52-Week Phase 3 Study Found Investigational Dapagliflozin Plus Metformin
Similar to Glipizide Plus Metformin in Improving Glycosylated Hemoglobin
(A1c) in Adults with Type 2 Diabetes Mellitus

MONTREAL AND TORONTO, Sept. 24 /CNW/ - Bristol-Myers Squibb Canada and AstraZeneca Canada today announced results from a randomized, double-blind Phase 3 clinical study in adults with type 2 diabetes inadequately controlled on metformin therapy alone. The study demonstrated dapagliflozin was non-inferior compared to glipizide (sulphonylurea) in improving glycosylated hemoglobin levels (A1c) when added to existing metformin therapy.¹ The study also demonstrated that dapagliflozin plus metformin achieved significant reductions in key secondary endpoints: reduction in total body weight from baseline (-3.22 kg),² compared with a weight gain on glipizide plus metformin therapy (+1.44 kg)³ and a reduced number of patients reporting one or more hypoglycemic events.⁴ Treatments were titrated during the first 18 weeks, up to 10 mg/day for dapagliflozin plus metformin or 20 mg/day for glipizide plus metformin.⁵ Results from the study were presented at the 46^th European Association for the Study of Diabetes (EASD) Annual Meeting.

Overall, the frequencies of adverse events, serious adverse events and study discontinuations were similar across the two treatment groups;⁶ although signs, symptoms and other reports suggestive of urinary tract or genital tract infections were more common in dapagliflozin treated subjects.⁷

Dapagliflozin, an investigational compound, is a potential first-in-class sodium-glucose cotransporter-2 (SGLT2) inhibitor and is currently in Phase 3 trials under joint development by Bristol-Myers Squibb and AstraZeneca as a once-daily oral therapy for the treatment of adult patients with type 2 diabetes. SGLT2 inhibitors, which act independently of insulin mechanisms, facilitate the excretion of glucose, thereby lowering blood glucose levels.⁸

"Results of this Phase 3 study are quite promising and provide further evidence that SGLT2 inhibitors may offer unique benefits in the treatment of type 2 diabetes as an oral medication that effectively lowers A1c levels with a low incidence of hypoglycemia, and the potential for weight loss" said Dr. Lawrence Leiter, Division of Endocrinology and Metabolism, St. Michael's Hospital and Professor of Medicine at the University of Toronto.  "New therapies such as dapagliflozin may eventually lead to more options for physicians in the treatment of patients with type 2 diabetes."

About The Study

This Phase 3 study was designed to assess whether, after 52 weeks, the change from baseline in A1c level with dapagliflozin plus metformin was non-inferior to glipizide plus metformin in adult patients with type 2 diabetes who had inadequate glycemic control on 1500 mg/day or higher doses of metformin therapy alone.⁹ Non-inferiority was defined in the study protocol as a treatment group numerical difference in the A1c reduction of less than 0.35%¹⁰ for the upper limit of the two-sided 95% confidence interval [CI] when either dapagliflozin or glipizide were added to a stable dose of metformin.¹¹ Key secondary endpoints included the change from baseline in body weight and number of patients reporting hypoglycemic events at week 52.¹²

The study was a 52-week, multicenter, randomized, parallel-group, double-blind, active-controlled Phase 3 study, which included 814 adult patients with type 2 diabetes (aged ≥ 18) whose A1c was greater than 6.5% and less than or equal to 10% at baseline.¹³ Individuals were randomized to one of two treatment groups: dapagliflozin plus metformin (n=406; starting 2.5 mg per day) or glipizide plus metformin (n=408; starting 5 mg per day).¹⁴ For the first 18 weeks, study drugs were up-titrated as needed (dapagliflozin to less than or equal to 10 mg per day; glipizide to less than or equal to 20 mg per day).¹⁵

Study Results

Using the full analysis, after 52 weeks, individuals taking dapagliflozin plus metformin, compared to those taking glipizide plus metformin, achieved an identical adjusted mean reduction in A1c from baseline of -0.52%.¹⁶  Results of the study demonstrated that therapy with dapagliflozin was non-inferior to glipizide when added to existing metformin therapy (difference in adjusted mean change from baseline vs. glipizide as added to existing metformin therapy was 0.00%, 95% CI -0.11 to 0.11).¹⁷

The study also demonstrated that patients treated with dapagliflozin plus metformin achieved a statistically significant weight loss at 52 weeks when compared to those treated with glipizide plus metformin (-3.22 kg vs. +1.44 kg respectively; p-value less than 0.0001).¹⁸ Significantly more patients achieved a weight loss of greater than or equal to 5% from baseline with dapagliflozin plus metformin (33.3%) compared to glipizide plus metformin (2.5%; p-value less than 0.0001) at week 52.¹⁹

