Important short-term and long-term data on a
potential new use of Farxiga (dapagliflozin) showed significant
reductions in HbA1c in patients with type 1 diabetes
AstraZeneca (NYSE: AZN) presented key data on the use of
FARXIGA® (dapagliflozin) in diverse patient populations with type 2
and type 1 diabetes (T2D, T1D) at the American Diabetes Association
(ADA) 78th Scientific Sessions this week in Orlando, FL, June
22-26, 2018.
These studies reinforce the use of dapagliflozin as a treatment
option to help improve glycemic control when used with the DPP-4
inhibitor ONGLYZA® (saxagliptin) versus older treatment options
(insulin, sulfonylurea) in patients with T2D. Data
investigating the impact of dapagliflozin across patients with a
spectrum of cardiovascular (CV) risks were also presented to help
further the scientific understanding of the effects of SGLT-2
inhibitors (SGLT-2i) on CV events. In addition, new data
investigating dapagliflozin in T1D was also presented.
Elisabeth Bj�rk, Vice President, Head of Cardiovascular, Renal
and Metabolism, Global Medicines Development, AstraZeneca said: “As
demonstrated by the broad data on Farxiga featured at ADA, we are
firmly committed to addressing the complex unmet needs of people
affected by diabetes, of whom many have interrelated CV risks.
Through our completed and ongoing research with Farxiga, we’re
proud to have developed a highly representative clinical program
that we believe will help change clinical practice for diverse
patient populations where there remains a need for earlier and more
aggressive treatment approaches with SGLT-2 inhibitors.”
Highlights from the 23 dapagliflozin abstracts presented
include:
Dapagliflozin in Combination with Saxagliptin Head-to-Head
vs. Insulin or Sulfonylurea in T2D
In T2D, two new phase IIIb studies evaluating the efficacy and
safety of dapagliflozin in combination with saxagliptin
demonstrated non-inferior HbA1c reduction compared to insulin
glargine with or without sulfonylurea and significant reduction in
HbA1c vs. glimepiride in patients inadequately controlled on
metformin. Specifically, results showed:
- In a 24-week non-inferiority study (N=
643), dapagliflozin 10mg and saxaglipitin 5mg plus metformin in
patients with T2D, compared to titrated insulin glargine plus
metformin, resulted in similar HbA1c reductions (-1.7% vs. -1.5%,
BL~9.0, p=0.118), reduction in body weight (-1.5 kg vs. 2.1 kg,
BL~89 kg, p<0.001), reduction in mean 24-hour glucose at week
two (-48.5 mg/dL vs. -28.5 mg/dL, p<0.0001) and was associated
with a lower prevalence of hypoglycemia (21.3% vs. 38.4%,
p<0.001). (Oral 260-OR)
- In a 52-week study (N=443),
dapagliflozin 10mg and saxaglipitin 5mg plus metformin in patients
with T2D compared to titrated glimepiride plus metformin, resulted
in significant reductions in HbA1c (-1.38% vs. -1.14%, BL~8.5,
p<0.001), body weight (-3.22 kg vs. 0.89 kg, BL~90 kg, p=0.001)
and systolic blood pressure (SBP) (-2.6 mm Hg vs. 1.0, p=0.007).
(Oral 261-OR)
Dapagliflozin and saxagliptin are not indicated for weight loss
or for treatment of hypertension.
AstraZeneca also presented extension data from the DURATION-8
study over 104 weeks (Late-breaking Poster 104-LB). In this
two-year follow-up analysis, the combination of once-daily
dapagliflozin 10mg and once-weekly exenatide extended-release 2mg
showed greater HbA1c reduction than either drug alone in adult
patients with T2D inadequately controlled by metformin alone. The
combination and each treatment alone were generally well-tolerated
with no unexpected adverse events.
Evaluating CV Outcomes in the SGLT-2i Class
New data from the ongoing multinational CVD-REAL study, the
first real-world evidence, study of its kind, were also presented
(Late-breaking Poster 124-LB). The late-breaking poster
compared the risk of CV events in patients with T2D (N=363,240),
75% of whom did not have established CV disease, starting treatment
with dapagliflozin vs. DPP-4is. Initiation of dapagliflozin was
associated with lower rates of all-cause death (Hazard Ratio [HR]:
0.61; 95% Confidence Interval [CI]: 0.54, 0.69), hospitalization
for heart failure (hHF) (HR: 0.68; 95% CI: 0.60, 0.78), myocardial
infarction (HR: 0.90; 95% CI: 0.81, 0.99) and stroke (HR: 0.84; 95%
CI: 0.76, 0.93) vs. treatment with DPP-4i. Dapagliflozin is not
indicated to reduce the risk of CV events, death or hHF.
