New Hypoglycemia and Pancreatitis Subanalyses from the Onglyza®
(saxagliptin) SAVOR Cardiovascular Outcomes Trial Presented at the 49th
Annual Meeting of the European Association for the Study of Diabetes (EASD)
*No increased rate of hypoglycemia when Onglyza was added to metformin
monotherapy compared to placebo
*Higher rates of hypoglycemia compared to placebo only observed in patients
receiving Onglyza in combination with sulfonylureas, agents known to cause
*More patients taking Onglyza vs. placebo achieved target HbA1c without
hypoglycemia, except those who had received sulfonylureas alone at
*Rates of pancreatitis were balanced between the Onglyza and placebo groups
and majority of cases resolved without study treatment being withdrawn
*Overall incidence of adverse events similar between Onglyza and placebo
WILMINGTON, Del. & PRINCETON, N.J. -- September 26, 2013
AstraZeneca (NYSE:AZN) and Bristol-Myers Squibb Company (NYSE:BMY) today
announced additional results from the SAVOR cardiovascular outcomes trial,
which found no increased rate of hypoglycemia among patients treated with
Onglyza^® (saxagliptin) compared to placebo when added to metformin
monotherapy and higher rates of hypoglycemia only in the Onglyza group
compared to the placebo group among patients taking sulfonylureas, agents
known to cause hypoglycemia, at baseline. Additionally, a greater percentage
of patients taking Onglyza reached their target HbA1c without hypoglycemia,
except patients who were treated with sulfonylureas alone at baseline. These
findings are consistent with previous studies of Onglyza. Results were
presented today at the 49^th Annual Meeting of the European Association for
the Study of Diabetes (EASD) in Barcelona, Spain.
“Treating diabetes often requires the use of multiple therapies to help lower
blood glucose levels without increasing the risk of hypoglycemia,” said Itamar
Raz, MD, Co-Primary Study Investigator and Head of the Diabetes Unit,
Department of Medicine, Hadassah University Hospital, Jerusalem, Israel. “In a
post-hoc analysisfrom SAVOR, the data reflected that when saxagliptin was
used in combination with metformin, there was a lowering of blood sugar and no
increase in the risk of hypoglycemia.”
Additionally, results from SAVOR found rates of any events of
adjudication-confirmed pancreatitis were balanced between the Onglyza and
placebo treatment groups (24 patients in the Onglyza arm versus 21 patients in
the placebo arm). Moreover, in patients who experienced pancreatitis, the
duration of the event, study drug actions and outcome of the adverse event
were balanced across the two treatment arms. Observed rates of pancreatic
cancer were also low (five patients in the Onglyza arm versus 12 patients in
the placebo arm).
“Recent discussions regarding the pancreatic safety of some type 2 diabetes
medicines, including incretin-based therapies such as DPP-4 inhibitors, have
been largely based on non-randomized studies with significant limitations,”
said Prof. Raz. “SAVOR is the first large-scale, randomized, blinded study of
a type 2 diabetes treatment to report an adjudicated review of pancreatitis
events, and results from this trial showed no overall increased risk of
pancreatitis or pancreatic cancer in patients taking saxagliptin.”
SAVOR (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with
Diabetes Mellitus), a randomized, double-blind, placebo-controlled trial of
16,492 adult patients with type 2 diabetes, was designed to minimize glycemic
control differences between Onglyza and placebo by allowing study physicians
to actively manage blood glucose through use of additional antidiabetic drugs
or dose titration.
In this assessment of hypoglycemia, patients were analyzed by antidiabetic
medication at baseline (not treated with antidiabetic drugs, treated with
metformin alone, treated with sulfonylurea, treated with insulin alone or
treated with insulin in combination with other antidiabetic drugs) and HbA1c
at baseline (entire study population, HbA1c < 7% or HbA1c ≥ 7%). Results
showed there was no significant increase in the incidence of hypoglycemia with
Onglyza compared to placebo when added to patients who were treated with
metformin alone (2.4 events per 100 patient years for Onglyza versus 2.6 for
placebo; Hazard Ratio [HR]: 0.92), insulin alone (17.4 events per 100 patient
years for both the Onglyza and placebo groups; HR: 1.00), or patients not
treated with other antidiabetic medications at baseline (3.0 events per 100
patient years for Onglyza versus 2.1 for placebo; HR: 1.44), regardless of
baseline HbA1c. There was an increased incidence of hypoglycemia with Onglyza
compared to placebo in patients who were taking a sulfonylurea (a class of
agents known to cause hypoglycemia) at baseline, regardless of HbA1c (9.7
events per 100 patient years for Onglyza versus 6.8 for placebo; HR: 1.42) and
in patients who were treated with insulin in combination with other
antidiabetic drugs, but only those with a baseline HbA1c < 7% (HR: 1.42).
