Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes (EXSCEL)
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Clinical Question
In patients with type 2 diabetes mellitus, with or without previous cardiovascular disease, does weekly extended-release (ER) exenatide reduce the occurrence of death from cardiovascular causes when compared to placebo?
Bottom Line
There was no statistical difference of exenatide ER from placebo in reducing the occurrence of death from cardiovascular causes.
Major Points
The LEADER trial showed that patients with Type 2 Diabetes Mellitus at an increased risk for cardiovascular events, who utilized daily liraglutide (GLP-1R agonist), had an associated decreased risk of cardiovascular events when compared to placebo.1 This randomized, placebo controlled trial laid the groundwork for cardiovascular risk reduction associated with GLP-1R agonists. Due to this promising data associated with liraglutide, researchers ventured to determine if the relative cardiovascular risk reduction was associated with other drugs in the GLP-1R agonist class.
In the ELIXA study, lixisenatide was tested against placebo in Type 2 Diabetes Mellitus patients with acute coronary syndrome. The conclusion of this study was that lixisenatide did not significantly alter the rate of major cardiovascular events or other serious adverse events.
Like the ELIXA study, the EXSCEL trial was unable to demonstrate superiority in reducing the occurrence of death from cardiovascular causes. Although non-inferior relative to safety when compared to placebo, the only other significant findings were an increase in heart rate of 2.51 beats/min (95% CI, 2.28 to 2.74; P<0.001) and modest reductions in the following risk factors: Glycated hemoglobin reduction, –0.53% (95% CI, –0.57 to –0.50); P<0.001, body weight reduction -1.27 kg (95% CI, –1.40 to –1.13; P<0.001), systolic blood pressure reduction –1.27 kg (95% CI, –1.40 to –1.13; P<0.0010).
Guidelines
As of October 2017, no guidelines have been published that reflect the results of this trial. Current AACE guidelines recommend GLP-1R agonists as first line, non-insulin therapy for intensifying prandial control for Type 2 Diabetes patients.
Design
Randomized, double blind, placebo-controlled, multicenter event-driven trial
- N=14,752
- Exenatide ER (n=7,356)
- Placebo (n=7,396)
- Setting: 687 sites in 35 countries
- Enrollment: 2010-2015
- Median follow-up: 5 months
- Analysis: Intention-to-treat
Primary outcome: Death from cardiovascular causes: Non-fatal myocardial infarction, or non-fatal stroke.
Population
Inclusion Criteria
T2DM and Hgb A1c 6.5-10.0%
- Age ≥18 years, with or without previous cardiovascular events
- Eligible previous cardiovascular events:
- History of major clinical manifestation of coronary artery disease
- Ischemic cerebrovascular disease
- Atherosclerotic peripheral arterial disease
Exclusion Criteria
- History of two or more episodes of severe hypoglycemia
- Defined as: Hypoglycemia which the patient required 3rd party assistance in the preceding 12 months
- History of major clinical manifestation of coronary artery disease
- End-stage kidney disease
- Estimated glomerular filtration rate (eGFR) at entry of less than 30 mL/min/1.73m2
- A personal or family history of:
- Medullary thyroid carcinoma
- Multiple endocrine neoplasia
- Baseline calcitonin level of greater than 40 ng/L
- Previous treatment with a GLP-1 receptor agonist
Baseline Characteristics
Presented in the order of treatment vs placebo
- Age
- < 65: 60% vs 60%
- ≥ 65: 40% vs 40%
- Sex
- Male: 62% vs 62%
- Female: 38% vs 38%
- Race or Ethnic Group
- White: 75.5% vs 76%
- Black: 6% vs 5.9%%
- Asian: 9.9% vs 9.8%
- Native American/Alaskan Native: 0.05% vs 0.05%
- Pacific Islander: 0.02% vs 0.02%
- Hispanic: 7.8% vs 7.5%
- Region
- Europe: 46% vs 46%
- North America: 25% vs 25.3%
- Latin America: 18.5% vs 18.4%
- Asia-Pacific: 10.5% vs 10.3%
Interventions
Open label glucose-lowering agents use, excluding GLP-1R agonists, were encouraged in each group in order to help patients achieve goal glycated hemoglobin targets. Patients were randomly assigned into a 1:1 ratio into the following groups:
Treatment
- Subcutaneous injections of extended-release exenatide at a dose of 2 mg, once weekly.
- Placebo
- Non-therapeutic, subcutaneous injections given once weekly.
Outcomes
Comparisons are once weekly exenatide ER injections vs. Placebo.
Primary Outcome
- Death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke
- 11.4% vs 12.2% (HR 0.91; 95% CI 0.83-1.00; P=0.06)
Secondary Outcomes
- Death from any cause
- 6.9% vs 7.9% (HR 0.86; 95% CI 0.77-0.97)
- Not considered statistically significant on the basis of hierarchical testing
- Death from cardiovascular causes, including unknown causes
- 4.6% vs 5.2% (HR 0.88; 95% CI 0.76-1.02)
- Fatal or nonfatal myocardial infarction
- 6.6% vs 6.7% (HR 0.97; 95% CI 0.85-1.10)
- Fatal or nonfatal stroke
- 2.5% vs 2.9% (HR 0.85; 95% CI 0.70-1.03)
- Hospitalization for heart failure
- 3.0% vs 3.1% (HR 0.94; 95% CI 0.78-1.13)
- Hospitalization for acute coronary syndrome
- 8.2% vs 7.7% (HR 1.05; 95% CI 0.94-1.18)
Subgroup Analysis
A subgroup analysis was performed on the duration in which individuals had diabetes, use of anti-hyperglycemic oral agents, insulin therapy, DPP-4 inhibitors, history of congestive heart failure, glycated hemoglobin levels below and above/equal to 8%, estimated GFR, body-mass index, and previous cardiovascular events at randomization. Each group was shown to be non-significant in nature.
Adverse Events
Authors did not provide statistical analysis on the adverse events, but note the treatment group was equivalent to placebo with respect to safety.
Criticisms
- Follow up time was limited to a median of 5 months.
- The LEADER trial, with significant cardioprotective findings, had a median follow up of 3.8 years. In relation, this 5 month follow up is unlikely to provide sufficient time to evaluate the benefits of exenatide ER on cardiovascular events.
- Liraglutide is more homologous to human GLP-1, than exenatide as it is obtained from a reptile.
- There has not been a comparison to determine whether or not the homology of the medication affects the therapeutic profile of the medications.
- Although other diabetes medications were shown, the use of other cardioprotective medication was not disclosed.
Funding
Funded by Amylin Pharmaceuticals; ClinicalTrials.gov number, NCT01144338.
Further Reading
Marso SP et al. Design of the liraglutide effect and action in diabetes: evaluation of cardiovascular outcome results (LEADER) trial. Am. Heart J. 2013. 166:823-30.e5.