AstraZeneca presents positive pooled analysis demonstrating the effect of dapagliflozin on albuminuria in hypertensive patients with type 2 diabetes

• Two Phase III clinical trials demonstrate the safety and efficacy profile of dapagliflozin compared to placebo when added to standard of care in patients with hypertension and type 2 diabetes
• Post-hoc analysis shows that dapagliflozin in addition to treatment with ACE inhibitors (ACEi) or Angiotensin II Receptor Blockers (ARBs) achieved greater reductions in albuminuria from baseline without increasing serious renal adverse events

AstraZeneca today announced findings from a new post-hoc analysis of two Phase III trials, in which dapagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, 5 and 10 mg/d demonstrated greater reductions on HbA1c and systolic blood pressure (SBP) in patients with type 2 diabetes (T2DM) and hypertension compared to placebo, despite ongoing antihypertensive therapy with an ACEI or ARB, considered to be the standard of care for these patients. In this new pooled, post-hoc analysis, the effect of dapagliflozin treatment on albuminuria and estimated glomerular filtration rate (eGFR) at 12 weeks resulted in greater reductions in albuminuria compared to placebo as well as a decrease in eGFR, which was readily reversed one week after the last dose. Secondary analysis of this data also demonstrated that the effect of dapagliflozin treatment on albuminuria appears to be independent of changes in HbA1c, SBP and eGFR.¹ These results were presented today at the 51^st Annual Meeting of the European Association for the Study of Diabetes (EASD) in Stockholm, Sweden.

“Adult patients with hypertension and type 2 diabetes are at high risk for developing cardiovascular and renal disease, so it’s imperative we investigate the effects of treatment on clinical factors that can help mitigate the risk of long-term microvascular and macrovascular complications,” said lead investigator Hiddo Lambers Heerspink, Pharm.D., Ph.D., Clinical Pharmacologist in the Department of Clinical Pharmacology at the University Medical Center Groningen, the Netherlands. “We know that dapagliflozin positively affects HbA1c and blood pressure, however, in this post-hoc analysis it was also associated with greater reductions in albuminuria, and a slight but reversible decrease in eGFR. Further clinical investigations are required to establish whether these effects translate into improvements in renal outcomes.”

Data were pooled from two Phase III studies in which patients with stable hypertension, various levels of baseline albuminuria and type 2 diabetes on ACEi or ARB therapy received dapagliflozin 5 mg (n=87), 10 mg (n=167) or placebo (PBO; n=189) for 12 weeks. Both doses of dapagliflozin resulted in greater percentage change from baseline in HbA1c compared to placebo (-0.5% for both dosages of dapagliflozin vs 0.01%) as well as numerically greater reduction in SBP (-12.5 and -9.8 mmHg, respectively, compared to -6.3 mmHg). Dapagliflozin is not indicated as a blood pressure lowering medication.

In this post-hoc analysis, patients receiving dapagliflozin showed greater adjusted percentage change in albuminuria from baseline, as assessed by albumin:creatinine ratio (ACR), compared to placebo (-47.4% and -45.8%, respectively, vs -18.9%).[1] Patients treated with dapagliflozin did experience numerically greater reductions in eGFR, compared to placebo (-1.5 and -3.1 mL/min/1.73m², versus -0.3 mL/min/1.73m², respectively); these decreases were reversible one week after treatment discontinuation.¹ This analysis noted that change in albuminuria from baseline produced by dapagliflozin was independent of the change from baseline in HbA1c, SBP and eGFR.¹ The efficacy of dapagliflozin is dependent on renal function, and is reduced in patients who have moderate renal impairment and likely absent in patients with severe renal impairment.

“This analysis provides new evidence evaluating the positive effects of dapagliflozin, particularly in patients with high cardiovascular and renal risk,” said Elisabeth Björk, Vice President, Head of Cardiovascular and Metabolic Diseases, Global Medicines Development, AstraZeneca. “These data will help inform important decisions for patients with type 2 diabetes and elevated cardiometabolic risk who may require more personalized treatment approaches.”