There was no increase in rates of major hypoglycemia between Onglyza and
placebo, in any subgroup, other than patients taking sulfonylurea with
baseline HbA1c < 7% (HR: 2.24). At two years, the percentage of patients
achieving HbA1c < 7% without hypoglycemic events was greater among patients
who were treated with Onglyza and metformin alone (36.1% vs. 23.6%), insulin
alone (12.1% vs. 7.6%) or other antidiabetic medications (16.1% vs. 11.4%),
compared to placebo. Among patients treated with Onglyza and sulfonylurea
alone, fewer patients (20.6% vs. 22.4%) achieved their target HbA1c without
hypoglycemia compared to placebo.
The SAVOR trial also included evaluation of possible events of pancreatitis
and pancreatic cancer, which were reported by investigators. All reports of
pancreatitis were, in addition, adjudicated without knowledge of treatment
assignment by an independent external expert committee, which included two
pancreatic disease experts. Reported cases of pancreatitis were classified
into four categories: definite acute pancreatitis, possible acute
pancreatitis, chronic pancreatitis or unlikely to be pancreatitis.
Overall, a total of 33 patients treated with Onglyza and 30 patients who
received placebo were reported by investigators to have pancreatitis, with 35
cases in each group. By adjudication, pancreatitis was confirmed in 24
patients (26 cases) in the Onglyza arm versus 21 patients (25 cases) in the
placebo arm. Additional results from the adjudicated analysis on pancreatitis
*Definite or possible acute pancreatitis was observed in 38 patients, 22
patients in the Onglyza arm versus 16 patients in the placebo arm. Out of
these patients, 17 (0.2%) in the Onglyza arm and nine (0.1%) in the
placebo arm were classified as having definite acute pancreatitis.
*Recovery rates from pancreatitis were similar between the two treatment
groups (21 patients [80.8%] in the Onglyza arm versus 21 patients [84.0%]
in the placebo arm were resolved, three patients [11.5%] versus one
patient [4.0%] was recovering, two patients [7.7%] versus one patient
[4.0%] was not resolved, zero patients versus one patient [4.0%] was
resolved with sequelae and zero patients vs. one patient [4.0%] died in
the Onglyza and placebo groups, respectively).
*Chronic pancreatitis was reported in two patients (0.02%) in the Onglyza
arm versus six patients (0.07%) in the placebo arm.
*Among patients with pancreatitis, the majority remained on treatment, with
four patients (15.4%) discontinuing study medication and two patients
(7.7%) interrupting study medication in the Onglyza arm versus six
patients (24.0%) discontinuing study medication and one patient (4.0%)
interrupting study medication in the placebo arm.
*Pancreatic cancer was reported in five patients in the Onglyza arm versus
12 patients in the placebo arm (p-value = 0.095).
Primary Study Results and Study Design
The primary study results from the SAVOR trial were presented at the 2013
European Society of Cardiology (ESC) Congress in Amsterdam, Netherlands and
published in The New England Journal of Medicine.
Led by the academic research organizations TIMI Study Group and Hadassah
University Medical Center and conducted at more than 700 sites worldwide,
SAVOR was a randomized, double-blind, placebo-controlled trial designed to
evaluate the cardiovascular safety and efficacy of Onglyza in adults with type
2 diabetes at risk for cardiovascular death, heart attack and stroke, compared
The study included 16,492 adult patients with type 2 diabetes, 8,280 of whom
were randomized to receive Onglyza and 8,212 of whom were randomized to
receive placebo. Recruitment included patients with type 2 diabetes and
baseline HbA1c levels of ≥ 6.5% and < 12% on any diabetes treatment including
diet, insulin and/or oral therapy (excluding GLP-1 agonists and DPP-4
inhibitors) who were at elevated risk for cardiovascular events according to
*Patients ≥ 40 years of age with established cardiovascular disease,
defined as ischemic heart disease, peripheral vascular disease or ischemic
*Males ≥ 55 years of age and females ≥ 60 years of age with at least one of
the following risk factors: dyslipidemia, hypertension or current smoking,
but without established cardiovascular disease.
