AstraZeneca PLC Presents Findings From Two Pooled Analyses At The 76th Scientific Sessions Of The American Diabetes Association Evaluating Dapagliflozin In Type 2 Diabetes Patients With Renal Impairment And In Combination With Potassium-Sparing Agents

• Effects were similar on body weight and systolic blood pressure regardless of renal function, while the A1C lowering effects of FARXIGA^® (dapagliflozin) decreased as renal function declined
• When co-administered with a potassium-sparing agent, FARXIGA reduced A1C, body weight and systolic blood pressure without significantly increasing potassium levels

WILMINGTON, Del.--(BUSINESS WIRE)--AstraZeneca today announced results of two pooled analyses involving more than 4,600 patients with type 2 diabetes. The two analyses, which represent AstraZeneca’s ongoing commitment to fully understanding the effects of dapagliflozin across subsets of patients with type 2 diabetes, will be presented at the 76^th Scientific Sessions of the American Diabetes Association (ADA) in New Orleans, June 10-14, 2016.

“Differential effects of dapagliflozon on cardiovascular risk factors at varying degrees of renal function.”

In one analysis of patients with type 2 diabetes and renal impairment (Poster 1095-P), FARXIGA reduced body weight and systolic blood pressure regardless of baseline estimated glomerular filtration rate (eGFR), when compared to placebo. Additionally, FARXIGA reduced urine albumin to creatinine ratio (UACR) in patients with a baseline UACR =30 mg/g when compared to placebo, including in patients with mild renal impairment (eGFR =60 to <90 mL/min/1.73m²). As seen in previous trials, the A1C lowering effects of FARXIGA^® (dapagliflozin) decreased as renal function declined. FARXIGA should not be used in patients with eGFR <60 mL/min/1.73 m².¹

Hiddo Lambers Heerspink, Pharm.D., Ph.D., Clinical Pharmacologist in the Department of Clinical Pharmacy Pharmacology at the University Medical Center Groningen, the Netherlands and lead investigator of the study said: “Approximately 1 in 3 adults with diabetes has renal impairment. This study is important as it helps further the understanding of dapagliflozin in type 2 diabetes patients with varying degrees of renal impairment.”²

FARXIGA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It is not recommended for patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. FARXIGA is not indicated for weight loss or the treatment of hypertension.³

The second analysis examined the effects of FARXIGA versus placebo in patients treated with potassium-sparing agents (Poster 1094-P). When co-administered with potassium-sparing agents, FARXIGA resulted in lower A1C, body weight and systolic blood pressure, with no evidence of increase in serum potassium.⁴

Jim McDermott, Head of Medical, US Medical Affairs, Diabetes, AstraZeneca said: “Physicians are often faced with difficult decisions on how to most effectively treat patients with type 2 diabetes with serious complications and comorbidities. For example, patients with kidney and cardiovascular disease are often being treated with concomitant medications, including potassium-sparing diuretics, to treat high blood pressure or heart failure. These analyses provide important insights and support the need for research into treating these patients.”

The first analysis assessed more than 4,400 patients with type 2 diabetes (n=2,226 and 2,178 for FARXIGA and placebo groups, respectively) using pooled data from 11 Phase 3 clinical trials with varying degrees of renal function as measured by eGFR (eGFR =45 to <60; eGFR =60 to <90; eGFR =90 mL/min/1.73m²) over 24 weeks. Results showed a difference of -0.27%, -0.47% and -0.57% in A1C, -2.1, -1.8 and -2.3 kilograms in body weight, -4.3, -2.6 and -3.4 mmHg in systolic blood pressure and -38.3%, -23.3% and -16.1% in UACR with FARXIGA compared to placebo for patients with the lowest to highest eGFR, respectively. Adverse events occurred more frequently in patients with the lowest eGFR in both the FARXIGA and placebo groups. In patients treated with dapagliflozin with varying degrees of renal function (eGFR =45 to <60; eGFR =60 to <90; eGFR =90 mL/min/1.73m²) 68.3%, 58.3%, and 59.4% respectively reported at least one adverse event.¹

