FARXIGA Achieved a Positive Result in the Phase III DECLARE-TIMI 58 Trial, a Large Cardiovascular Outcomes Trial in 17,000 Patients with Type 2 Diabetes

WILMINGTON, Del.--(BUSINESS WIRE)-- AstraZeneca today announced positive results from the Phase III DECLARE-TIMI 58 cardiovascular (CV) outcomes trial (CVOT) for FARXIGA^® (dapagliflozin), the broadest SGLT-2 inhibitor CVOT conducted to date. The trial evaluated the CV outcomes of FARXIGA vs. placebo over a period of up to five years, across 33 countries and in more than 17,000 adults with type 2 diabetes (T2D) who have multiple CV risk factors or established CV disease.

In the DECLARE (Dapagliflozin Effect on Cardiovascular Events)-TIMI 58 trial, FARXIGA met its primary safety endpoint of non-inferiority for major adverse cardiovascular events (MACE). FARXIGA achieved a statistically-significant reduction in the composite endpoint of hospitalization for heart failure (hHF) or CV death, one of the two primary efficacy endpoints. Additionally, fewer MACE events were observed with FARXIGA for the other primary efficacy endpoint, however, this did not reach statistical significance. FARXIGA is not indicated to reduce the risk of CV events or hHF.

Data from DECLARE-TIMI 58 confirmed the well-established safety profile of FARXIGA.

Elisabeth Björk, Vice President, Head of Cardiovascular, Renal and Metabolism, Global Medicines Development at AstraZeneca said: “FARXIGA has achieved a statistically-significant and clinically-important reduction in hospitalization for heart failure or CV death in a broad range of patients with type 2 diabetes and cardiovascular risk. The results from this landmark trial are especially important since heart failure is an early and frequent complication of diabetes and associated with hospitalizations that result in a considerable societal and economic burden.” ^1-7

Dr Stephen Wiviott of Brigham and Women’s Hospital and Harvard Medical School, a senior investigator with the Thrombolysis in Myocardial Infarction (TIMI) study group and co-principal investigator of the trial, commented: “The DECLARE-TIMI 58 results offer compelling evidence that dapagliflozin helps to address an important medical need among a diverse group of patients with type 2 diabetes by reducing the composite of hospitalization for heart failure or CV death, with a safety profile supportive of broad use.”

Detailed trial results will be presented on November 10 at the American Heart Association Scientific Sessions 2018 in Chicago, IL.

INDICATION AND LIMITATIONS OF USE FOR FARXIGA (dapagliflozin) tablets 5 mg and 10 mg

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.

IMPORTANT SAFETY INFORMATION FOR FARXIGA

Contraindications

• Prior serious hypersensitivity reaction to FARXIGA
• Severe renal impairment (eGFR <30 mL/min/1.73 m²), end-stage renal disease, or patients on dialysis

Warnings and Precautions

• Hypotension: FARXIGA causes intravascular volume contraction, and symptomatic hypotension can occur. Assess and correct volume status before initiating FARXIGA in patients with impaired renal function, elderly patients, or patients on loop diuretics. Monitor for hypotension
• Ketoacidosis has been reported in patients with type 1 and type 2 diabetes receiving FARXIGA. Some cases were fatal. 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 in situations known to predispose to ketoacidosis
• Acute Kidney Injury and Impairment in Renal Function: FARXIGA causes intravascular volume contraction and renal impairment, with reports of acute kidney injury requiring hospitalization and dialysis. Consider temporarily discontinuing in settings of reduced oral intake or fluid losses. If acute kidney injury occurs, discontinue and promptly treat.
  FARXIGA increases serum creatinine and decreases eGFR. Elderly patients and patients with impaired renal function may be more susceptible to these changes. Before initiating FARXIGA, evaluate renal function and monitor periodically. FARXIGA is not recommended in patients with an eGFR persistently between 30 and <60 mL/min/1.73 m²
• Urosepsis and Pyelonephritis: SGLT2 inhibitors increase the risk for urinary tract infections [UTIs] and serious UTIs have been reported with FARXIGA. Evaluate for signs and symptoms of UTIs and treat promptly
• Hypoglycemia: FARXIGA can increase the risk of hypoglycemia when coadministered with insulin and insulin secretagogues. Consider lowering the dose of these agents when coadministered with FARXIGA
• Genital Mycotic Infections: FARXIGA increases the risk of genital mycotic infections, particularly in patients with prior genital mycotic infections. Monitor and treat appropriately
• Increases in Low-Density Lipoprotein Cholesterol (LDL-C) occur with FARXIGA. Monitor LDL-C and treat per standard of care
• Bladder cancer: An imbalance in bladder cancers was observed in clinical trials. There were too few cases to determine whether the emergence of these events is related to FARXIGA, and 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 history of bladder cancer
• Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with FARXIGA

