First Sub-Analyses from the DECLARE-TIMI 58 Trial Further Support the Cardiovascular Effects of FARXIGA in Type 2 Diabetes

Business Wire 18-Mar-2019 9:01 AM

FARXIGA reduced major adverse cardiovascular events by 16% in patients who had a prior heart attack

FARXIGA reduced hospitalization for heart failure regardless of ejection fraction status

Positive results from a pre-specified sub-analysis of the Phase III DECLARE-TIMI 58 trial showed that FARXIGA (dapagliflozin) reduced the relative risk of major adverse cardiovascular events (MACE) by 16% compared to placebo (15.2% vs 17.8%; HR 0.84, [95% CI 0.72-0.99]) in patients with type 2 diabetes (T2D) who had a prior heart attack (myocardial infarction).

In another pre-specified sub-analysis, FARXIGA compared to placebo reduced the relative risk of hospitalization for heart failure (hHF) in patients with T2D regardless of their ejection fraction (EF) status, a measurement of the percentage of blood leaving the heart with each contraction. FARXIGA reduced hospitalization for heart failure by 36% in patients with HF reduced ejection fraction (HFrEF) (13.5% vs 19.0%; HR 0.64, [95% CI, 0.43-0.95]) and by 24% in patients without HFrEF (2.1% vs 2.7%; HR 0.76, [95% CI 0.62-0.92]).

The data were presented today at the American College of Cardiology's (ACC) 68th Annual Scientific Session, New Orleans, USA and were published in Circulation.^1,2

Elisabeth Björk, Senior Vice President, Head of late Cardiovascular, Renal and Metabolism, R&D BioPharmaceuticals, said: "These data build upon the existing evidence of the cardio-renal effects of FARXIGA, with important new evidence on heart failure and MACE. Heart failure is one of the most common early cardiovascular complications of type 2 diabetes. Despite advances in healthcare, it remains as life-threatening and prevalent as the combined incidence of the top-four most common forms of cancer. Therefore, more needs to be done for patients."

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, said: "Data from these pre-specified sub-analyses offer important and clinically-relevant insights for cardiologists and their patients. We now have new evidence from DECLARE-TIMI 58 that shows FARXIGA consistently reduced hospitalization for heart failure across a broad range of patients with type 2 diabetes, regardless of their history of existing CV disease, including heart attack, or heart failure."

These pre-specified sub-analyses of DECLARE-TIMI 58 add to the positive primary results of the trial presented in November 2018, which showed that FARXIGA significantly reduced the risk of the composite of hHF or CV death compared to placebo, consistently across the trial's entire patient population. Additionally, there were fewer major adverse cardiovascular events observed with FARXIGA in the broad patient population, however this did not reach statistical significance. FARXIGA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. FARXIGA is not indicated to reduce the risk of CV events, HF, or death.

Indication and Limitations of Use for FARXIGA^® (dapagliflozin) tablets

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^® (dapagliflozin) tablets

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 when the eGFR is <45 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
• Necrotizing Fasciitis of the Perineum (Fournier's Gangrene): Rare but serious, life-threatening cases have been reported in patients receiving SGLT2 inhibitors including FARXIGA. Cases have been reported in females and males. Serious outcomes have included hospitalization, surgeries, and death. Assess patients presenting with pain or tenderness, erythema, swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment and discontinue 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 see accompanying 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, multicentre 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).

About DapaCare

DECLARE is part of the extensive DapaCare clinical programme for FARXIGA, which will enroll patients in randomized clinical trials including a wide range of mechanistic trials and is supported by a multinational real-world evidence study (CVD-REAL). The DapaCare clinical programme 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. FARXIGA is not indicated to reduce the risk of CV events, CV death, or hHF, or the treatment of 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. 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 and follow us on Twitter @AstraZenecaUS.

US-26487 Last Updated 3/19

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