DURATION-8 trial met primary and secondary
endpoints, significantly reducing blood sugar (HbA1c), weight and
systolic blood pressure versus either medicine alone
The first Phase III trial to assess
GLP-1RA/SGLT-2i combination therapy
Positive results from the Phase III DURATION-8 trial
demonstrated that BYDUREON (exenatide extended-release) for
injectable suspension 2 mg once-weekly in combination with FARXIGA
(dapagliflozin) 10 mg once-daily significantly reduced blood sugar
as measured by HbA1c, versus the individual medicines alone in
patients with type 2 diabetes inadequately controlled on
metformin.1
This was the first clinical trial to combine these two different
anti-diabetes medicines, a GLP-1 receptor agonist and an SGLT-2
inhibitor, as an addition to standard-of-care therapy to evaluate
potential benefits for patients with type 2 diabetes with
inadequate glycemic control. The results were presented today at
the 52nd Annual Meeting of the European Association for the Study
of Diabetes (EASD) in Munich, Germany, and simultaneously published
in The Lancet Diabetes & Endocrinology.1
The trial achieved its primary endpoint with the combination of
exenatide once-weekly and dapagliflozin significantly reducing
HbA1c from baseline compared with exenatide once-weekly or
dapagliflozin alone (-2.0% versus -1.6% and -1.4% respectively,
both P<0.01), at 28 weeks.1
Serge A. Jabbour, MD, FACP, FACE, Professor of Medicine,
Director of the Division of Endocrinology and Director of the
Diabetes Center at the Sidney Kimmel Medical College at Thomas
Jefferson University, Philadelphia, said: “Because of the
progressive nature of type 2 diabetes, patients often require
multiple anti-diabetic medicines to achieve and maintain glycemic
control. The results of DURATION-8 show that combining medicines
that work in different ways can significantly reduce HbA1c, as well
as weight and systolic blood pressure.”
Elisabeth Bj�rk, Vice President, Head of Cardiovascular and
Metabolic Diseases, Global Medicines Development at AstraZeneca,
said: “With DURATION-8, AstraZeneca is the first company to
highlight the results of combining a GLP-1 receptor agonist and
SGLT-2 inhibitor as a potential treatment alternative to existing
non-insulin therapies for patients with severe, uncontrolled type 2
diabetes. Further, it reinforces our commitment to pushing the
boundaries of science in the treatment of a disease that affects an
estimated 415 million adults worldwide.”2
Secondary endpoints for the trial included changes in body
weight and systolic blood pressure. Patients receiving the
combination of exenatide once-weekly and dapagliflozin versus
either exenatide once-weekly or dapagliflozin alone
experienced:
- Significantly greater body weight
reduction (–3.4 kg versus –1.5 kg and –2.2 kg, respectively; both
P<0.01)
- Significantly greater systolic blood
pressure reduction (–4.2 mmHg vs –1.3 mmHg and –1.8 mmHg
respectively; both P<0.05)1
This combination of products is not FDA approved, and neither
product is approved for weight loss or the treatment of
hypertension.
The combination of exenatide once-weekly and dapagliflozin
exhibited similar rates of adverse events and serious adverse
events to the individual medicine treatment groups. The most common
adverse events (≥5% of patients in any group) were diarrhea,
injection-site nodule, nausea and urinary tract infection.1
Indication and Important Limitations of Use for
BYDUREON® (exenatide extended-release) for injectable
suspension
BYDUREON is indicated as an adjunct to diet and exercise to
improve glycemic control in adults with type 2 diabetes
mellitus.
- BYDUREON is not recommended as
first-line therapy for patients who have inadequate glycemic
control on diet and exercise because of the uncertain relevance of
the rat thyroid C-cell tumor findings to humans. Prescribe only to
patients for whom potential benefits are considered to outweigh
potential risk.
- Not a substitute for insulin, should
not be used in patients with type 1 diabetes or diabetic
ketoacidosis, and cannot be recommended for use with insulin.
- BYDUREON and BYETTA® (exenatide)
injection both contain the same active ingredient, exenatide, and
should not be used together.