Further grouping was based on renal function, including patients with
normal/mild (eGFR > 50 mL/min), moderate (30 - 50 mL/min) or severe (eGFR < 30
mL/min) renal impairment.
The primary safety objective was to establish that the upper bound of the 95%
confidence interval for the estimated risk ratio comparing the incidence of
the composite endpoint (cardiovascular death, non-fatal myocardial infarction
[MI] or non-fatal ischemic stroke) observed with Onglyza to that observed in
the placebo group was less than 1.3. The primary efficacy objective was to
determine, as a superiority assessment, whether treatment with Onglyza
compared to placebo when added to current background therapy would result in a
reduction in the composite endpoint of cardiovascular death, non-fatal MI or
non-fatal ischemic stroke in patients with type 2 diabetes. Secondary efficacy
objectives included a reduction in the primary composite endpoint together
with hospitalization for heart failure, coronary revascularization or unstable
angina pectoris, and reduction of all-cause mortality. Secondary safety
objectives included the evaluation of safety and tolerability by assessment of
overall adverse events and adverse events of special interest.
Patients were randomized between May 2010 and December 2011. The median
follow-up was 2.1 years and maximum follow-up was 2.9 years.
Results from the primary analysis of SAVOR found that the primary composite
endpoint of cardiovascular death, non-fatal MI or non-fatal ischemic stroke
occurred in 613 patients (7.3%) in the Onglyza group vs. 609 patients (7.2%)
in the placebo group (HR: 1.00; 95% Confidence Interval [CI]: 0.89, 1.12;
non-inferiority p-value < 0.001). Onglyza did not meet the primary efficacy
endpoint of superiority to placebo for the same composite endpoint
(superiority p-value = 0.99). The major secondary endpoint, consisting of the
primary composite endpoint and hospitalization for heart failure, unstable
angina or coronary revascularization, occurred in 1,059 patients (12.8%) in
the Onglyza group vs. 1,034 patients (12.4%) in the placebo group (HR: 1.02;
95% CI: 0.94, 1.11; p-value = 0.66). Hospitalization for heart failure, a
component of this secondary composite endpoint, occurred at a greater rate in
the Onglyza group (3.5%) than in the placebo group (2.8%) (HR: 1.27; 95% CI:
1.07, 1.51; p-value = 0.007). The pre-specified secondary endpoint of
all-cause mortality occurred in 420 patients (4.9%) in the Onglyza group
compared to 378 patients (4.2%) in the placebo group (HR: 1.11; 95% CI: 0.96,
1.27; p-value = 0.15).
About Onglyza (saxagliptin)
As of September 2013, Onglyza is approved in 86 countries including those in
the European Union, the United States, Canada, Mexico, India, Brazil and
Indication and Limitations of Use for Onglyza
Onglyza is indicated as an adjunct to diet and exercise to improve glycemic
control in adults with type 2 diabetes mellitus in multiple clinical settings.
Onglyza should not be used for the treatment of type 1 diabetes mellitus or
Onglyza has not been studied in patients with a history of pancreatitis.
Important Safety Information for Onglyza
*History of a serious hypersensitivity reaction to Onglyza (e.g.,
anaphylaxis, angioedema, or exfoliative skin conditions)
Warnings and Precautions
*Pancreatitis: There have been post-marketing reports of acute pancreatitis
in patients taking Onglyza. After initiating Onglyza, observe patients
carefully for signs and symptoms of pancreatitis. If pancreatitis is
suspected, promptly discontinue Onglyza and initiate appropriate
management. It is unknown whether patients with a history of pancreatitis
are at increased risk of developing pancreatitis while using Onglyza.
*Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin: When Onglyza
was used in combination with a sulfonylurea or with insulin, medications
known to cause hypoglycemia, the incidence of confirmed hypoglycemia was
increased over that of placebo used in combination with a sulfonylurea or
with insulin. Therefore, a lower dose of the insulin secretagogue or
insulin may be required to minimize the risk of hypoglycemia when used in
combination with Onglyza.
*Hypersensitivity Reactions: There have been post-marketing reports of
serious hypersensitivity reactions 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,
assess for other potential causes for the event, and institute alternative
treatment for diabetes. Use caution in patients with a history of
angioedema to another DPP-4 inhibitor as it is unknown whether they will
be predisposed to angioedema with Onglyza.