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NOTES TO EDITORS

About Dapagliflozin

Dapagliflozin (marketed as Farxiga^® in the US and Forxiga^® outside the US) is part of a newer class of medicines called sodium-glucose cotransporter 2 (SGLT2) inhibitors, which remove glucose via the kidneys.

About SGLT2 inhibitors

The kidney plays a contributing role in maintaining normal glucose balance, in part by filtering and subsequently reabsorbing glucose back into circulation. SGLT2, a sodium-glucose cotransporter found predominantly in the kidney, is responsible for the majority of glucose reabsorption. Selective inhibition of SGLT2 reduces the reabsorption of glucose and enables its removal via the urine.[2]

About Type 2 Diabetes

Type 2 diabetes is a chronic disease resulting from the body’s ineffective use of insulin.[3] It comprises 90% of people with diabetes around the world and increases the risk of cardiovascular disease and kidney failure.[4] It is estimated to affect more than 387 million people worldwide and is projected to reach more than 592 million people by 2035.[5] Approximately 77% of people with diabetes live in low- and middle-income countries and 179 million people with diabetes are undiagnosed.5 It is estimated that more than half of people living with type 2 diabetes are not achieving recommended HbA1c goals based on guidelines established by professional societies and advocacy organisations for diabetes management.[6] The costs and consequences of diabetes are immense globally, resulting in at least USD 612 billion dollars in healthcare expenditures and causing 4.9 million deaths – one person every seven seconds – in 2014.⁵

About AstraZeneca in Diabetes

AstraZeneca is pushing the boundaries of science to create life-changing medicines that aim to reduce the global burden and complications of diabetes. Driven to redefine outcomes for diabetes patients, 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. Our commitment to diabetes is exemplified by the depth and breadth of our global clinical research programme. This commitment is advancing understanding of the treatment effects of our diabetes medicines in broad patient populations, as well as exploring combination treatment approaches resulting in more patients achieving treatment success earlier in their disease progression. Our ambition is to reduce the long-term impact of diabetes. As a core strategic area for the company, we are focusing our research and development efforts in diverse populations and patients with significant co-morbidities, such as cardiovascular disease, heart failure, obesity, non-alcoholic steatohepatitis (NASH), and chronic kidney disease.

About AstraZeneca

AstraZeneca is a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of cardiovascular, metabolic, respiratory, inflammation, autoimmune, oncology, infection and neuroscience diseases. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information please visit: www.astrazeneca.com.

CONTACTS

Petra Eurenius, External Communications, AstraZeneca Nordic-Baltic marketing company, 0709-186562

Kirsten Evraire +1 (215) 219-0368 (US)

[1]Lambers Heerspink, H. et al. “Dapagliflozin reduces albuminuria on top of renin-angiotensin system blockade in hypertensive patients with diabetes.” 51st Annual Meeting of the European Association for the Study of Diabetes. Abstract #185.

[2]Forxiga summary of product characteristics. Available at: https://www.medicines.org.uk/emc/medicine/27188. Last accessed September 2015.

[3]Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus. Geneva, World Health Organization, 1999 (WHO/NCD/NCS/99.2).

[4]Levitan B, Song Y, Ford ES, Liu S. Is nondiabetic hyperglycaemia a risk factor for cardiovascular

disease? A meta-analysis of prospective studies. Arch Intern Med. 2004;164:2147−55.

[5]International Diabetes Federation. IDF Diabetes Atlas, 6th edn. Poster Update 2014. Brussels, Belgium: International Diabetes Federation, 2014. http://www.idf.org/diabetesatlas/update-2014

[6]Cook M.N., et al. “Initial monotherapy with either metformin or sulphonylureas often fails to achieve or maintain current glycaemic goals in patients with type 2 diabetes in UK primary care.” Diabetic Med 2007: 24; 350-358.

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