The second analysis assessed more than 200 patients with type 2 diabetes treated with potassium-sparing agents (n=108 and 119 for FARXIGA and placebo groups, respectively) using pooled data from 14 Phase 2b/3 clinical trials of up to 24 weeks. Results showed a difference of -0.39% in A1C, -2.2 kg in body weight, -5.2 mmHg in systolic blood pressure, -3.2 mL/min/1.73m² in eGFR, and -0.12 mEq/L in serum potassium with FARXIGA compared to placebo. Potassium levels =6 mEq/L during follow up were observed in two patients versus nine patients for the FARXIGA and placebo groups, respectively. The rate of adverse events was similar between the FARXIGA and placebo groups, including adverse events of renal impairment/failure (3.7% vs. 6.7%); hypotension/volume reduction (2.8% vs. 1.7%), and potassium =6 mEq/L (1.9% vs. 7.6%).⁴

Effects of Dapagliflozin on Cardiovascular Risk Factors at Varying Degrees of Renal Function (Poster 1095-P), and Safety and Efficacy of Dapagliflozin (DAPA) in Combination with Potassium (K)-sparing Agents (Poster 1094-P) will be presented during a poster session with a moderated discussion on June 12, 2016.

Important Safety Information For FARXIGA^® (dapagliflozin)

Contraindications

• History of a serious hypersensitivity reaction to FARXIGA
• Severe renal impairment, end stage renal disease, or patients on dialysis

Warnings and Precautions

• Hypotension: FARXIGA causes intravascular volume contraction. Symptomatic hypotension can occur after initiating FARXIGA, particularly in patients with impaired renal function (eGFR <60 mL/min/1.73 m²), elderly patients, or patients on loop diuretics. Before initiating FARXIGA in patients with one or more of these characteristics, assess and correct volume status. After initiating therapy, monitor for signs and symptoms of hypotension.
• Ketoacidosis has been reported in patients with type 1 and type 2 diabetes receiving SGLT2 inhibitors, including FARXIGA. Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level. If suspected, discontinue FARXIGA, evaluate and treat promptly. Before initiating FARXIGA, consider risk factors for ketoacidosis. Patients on FARXIGA may require monitoring and temporary discontinuation of therapy in clinical situations known to predispose to ketoacidosis.
• Impairment in Renal Function: FARXIGA increases serum creatinine and decreases eGFR. Elderly patients and patients with impaired renal function may be more susceptible to these changes. Adverse reactions related to renal function can occur after initiating FARXIGA. Before initiating FARXIGA, evaluate renal function and monitor periodically thereafter. Discontinue FARXIGA when eGFR is persistently <60 mL/min/1.73 m².
• Urosepsis and Pyelonephritis: Serious urinary tract infections have been reported with SGLT2 inhibitors, including FARXIGA. SGLT2 inhibitors increase the risk for urinary tract infections. Evaluate for signs and symptoms of urinary tract infections and treat promptly.
• Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues: Insulin and insulin secretagogues are known to cause hypoglycemia. FARXIGA can increase the risk of hypoglycemia when combined with these agents. Consider a lower dose of insulin or the insulin secretagogue to reduce the risk of hypoglycemia when used in combination with FARXIGA.
• Genital Mycotic Infections: FARXIGA increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections. Monitor and treat appropriately.
• Increases in Low-Density Lipoprotein Cholesterol (LDL-C) occur with FARXIGA. After initiating FARXIGA, monitor LDL-C and treat per standard of care.