*Macrovascular Outcomes: There have been no clinical studies establishing
conclusive evidence of macrovascular risk reduction with Onglyza or any
other antidiabetic drug.
Most Common Adverse Reactions
*Most common adverse reactions reported in ≥5% of patients treated with
Onglyza and more commonly than in patients treated with control were upper
respiratory tract infection (7.7%, 7.6%), headache (7.5%, 5.2%),
nasopharyngitis (6.9%, 4.0%) and urinary tract infection (6.8%, 6.1%).
*When used as add-on combination therapy with a thiazolidinedione, the
incidence of peripheral edema for Onglyza 2.5 mg, 5 mg, and placebo was
3.1%, 8.1% and 4.3%, respectively.
*Confirmed hypoglycemia was reported more commonly in patients treated with
Onglyza 2.5 mg and Onglyza 5 mg compared to placebo in the add-on to
glyburide trial (2.4%, 0.8% and 0.7%, respectively), with Onglyza 5 mg
compared to placebo in the add-on to insulin (with or without metformin)
trial (5.3% and 3.3%, respectively),with Onglyza 2.5 mg compared to
placebo in the renal impairment trial (4.7% and 3.5%, respectively), and
with Onglyza 5 mg compared to placebo in the add-on to metformin plus
sulfonylurea trial (1.6% and 0.0%, respectively).
Because ketoconazole, a strong CYP3A4/5 inhibitor, increased saxagliptin
exposure, the dose of Onglyza should be limited to 2.5 mg when coadministered
with a strong CYP3A4/5 inhibitor (eg, atazanavir, clarithromycin, indinavir,
itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and
Use in Specific Populations
*Patients with Renal Impairment: The dose of Onglyza is 2.5 mg once daily
for patients with moderate or severe renal impairment, or with end-stage
renal disease requiring hemodialysis (creatinine clearance [CrCl] ≤50
mL/min). Onglyza should be administered following hemodialysis. Onglyza
has not been studied in patients undergoing peritoneal dialysis.
Assessment of renal function is recommended prior to initiation of Onglyza
and periodically thereafter.
*Pregnant and Nursing Women: There are no adequate and well-controlled
studies in pregnant women. Onglyza, like other antidiabetic medications,
should be used during pregnancy only if clearly needed. It is not known
whether saxagliptin is secreted in human milk. Because many drugs are
secreted in human milk, caution should be exercised when Onglyza is
administered to a nursing woman.
*Pediatric Patients: Safety and effectiveness of Onglyza in pediatric
patients have not been established.
Please click here for full U.S. Prescribing Information and Medication Guide
for Onglyza (saxagliptin).
In 2012, diabetes was estimated to affect more than 370 million people
worldwide. The prevalence of diabetes is projected to reach more than 550
million by 2030. Type 2 diabetes accounts for approximately 90% to 95% of all
cases of diagnosed diabetes in adults. Type 2 diabetes is a chronic disease
characterized by insulin resistance and dysfunction of beta cells in the
pancreas, leading to elevated glucose levels.Over time, this sustained
hyperglycemia contributes to further progression of the disease. Significant
unmet needs still exist, as many patients remain inadequately controlled on
their current glucose-lowering regimen.
The major cause of death and complications in patients with type 2 diabetes is
cardiovascular disease. As many as 80% of patients with type 2 diabetes will
develop and possibly die from a cardiovascular event.
About the AstraZeneca / Bristol-Myers Squibb Diabetes Alliance
Dedicated to addressing the global burden of diabetes by advancing
individualized patient care, AstraZeneca and Bristol-Myers Squibb are working
in collaboration to research, develop and commercialize a versatile portfolio
of innovative treatment options for diabetes and related metabolic disorders
that aim to provide treatment effects beyond glucose control. Find out more
about the Alliance and our commitment to meeting the needs of health care
professionals and people with diabetes at www.astrazeneca.com or www.bms.com.
AstraZeneca is a global, innovation-driven biopharmaceutical business with a
primary focus on the discovery, development and commercialization of
prescription medicines for gastrointestinal, cardiovascular, neuroscience,
respiratory and inflammation, oncology and infectious disease. AstraZeneca
operates in over 100 countries and its innovative medicines are used by
millions of patients worldwide. For more information please visit:
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to
discover, develop and deliver innovative medicines that help patients prevail
over serious diseases. For more information, please visit http://www.bms.com
or follow us on Twitter at http://twitter.com/bmsnews.
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