Fewer MACE events observed with FARXIGA vs.
placebo, but this finding did not reach statistical
significance
No imbalance in amputations, fractures,
bladder cancer or Fournier’s gangrene with FARXIGA vs.
placebo
AstraZeneca today announced positive full results from the
DECLARE-TIMI 58 cardiovascular (CV) outcomes trial (CVOT) for
FARXIGA (dapagliflozin). The data were presented as a late-breaking
abstract (#19485) at the American Heart Association (AHA)
Scientific Sessions 2018 in Chicago, IL, and simultaneously
published in the New England Journal of Medicine (NEJM).1
Results from DECLARE-TIMI 58, the largest SGLT-2 inhibitor
(SGLT-2i) CVOT conducted to date, including more than 17,000
patients across 33 countries, showed that FARXIGA significantly
reduced the risk of hospitalization for heart failure (hHF) or
CV death composite vs. placebo by 17% (4.9% vs. 5.8%; HR 0.83 [95%
CI 0.73-0.95], p=0.005), one of the two primary efficacy endpoints.
The reduction in hHF or CV death was consistent across the entire
patient population, which included those with CV risk factors and
those with established CV disease.1 FARXIGA is not indicated to
reduce the risk of CV events or hHF.
Additionally, there were fewer major adverse cardiovascular
events (MACE) observed with FARXIGA for the other primary efficacy
endpoint, however this did not reach statistical significance (8.8%
for FARXIGA vs. 9.4% for placebo; HR 0.93 [95% CI 0.84-1.03],
p=0.17).1
DECLARE-TIMI 58 also confirmed the well-established safety
profile for FARXIGA, which met the primary safety endpoint of
non-inferiority vs. placebo, demonstrating no increase in the
composite of MACE, defined as CV death, heart attack (myocardial
infarction), or stroke.1
Further, on other relevant safety measures, the trial showed no
imbalance with FARXIGA vs. placebo in amputations (1.4% vs. 1.3%),
fractures (5.3% vs. 5.1%), bladder cancer (0.3% vs. 0.5%) or
Fournier’s gangrene (1 case vs. 5 cases). The respective incidences
of diabetic ketoacidosis (0.3% vs. 0.1%) and genital infections
(0.9% vs. 0.1%) were rare.1
Elisabeth Bj�rk, Vice President, Head of Cardiovascular, Renal
and Metabolism, Global Medicines Development, said: “These positive
results are clinically relevant to the 425 million people worldwide
living with diabetes, of whom those with type 2 diabetes have a
two-to-five times greater risk of heart failure along with an
increased risk of a heart attack or stroke. Heart failure survival
rates are only 50% after five years from diagnosis, which is why
these new findings are so important in broadening our understanding
of how to go beyond blood glucose so we may better address this
serious and often overlooked cardiovascular complication.”2-6
Although secondary endpoints were only nominally significant,
the renal composite endpoint showed that FARXIGA reduced the rate
of new or worsening nephropathy by 24% vs. placebo across the broad
patient population studied (4.3% vs. 5.6%; HR 0.76 [95% CI
0.67-0.87]), and there were fewer all-cause mortality events with
FARXIGA vs. placebo (6.2% vs. 6.6%; HR 0.93 [95% CI 0.82-1.04]).1
FARXIGA is not indicated to reduce the risk of HF, other CV
outcomes, nephropathy or all-cause mortality.
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
- 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 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).
About DapaCare
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. Wiviott SD, et al. Dapagliflozin and Cardiovascular
Outcomes in Type 2 Diabetes. New England Journal of Medicine. 2018
Nov. DOI: 10.1056/NEJMoa181289 2. International Diabetes
Federation. IDF Diabetes Atlas, 8th ed. Brussels, Belgium:
International Diabetes Federation; 2017. Available at
http://www.diabetesatlas.org/resources/2017-atlas.html. Accessed
November 10, 2018 3. Low Wang CC, Hess CNm Hiatt WR, et al.
Clinical Update: Cardiovascular Disease in Diabetes Mellitus
Atherosclerotic Cardiovascular Disease and Heart Failure in Type 2
Diabetes Mellitus – Mechanisms, Management, and Clinical
Considerations. Circulation. 2016 Jun 14;133(24):2459-502 4. Wu Y,
Ding Y, Tanaka Y, et al. Risk Factors Contributing to Type 2
Diabetes and Recent Advances in the Treatment and Prevention. Int.
J. Med. Sci. 2014;11(11):1185-1200. 5. Nichols, et al. The
incidence of congestive heart failure in type 2 diabetes. Diabetes
Care. 2004 Aug;27(8):1879-84 6. Roger VL. Epidemiology of heart
failure. Circulation Research. 2013;113:646-659
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