Results from a 24-week phase 3 clinical study demonstrated that the addition of the investigational drug dapagliflozin achieved reductions in the primary endpoint, glycosylated haemoglobinn level (HbA1c), in inadequately controlled type 2 diabetes patients who were treated with insulin (with or without oral anti-diabetes medications (OADs)), compared to placebo plus insulin (with or without OADs).

The study also demonstrated that dapagliflozin achieved reductions in the secondary endpoints that evaluated the change in total body weight from baseline, change from baseline in mean daily insulin dose, and change from baseline in fasting plasma glucose (FPG). Generally, adverse events, serious adverse events and study discontinuations were similar across all treatment groups. Signs, symptoms and other reports suggestive of urinary tract and genital infections were more frequently noted in the dapagliflozin treatment arms compared to placebo and rarely led to discontinuation. Results from the 24-week study were presented at the 70th American Diabetes Association (ADA) Annual Scientific Sessions.

Dapagliflozin, an investigational compound, is a potential first-in-class sodium-glucose cotransporter-2 (SGLT2) inhibitor currently in phase 3 trials under joint development by Bristol-Myers Squibb Company and AstraZeneca as a once-daily oral therapy for the treatment of adult patients with type 2 diabetes. SGLT2 inhibitors facilitate the elimination of glucose by the kidney, which should result in lowering serum glucose levels.

"Many type 2 diabetes patients who are treated with insulin are not able to achieve their blood sugar goals," said John Wilding, DM, FRCP, Professor of Medicine and Honorary Consultant Physician, Head of Diabetes and Endocrinology Clinical Research Unit, University Hospital Aintree (UK). "The phase 3 data on glycemic and weight parameters presented today suggest that further study of dapagliflozin in this patient population is warranted."

The study was a randomized, double-blind, placebo-controlled study of 800 individuals with type 2 diabetes (ages 18 - 80) and inadequate glycemic control whose HbA1c level was greater than or equal to 7.5% and less than or equal to 10.5% at baseline, with a mean baseline HbA1c level of 8.5%. The study was designed to assess the efficacy and safety of dapagliflozin in patients with inadequately controlled type 2 diabetes receiving treatment with a mean insulin dose of greater than or equal to 30 IU for at least 8 weeks (mean baseline dose: 77 IU per day) with or without concomitant OADs. Individuals were equally randomized to one of four separate treatment groups: dapagliflozin 2.5 mg (n= 202), dapagliflozin 5 mg (n= 211), dapagliflozin 10 mg (n= 194), or placebo (n= 193).

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 in body weight from baseline, change from baseline in mean daily insulin dose, and change from baseline in fasting plasma glucose (FPG).

After 24 weeks, individuals receiving dapagliflozin 2.5 mg, 5 mg and 10 mg demonstrated a statistically significant adjusted mean change in HbA1c from baseline of -0.75%, -0.82% and -0.90%, respectively, compared to -0.30% for placebo (p-value less than or equal to 0.0001 for all treatment groups).

The study also evaluated the potential impact of dapagliflozin on total body weight at week 24. At week 24, the study found that individuals treated with dapagliflozin demonstrated an adjusted mean change in total body weight: -0.98 kg for dapagliflozin 2.5 mg, -0.98 kg for dapagliflozin 5 mg and -1.67 kg for dapagliflozin 10 mg, compared to a weight gain of 0.02 kg for placebo (p-value less than or equal to 0.0001 for all treatment groups).

Individuals treated with dapagliflozin also demonstrated a reduction in daily insulin dose at week 24: -1.80 IU/d for dapagliflozin 2.5 mg, -0.61 IU/d for dapagliflozin 5 mg and -1.16 IU/d for dapagliflozin 10 mg, compared to an increase of 5.08 IU/d for placebo (p-value less than or equal to 0.0001 for all treatment groups).

Individuals treated with dapagliflozin demonstrated a reduction in FPG, a secondary endpoint, from baseline at week 24: -12.5 mg/dL for dapagliflozin 2.5 mg, -18.8 mg/dL for dapagliflozin 5 mg and -21.7 mg/dL for dapagliflozin 10 mg, compared to an increase of 3.3 mg/dL for placebo (p-value equal to 0.0008 for dapagliflozin 2.5 mg; p-value less than or equal to 0.0001 for dapagliflozin 10 mg. (Note that due to the study testing procedure, the p-value for dapagliflozin 5 mg could not be assessed).

Generally, adverse events, serious adverse events and study discontinuations were similar across all treatment groups. The percentage of patients experiencing the most common adverse events (greater than or equal to 5 %) for dapagliflozin 2.5 mg, 5 mg 10 mg, and placebo, respectively are as follows: nasopharyngitis: 13.9%, 13.7%, 8.7%, 11.2%; hypertension: 5.4%, 6.1%, 3.6%, 7.6%; headache: 4.0%, 4.2%, 1.0%, 7.1%; back pain: 4.5%, 1.9%, 4.6%, 5.1%; upper respiratory tract infection: 2.5%, 2.8%, 3.1%, 5.1%.

The percentage of patients with signs, symptoms and other reports suggestive of urinary tract and genital infections were higher for the dapagliflozin treatment arms compared to placebo. Events suggestive of urinary tract infections were as follows: 5.9%, 7.5%, 7.7% with dapagliflozin 2.5 mg, 5 mg and 10 mg respectively, versus 2.0% with placebo. Events suggestive of genital infections were as follows: 5.4%, 8.0%, 9.2% with dapagliflozin 2.5 mg, 5 mg and 10 mg respectively, versus 2.0% with placebo.

Reports of hypoglycemia observed in the dapagliflozin treatment groups compared to placebo were 55% for dapagliflozin 2.5 mg, 47.6% for dapagliflozin 5 mg, 44.9% for dapagliflozin 10 mg and 42.1% for placebo. Of these hypoglycemic events, 1% were major and were equally distributed across groups.

Reductions in blood pressure were observed without associated signs of orthostatic hypotension.

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.