Pooled Analysis Showed Onglyza® (saxagliptin) Provided Improvements In Key Measures Of Blood Sugar Control In Adults With Type 2 Diabetes At High Risk For CV Disease

Bristol-Myers Squibb Company (NYSE: BMY) and AstraZeneca (NYSE: AZN) today announced the results of analyses showing that Onglyza ^® (saxagliptin) 5 mg demonstrated improvements across key measures of blood sugar control (glycosylated hemoglobin levels, or HbA1c; fasting plasma glucose, or FPG and post-prandial glucose, or PPG) compared to placebo in adult patients with type 2 diabetes at high risk for cardiovascular disease. These results were from a pooled, post-hoc assessment of five, 24-week, Phase III studies encompassing 1,681 patients with type 2 diabetes and varying degrees of cardiovascular risk, characterized by the presence of known risk factors or a history of cardiovascular disease. Adverse events, serious adverse events, death, discontinuation and hypoglycemia were also evaluated by various patient sub-groups. The data were presented today in two oral presentations at the 17 ^th World Congress on Heart Disease in Toronto, Canada.

“The population of patients with type 2 diabetes who are at increased risk for cardiovascular disease was highlighted in a recently issued position statement by the American Diabetes Association and the European Association for the Study of Diabetes,” said William Cook, Ph.D., lead investigator and Global Medical Affairs manager, AstraZeneca. “These data are important because they further our understanding of the safety and efficacy of lowering blood sugar with Onglyza in adult patients with type 2 diabetes who are also at risk for cardiovascular disease.”

Onglyza is indicated as an adjunct to diet and exercise to improve blood sugar control in adults with type 2 diabetes mellitus in multiple clinical settings. Onglyza should not be used for the treatment of patients with type 1 diabetes mellitus or diabetic ketoacidosis (increased levels of ketones in the blood or urine), as it would not be effective in these settings.

Onglyza is contraindicated in patients with a history of a serious hypersensitivity reaction to Onglyza (e.g., anaphylaxis, angioedema or exfoliative skin conditions). There have been reports of acute pancreatitis and serious hypersensitivity reactions in patients taking Onglyza. If pancreatitis or a serious hypersensitivity reaction is suspected, promptly discontinue Onglyza and institute appropriate medical treatment. Onglyza has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at an increased risk for development of pancreatitis while using Onglyza (saxagliptin).

When Onglyza was used in combination with a sulfonylurea or with insulin (two medications known to cause hypoglycemia), the incidence of confirmed hypoglycemia was increased over that of placebo used in combination with a sulfonylurea or with insulin. Therefore, a lower dose of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia when used in combination with Onglyza.

Results

In the analyses presented today, researchers found that patients taking Onglyza 5 mg demonstrated glycemic improvements compared to placebo in HbA1c, FPG and two-hour PPG in a pool of patients assessed by multiple characteristics indicating increased risk of cardiovascular disease (patients with hypertension, statin use, multiple cardiovascular risk factors and previous cardiovascular disease history) across the five pooled Phase III studies at the end of 24 weeks.

Differences from placebo in adjusted mean change from baseline in HbA1c at week 24 were as follows:

In patients with hypertension		n = 457		-0.69%		95% CI: -0.82, -0.57
In patients without hypertension		n = 402		-0.66%		95% CI: -0.80, -0.52
In patients with statin use		n = 211		-0.70%		95% CI: -0.89, -0.52
In patients without statin use		n = 650		-0.66%		95% CI: -0.77, -0.56
In patients with at least two cardiovascular risk factors		n = 459		-0.73%		95% CI: -0.85, -0.60
In patients with one or no risk factors		n = 402		-0.62%		95% CI: -0.75, -0.48
In patients with a history of cardiovascular disease		n = 110		-0.64%		95% CI: -0.90, -0.38
In patients without a history of cardiovascular disease		n = 746		-0.68%		95% CI: -0.78, -0.58

In these same patient subgroups, decreases in FPG for Onglyza 5 mg at week 24 ranged from -14.2 mg/dL to -16.0 mg/dL vs. placebo. Similarly, PPG results at week 24 ranged from -36.1 mg/dL to -47.0 mg/dL compared to placebo. Finally, achievement of target HbA1c (less than 7.0%) ranged from 15.7% to 21.8% versus placebo.

Rates of confirmed hypoglycemia (as defined by a glucose measurement of less than or equal to 50 mg/dL) for patients treated with Onglyza (saxagliptin) 5 mg compared to placebo, respectively, across the sub-groups were as follows:

In patients with hypertension		0.6% vs. 0.7%
In patients without hypertension		0.2% vs. 0.0%
In patients with statin use		0.5% vs. 0.9%
In patients without statin use		0.4% vs. 0.2%
In patients with at least two cardiovascular risk factors		0.6% vs. 0.7%
In patients with one or no risk factors		0.2% vs. 0.0%
In patients with a history of cardiovascular disease		0.0% vs. 2.1%
In patients without a history of cardiovascular disease		0.5% vs. 0.1%

Corresponding rates of reported hypoglycemia ranged from 6.7% to 11.2% in patients treated with Onglyza 5 mg vs. 6.2% to 7.2% in patients treated with placebo. The proportion of patients who experienced at least one adverse event with Onglyza 5 mg ranged from 68.6% to 77.1% compared to 67.9% to 75.5% with placebo.