- Exenatide has been associated with
acute pancreatitis, including fatal and non-fatal hemorrhagic or
necrotizing pancreatitis, based on postmarketing data. It is
unknown whether patients with a history of pancreatitis are at
increased risk for pancreatitis while using BYDUREON; consider
other antidiabetic therapies for these patients.
- BYDUREON is not indicated for weight
loss.
- BYDUREON is not indicated for the
treatment of hypertension.
IMPORTANT SAFETY INFORMATION
WARNING: RISK OF THYROID C-CELL TUMORS
- Exenatide extended-release causes an
increased incidence in thyroid C-cell tumors at clinically relevant
exposures in rats compared to controls. It is unknown whether
BYDUREON causes thyroid C-cell tumors, including medullary thyroid
carcinoma (MTC), in humans, as the human relevance of exenatide
extended-release-induced rodent thyroid C-cell tumors has not been
determined
- BYDUREON is contraindicated in
patients with a personal or family history of MTC or in patients
with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel
patients regarding the potential risk of MTC with the use of
BYDUREON and inform them of symptoms of thyroid tumors (e.g., mass
in the neck, dysphagia, dyspnea, persistent hoarseness). Routine
monitoring of serum calcitonin or using thyroid ultrasound is of
uncertain value for detection of MTC in patients treated with
BYDUREON
CONTRAINDICATIONS
- Personal or family history of MTC,
patients with MEN 2
- Prior serious hypersensitivity
reactions to exenatide or product components
WARNINGS AND PRECAUTIONS
- Pancreatitis Exenatide has been
associated with acute pancreatitis, including fatal and non-fatal
hemorrhagic or necrotizing pancreatitis. After initiation, observe
patients carefully for symptoms of pancreatitis. If suspected,
discontinue promptly and do not restart if confirmed. Consider
other antidiabetic therapies in patients with a history of
pancreatitis
- Hypoglycemia BYDUREON increased
the risk of hypoglycemia when coadministered with insulin and
insulin secretagogues. Consider lowering the dose of these agents
when coadministered with BYDUREON
- Renal Impairment Altered renal
function, including increased serum creatinine, renal impairment,
worsened chronic renal failure, and acute renal failure, sometimes
requiring hemodialysis and kidney transplantation has been
reported. Not recommended in patients with severe renal impairment
or end-stage renal disease. Use caution in patients with renal
transplantation or moderate renal failure
- Severe Gastrointestinal Disease
Because exenatide is commonly associated with gastrointestinal
adverse reactions, not recommended in patients with severe
gastrointestinal disease (eg, gastroparesis)
- Immunogenicity Patients may
develop antibodies to exenatide. In 5 registration trials,
attenuated glycemic response was associated in 6% of
BYDUREON-treated patients with antibody formation. If worsening of
or failure to achieve adequate glycemic control occurs, consider
alternative antidiabetic therapy
- Hypersensitivity Reports of
serious hypersensitivity reactions (eg, anaphylaxis and
angioedema). If this occurs, patients should discontinue BYDUREON
and promptly seek medical advice
- Injection-Site Reactions Serious
reactions (eg, abscess, cellulitis, and necrosis), with or without
subcutaneous nodules, have been reported
- Macrovascular Outcomes No
clinical studies establishing conclusive evidence of macrovascular
risk reduction with BYDUREON or any other antidiabetic drug
ADVERSE REACTIONS
Most common (≥5%) and occurring more frequently than comparator
in clinical trials: nausea (16.9%), diarrhea (12.7%), headache
(8.0%), vomiting (6.8%), constipation (5.9%), injection-site
pruritus (5.9%), injection-site nodule (5.3%), and dyspepsia
(5.1%)
DRUG INTERACTIONS
- Oral Medications BYDUREON slows
gastric emptying and may reduce the rate of absorption of orally
administered drugs
- Warfarin Increased international
normalized ratio (INR) sometimes associated with bleeding has been
reported with concomitant use of exenatide with warfarin. Monitor
INR frequently until stable upon initiation of BYDUREON
PREGNANT AND NURSING WOMEN
- Pregnant Women Based on animal
data, may cause fetal harm. Use during pregnancy only if the
potential benefit justifies the potential risk to the fetus. Report
drug exposure during pregnancy at 1- 800-633-9081
- Nursing Women Discontinue
BYDUREON or discontinue nursing
Please click here for Full Prescribing
Information and click here for Medication Guide for
BYDUREON 2 mg, including Boxed WARNING regarding risk of thyroid
C-cell tumors.
