Top-line results from the large cardiovascular safety outcomes trial for AstraZeneca's once-weekly version of the glucagonlike peptide-1 (GLP-1) receptor agonist drug for type 2 diabetes,
exenatide (Bydureon), show the agent met the goal of cardiovascular safety but failed to show any cardiovascular benefit.
The Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial involved 14,000 people with type 2 diabetes at a wide range of cardiovascular risk, from 35 countries, and randomized them to once-weekly exenatide (2 mg subcutaneously) or placebo on top of usual care.
"Fewer cardiovascular events were observed in the Bydureon arm of the trial; however, the efficacy objective of a superior reduction in major adverse cardiovascular events did not reach statistical significance," the company notes in a statement.
It adds that the full results of EXSCEL will be reported on September 14, at the European Association for the Study of Diabetes meeting in Lisbon, Portugal.
Showing CV Benefit Is the New Norm in Type 2 Diabetes
Trials such as EXSCEL were designed to demonstrate cardiovascular safety of type 2 diabetes drugs in the wake of the rosiglitazone (Avandia, GlaxoSmithKline) scandal.
But surprisingly, some of these trials have also demonstrated cardiovascular benefit, rather than simply lack of harm, and so this has now become the expectation as more and more of these studies are reported.
These include two with other GLP-1 agonists, the LEADER trial with liraglutide (Victoza, Novo Nordisk), a once-daily subcutaneous injection product that has been on the market for some time, and the SUSTAIN-6 trial with another Novo Nordisk GLP-1 agonist, semaglutide.
Semaglutide is a once-weekly subcutaneous injectable product that has not yet been approved; the company is also trying to develop an oral version.
In addition, the landmark EMPA-REG trial — with a different class of type 2 diabetes drug, the sodium glucose cotransporter-2 (SGLT-2) inhibitors — was the first to show a reduction in cardiovascular deaths with a diabetes drug, empagliflozin (Jardiance, Boehringer Ingelheim/Lilly) and last December, the FDA allowed a label to be added to that product indicating that it can improve survival.
Therefore, the fact that EXSCEL has failed to show any cardiovascular benefit with once-weekly exenatide when other trials of GLP-1 agonists have shown this to be the case will be viewed as somewhat disappointing.
In the meantime, two more large cardiovascular safety outcomes trials are due to be reported at the American Diabetes Association Scientific Sessions next month.
Those from two trials with the SGLT-2 inhibitor canagliflozin (Invokana, Johnson & Johnson), the Canagliflozin Cardiovascular Assessment Study (CANVAS) and CANVAS-R — the latter looking at renal outcomes — in more than 10,000 patients with type 2 diabetes and a history of or at high risk for cardiovascular events will be eagerly anticipated.
And the data from the DEVOTE study will examine the cardiovascular safety of insulin degludec (Tresiba, Novo Nordisk) compared with insulin glargine.
From www.medscape.com
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Bydureon EXSCEL trial meets primary safety objective in type-2 diabetes patients at wide range of cardiovascular risk
Based on a composite measure of major adverse CV events (MACE), Bydureon did not increase cardiovascular (CV) risk and showed a consistent safety profile
Fewer CV events were observed in the Bydureon arm, however, the efficacy objective of reduction in CV risk did not reach statistical significance
AstraZeneca today announced top-line results from the Phase IIIb/IV EXSCEL (EXenatide Study of Cardiovascular Event Lowering) trial. The trial compared the effect of once-weekly Bydureon (exenatide extended-release) versus placebo, when added to usual type-2 diabetes care, on the risk of MACE, a composite endpoint of CV death, non-fatal myocardial infarction or non-fatal stroke, in adults with type-2 diabetes (T2D) at a wide range of CV risk.
The EXSCEL trial met its primary safety objective of non-inferiority for MACE. These results address the US Food and Drug Administration (FDA) requirement that medicines to treat T2D are not associated with an increase in CV risk. Fewer CV events were observed in the Bydureon arm of the trial, however, the efficacy objective of a superior reduction in MACE did not reach statistical significance. Data were consistent with the known safety profile of Bydureon.
Elisabeth Björk, Vice President, Head of Cardiovascular and Metabolic Diseases, Global Medicines Development, AstraZeneca, said: “These top-line results from the EXSCEL trial provide robust evidence of the cardiovascular safety profile of Bydureon across a wide range of patients with type-2 diabetes.
Furthermore, the trial design and broad inclusion criteria of EXSCEL offer physicians relevant data applicable to clinical practice.”
The EXSCEL trial is 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 14,000 patients from 35 countries.
A full evaluation of the EXSCEL data is ongoing. The results will be presented at the European Association for the Study of Diabetes (EASD) annual meeting on Thursday, 14 September 2017 in Lisbon, Portugal.
About EXSCEL
EXSCEL is a Phase IIIb/IV, double-blind, placebo-controlled, global CV outcomes trial conducted in 35 countries and enrolled more than 14,000 patients with type-2 diabetes with or without additional CV risk factors or prior CV events. Participants were randomised to receive exenatide once-weekly 2mg or matching placebo by subcutaneous injections. EXSCEL was run jointly by two academic research organisations - the Duke Clinical Research Institute (Durham, NC, US) and the University of Oxford Diabetes Trials Unit (Oxford, UK).