About the Analysis

Data from five Phase III, randomized, placebo-controlled, 24-week studies of Onglyza 5 mg were pooled for the purposes of these post-hoc analyses, with the overall objective of assessing the efficacy and safety of Onglyza 5 mg compared to placebo in adult patients with type 2 diabetes and cardiovascular risk factors or a history of cardiovascular disease. Two studies evaluated Onglyza 5 mg as a monotherapy in treatment-naïve patients, while three studies evaluated Onglyza 5 mg as add-on therapy to other treatments including metformin, glyburide and a thiazolidinedione. Efficacy measures included change from baseline in HbA1c, FPG, 120-minute PPG and the proportion of patients achieving a therapeutic glycemic response of HbA1c that was less than 7.0%.

The analyses included 1,681 patients with type 2 diabetes (aged 18-77) with inadequate glycemic control (HbA1c inclusion criteria: 7.0% – 10.0%, 7.5% – 10.0%, 7.0% – 10.5% or greater than or equal to 7.0%). Patients were treated with Onglyza 5 mg (n = 882) or placebo (n = 799), both alone or as add-on to metformin, glyburide or a thiazolidinedione.

About Onglyza ^® (saxagliptin)

As of July 2012, Onglyza has been submitted for regulatory review in 93 countries and is approved in 78 countries including the U.S., Canada, Mexico, Europe, India, Brazil and China.

IMPORTANT SAFETY INFORMATION for ONGLYZA

Contraindications

• History of a serious hypersensitivity reaction to Onglyza (e.g., anaphylaxis, angioedema, or exfoliative skin conditions)

Warnings and Precautions

• Pancreatitis: There have been post-marketing reports of acute pancreatitis in patients taking Onglyza. After initiating Onglyza, observe patients carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue Onglyza and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk of developing pancreatitis while using Onglyza.
• Use with Medications Known to Cause Hypoglycemia: When Onglyza was used in combination with a sulfonylurea or with insulin, medications known to cause hypoglycemia, the incidence of confirmed hypoglycemia was increased over that of placebo used in combination with a sulfonylurea or with insulin. Therefore, a lower dose of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia when used in combination with Onglyza.
• Hypersensitivity Reactions: There have been post-marketing reports of serious hypersensitivity reactions in patients treated with Onglyza, including anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred within the first 3 months after initiation of treatment with Onglyza, with some reports occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue Onglyza, assess for other potential causes for the event, and institute alternative treatment for diabetes. Use caution in patients with a history of angioedema to another DPP-4 inhibitor as it is unknown whether they will be predisposed to angioedema with Onglyza.
• Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Onglyza (saxagliptin) or any other antidiabetic drug.

Most Common Adverse Reactions

• Most common adverse reactions (regardless of investigator assessment of causality) reported in ≥5% of patients treated with Onglyza and more commonly than in patients treated with control were upper respiratory tract infection (7.7%, 7.6%), headache (7.5%, 5.2%), nasopharyngitis (6.9%, 4.0%) and urinary tract infection (6.8%, 6.1%).
• When used as add-on combination therapy with a thiazolidinedione, the incidence of peripheral edema for Onglyza 2.5 mg, 5 mg, and placebo was 3.1%, 8.1% and 4.3%, respectively.
• Confirmed hypoglycemia was reported more commonly in patients treated with Onglyza 2.5 mg and Onglyza 5 mg compared to placebo in the add-on to glyburide trial (2.4%, 0.8% and 0.7%, respectively) and with Onglyza 5 mg compared to placebo in the add-on to insulin (with or without metformin) trial (5.3% and 3.3%, respectively).

Drug Interactions

Because ketoconazole, a strong CYP3A4/5 inhibitor, increased saxagliptin exposure, the dose of Onglyza should be limited to 2.5 mg when coadministered with a strong CYP3A4/5 inhibitor (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin).

Use in Specific Populations

• Patients with Renal Impairment: The dose of Onglyza is 2.5 mg once daily for patients with moderate or severe renal impairment, or with end-stage renal disease requiring hemodialysis (creatinine clearance [CrCl] ≤50 mL/min). Onglyza should be administered following hemodialysis. Onglyza has not been studied in patients undergoing peritoneal dialysis. Assessment of renal function is recommended prior to initiation of Onglyza and periodically thereafter.
• Pregnant and Nursing Women: There are no adequate and well-controlled studies in pregnant women. Onglyza (saxagliptin), like other antidiabetic medications, should be used during pregnancy only if clearly needed. It is not known whether saxagliptin is secreted in human milk. Because many drugs are secreted in human milk, caution should be exercised when Onglyza is administered to a nursing woman.
• Pediatric Patients: Safety and effectiveness of Onglyza in pediatric patients have not been established.

Please click here for full U.S. Prescribing Information and Medication Guide for Onglyza (saxagliptin).

About Type 2 Diabetes

In 2011, diabetes was estimated to affect more than 365 million people aged 20-79 worldwide. Because of the aging population and the growing trend of obesity, the prevalence of diabetes is projected to reach more than 550 million by 2030. Type 2 diabetes accounts for approximately 90% to 95% of all cases of diagnosed diabetes in adults. Type 2 diabetes is a chronic disease characterized by insulin resistance and dysfunction of beta cells in the pancreas, which decreases insulin sensitivity and secretion, leading to elevated glucose levels. Over time, this sustained hyperglycemia contributes to worsening insulin resistance and further beta cell dysfunction. Significant unmet needs still exist, as many patients remain inadequately controlled on their current glucose-lowering regimen.

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