Indication 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.
FARXIGA is not recommended for patients with type 1 diabetes
mellitus or for the treatment of diabetic ketoacidosis.
FARXIGA is not indicated for weight loss or the treatment of
hypertension.
10 mg is not the recommended starting dose for FARXIGA.
Important Safety Information for FARXIGA®
(dapagliflozin)
Contraindications
- History of a 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
- 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 or any other antidiabetic
drug
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
- Pregnant Women: There are no
adequate and well-controlled studies of FARXIGA in pregnant women.
Consider appropriate alternative therapies, especially during the
second and third trimesters. Use during pregnancy only if the
potential benefit justifies the potential risk to the fetus
- Nursing Mothers: Discontinue
FARXIGA or discontinue nursing
Please click here for US Full Prescribing
Information and Medication Guide for FARXIGA.
NOTES TO EDITORS
About DURATION-8
DURATION-8 was a Phase III, randomized, multi-center,
double-blind, active-controlled trial which evaluated the safety
and efficacy of simultaneous administration of exenatide
once-weekly and dapagliflozin once-daily compared to treatment with
the individual medicines in adult patients with type 2 diabetes who
were inadequately controlled on metformin.1
The trial was conducted over a 28-week treatment period, with an
extension to two years, and enrolled approximately 700 patients in
six countries. Eligible participants included adult patients with
type 2 diabetes who had uncontrolled HbA1c (a protein within red
blood cells that when bound with glucose is measurable to determine
average blood sugar levels during a specific period) levels at
baseline ranging from 8.0% to 12.0%. The primary endpoint was
change in HbA1c from baseline to week 28. Secondary endpoints
included changes in body weight, systolic blood pressure, fasting
plasma glucose, two hour postprandial glucose and the proportion of
patients achieving HbA1c <7.0% over the 28-week treatment
period.1
About AstraZeneca in Diabetes
AstraZeneca is pushing the boundaries of science with the goal
of developing life-changing medicines that aim to reduce the global
burden and complications of diabetes. As a core therapy area for
the company, we are focusing our research and development efforts
on diverse populations and patients with significant
co-morbidities, such as cardiovascular disease, obesity,
non-alcoholic steatohepatitis (NASH), and chronic kidney
disease.
Our commitment to diabetes is exemplified by the depth and
breadth of our global clinical research program. This commitment is
advancing understanding of the treatment effects of our diabetes
medicines in broad patient populations, as well as exploring
combination product approaches to help more patients achieve
treatment success earlier in their disease progression. Our
ambition is to reduce the long-term impact of diabetes.
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 – Respiratory and Autoimmunity, Cardiovascular
and Metabolic Diseases, and Oncology. The company is also active in
inflammation, infection and neuroscience through numerous
collaborations. 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
References
- Frias JP, Guja C, Hardy E, et al.
Exenatide once weekly plus dapagliflozin once daily versus
exenatide or dapagliflozin alone in patients with type 2 diabetes
inadequately controlled with metformin monotherapy (DURATION-8): a
28 week, multicenter, double-blind, phase 3, randomized controlled
trial [published online ahead of print September 16, 2016]. Lancet
Diabetes Endocrinol. 2016.
http://dx.doi.org/10.1016/S2213-8587(16)30267-4. Accessed September
16, 2016.
- International Diabetes Federation. IDF
Diabetes Atlas, 7th ed. Brussels, Belgium: International Diabetes
Federation, 2015. http://www.idf.org/about-diabetes/facts-figures.
Accessed September 15, 2015.
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