The number of individuals with any hypoglycemic event was significantly lower for patients treated with dapagliflozin plus metformin as compared to those treated with glipizide plus metformin (3.5% vs. 40.8% respectively; p-value less than 0.0001) at week 52.²⁰

The overall proportions of individuals experiencing adverse events after 52 weeks were similar between the two treatment groups: 78.3% for dapagliflozin plus metformin vs. 77.9% for glipizide plus metformin.²¹ The most common adverse events for dapagliflozin plus metformin compared to glipizide plus metformin were nasopharyngitis (10.6% vs. 15.0%), hypertension (7.4% vs. 8.6%) and influenza (7.4% vs. 7.4%).²² Discontinuations due to adverse events were 9.1% for dapagliflozin plus metformin vs. 5.9% for glipizide plus metformin.²³

Adverse events suggestive of urinary tract infection and genital infection were analyzed based on predefined groupings of preferred terms for each of these two categories.²⁴ The percentage of patients with signs, symptoms and other reports suggestive of urinary tract and genital infections was higher for dapagliflozin plus metformin compared to glipizide plus metformin.²⁵ Signs, symptoms and other reports suggestive of urinary tract infections were 10.8% with dapagliflozin plus metformin vs. 6.4% with glipizide plus metformin.²⁶ Signs, symptoms and other reports suggestive of genital infections were 12.3% with dapagliflozin plus metformin compared to 2.7% with glipizide plus metformin and most were mild to moderate in intensity.²⁷ One case of urinary tract infection led to discontinuation in the dapagliflozin group and one case in the glipizide group.²⁸ Three cases of genital infections led to discontinuation in the dapagliflozin treatment group.²⁹ Two cases of pyelonephritis were reported in the glipizide group.³⁰

The overall proportions of individuals experiencing serious adverse events after 52 weeks were similar between the two treatment groups: 8.6% for dapagliflozin plus metformin vs. 11.3% for glipizide plus metformin.³¹

Effects upon blood pressure were examined as exploratory endpoints.  Reductions in systolic and diastolic blood pressure by 4.3 mmHg and 1.6 mmHg, respectively, were observed in the dapagliflozin plus metformin group.³²  Glipizide plus metformin was associated with an increase of 0.8 mmHg and a reduction of 0.4 mmHg, in systolic and diastolic blood pressure, respectively.³³ 

About Type 2 Diabetes

Type 2 diabetes, which represents 90 per cent of diabetes diagnoses in Canada,³⁴ is a progressive disease³⁵ that occurs when the pancreas does not produce an adequate supply of insulin or when the body is ineffective at using the insulin that is produced.³⁶  More than three million Canadians are living with diabetes and experts suggest this number will reach 3.7 million by 2020.³⁷Significant unmet needs exist as nearly half of people living with type 2 diabetes remain uncontrolled on their current treatment regime.³⁸

Over time, sustained hyperglycemia can lead to serious complications including heart disease, kidney problems, blindness, nerve damage and erectile dysfunction.³⁹  As the disease progresses so too does the need to adjust and intensify treatment.⁴⁰  Conventional oral therapies for type 2 diabetes target the body's production and uptake of insulin through the pancreas, liver and stomach enzymes.⁴¹ An approach that acts independently of insulin could provide an option for patients in helping manage blood glucose levels.⁴²

About SGLT2 Inhibition

The renal SGLT system plays a major role in overall glucose balance in the body.⁴³ Normally, the kidney filters ~180g of glucose each day, and virtually all is reabsorbed back into circulation.⁴⁴ Glucose reabsorbtion occurs in the proximal tubule of the kidney via the SGLT system.⁴⁵ Selective inhibition of SGLT2 by an insulin independent mechanism of action facilitates the excretion of glucose in the urine,⁴⁶ thereby lowering blood glucose levels.⁴⁷

Bristol-Myers Squibb and AstraZeneca Collaboration

Bristol-Myers Squibb and AstraZeneca entered into a collaboration in January 2007 to enable the companies to research, develop and commercialize select investigational drugs for type 2 diabetes. 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 Canada

Bristol-Myers Squibb Canada is a global biopharmaceutical company whose mission is to extend and enhance human life.  For more information about Bristol-Myers Squibb Canada, please visit: www.bmscanada.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.ca.

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¹ Bristol-Myers Squibb/AstraZeneca data on file.

² Bristol-Myers Squibb/AstraZeneca data on file.

³ Bristol-Myers Squibb/AstraZeneca data on file.

⁴ Bristol-Myers Squibb/AstraZeneca data on file.

⁵ Bristol-Myers Squibb/AstraZeneca data on file.

⁶ Bristol-Myers Squibb/AstraZeneca data on file.

⁷ Bristol-Myers Squibb/AstraZeneca data on file.