AstraZeneca also presented results from a post-hoc analysis of
the EXSCEL (Effects of Once-Weekly Exenatide on CV Event Lowering)
study, which evaluated CV outcomes for adult patients with T2D at a
wide range of CV risk in the placebo arm taking SGLT-2is
(Late-breaking Poster 130-LB). This analysis showed an
adjusted HR for major adverse cardiac event (MACE), a composite of
CV death, nonfatal myocardial infarction, or nonfatal stroke, of
0.79 (95% CI: 0.49,1.28) with the SGLT-2i class and an adjusted HR
for of 0.55 (95% CI: 0.26,1.15) with dapagliflozin specifically.
Additionally, the adjusted HR for all-cause mortality was 0.51 (95%
CI: 0.27,0.95) with the SGLT-2i class and 0.66 (95% CI: 0.25,1.72)
with dapagliflozin. Estimated glomerular filtration rate (eGFR)
slope increased for both the SGLT-2i class (increased by 0.87
mL/min/m2/year) and dapagliflozin (1.24 mL/min/m2/year).
Dapagliflozin is not indicated to improve renal outcomes.
The CV outcomes trial (CVOT) for dapagliflozin, DECLARE
(Dapagliflozin Effect on Cardiovascular Events), will evaluate the
CV safety and efficacy of dapagliflozin in the largest SGLT-2i
CVOT. DECLARE includes a broad range of patients with T2D,
including those with multiple CV risk factors or established CV
disease. The trial is anticipated to read out in the second half of
2018.
Investigating Dapagliflozin as Add-on to Insulin in T1D to
Address an Unmet Need for Oral Therapy
In adults with T1D, AstraZeneca presented short-term and
long-term results from the DEPICT (Dapagliflozin Evaluation in
Patients with Inadequately Controlled Type-1 Diabetes) program. The
new data included results evaluating the efficacy and safety of
dapagliflozin as add-on to insulin over 52 weeks (from DEPICT-1)
and 24 weeks (from DEPICT-2), as well as a pooled analysis of
continuous glucose monitoring (CGM) data from both studies.
Dapagliflozin is not indicated for T1D.
In both DEPICT-1 and 2, dapagliflozin demonstrated reductions in
HbA1C and body weight, and increased time in glycemic target range
vs. placebo in adult patients with T1D. Specifically, results
showed:
- DEPICT-1: At week 52 (N=747),
dapagliflozin 5mg and 10mg, respectively, demonstrated a difference
vs. placebo in HbA1c of -0.33% [95% CI: -0.49, -0.17] and -0.36%
(95% CI: -0.53, -0.20) and percent change in body weight of -2.95%
(95% CI: -3.83, -2.06) and -4.54% (95% CI: -5.40, -3.66).
(Late-breaking Poster 119-LB)
- DEPICT-2: At week 24 (N=813),
dapagliflozin 5mg and 10mg respectively, demonstrated a difference
vs. placebo in HbA1c (-0.37% [95% CI: -0.49, -0.26] and -0.42% [95%
CI: -0.53, -0.30],], BL~8.4, p<0.0001) and percent change in
body weight (-3.21% [95% CI: -3.96, -2.45] and -3.74% [95% CI:
-4.49, -2.99], p<0.0001). HbA1c (Oral 213-OR)
- Post-hoc pooled analyses from DEPICT-1
and 2: At week 24, dapagliflozin 5mg and 10mg, respectively,
demonstrated a difference vs. placebo in reduced mean interstitial
glucose (-15.48 and -18.90), increased percentage of time in the
target glycemic range, (9.07% equating to more than 2 hours, and
10.67% equating to 2 hours 30 minutes), reduced the Mean Amplitude
of Glucose Excursions (MAGE) (-13.36 and -13.94) and reduced
postprandial glucose (-8.55 and -12.76), compared to placebo.
Dapagliflozin compared to placebo demonstrated no notable
difference in hypoglycemia (≤70 mg/dL or ≤54 mg/dL) or nocturnal
glucose (≤70 mg/dL). (Late-breaking Poster 125-LB)
Across treatment groups (dapagliflozin 5mg and 10mg compared to
placebo), in both DEPICT-1 and 2, hypoglycemic events, including
severe hypoglycemia, were similar. There were numerically more
adjudicated definite diabetic ketoacidosis (DKA) events observed in
the dapagliflozin group vs. placebo across studies (4.0% and 3.4%
vs. 1.9% for 52-week in DEPICT-1, and 2.6% and 2.2% vs. 0% for 24
weeks in DEPICT-2). The majority of events were mild or moderate,
with the most common identified causes related to missed insulin
doses or pump failure.
The full list of highlighted AstraZeneca scientific
presentations is available in our curtain raiser here, and the
comprehensive list can be accessed on the ADA website here. You can
also follow us live during ADA 2018 on Twitter.
