Elsevier

American Heart Journal

Volume 169, Issue 5, May 2015, Pages 631-638.e7
American Heart Journal

Trial Design
Rationale, design, and baseline characteristics in Evaluation of LIXisenatide in Acute Coronary Syndrome, a long-term cardiovascular end point trial of lixisenatide versus placebo

https://doi.org/10.1016/j.ahj.2015.02.002Get rights and content

Background

Cardiovascular (CV) disease is the leading cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). Furthermore, patients with T2DM and acute coronary syndrome (ACS) have a particularly high risk of CV events. The glucagon-like peptide 1 receptor agonist, lixisenatide, improves glycemia, but its effects on CV events have not been thoroughly evaluated.

Methods

ELIXA (www.clinicaltrials.gov no. NCT01147250) is a randomized, double-blind, placebo-controlled, parallel-group, multicenter study of lixisenatide in patients with T2DM and a recent ACS event. The primary aim is to evaluate the effects of lixisenatide on CV morbidity and mortality in a population at high CV risk. The primary efficacy end point is a composite of time to CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. Data are systematically collected for safety outcomes, including hypoglycemia, pancreatitis, and malignancy.

Results

Enrollment began in July 2010 and ended in August 2013; 6,068 patients from 49 countries were randomized. Of these, 69% are men and 75% are white; at baseline, the mean ± SD age was 60.3 ± 9.7 years, body mass index was 30.2 ± 5.7 kg/m2, and duration of T2DM was 9.3 ± 8.2 years. The qualifying ACS was a myocardial infarction in 83% and unstable angina in 17%. The study will continue until the positive adjudication of the protocol-specified number of primary CV events.

Conclusion

ELIXA will be the first trial to report the safety and efficacy of a glucagon-like peptide 1 receptor agonist in people with T2DM and high CV event risk.

Section snippets

Glucose-lowering therapy and CV risk

Evidence-based primary and secondary CV risk reduction strategies, such as the use of statins,13, 14 angiotensin-converting enzyme inhibitors, and β-blockers,15, 16, 17 are effective in patients with T2DM. However, the role of glycemic control in CV risk reduction is less clear. A meta-analysis of clinical trials suggested that intensive glycemic control in patients with T2DM reduced the risk of nonfatal myocardial infarction (MI) but did not reduce total or CV-related mortality.18 Furthermore,

Study design and objectives

ELIXA (www.clinicaltrials.gov no. NCT01147250) is a randomized, double-blind, placebo-controlled, parallel-group, multicenter phase III event-driven trial designed to assess the effects of lixisenatide added to current T2DM therapy on CV morbidity and mortality in patients with a recent ACS. The primary outcome is the composite of CV death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina (UA). Secondary trial objectives include the examination of lixisenatide's effects on

Results

Screening and enrollment into ELIXA began June 24, 2010, and randomization was completed on August 2, 2013. There were 7,718 candidates screened and 6,068 participants randomized to either lixisenatide or placebo (online Appendix A) from 49 countries across 6 regions (online Appendix E) with the support of 782 principal investigators (online Appendix F). One additional candidate was screened and randomized but excluded from analysis due to inadequate consent. Baseline data include data

Discussion

ELIXA will determine the effects of lixisenatide, a GLP-1RA, compared to placebo on the burden of CV disease in patients with T2DM and ACS. Although native GLP-1 and GLP-1RAs exert favorable CV effects in animal models of MI and ischemia/reperfusion injury,40, 41, 42 few data exist in humans. In small placebo-controlled studies, GLP-1RA treatment improved myocardial salvage and reduced infarct size.43, 44 A larger retrospective analysis revealed that the nonrandomized use of GLP-1RA was

Disclosures

The authors have the following disclosures:

R. Bentley-Lewis: consultant and research support—Sanofi; research support, spouse/partner—Sanofi; Amgen, Inc; and Novartis Pharmaceuticals Corporation. D. Aguilar: consultant—Bristol-Myers Squibb Company and Sanofi. M.C. Riddle: consultant—Eli Lilly and Company, AstraZeneca Pharmaceuticals LP, Sanofi, Valeritas, LLC, and Elcelyx Therapeutics, Inc; research support—AstraZeneca Pharmaceuticals LP, Eli Lilly, and Company, Sanofi, Novo Nordisk, Inc; other

Acknowledgements

We thank Jennifer Huynh, BA, and Rebecca Walmer, BA, salaried research assistants employed by Rhonda Bentley-Lewis, MD, for their assistance with literature review and manuscript formatting.

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