Dapagliflozen Study Demonstrated Significantly Improved Glycemic Control and Weight Reduction in Type 2 Diabetes Patients Inadequately Controlled with Metformin

Results from a 24-week phase 3 clinical study demonstrated that the investigational drug dapagliflozin, added to metformin, demonstrated significant mean reductions in the primary endpoint, glycosylated hemoglobin level (HbA1c) and in the secondary endpoint, fasting plasma glucose (FPG) in patients with type 2 diabetes inadequately controlled with metformin alone, as compared to placebo plus metformin. Dapagliflozin is a novel, selective, sodium glucose co-transporter 2 (SGLT2) inhibitor, currently in Phase 3 trials under joint development by Bristol-Myers Squibb Company and AstraZeneca. The study also showed that individuals receiving dapagliflozin had statistically greater mean reductions in body weight compared to individuals taking placebo. Results from the 24-week study were presented at the 45th European Association for the Study of Diabetes Annual Meeting. This is the first public presentation of dapagliflozin Phase 3 data.

Dapagliflozin, an investigational compound, is a potential first-in-class SGLT2 inhibitor currently in Phase 3 trials under joint development as a once-daily oral therapy for the treatment of type 2 diabetes. SGLT2 inhibitors facilitate the elimination of glucose by the kidney, thereby returning serum glucose levels towards normal.



“Given the continued rising prevalence of type 2 diabetes, development of novel treatments such as SGLT2 inhibitors are needed to help improve glycemic control. The preliminary data on weight loss and blood pressure may be important adjuvants to glycemic control, said Cliff Bailey, Professor of Clinical Science and Head of Diabetes Research at Aston University, Birmingham, UK. “We look forward to additional data from pivotal dapagliflozin studies which will explore the potential benefits of this new class of medicine for type 2 diabetes patients.”



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About the Study

The study was designed to assess the efficacy and safety of dapagliflozin as an add-on to metformin over 24 weeks in patients with inadequately controlled type 2 diabetes. The data represent findings from a randomized, double-blind, placebo-controlled study of 546 individuals with type 2 diabetes (ages 18 –77) whose HbA1c was greater than or equal to 7.0 percent and less than or equal to 10 percent at baseline. After a two-week lead-in phase, individuals were randomized to one of four separate treatment arms: dapagliflozin 2.5 mg (n= 137), dapagliflozin 5 mg (n= 137), dapagliflozin 10 mg (n= 135), or placebo (n= 137). Patients in all arms also received metformin (greater than or equal to 1500 mg/d). The primary endpoint of the study compared mean HbA1c change from baseline for each dapagliflozin treatment arm compared to placebo after 24 weeks. Secondary endpoints included change from baseline in FPG and body weight at week 24 as compared to placebo, and adjusted percentage of individuals treated with dapagliflozin who achieved HbA1c of less than 7 percent at 24 weeks. Exploratory endpoints included body weight decrease of greater than or equal to 5 percent or greater than or equal to 10 percent as well as body weight percent change from baseline. The study includes an extension phase for a total duration of two years.



Study Results

After 24 weeks, individuals receiving dapagliflozin 2.5 mg, 5 mg and 10 mg plus metformin demonstrated a statistically significant adjusted mean change in HbA1c from baseline of -0.67 percent, -0.70 percent and -0.84 percent, respectively, compared to -0.30 percent for placebo (p-value less than 0.0005 for all treatment arms). Individuals treated with dapagliflozin demonstrated a statistically significant adjusted mean change in FPG, a secondary endpoint, from baseline at Week 24: -17.8 mg/dL for dapagliflozin 2.5 mg -21.5 mg/dL for dapagliflozin 5 mg and -23.5 mg/dL /dl for dapagliflozin 10 mg, compared to -6.0 mg/dL for placebo (p-value less than 0.005 for all treatment arms).



The adjusted percentage of individuals treated with dapagliflozin who achieved HbA1c of less than 7 percent at 24 weeks, a secondary endpoint, was 33.0 percent for dapagliflozin 2.5 mg, not significant (p-value 0.1775), 37.5 percent for dapagliflozin 5 mg, and 40.6 percent for dapagliflozin 10 mg statistically significant (both p-values less than 0.05) compared to 25.9 percent for placebo.



The study also evaluated the potential impact of dapagliflozin on weight loss. These findings included data measuring changes in total body weight over the 24-week study period. At 24 weeks, the change in total body weight in kg, a secondary endpoint, was -2.21 kg for dapagliflozin 2.5 mg, -3.04 kg for dapagliflozin 5 mg and -2.86 kg for dapagliflozin 10 mg, compared to -0.89 kg for placebo (p-values less than 0.0001). Overall, more patients taking dapagliflozin achieved weight losses greater than or equal to 5 percent compared to placebo, an exploratory endpoint (24 percent for dapagliflozin 2.5 mg, 25.4 percent for dapagliflozin 5 mg, 28.0 percent for dapagliflozin 10 mg, compared to 5.9 percent for placebo).



Generally, adverse events were balanced across all groups. Overall, the number of individuals reporting at least one adverse event for dapagliflozin 2.5 mg, dapagliflozin 5 mg, dapagliflozin 10 mg, and placebo were 89, 95, 98 and 88, respectively. Rates of urinary tract infections were similar for dapagliflozin 2.5 mg, 5 mg, 10 mg and placebo [4.4 percent, 7.3 percent, 8.1 percent and 8.0 percent, respectively]. Rates of genital infections were higher for 2.5 mg, 5mg and 10 mg the dapagliflozin treatment arms compared to placebo [8.0 percent, 13.1 percent, 8.9 percent, and 5.1 percent, respectively]. Genital tract infections were mild or moderate in nature and did not lead to discontinuation from the study. There were no clinically meaningful changes in markers for renal impairment, increases in mean serum creatinine, or increases in electrolyte abnormalities associated with dapagliflozin therapy.



The number of reported hypoglycemic events was similar across all treatment arms: 2.2 percent for dapagliflozin 2.5 mg, 3.6 percent for dapagliflozin 5 mg, 3.7 percent for dapagliflozin 10 mg and 2.9 percent for placebo. There was no occurrence of hypoglycemia that led to discontinuation of the study.



Reductions in blood pressure were observed without associated signs of hypotension. Changes in blood pressure at week 24 ranged from -3.1 to -5.9 systolic/-2.1 to -2.7 diastolic mmHg with dapagliflozin, compared to -0.3 systolic/-0.4 diastolic mmHg with placebo. A similar proportion of patients across all treatment arms, including placebo, had measured orthostatic hypotension.



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 a collaboration in January 2007 to develop and commercialize select investigational drugs for type 2 diabetes. These therapies address two key pathways in managing type 2 diabetes and seek to expand the range of current and future therapeutic options. Our collaboration is dedicated to global patient care, improving patient outcomes and creating a new vision for the treatment of patients living with type 2 diabetes.



About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company committed to discovering, developing and delivering innovative medicines that help patients prevail over serious diseases. For more information, please 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.