⁸ Bailey, Clifford J., et al. "Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomized, double-blind, placebo-controlled trial," The Lancet, Vol 375, June 26, 2010, page 2230.

⁹ Bristol-Myers Squibb/AstraZeneca data on file.

¹⁰ Bristol-Myers Squibb/AstraZeneca data on file.

¹¹ Bristol-Myers Squibb/AstraZeneca data on file.

¹² Bristol-Myers Squibb/AstraZeneca data on file.

¹³ Bristol-Myers Squibb/AstraZeneca data on file.

¹⁴ Bristol-Myers Squibb/AstraZeneca data on file.

¹⁵ Bristol-Myers Squibb/AstraZeneca data on file.

¹⁶ Bristol-Myers Squibb/AstraZeneca data on file.

¹⁷ Bristol-Myers Squibb/AstraZeneca data on file.

¹⁸ Bristol-Myers Squibb/AstraZeneca data on file.

¹⁹ Bristol-Myers Squibb/AstraZeneca data on file.

²⁰ Bristol-Myers Squibb/AstraZeneca data on file.

²¹ Bristol-Myers Squibb/AstraZeneca data on file.

²² Bristol-Myers Squibb/AstraZeneca data on file.

²³ Bristol-Myers Squibb/AstraZeneca data on file.

²⁴ Bristol-Myers Squibb/AstraZeneca data on file.

²⁵ Bristol-Myers Squibb/AstraZeneca data on file.

²⁶ Bristol-Myers Squibb/AstraZeneca data on file.

²⁷ Bristol-Myers Squibb/AstraZeneca data on file.

²⁸ Bristol-Myers Squibb/AstraZeneca data on file.

²⁹ Bristol-Myers Squibb/AstraZeneca data on file.

³⁰ Bristol-Myers Squibb/AstraZeneca data on file.

³¹ Bristol-Myers Squibb/AstraZeneca data on file.

³² Bristol-Myers Squibb/AstraZeneca data on file.

³³ Bristol-Myers Squibb/AstraZeneca data on file.

³⁴ Canadian Diabetes Association website http://www.diabetes.ca/diabetes-and-you/what/facts/, accessed September 16, 2010.

³⁵ Canadian Diabetes Association website http://www.diabetes.ca/diabetes-and-you/living/just-diagnosed/type2/, accessed September 16, 2010.

³⁶ Canadian Diabetes Association website http://www.diabetes.ca/diabetes-and-you/what/facts/, accessed September 16, 2010.

³⁷ Canadian Diabetes Association website http://www.diabetes.ca/diabetes-and-you/what/prevalence/, accessed September 16, 2010.

³⁸ Harris, Stewart B., et al. "Glycemic control and morbidity in the Canadian primary care setting (results of the diabetes in Canada evaluation study)," Diabetes Research and Clinical Practice, 70 (2005), page 90.

³⁹ Canadian Diabetes Association website http://www.diabetes.ca/diabetes-and-you/what/facts/, accessed September 16, 2010.

⁴⁰ Canadian Diabetes Association, "Your Guide to Diabetes Medications," Spring 2006, page 3.

⁴¹ Mayo Clinic website: http://www.mayoclinic.com/health/diabetes-treatment/DA00089, accessed August 26, 2010.

⁴² Bailey, Clifford J., et al. "Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomized, double-blind, placebo-controlled trial," The Lancet, Vol 375, June 26, 2010, page 2230.

⁴³ Abdul-Ghani MA, DeFronzo RA. Inhibition of renal glucose reabsorption: a novel strategy for achieving glucose control in type 2 diabetes mellitus. Endocr Pract. 2008:14(6):782-790.  Page 783.

⁴⁴ Wright, E.M. Renal NA⁺-Glucose Cotransporters. Am J Physiol Renal Physiol, 2001. 280: F10-F18.  Page F10.

⁴⁵ Abdul-Ghani MA, DeFronzo RA. Inhibition of renal glucose reabsorption: a novel strategy for achieving glucose control in type 2 diabetes mellitus. Endocr Pract. 2008:14(6):782-790. Page 783.

⁴⁶ Bailey, Clifford J., et al. "Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomized, double-blind, placebo-controlled trial," The Lancet, Vol 375, June 26, 2010, page 2230.

⁴⁷ Abdul-Ghani MA, DeFronzo RA. Inhibition of renal glucose reabsorption: a novel strategy for achieving glucose control in type 2 diabetes mellitus. Endocr Pract. 2008:14(6):782-790. Page 782.

For further information:

Contacts:

Leslie Walsh, Fleishman-Hillard Canada, 416.645.8175, [email protected]

Lee Rammage, AstraZeneca Canada, 905.804.4913, [email protected]

Sabrina Tremblay, Bristol-Myers Squibb Canada, 514.333.2463, [email protected]