dapagliflozin 20 mg, compared to 15.8 percent for placebo. The change from baseline in FPG at 12 weeks was +2.4 mg/dL for dapagliflozin 10 mg and -9.6 mg/dL for dapagliflozin 20 mg, compared to +17.8 mg/dL for placebo.

Overall adverse events across the dapagliflozin treatment arms were reported at a similar rate to placebo. The number of individuals reporting at least one adverse event for dapagliflozin 10 mg, dapagliflozin 20 mg, and placebo were 18, 16, and 15, respectively. The most commonly reported (greater than or equal to 5 percent overall) adverse events for dapagliflozin 10 mg, 20 mg and placebo were: urinary frequency (pollakiuria), back pain, nasopharyngitis, nausea, headache, and upper respiratory tract infection. Reported adverse events of special interest for dapagliflozin 10 mg, 20 mg and placebo, were urinary tract infection [0, 1, 0] and genital tract infection [0, 5, 1].

The number of reported hypoglycemic events was 7 for dapagliflozin 10 mg, 6 for dapagliflozin 20 mg, and 3 for placebo. There was no occurrence of major hypoglycemia (neurological symptoms of hypoglycemia such as confusion, fingerstick glucose less than or equal to 54 mg/dL and needing external treatment).

Effect of Dapagliflozin on Weight Loss

The study also evaluated the potential impact of dapagliflozin-induced glucosuria on weight loss in this type 2 diabetes patient population. These findings included data measuring changes in total body weight and body mass index over the 12-week study period.

Overall, greater decreases in body weight occurred in the dapagliflozin treatment groups: 4.51 kg for dapagliflozin 10 mg and 4.3 kg for dapagliflozin 20 mg, compared to 1.88 kg for placebo.

About Type 2 Diabetes

Diabetes (diabetes mellitus) is a chronic disease in which the body does not produce or properly use insulin (a hormone that is needed for the cells of the body to properly take up glucose). This leads to elevated blood glucose levels (hyperglycemia) that are sustained over time. Sustained hyperglycemia, the hallmark of diabetes, is associated with long-term complications that can affect almost every part of the body.

The genesis of diabetes continues to be investigated, and both genetic and environmental factors such as obesity and lack of exercise appear to play a role. There are two primary underlying causes associated with type 2 diabetes: the body does not produce enough insulin (insulin deficiency), and the cells are resistant to the effect of insulin (insulin resistance).

The kidneys play a key but underappreciated role in the overall regulation of blood glucose levels in the body. Normally, in healthy individuals, the kidneys filter a large volume of glucose and actively reabsorb virtually all of it. Glucose reabsorption is necessary to retain calories, but becomes counterproductive in type 2 diabetes. In patients with type 2 diabetes who have hyperglycemia, a greater amount of glucose is filtered and reabsorbed by the kidneys despite the fact that this retention process contributes to sustaining the hyperglycemia of diabetes.

Over time, sustained hyperglycemia leads to glucotoxicity, which worsens insulin resistance and contributes to dysfunction in the beta cells of the pancreas. The degree of sustained hyperglycemia is directly related to diabetic microvascular complications and may also contribute to macrovascular complications. In this way, hyperglycemia appears to perpetuate a vicious cycle of deleterious effects that exacerbate type 2 diabetes control and complications.

About SGLT2 Inhibitors

The kidney continuously filters glucose through the glomerulus; however, nearly all of this glucose is reabsorbed. A protein called SGLT2 is responsible for the majority of glucose reabsorption and helps the body retain glucose for its energy requirements. For patients with diabetes, retention of excess glucose by this pathway contributes to persistent hyperglycemia. Suppressing the activity of SGLT2 inhibits renal-glucose reabsorption in the body, thereby leading to the excretion of glucose in the urine

Bristol-Myers Squibb and AstraZeneca Collaboration

Bristol-Myers Squibb and AstraZeneca entered into collaboration in January 2007 to enable the companies to research, develop and commercialize two investigational drugs for type 2 diabetes – ONGLYZA and dapagliflozin. The Bristol-Myers Squibb/AstraZeneca diabetes collaboration is dedicated to global patient care, improving patient outcomes and creating a new vision for the treatment of type 2 diabetes.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to extend and enhance human life. For more information, visit www.bms.com.

About AstraZeneca

AstraZeneca is a major international healthcare business engaged in the research, development, manufacturing and marketing of meaningful prescription medicines and supplier for healthcare services. AstraZeneca is one of the world's leading pharmaceutical companies with healthcare sales of US $31.6 billion and is a leader in gastrointestinal, cardiovascular, neuroscience, respiratory, oncology and infectious disease medicines. For more information about AstraZeneca, please visit: www.astrazeneca.com.

Contact: Media:
Bristol-Myers Squibb
Ken Dominski, 609-252-5251
ken.dominski@bms.com
or
AstraZeneca
Jim Minnick, 302-886-5135
jim.minnick@astrazeneca.com
or
Investors:
Bristol-Myers Squibb
John Elicker, 609-252-4611
john.elicker@bms.com
or
AstraZeneca
Karl Hard, 44-20-7304-5322
karl.hard@astrazeneca.com

Posted: June 2009

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