Results presented at European Society of
Cardiology Congress 2022, and published in New England Journal of
Medicine
Data extend the clinically meaningful
benefits of FARXIGA in patients with heart failure regardless of
ejection fraction
Heart failure is a chronic, progressive
disease impacting nearly 64 million people
Detailed results from the DELIVER Phase III trial showed
AstraZeneca’s FARXIGA® (dapagliflozin) significantly reduced the
composite of cardiovascular (CV) death or worsening heart failure
(HF) in patients with HF and mildly reduced or preserved ejection
fraction (EF), compared to placebo. The results were presented
today at the European Society of Cardiology Congress 2022 in
Barcelona, Spain, and simultaneously published in The New England
Journal of Medicine.1
FARXIGA reduced the composite outcome of CV death or worsening
of HF by 18% (p<0.001, 16.4% in the dapagliflozin group and
19.5% (absolute risk reduction [ARR] 3.1%) in the placebo group
over a median follow-up of 2.3 years). All individual components
contributed to the superiority of the primary endpoint. The
findings were consistent across key subgroups examined and extend
the benefits of FARXIGA to the full spectrum of patients with HF
irrespective of left ventricular ejection fraction (LVEF) status.
The trial results also showed a symptom benefit in patient-reported
outcomes measured by the Kansas City Cardiomyopathy Questionnaire
(KCCQ) total symptom score.1
Dr. Scott Solomon, Professor of Medicine at Harvard Medical
School and Brigham and Women’s Hospital and Principal Investigator
of the DELIVER Phase III trial, said: “These results from DELIVER
are important for patients and clinical care as it shows that
dapagliflozin is effective regardless of ejection fraction and
therefore can be used as foundational therapy in all eligible
patients with heart failure. Earlier heart failure with preserved
ejection fraction trials have shown attenuation in the highest left
ventricular ejection fraction but with dapagliflozin results are
consistent across the ejection fraction range. The findings also
reinforce most recent treatment guidelines, recommending earlier
initiation of guideline-directed medical treatment and may support
broader use of SGLT2 inhibitors in clinical practice.”
The updated 2022 joint HF guidelines issued by the American
College of Cardiology, the American Heart Association and the Heart
Failure Society of America, now recommend sodium-glucose
cotransporter 2 (SGLT2) inhibitors such as FARXIGA for HF with
mildly reduced EF (HFmrEF) and HF with preserved EF (HFpEF). This
expands upon previous recommendations supporting the use of SGLT2
inhibitors in HF with reduced EF (HFrEF).2
Mene Pangalos, Executive Vice President, BioPharmaceuticals
R&D, AstraZeneca, said: “Heart failure patients with left
ventricular ejection fraction greater than 40% are the most
difficult to treat with few treatment options available to them. We
are proud to share the groundbreaking DELIVER results, which have
expanded our understanding of the complexities of HF. These data
build upon our previous studies demonstrating cardiorenal
protection of FARXIGA across patients with type 2 diabetes, chronic
kidney disease and heart failure.”
DELIVER was designed with broader inclusion criteria than prior
trials in this patient population to also include patients who were
hospitalized, recently hospitalized, or those with HF with improved
LVEF, for whom evidence-based therapy is limited.1,2 These findings
build upon the previously reported results from DAPA-HF, the only
SGLT2 inhibitor outcomes trial in HF to demonstrate a significant
reduction in mortality, to provide further evidence to support the
use of FARXIGA as foundational therapy for patients with HF,
regardless of EF.
The safety and tolerability profile of FARXIGA in the DELIVER
Phase III trial was consistent with the well-established safety
profile of the medicine.
INDICATIONS AND LIMITATIONS OF USE for FARXIGA®
(dapagliflozin)
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 either established
cardiovascular (CV) disease or multiple CV risk factors
- to reduce the risk of cardiovascular death and hospitalization
for heart failure in adults with heart failure (NYHA class II-IV)
with reduced ejection fraction
- to reduce the risk of sustained eGFR decline, end‑stage kidney
disease, cardiovascular death, and hospitalization for heart
failure in adults with chronic kidney disease at risk of
progression
FARXIGA is not recommended for patients with type 1 diabetes
mellitus. It may increase the risk of diabetic ketoacidosis in
these patients.
FARXIGA is not recommended for use to improve glycemic control
in adults with type 2 diabetes mellitus with an eGFR less than 45
mL/min/1.73 m2. FARXIGA is likely to be ineffective in this setting
based upon its mechanism of action.
FARXIGA is not recommended for the treatment of chronic kidney
disease in patients with polycystic kidney disease or patients
requiring or with a recent history of immunosuppressive therapy for
kidney disease. FARXIGA is not expected to be effective in these
populations.
DOSING
To improve glycemic control, the recommended starting dose is 5
mg orally once daily. Dose can be increased to 10 mg orally once
daily for additional glycemic control.
For all other indications, the recommended dose is 10 mg orally
once daily.
