Bristol-Myers Squibb Company and AstraZeneca announced results from a long-term (104 weeks) phase 3 clinical study which showed that the investigational compound dapagliflozin added to metformin sustained reductions of blood sugar levels (glycosylated haemoglobin levels, or HbA1c) from 52-weeks to 104-weeks, in adults with type 2 diabetes when compared to glipizide (a common sulphonylurea treatment) added to metformin. The proportion of patients with adverse events was similar between the treatment groups. Within the new class of insulin-independent, investigational type 2 diabetes agents that inhibit sodium-glucose cotransporter-2 (SGLT2) in the kidney, 104-week results are the longest-term clinical data presented to date. These results announced are from a 52-week extension period of an initial 52-week trial. The initial 52-week results were presented during the 46th European Association for the Study of Diabetes (EASD) Annual Meeting in 2010.

In addition to sustained reductions in blood sugar levels, the 104-week study, presented as a late breaking poster at the 71st American Diabetes Association (ADA) Scientific Sessions in San Diego, CA, reported that both the weight reduction achieved by patients taking dapagliflozin added to metformin and the weight gain experienced by patients taking glipizide added to metformin in the initial 52-week trial, were sustained at 104 weeks. Moreover, hypoglycaemic (low blood sugar) episodes during the 104 weeks were reported approximately 10 times more frequently in patients treated with glipizide added to metformin (45.8%) than in patients treated with dapagliflozin added to metformin (4.2%).

Signs, symptoms and other reports suggestive of genital infections or urinary tract infections were more common in patients taking dapagliflozin added to metformin. These events were proactively monitored and were generally mild to moderate in intensity, with most patients responding to standard treatment. Events mostly occurred in the first year and rarely led to discontinuation.

“As we advance our knowledge of how SGLT2 inhibitors may work as a potential treatment for patients with type 2 diabetes, long-term data become critical to assess a compound’s safety and its ability to sustain glycemic control,” said Michael A. Nauck, MD, Head of Diabetes Center, Bad Lauterberg (Germany), principal investigator of the study. “These two-year data demonstrated that patients taking dapagliflozin added to metformin sustained reductions in blood sugar levels over an extended period of time.”

A New Drug Application (NDA) for dapagliflozin was accepted for review by the US Food and Drug Administration (FDA) in March 2011 with a Prescription Drug User Fee Act (PDUFA) date set for October 28, 2011. In addition, a Marketing Authorisation Application (MAA) was validated by the European Medicines Agency (EMA) in January 2011. If approved, dapagliflozin--an inhibitor of SGLT2, a target in the kidney -- would potentially be the first in a new class of insulin-independent, oral type 2 diabetes agents.

This was a 52-week phase 3, multicenter, randomized, parallel-group, double-blind, active-controlled study with a 52-week extension. The primary endpoint at 52 weeks was non-inferiority of dapagliflozin added to metformin compared to glipizide added to metformin for HbA1c mean change from baseline. The 52-week extension was designed to assess the maintenance of efficacy of dapagliflozin (up to 10 mg/day) added to metformin, as well as safety and tolerability, over 104 weeks of treatment compared to glipizide (up to 20 mg/day) added to metformin in patients with type 2 diabetes. The median dose of metformin was 2,000 mg/day.

The study included more than 800 adults with type 2 diabetes (aged = 18) whose HbA1c was between 6.5% and 10% (mean baseline (%) ± (SD) 7.69 (0.86), 7.74 (0.89) for dapagliflozin added to metformin and glipizide added to metformin, respectively). Individuals were randomized to one of two treatment groups at the onset of the study: dapagliflozin added to metformin or glipizide added to metformin.

There were 624 patients when the 52-week extension began, and of these, 445 patients completed the extension.

At the end of 104 weeks, change from baseline in HbA1c in patients taking dapagliflozin added to metformin compared to those taking glipizide added to metformin was -0.32% (95% CI -0.42, -0.21) vs. -0.14% (-0.25, -0.03). The weight reduction with dapagliflozin added to metformin at 52 weeks and the weight gain with glipizide added to metformin at 52 weeks were both sustained at 104 weeks: -3.70 kg (95% CI -4.16, -3.24) [3.70 kg = 8.14 lb] vs. +1.36 kg (0.88, 1.84) [1.36 kg = 2.99 lb], respectively. A low incidence of hypoglycemic episodes was reported throughout the trial in patients treated with dapagliflozin added to metformin (4.2%) compared to patients treated with glipizide added to metformin (45.8%). No major hypoglycemic episodes were reported with dapagliflozin treatment, whereas three were reported with glipizide treatment.

The kidney plays an important role in glucose balance, normally filtering ~180g of glucose each day, with virtually all glucose being reabsorbed back into circulation. SGLT2 is the major sodium-glucose cotransporter in the kidney and is an insulin-independent pathway for the reabsorption of glucose back into the blood.

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.

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.

AstraZeneca is a global, innovation-driven biopharmaceutical business with a primary focus on the discovery, development and commercialization of prescription medicines for gastrointestinal, cardiovascular, neuroscience, respiratory and inflammation, oncology and infectious disease.