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
- 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
INDICATION AND LIMITATIONS OF USE FOR BYDUREON®
(exenatide extended-release) for injectable suspension
2mg
BYDUREON is indicated as an adjunct to diet and exercise to
improve glycemic control in adults with type 2 diabetes
mellitus
- Not recommended as first-line therapy
for patients inadequately controlled on diet and exercise
- Not a substitute for insulin. Should
not be used to treat type 1 diabetes mellitus or diabetic
ketoacidosis
- Use with prandial insulin has not been
studied
- Do not coadminister with other
exenatide-containing products
- Not studied in patients with a history
of pancreatitis. Consider other antidiabetic therapies in patients
with a history of pancreatitis
IMPORTANT SAFETY INFORMATION FOR BYDUREON
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 (eg, 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
- Acute Pancreatitis including
fatal and non-fatal hemorrhagic or necrotizing pancreatitis has
been reported. 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 Risk of
hypoglycemia is increased when exenatide is coadministered with
insulin or insulin secretagogues. Consider lowering the dose of
these agents when coadministered with BYDUREON
- Acute Kidney Injury and Impairment
of Renal Function Altered renal function, including increased
serum creatinine, renal impairment, worsened chronic renal failure,
and acute renal failure, sometimes requiring hemodialysis and
kidney transplantation have 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 impairment
- 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. Patients with higher titer
antibodies may have an attenuated HbA1c response. In clinical
trials, attenuated glycemic response was associated with
BYDUREON-treated patients. 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 exenatide
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
PREGNANCY
Use during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
Please read US Full Prescribing
Information and Medication
Guide for BYDUREON.
INDICATIONS AND LIMITATIONS OF USE FOR ONGLYZA®
(saxagliptin) tablets 5mg
ONGLYZA is indicated as an adjunct to diet and exercise to
improve glycemic control in adults with type 2 diabetes
mellitus.
ONGLYZA is not indicated for the treatment of type 1 diabetes
mellitus or diabetic ketoacidosis.
IMPORTANT SAFETY INFORMATION FOR ONGLYZA
Contraindications
Prior serious hypersensitivity reaction to ONGLYZA
Pancreatitis: There have been postmarketing reports of
acute pancreatitis in patients taking ONGLYZA, and in the SAVOR
cardiovascular outcomes trial. Observe for pancreatitis. If
pancreatitis is suspected, discontinue ONGLYZA.
Heart Failure: In the SAVOR cardiovascular outcomes
trial, more patients treated with ONGLYZA were hospitalized for
heart failure compared to placebo. Patients with a prior history of
heart failure or renal impairment had a higher risk for
hospitalization for heart failure. Consider the risks and benefits
of ONGLYZA in patients who have known risk factors for heart
failure. Monitor for signs and symptoms. If heart failure develops,
consider discontinuation of ONGLYZA.
Hypoglycemia: When ONGLYZA was used in combination with a
sulfonylurea or with insulin, the incidence of confirmed
hypoglycemia was increased over that of placebo. Consider lowering
the dose of these agents when coadministered with ONGLYZA.
Hypersensitivity Reactions: Serious reactions have been
reported in patients treated with ONGLYZA, including anaphylaxis,
angioedema, and exfoliative skin conditions. Onset of these
reactions occurred within the first 3 months after initiation of
treatment with ONGLYZA, with some reports occurring after the first
dose. If a serious hypersensitivity reaction is suspected,
discontinue ONGLYZA. Use caution in patients with a history of
angioedema to another DPP-4 inhibitor.
Severe and Disabling Arthralgia has been reported in
patients taking DPP-4 inhibitors. The time to onset of symptoms
following initiation of drug therapy varied from one day to years.
Patients experienced relief of symptoms upon discontinuation. A
subset of patients experienced a recurrence of symptoms when
restarting the same drug or a different DPP-4 inhibitor. Consider
discontinuing drug if appropriate.
Bullous Pemphigoid: There have been postmarketing reports
of bullous pemphigoid requiring hospitalization in patients taking
DPP-4 inhibitors. Tell patients to report development of blisters
or erosions. If suspected, discontinue ONGLYZA.
Macrovascular Outcomes: There have been no clinical
studies establishing conclusive evidence of macrovascular risk
reduction with ONGLYZA.
Most Common Adverse Reactions
Most common adverse reactions reported in ≥5% of patients
treated with ONGLYZA and more commonly than in patients treated
with placebo were upper respiratory tract infection (7.7%, 7.6%),
urinary tract infection (6.8%, 6.1%), and headache (6.5%,
5.9%).
Peripheral edema was reported more commonly in patients treated
with the combination of ONGLYZA 5 mg and a thiazolidinedione (TZD)
than in patients treated with the combination of placebo and TZD
(8.1% vs. 4.3%, respectively).
Drug Interactions
Strong CYP3A4/5 inhibitors (eg, ketoconazole): Coadministration
with ONGLYZA significantly increases saxagliptin concentrations.
Recommend limiting ONGLYZA dosage to 2.5 mg once daily.
Use in Specific Populations
In patients with moderate or severe renal impairment, or
end-stage renal disease (eGFR <45 mL/min/1.73 m2), recommended
dosage is 2.5 mg once daily regardless of meals. ONGLYZA should be
administered following hemodialysis. Assess renal function before
starting ONGLYZA and periodically thereafter.
Please see US Full Prescribing
Information and Medication
Guide for ONGLYZA.
NOTES TO EDITORS
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.
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