IMPORTANT SAFETY INFORMATION for FARXIGA® (dapagliflozin) 5
mg and 10 mg tablets
Contraindications
- Prior serious hypersensitivity reaction to FARXIGA
- Patients on dialysis
Warnings and Precautions
- Ketoacidosis in Diabetes Mellitus has been reported in
patients with type 1 and type 2 diabetes receiving FARXIGA. In
placebo-controlled trials of patients with type 1 diabetes, the
risk of ketoacidosis was increased in patients who received SGLT2
inhibitors compared to patients who received placebo. 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
- Volume Depletion: FARXIGA can cause intravascular volume
depletion which may manifest as symptomatic hypotension or acute
transient changes in creatinine. Acute kidney injury requiring
hospitalization and dialysis has been reported in patients with
type 2 diabetes receiving SGLT2 inhibitors, including FARXIGA.
Patients with impaired renal function (eGFR less than 60
mL/min/1.73 m2), elderly patients, or patients on loop diuretics
may be at increased risk for volume depletion or hypotension.
Before initiating FARXIGA in these patients, assess volume status
and renal function. After initiating therapy, monitor for signs and
symptoms of hypotension and renal function
- 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 with diabetes mellitus 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
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 link to US Full Prescribing Information for
FARXIGA.
Notes
HF
HF is a chronic, long-term condition that worsens over time.3 It
affects nearly 64 million people globally and is associated with
substantial morbidity and mortality.4,5 Chronic HF is the leading
cause of hospitalization for those over the age of 65 and
represents a significant clinical and economic burden.6 There are
several types of HF often defined by LVEF, a measurement of the
percentage of blood leaving the heart each time it contracts,
including: HFrEF (LVEF less than or equal to 40%), HFmrEF (LVEF
41-49%) and HFpEF (LVEF greater than or equal to 50%).2
Approximately half of all HF patients have HFmrEF or HFpEF, with
few therapeutic options available.2,7
DELIVER
DELIVER was an international, randomized, double-blind,
parallel-group, placebo-controlled, event-driven Phase III trial
designed to evaluate the efficacy of FARXIGA, compared with
placebo, in the treatment of HF patients with LVEF greater than
40%, with or without type 2 diabetes (T2D). FARXIGA was given once
daily in addition to background therapy (regional standard of care
[SoC] for all comorbidities, including diabetes and hypertension,
with the exception of concomitant use of a sodium-glucose
cotransporter 2 (SGLT2) inhibitor).8 DELIVER is the largest
clinical trial to date in HF patients with LVEF above 40%, with
6,263 randomized patients.8,9
The primary endpoint was the time to first occurrence of CV
death, hospitalization for HF (hHF) or an urgent HF visit. The
secondary endpoint includes the total number of HF events (hHF or
urgent HF visit) and CV death, change from baseline in the total
symptom score of the KCCQ at eight months, time to the occurrence
of CV death and time to the occurrence of death from any
cause.8
AstraZeneca in CVRM
Cardiovascular, Renal and Metabolism (CVRM), part of
BioPharmaceuticals, forms one of AstraZeneca’s main disease areas
and is 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 for organ protection and improving outcomes
by slowing disease progression, reducing risks and tackling
co-morbidities. The Company’s ambition is to modify or halt the
natural course of CVRM 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.
About AstraZeneca
AstraZeneca is a global, science-led biopharmaceutical company
that focuses on the discovery, development, and commercialization
of prescription medicines in Oncology, Rare Diseases, and
BioPharmaceuticals, including Cardiovascular, Renal &
Metabolism, and Respiratory & Immunology. Based in Cambridge,
UK, 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.
References
- Solomon S, et al. Dapagliflozin in Heart Failure with Mildly
Reduced or Preserved Ejection Fraction. N Engl J Med 2022
- Heidenreich PA, et al. 2022 AHA/ACC/HFSA Guideline for the
Management of Heart Failure: A report of the American College of
Cardiology/American Heart Association Joint Committee on Clinical
Practice Guidelines. J Am Coll Cardiol. 2022;79(17):e263-421.
- Cleveland Clinic [Internet]. Heart failure; [cited 2022 Jul 26]
Available from:
https://my.clevelandclinic.org/health/diseases/17069-heart-failure-understanding-heart-failure
- Vos T, et al. Global, regional, and national incidence,
prevalence, and years lived with disability for 328 diseases and
injuries for 195 countries, 1990–2016: A systematic analysis for
the Global Burden of Disease Study 2016. Lancet 2017;
390(10100):1211–59.
- Mozaffarian D, et al. Heart disease and stroke statistics—2016
update. Circulation. 2016; 133(4):e38–360.
- Azad N, et al. Management of chronic heart failure in the older
population. J Geriatr Cardiol. 2014; 11(4):329–37.
- Dunlay SM, et al. Epidemiology of heart failure with preserved
ejection fraction. Nat Rev Cardiol 2017;14(10):591–602.
- Solomon SD, et al. Dapagliflozin in heart failure with
preserved and mildly reduced ejection fraction: rationale and
design of the DELIVER trial. Eur J Heart Fail 2021;
23(7):1217–25.
- Clinicaltrials.gov [Internet]. Dapagliflozin Evaluation to
Improve the LIVEs of Patients With Preserved Ejection Fraction
Heart Failure; [cited 2022 Jul 26]. Available from:
https://clinicaltrials.gov/ct2/show/NCT03619213.
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