Results from the DELIVER and DAPA-HF Phase
III trials demonstrate FARXIGA’s efficacy in heart failure
regardless of ejection fraction
High-level results from the DELIVER Phase III trial showed
AstraZeneca’s FARXIGA (dapagliflozin) reached a statistically
significant and clinically meaningful reduction in the primary
composite endpoint of cardiovascular (CV) death or worsening heart
failure (HF). The trial was conducted in patients with HF with
mildly reduced or preserved ejection fraction (defined as left
ventricular ejection fraction [LVEF] greater than 40%).
HF is a chronic, long-term condition that worsens over time1. It
affects nearly 64 million people globally2 and is associated with
substantial morbidity and mortality3. There are several main
categories of HF related to ejection fraction (EF), a measurement
of the percentage of blood leaving the heart each time it contracts
including: HF with reduced EF (HFrEF) (LVEF less than or equal to
40%), HF with mildly reduced EF (HFmrEF) (LVEF 41-49%) and
preserved EF (HFpEF) (LVEF greater than or equal to 50%)4.
Approximately half of all HF patients have mildly reduced or
preserved EF with few therapeutic options available4,5. FARXIGA
already has approved indications relating to the treatment of type
2 diabetes (T2D), HFrEF and chronic kidney disease (CKD).
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: “We are delighted to have met
the primary endpoint in this patient population which has few
treatment options. DELIVER is the largest and broadest trial to
date in heart failure with mildly reduced or preserved ejection
fraction. The results of DELIVER extend the benefit of
dapagliflozin to the full spectrum of patients with heart
failure.”
Mene Pangalos, Executive Vice President, BioPharmaceuticals
R&D, AstraZeneca, said: "Today’s groundbreaking results coupled
with those from the DAPA-HF trial show that FARXIGA is effective in
treating heart failure regardless of ejection fraction. These data
build upon our previous studies demonstrating cardiorenal
protection across patients with either diabetes, chronic kidney
disease or heart failure.”
The safety and tolerability profile of FARXIGA in the DELIVER
Phase III trial were consistent with the well-established safety
profile of the medicine.
The full DELIVER Phase III trial results will be submitted for
presentation at a forthcoming medical meeting and regulatory
submissions will be made in the coming months.
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 diseaseat 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 Mellitushas 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 affects approximately 64 million people worldwide2, at least
half of whom have a reduced EF6, including approximately 15 million
in the EU7, six million in the US8, and 13.7 million treated adults
in China9. There are several main categories of HF related to EF, 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%)1,4. HF with EF above 40% represents about half of all HF
cases, and is highly prevalent in patients with hypertension, T2D,
obesity, metabolic syndrome or CKD4,5,10. HF remains as fatal as
some of the most common cancers in both men (prostate and bladder
cancers) and women (breast cancer)11. Chronic HF is the leading
cause of hospitalization for those over the age of 65 and
represents a significant clinical and economic burden12.
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 T2D. FARXIGA was given once daily in addition to
background therapy (regional standard of care for all
comorbidities, including diabetes and hypertension, with the
exception of concomitant use of a sodium-glucose cotransporter 2
[SGLT2] inhibitor)13. DELIVER is the largest clinical trial to date
in HF patients with EF above 40%, with 6,263 randomized patients13,
14.
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 Kansas City Cardiomyopathy Questionnaire at
eight months, time to the occurrence of CV death and time to the
occurrence of death from any cause13.
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
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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;
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update. Circulation. 2016; 133(4):e38–360.
- Dunlay SM, et al. Epidemiology of heart failure with preserved
ejection fraction. Nat Rev Cardiol 2017;14(10):591–602.
- 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.
- Travessa AMR, et al. Treatment of heart failure with reduced
ejection fraction-recent developments. Am J Ther 2016;
23(2):e531–49.
- Dickstein K, et al. ESC Guidelines for the diagnosis and
treatment of acute and chronic heart failure 2008: the Task Force
for the Diagnosis and Treatment of Acute and Chronic Heart Failure
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- Virani SS, et al. Heart disease and stroke statistics-2020
update: a report from the American Heart Association. Circulation
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- AstraZeneca. Data on File. February 2020.
- Triposkiadis F, et al. Reframing the association and
significance of co-morbidities in heart failure. Eur J Heart Fail
2016;18(7):744–58.
- Mamas MA, et al. Do patients have worse outcomes in heart
failure than in cancer? A primary care-based cohort study with
10-year follow-up in Scotland. Eur J Heart Fail 2017;
19(9):1095–104.
- Azad N, et al. Management of chronic heart failure in the older
population. J Geriatr Cardiol. 2014; 11(4):329–37.
- 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.
14. Clinicaltrials.gov [Internet]. Dapagliflozin Evaluation to
Improve the LIVEs of Patients With Preserved Ejection Fraction
Heart Failure; [cited 2022 Jan 11]. Available from:
https://clinicaltrials.gov/ct2/show/NCT03619213. 15. McMurray JJV,
et al. Dapagliflozin in patients with heart failure and reduced
ejection fraction. N Engl J Med 2019; 381(21):1995–2008. 16.
Heerspink HJL, et al. Dapagliflozin in patients with chronic kidney
disease. N Engl J Med 2020; 383(15):1436–46. 17. Wiviott SD, et al.
for the DECLARE-TIMI 58 Investigators. Dapagliflozin and
cardiovascular outcomes in type-2 diabetes [article and
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