November 13, 2019 — AstraZeneca announced a pre-specified sub-analysis from the landmark Phase III DAPA-HF trial investigating FARXIGA® (dapagliflozin) for the treatment of heart failure (HF). The data showed that FARXIGA on top of standard of care reduced the incidence of the primary composite endpoint of cardiovascular (CV) death or worsening of HF in patients with HF with reduced ejection fraction (HFrEF), irrespective of the presence of chronic kidney disease (CKD).
These data were presented at the American Society of Nephrology (ASN) Kidney Week 2019, which takes place from November 5-10, 2019 in Washington, DC.
Elisabeth Björk, Senior Vice President, Head of Late-stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, said: “These results underscore our commitment to reduce the burden of cardiovascular, renal and metabolic diseases. Heart failure affects 64 million patients worldwide, and more than 40% of people living with heart failure have chronic kidney disease, considerably worsening their prognoses and reducing their probability of survival. We are proud our research will help support potential solutions for the millions of people impacted by these interrelated diseases.”
DAPA-HF is the first outcomes trial with an SGLT2 inhibitor investigating the treatment of HF in patients with HFrEF with and without type 2 diabetes (T2D). In the sub-analysis, FARXIGA treatment was associated with a 28% relative risk reduction (absolute risk reduction 19.9% vs 26.3%, HR 0.72 [95% CI 0.59-0.86]) for the composite of CV death or worsening HF event in patients with CKD (estimated glomerular filtration rate [eGFR] < 60 ml/min/1.73m2 at baseline) and by a similar magnitude in those patients without CKD (13.8% vs 17.6%, HR 0.76 [95% CI 0.63, 0.92]).
The sub-analysis also suggested that FARXIGA may attenuate the long-term decline in glomerular filtration rate (GFR) in patients with HF after the expected initial small reduction in eGFR. The rates of amputation, fracture, volume depletion and renal adverse events were balanced between treatment groups in both the patients with and without CKD.
These data add to the scientific evidence for FARXIGA, which is now approved in the US to reduce the risk of hospitalization for heart failure (hHF) in adults with T2D and established CV disease or multiple CV risk factors, based on results from the landmark Phase III DECLARE-TIMI 58 trial.
DECLARE-TIMI 58 is the largest CV outcomes trial conducted for an SGLT2 inhibitor to date, evaluating T2D patients with multiple CV risk factors or established CV disease. A new sub-analysis from that trial showed that FARXIGA slowed the progression of renal disease across all subgroups of patients with T2D, including patients with normal kidney function and in patients with normo-albuminuria. FARXIGA attenuated the eGFR decline in patients with T2D overall and in subgroups based on baseline eGFR, urine albumin-to-creatinine ratio (UACR), use of ACEi/ARB and diuretics. Although only nominally significant, as endpoints were exploratory, fewer patients experienced an eGFR decline of 30% (HR 0.68 [95% CI 0.58, 0.79], p<0.002), 40% (HR 0.54 [95% CI 0.43, 0.67], p<0.002), or 50% (HR 0.57 [95% CI 0.40, 0.81], p<0.002) to eGFR <60 ml/min/1.73m2 with FARXIGA versus placebo.
AstraZeneca announced in August 2019 that the US Food and Drug Administration (FDA) granted Fast Track designation for the development of FARXIGA to delay the progression of renal failure and prevent CV and renal death in patients with CKD. The Phase III DAPA-CKD trial evaluates the effect of FARXIGA on renal outcomes and CV mortality in patients with CKD with and without T2D versus placebo, on top of standard of care. Additionally, in September 2019, the FDA granted Fast Track designation for FARXIGA to reduce the risk of CV death, or the worsening of HF in adults with HFrEF or HF with preserved ejection fraction (HFpEF) based on the Phase III DAPA-HF and DELIVER trials. FARXIGA is not approved to reduce the risk of HF in patients without T2D, or to reduce the risk of CV death or renal disease.
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
- to reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and established cardiovascular disease or multiple cardiovascular risk factors
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
- 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: FARXIGA causes intravascular volume contraction and can cause acute kidney injury. Reports of acute kidney injury requiring hospitalization and dialysis have occurred with FARXIGA. If acute kidney injury occurs, discontinue and promptly treat
Increases in serum creatinine and decreases in eGFR may be observed with initiation of FARXIGA. Elderly patients and patients with impaired renal function may be more susceptible to these changes. Consider temporarily discontinuing in settings of reduced oral intake or fluid losses
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
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.
DAPA-HF (Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure) is an international, multicenter, parallel group, randomized, double-blind trial in patients with heart failure and reduced ejection fraction (LVEF ≤ 40%), with and without T2D, designed to evaluate the effect of FARXIGA 10mg, compared with placebo, given once daily in addition to standard of care. The primary composite outcome was time to a worsening heart failure event (hospitalization or equivalent event; i.e. an urgent heart failure visit), or cardiovascular death.
About DECLARE-TIMI 58
DECLARE (Dapagliflozin Effect on Cardiovascular Events)-TIMI 58 is the largest CV outcomes trial conducted for a selective inhibitor of SGLT2 to date in a broad patient population. It is an AstraZeneca-sponsored, Phase III, randomized, double-blind, 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 and also assessed key renal secondary endpoints. The trial includes 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, US) and the Hadassah Hebrew University Medical Center (Jerusalem, Israel).
About AstraZeneca in CV, Renal & Metabolism (CVMD)
CV, renal and metabolism together form one of AstraZeneca’s main therapy areas and a key growth driver for the Company. By following the science to understand more clearly the underlying links between the heart, kidneys 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 potentially regenerate organs and restore function, by continuing to deliver transformative science that improves treatment practices and CV health for millions of patients worldwide.
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.