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

• Pregnancy: Advise females of potential risk to a fetus especially during the second and third trimesters.
• Lactation: FARXIGA is not recommended when breastfeeding

Please read US Full Prescribing Information and Medication Guide for FARXIGA

Notes to Editors:

About DECLARE-TIMI 58:
DECLARE (Dapagliflozin Effect on Cardiovascular Events)-TIMI-58 is an AstraZeneca-sponsored, randomized, double-blinded, placebo-controlled, multicenter trial designed to evaluate the effect of FARXIGA compared with placebo on CV outcomes in adults with T2D at risk of CV events, including patients with multiple CV risk factors or established CV disease. DECLARE included more than 17,000 patients across 882 sites in 33 countries and was independently run in collaboration with academic investigators from the TIMI study group (Boston, USA) and the Hadassah Hebrew University Medical Center (Jerusalem, Israel).⁸

DECLARE is part of the extensive DapaCare clinical program for FARXIGA, which will enroll patients in randomized clinical trials, including a wide range of mechanistic studies, and is supported by a multinational real-world evidence study (CVD-REAL). The DapaCare clinical program will generate data across a spectrum of people with CV risk factors, established CV disease and varying stages of renal disease, both with and without T2D. DECLARE is paving the way for three Phase III trials: Dapa-HF, DELIVER and Dapa-CKD.

About AstraZeneca in Cardiovascular, Renal & Metabolism (CVMD)
Cardiovascular, renal and metabolic diseases together form one of AstraZeneca’s main therapy areas and platforms for future growth. By following the science to understand more clearly the underlying links between the heart, kidney and pancreas, AstraZeneca is investing in a portfolio of medicines to protect organs and improve outcomes by slowing disease progression, reducing risks and tackling co-morbidities. Our ambition is to modify or halt the natural course of CVMD diseases and even regenerate organs and restore function, by continuing to deliver transformative science that improves treatment practices and cardiovascular health for millions of patients worldwide.

About AstraZeneca
AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of diseases in three therapy areas – Oncology, Cardiovascular, Renal & Metabolism and Respiratory. The Company also is selectively active in the areas of autoimmunity, neuroscience and infection. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information, please visit http://www.astrazeneca-us.com and follow us on Twitter @AstraZenecaUS.

References

1. International Diabetes Federation, IDF Diabetes Atlas, Eighth Edition Update, 2017.
2. Shah AD, Langenberg C, Rapsomaniki E, et al. Type 2 diabetes and incidence of cardiovascular diseases: a cohort study in 1·9 million people. Lancet Diabetes Endocrinol. 2015;3:105-113.
3. Faden, et al. The increasing detection of asymptomatic left ventricular dysfunction in patients with type 2 diabetes mellitus without overt cardiac disease: Data from the SHORTWAVE study. Diabetes Res Clin Pract. 2013;101(3):309-16.
4. Low Wang, Cecilia C. et al. “Atherosclerotic Cardiovascular Disease and Heart Failure in Type 2 Diabetes – Mechanisms, Management, and Clinical Considerations.” Circulation 133.24 (2016): 2459–2502. PMC. Web. 19 Sept. 2018.
5. Heidenreich, Paul A. et al. “Forecasting the Impact of Heart Failure in the United States: A Policy Statement From the American Heart Association.” Circulation. Heart failure 6.3 (2013): 606–619. PMC. Web. 19 Sept. 2018.
6. Nichols GA, Brown JB: The impact of cardiovascular disease on medical care costs in subjects with and without type 2 diabetes. Diabetes Care 25:482–486, 2002.
7. Nichols, et al. The incidence of congestive heart failure in type 2 diabetes. Diabetes Care, Volume 27, Number 8, August 2004: http://care.diabetesjournals.org/content/27/8/1879.
8. DECLARE - Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events(DECLARE-TIMI58). Accessed September 2018. https://clinicaltrials.gov/ct2/show/NCT01730534.

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