AstraZeneca
(NYSE: AZN) and Bristol-Myers
Squibb Company (NYSE: BMY) today announced the full results of the
SAVOR clinical trial in 16,492 adult patients with type 2 diabetes at
high risk for cardiovascular events. In this study, Onglyza®
(saxagliptin) met the primary safety objective, demonstrating no
increased risk for the primary composite endpoint of cardiovascular
death, non-fatal myocardial infarction (MI) or non-fatal ischemic
stroke, when added to a patient’s current standard of care (with or
without other anti-diabetic therapies), as compared to placebo. Onglyza
did not meet the primary efficacy endpoint of superiority to placebo for
the same composite endpoint. Patients treated with Onglyza
experienced improved glycemic control and reduced development and
progression of microalbuminuria over two years as assessed in
exploratory analyses.
The major secondary composite endpoint of cardiovascular death,
non-fatal MI, non-fatal ischemic stroke or hospitalization for heart
failure, unstable angina or coronary revascularization was balanced
across the two arms. One component of the composite secondary endpoint,
hospitalization for heart failure, occurred more in the Onglyza
group compared to placebo. Rates of pancreatitis were low and balanced
between Onglyza and placebo. Overall rates of malignancy were
balanced, and the observed rates of pancreatic cancer were lower in the Onglyza
group than in the placebo group. More patients in the Onglyza
group reported at least one hypoglycemic event compared to placebo.
Results were presented today during a Hot Line session at the ESC
Congress 2013 in Amsterdam, Netherlands, and published in The New
England Journal of Medicine.
In the past, questions have been raised about the safety of many
diabetes treatments, in particular regarding their impact on the risk of
cardiovascular death, heart attack or stroke. Led by the academic
research organizations TIMI Study Group and Hadassah University Medical
Center and conducted at more than 700 sites worldwide, SAVOR
(Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with
Diabetes Mellitus) was a randomized, double-blind, placebo-controlled
trial of 16,492 patients designed to evaluate the cardiovascular safety
and efficacy of Onglyza (saxagliptin) in adults with type 2
diabetes at risk for cardiovascular death, heart attack and stroke,
compared to placebo.
“Given the correlation between diabetes and cardiovascular
complications, there is a need for thorough assessments of the
cardiovascular risks among therapies that improve glycemic control,”
said Deepak L. Bhatt, MD, MPH, Senior Investigator of the TIMI Study
Group, Brigham and Women’s Hospital, and a Principal Investigator for
the trial. “The results from SAVOR add important evidence to the overall
body of data to further define the clinical profile of saxagliptin for
the treatment of type 2 diabetes.”
“No other DPP-4 inhibitor and few other anti-hyperglycemic agents have
been studied as extensively as Onglyza to address the question of
cardiovascular safety,” said Brian
Daniels, MD, senior vice president, Global Development and Medical
Affairs, Research and Development, Bristol-Myers Squibb. “Bristol-Myers
Squibb and AstraZeneca are dedicated to meeting needs of physicians and
patients in diabetes care and helping to ensure a better understanding
of the value of our medications.”
“SAVOR is an important contribution to our knowledge of the safety of Onglyza
in type 2 diabetes patients at an increased risk for cardiovascular
events similar to those found in a real-world population,” said Briggs
Morrison, MD, executive vice president, Global Medicines
Development, AstraZeneca. “In addition, the data on pancreatitis and
pancreatic cancer in a study of more than 16,000 patients provide
important and timely scientific information from a robust, randomized
trial for the diabetes community.”
Study Results
In the study, 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 (Hazard Ratio [HR]: 1.00; 95% Confidence Interval [CI]:
0.89, 1.12; non-inferiority p-value < 0.001; 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
(saxagliptin) 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).
Study physicians were allowed to actively manage patients’ glucose
through concomitant use of other anti-diabetic drugs and dose titration.
Fewer patients in the Onglyza group required the addition or
increase of any new anti-diabetic medication compared to placebo (1,938
patients [23.7%] vs. 2,385 patients [29.3%], respectively; HR: 0.77; 95%
CI: 0.73, 0.82; p-value < 0.001) or the initiation of insulin therapy
for more than three months (454 patients [5.5%] vs. 634 patients [7.8%],
respectively; HR: 0.70; 95% CI: 0.62, 0.79; p-value < 0.001).Patients
in the Onglyza group had greater reductions in blood sugar levels
both from baseline and compared to those in the placebo group, with mean
reductions in glycosylated hemoglobin (HbA1c) levels of 0.5% at two
years of treatment in the Onglyza group vs. 0.2% in the placebo
group (p-value < 0.001). More patients in the Onglyza group
achieved or maintained goal HbA1c of less than seven percent compared to
those in the placebo group at two years (40.0% vs. 30.3%; p-value <
0.001).
A total of 1,264 patients (15.3%) in the Onglyza group reported
at least one hypoglycemic event compared to 1,104 (13.4%) in the placebo
group (p-value < 0.001), which included patients with both major (177
patients [2.1%] vs. 140 patients [1.7%]; p-value = 0.047) and minor
(1,172 patients [14.2%] vs. 1,028 patients [12.5%]; p-value = 0.002)
events for the Onglyza and placebo groups, respectively.
Hospitalization for hypoglycemia was infrequent and similar between
groups (0.6% vs. 0.5%; p-value = 0.33).
Patients in the Onglyza group experienced reduced development and
progression of microalbuminuria, and were more likely to have an
improved albumin:creatinine ratio at two years (372 patients [11.1%] in
the Onglyza group vs. 295 patients [9.2%] in the placebo group),
and less likely to have a worsening ratio (414 patients [12.4%] in the Onglyza
group vs. 457 patients [14.2%] in the placebo group), compared to
placebo.
A number of pre-specified safety endpoints for diabetes treatments were
evaluated (pancreatitis, cancer, liver abnormalities, renal
abnormalities, thrombocytopenia, lymphocytopenia, infections,
hypersensitivity or skin reactions, bone fractures and hypoglycemia).
All suspected cases of pancreatitis were independently reviewed and
adjudicated by a committee of medical experts external to the sponsors
and investigators. Pancreatitis occurred infrequently and the number of
patients with acute or chronic pancreatitis was similar between the
treatment groups (24 [0.3%] in the Onglyza (saxagliptin) group
vs. 21 [0.3%], in the placebo group; p-value = 0.77). Definite/possible
acute pancreatitis occurred in 22 patients (0.3%) in the Onglyza
group vs. 16 patients (0.2%) in the placebo group (p-value = 0.42);
definite acute pancreatitis in 17 patients (0.2%) vs. nine patients
(0.1%) (p-value = 0.17); and chronic pancreatitis in two patients (<
0.1%) vs. six patients (0.1%) (p-value = 0.18), respectively. There were
five cases of pancreatic cancer in the Onglyza group and 12 cases
in the placebo group (p-value = 0.095). Renal abnormalities were
observed more frequently in the Onglyza group compared to the
placebo group (5.8% vs. 5.1%, respectively; p-value = 0.04). The
incidence of the other pre-specified safety endpoints was balanced
between the two groups.
Study Design
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% to 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 two categories:
-
Patients ≥ 40 years of age with established cardiovascular disease,
defined as ischemic heart disease, peripheral vascular disease or
ischemic stroke.
-
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 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.
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 China.
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 diabetic ketoacidosis.
Onglyza has not been studied in patients with a history of
pancreatitis.
Important Safety Information for Onglyza
Contraindications
-
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).
Drug Interactions
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 telithromycin).
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).
About Diabetes
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.
About AstraZeneca
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: www.astrazeneca.com.
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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