• Bladder cancer: Across 22 clinical studies, newly diagnosed cases of bladder cancer were reported in 0.17% of FARXIGA-treated patients and 0.03% of placebo/comparator-treated patients. After excluding patients in whom exposure to study drug was <1 year at the time of diagnosis of bladder cancer, there were 4 cases with FARXIGA and no cases with placebo/comparator. Bladder cancer risk factors and hematuria (a potential indicator of pre-existing tumors) were balanced between treatment arms at baseline. There were too few cases to determine whether the emergence of these events is related to FARXIGA.

  There are insufficient data to determine whether FARXIGA has an effect on pre-existing bladder tumors. FARXIGA should not be used in patients with active bladder cancer. Use with caution in patients with a prior history of bladder cancer.

• Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with FARXIGA or any other antidiabetic drug.

Adverse Reactions

• In a pool of 12 placebo-controlled studies, the most common adverse reactions (=5%) associated with FARXIGA 5 mg, 10 mg, and placebo respectively were female genital mycotic infections (8.4% vs 6.9% vs 1.5%), nasopharyngitis (6.6% vs 6.3% vs 6.2%), and urinary tract infections (5.7% vs 4.3% vs 3.7%).

Use in Specific Populations

• Pregnant Women: There are no adequate and well-controlled studies of FARXIGA in pregnant women. Consider appropriate alternative therapies, especially during the second and third trimesters.
• Nursing Mothers: It is not known whether FARXIGA is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from FARXIGA, discontinue nursing or discontinue FARXIGA.
• Geriatric Use: A higher proportion of patients =65 years treated with FARXIGA had adverse reactions related to volume depletion and renal impairment or failure compared to patients treated with placebo. No FARXIGA dose change is recommended based on age.

Indication and Limitations of Use for FARXIGA

FARXIGA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

FARXIGA is not recommended for patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

Please see US Full Prescribing Information and Medication Guide for FARXIGA.

NOTES TO EDITORS

About SGLT-2 inhibitors

Dapagliflozin (marketed as FARXIGA^® in the US and FORXIGA^® outside the US) is part of a class of medicines called sodium-glucose cotransporter 2 (SGLT-2) inhibitors, which remove glucose via the kidneys.³

About Type 2 Diabetes

Diabetes is estimated to affect 29.1 million people in the US⁵ and 415 million people worldwide.⁶ Type 2 diabetes accounts for approximately 90-95 percent of adults diagnosed with diabetes in the US.⁵ The prevalence of diabetes is projected to reach more than 642 million people worldwide by 2040.⁶ Type 2 diabetes is a chronic and progressive disease characterized by multiple pathophysiologic defects leading to elevated glucose levels.^6,7 Significant unmet needs still exist, as many patients remain inadequately controlled on their current glucose-lowering regimen.⁸ It is estimated that nearly half of people living with type 2 diabetes are not achieving recommended A1C goals based on guidelines established by professional societies and advocacy organizations for diabetes management.^8,9

About AstraZeneca in Diabetes

AstraZeneca is pushing the boundaries of science with the goal of developing life-changing medicines that aim to reduce the global burden and complications of diabetes. Our current portfolio consists of the three newest classes of non-insulin, anti-diabetic treatments that support individualized treatment approaches: SGLT-2 inhibitors, GLP-1 receptor agonists and DPP-4 inhibitors.

As a strategic therapy area for the company, we are focusing our research and development efforts on diverse populations and patients with significant co-morbidities, such as cardiovascular disease, obesity, non-alcoholic steatohepatitis (NASH), and chronic kidney disease.

Our commitment to diabetes is exemplified by the depth and breadth of our global clinical research program. This commitment is advancing understanding of the treatment effects of our diabetes medicines in broad patient populations, as well as exploring combination treatment approaches to help more patients achieve treatment success earlier in their disease progression. Our ambition is to reduce the long-term impact of diabetes.

About AstraZeneca

AstraZeneca is a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of diseases in three main therapy areas - respiratory, inflammation, autoimmune disease (RIA), cardiovascular and metabolic disease (CVMD) and oncology – as well as in infection and neuroscience. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information please visit: www.astrazeneca-us.com

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