AstraZeneca PLC Release: Bydureon EXSCEL Trial Demonstrates Favorable Cardiovascular (CV) Safety Profile And Fewer CV Events In Patients With Type-2 Diabetes At Wide Range Of CV Risk
Published: Sep 15, 2017
Largest and most inclusive patient population of any GLP-1 CV outcomes trial with 14,500 patients at 687 trial sites across 35 countries
Full trial results presented at the annual meeting of the European Association for the Study of Diabetes (EASD) and simultaneously published in the New England Journal of Medicine
WILMINGTON, Del.--(BUSINESS WIRE)--AstraZeneca today announced full results from the EXSCEL (EXenatide Study of Cardiovascular Event Lowering) trial that showed cardiovascular safety with Bydureon (exenatide extended-release) in patients with type-2 diabetes (T2D) at a wide range of CV risk.
Exenatide once-weekly did not increase the incidence of major adverse cardiovascular events (MACE), a composite endpoint of CV death, non-fatal heart attack (myocardial infarction) or non-fatal stroke, compared to placebo (Hazard Ratio [HR]: 0.91; 95% Confidence Interval [CI]: 0.83-1.00; p<0.001 for non-inferiority).
There were also fewer CV events observed in the exenatide arm of the trial (839 [11.4%] versus 905 [12.2%]), although the primary efficacy objective of a superior reduction in MACE narrowly missed statistical significance (p=0.061). The direction of the cardiovascular outcomes results in EXSCEL was consistent with those seen in recently completed outcomes trials within the GLP-1 receptor agonist class. Additionally, in a prespecified secondary analysis, patients on exenatide had a 14% lower incidence of death from all causes (HR: 0.86; 95% CI: 0.77-0.97).
The full results of EXSCEL, including important secondary endpoints, sensitivity analyses and regional data, were presented at the 53rd annual meeting of EASD and simultaneously published today online in the New England Journal of Medicine.
Investigator Rury Holman, Professor of Diabetic Medicine and Diabetes Trials Unit Director, University of Oxford, UK, said: “People with type-2 diabetes have up to a two-times increased risk for all-cause mortality and four-times increased risk for cardiovascular death compared to the general population, making it imperative that their type-2 medication does not further increase their risk for cardiovascular disease and related complications. The EXSCEL study results demonstrated that exenatide could be used safely in patients with type-2 diabetes with a wide range of cardiovascular risk and suggested potential benefit with respect to all-cause mortality.”
Elisabeth Björk, Vice President, Head of Cardiovascular and Metabolic Diseases, Global Medicines Development, said: “The results from the EXSCEL trial provide important evidence supporting the use of once-weekly Bydureon in a broad population of patients with type-2 diabetes at a wide range of cardiovascular risk. This comprehensive trial is representative of our commitment to address multiple risk factors or co-morbidities associated with cardiovascular and metabolic diseases and helps to inform clinical practice for the benefit of millions of patients with type-2 diabetes.”
Multiple sensitivity analyses for MACE, recalculating the outcome under alternative assumptions to determine the potential impact of different variables, were consistent with primary analyses. No safety issues were identified during the EXSCEL trial and data were consistent with the known safety profile of exenatide. Specifically, there was no imbalance in retinopathy, a microvascular complication that commonly occurs from type-2 diabetes and can lead to serious visual disability and blindness.
The EXSCEL trial enrolled the largest and most inclusive patient population of any CV outcomes trial of the glucagon-like peptide-1 (GLP-1) receptor agonist class conducted to date, having included more than 14,500 patients at 687 trial sites across 35 countries, incorporating usual care and wide-ranging eligibility criteria.
BYDUREON is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. BYDUREON is not indicated to reduce the risk of MACE or all-cause mortality, and there are no clinical trials establishing conclusive evidence of macrovascular risk reduction with BYDUREON. AstraZeneca is working with regulatory authorities to incorporate these data into the Bydureon label.
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
- Personal or family history of MTC, patients with MEN 2
- Patients with prior serious hypersensitivity reactions to exenatide or to any of the 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
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%)
- 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.
- Nursing Women Discontinue BYDUREON or discontinue nursing
INDICATION AND LIMITATIONS OF USE
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 in patients with type 1 diabetes or diabetic ketoacidosis
- Not recommended for use with insulin
- BYDUREON and BYETTA® (exenatide) injection contain the same active ingredient, exenatide. Do not coadminister with BYETTA
- Not studied in patients with a history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis
NOTES TO EDITORS
EXSCEL is a Phase IIIb/IV, double-blind, placebo-controlled, global CV outcomes trial conducted in 35 countries and enrolled more than 14,500 patients with type-2 diabetes with or without additional CV risk factors or prior CV events. Participants were randomized to receive exenatide once-weekly 2mg or matching placebo by subcutaneous injections. EXSCEL was run jointly by two academic research organizations - the Duke Clinical Research Institute (Durham, NC, US) and the University of Oxford Diabetes Trials Unit (Oxford, UK).
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 main 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 products to help more patients achieve treatment success earlier in their disease.
About AstraZeneca in Cardiovascular & Metabolic Diseases (CVMD)
Cardiovascular, renal and metabolic diseases are key areas of focus for AstraZeneca as part of the company’s strategy for achieving scientific leadership and returning to growth. By collaborating across therapeutic disciplines within the CVMD therapy area, we are addressing the underlying disorders that drive CVMD risk, with the goal of reducing morbidity, mortality and organ damage through innovative therapies. Recognizing the growing unmet needs and challenges faced by the millions of people worldwide living with these interrelated diseases, we are determined to understand how they interact and impact one another – and how they can be treated together to save more patients’ lives.
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 main therapy areas - Oncology, Cardiovascular & Metabolic Diseases 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 www.astrazeneca-us.com and follow us on Twitter @AstraZenecaUS.
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