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Exenatide Study of Cardiovascular Event Lowering Trial (EXSCEL): A Trial To Evaluate Cardiovascular Outcomes After Treatment With Exenatide Once Weekly In Patients With Type 2 Diabetes Mellitus
The primary safety outcome variable is defined as the composite endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke. [ Time Frame: Time to first event. Information collected during study period (anticipated to be up to 7.5 years). ]
Components of the primary composite endpoint (cardiovascular death, fatal or nonfatal MI, fatal or nonfatal stroke). [ Time Frame: Time to first event. Information collected during study period (anticipated to be up to 7.5 years). ]
Hospitalization for acute coronary syndrome [ Time Frame: Time to first event. Information collected during study period (anticipated to be up to 7.5 years). ]
Hospitalization for heart failure [ Time Frame: Time to first event. Information collected during study period (anticipated to be up to 7.5 years). ]
This study is ongoing, but not recruiting participants.
Sponsor:
AstraZeneca
Information provided by (Responsible Party):
AstraZeneca
ClinicalTrials.gov Identifier:
NCT01144338
First received: June 10, 2010
Last updated: January 5, 2016
Last verified: January 2016
History of Changes
Full Text View Tabular ViewNo Study Results PostedDisclaimerHow to Read a Study Record
Purpose
This study will compare the impact of including exenatide once weekly in addition to usual care vs. usual care without exenatide on major cardiovascular outcomes as measured by the primary composite endpoint of cardiovascular-related death, nonfatal myocardial infarction (MI), or nonfatal stroke.
ConditionInterventionPhase
Type 2 Diabetes Mellitus Drug: Exenatide Once Weekly
Drug: Placebo Phase 3
Type 2 Diabetes Mellitus Drug: Exenatide Once Weekly
Drug: Placebo Phase 3
Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Exenatide Study of Cardiovascular Event Lowering Trial (EXSCEL). A Randomized, Placebo Controlled Clinical Trial to Evaluate Cardiovascular Outcomes After Treatment With Exenatide Once Weekly in Patients With Type 2 Diabetes Mellitus.
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Exenatide Study of Cardiovascular Event Lowering Trial (EXSCEL). A Randomized, Placebo Controlled Clinical Trial to Evaluate Cardiovascular Outcomes After Treatment With Exenatide Once Weekly in Patients With Type 2 Diabetes Mellitus.
Resource links provided by NLM:
Drug Information available for: Exenatide
U.S. FDA Resources
Further study details as provided by AstraZeneca:
Primary Outcome Measures:
The primary efficacy outcome variable is defined as the composite endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke [ Time Frame: Time to first event. Information collected during study period (anticipated to be up to 7.5 years). ]
The primary safety outcome variable is defined as the composite endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke. [ Time Frame: Time to first event. Information collected during study period (anticipated to be up to 7.5 years). ]
Secondary Outcome Measures:
All-cause mortality [ Time Frame: Time to event. Information collected during study period (anticipated to be up to 7.5 years). ]
Components of the primary composite endpoint (cardiovascular death, fatal or nonfatal MI, fatal or nonfatal stroke). [ Time Frame: Time to first event. Information collected during study period (anticipated to be up to 7.5 years). ]
Hospitalization for acute coronary syndrome [ Time Frame: Time to first event. Information collected during study period (anticipated to be up to 7.5 years). ]
Hospitalization for heart failure [ Time Frame: Time to first event. Information collected during study period (anticipated to be up to 7.5 years). ]
Estimated Enrollment: 14000
Study Start Date: June 2010
Estimated Study Completion Date: April 2018
Estimated Primary Completion Date: April 2018 (Final data collection date for primary outcome measure)
Study Start Date: June 2010
Estimated Study Completion Date: April 2018
Estimated Primary Completion Date: April 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Exenatide Once Weekly Drug: Exenatide Once WeeklySubcutaneous injection, 2 mg, administered once weekly.
Experimental: Exenatide Once Weekly Drug: Exenatide Once WeeklySubcutaneous injection, 2 mg, administered once weekly.
Placebo Comparator: Placebo Drug: PlaceboSubcutaneous injection, matching volume of placebo, administered once weekly.
Eligibility
Ages Eligible for Study: 18 Years to 130 Years (Adult, Senior)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No
Criteria
Inclusion Criteria:
Patient has type 2 diabetes mellitusPatient has an HbA1c of ≥ 6.5 % and ≤ 10.0% and is currently using one of the following treatment regimens: A) Treatment with 0-3 oral antihyperglycemic agents B) Insulin therapy, either alone or in combination with up to two oral agentsFemale patients must not be breast feeding and agree to use an effective method of contraception or must not otherwise be at risk of becoming pregnant.
Exclusion Criteria:
Patient has a diagnosis of type 1 diabetes mellitus, or a history of ketoacidosis.Patient has ever been treated with an approved or investigational GLP-1 receptor agonist.Patient is enrolled in another experimental protocol which involves the use of an investigational drug or device, or an intervention that would interfere with the conduct of the trial.Patient has a planned or anticipated revascularization procedure.Pregnancy or planned pregnancy during the trial period.Patient has end-stage renal disease or an estimated glomerular filtration rate (eGFR) of <30 mL/min/1.73m2.Patient has a history of gastroparesis or pancreatitis.Personal or family history of medullary thyroid cancer or MEN2 (Multiple EndocrineNeoplasia Type 2) or calcitonin level of >40 ng/L at baseline.
Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01144338
Show 528 Study Locations
Sponsors and Collaborators
AstraZeneca
Investigators
Study Director: Nardev Khurmi, MD AstraZeneca
Nyhetsinfo
www red DiabetologNytt