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Diabetes Drug Lixisenatide Demonstrates Cardiovascular Safety in Patients With High CV Risk

Treatment noninferior to placebo in phase III trial

Mixed results have been reported from a phase IIIb study that was designed to assess the cardiovascular (CV) safety of lixisenatide (Sanofi) in adults with type-2 diabetes mellitus (T2DM) and a high CV risk.

In previously reported data from the same trial, lixisenatide met the prespecified criterion of noninferiority versus placebo for the composite primary endpoint of CV death, nonfatal myocardial infarction (MI), nonfatal stroke, and hospitalization for unstable angina, but did not demonstrate superiority. The complete results will be included in the new drug application for lixisenatide, which is on track to be resubmitted to the FDA in the third quarter of 2015.

Additional safety findings include no signal for an increased risk of heart failure, pancreatitis, pancreatic cancer, or severe symptomatic hypoglycemia. Lixisenatide was generally safe and well tolerated; nausea and vomiting, which are known adverse effects of the glucagon-like peptide-1 receptor agonist (GLP-1 RA) class, were observed more often with lixisenatide than with placebo.

The ELIXA (Evaluation of Cardiovascular Outcomes in Patients With Type-2 Diabetes After Acute Coronary Syndrome During Treatment With Lixisenatide) trial was the first event-driven cardiovascular outcomes study to provide data for a GLP-1 RA. ELIXA was a global, randomized, double-blind, parallel-group trial designed to evaluate CV risk, comparing lixisenatide with placebo in a high-risk population of adults with T2DM. More than 6,000 adults with T2DM and a high CV risk (i.e., patients who recently experienced a spontaneous acute coronary syndrome event) participated in the trial. The composite primary endpoint, which was evaluated for noninferiority and superiority, comprised CV death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina. The study began in June 2010 and was completed in 2015.

Lixisenatide met the prespecified criterion of noninferiority versus placebo for the composite primary endpoint (hazard ratio [HR], 1.017). However, since the upper bound of the 95% confidence interval was greater than 1.0, superiority over placebo in reducing the composite primary endpoint was not met.

The CV safety of lixisenatide was confirmed by further analyses (e.g., major adverse cardiac events [MACE] HR, 1.02). No signal for an increased risk of heart failure was observed (HR, 0.96).

Measures of non-CV safety showed pancreatitis (0.2% with lixisenatide vs. 0.3% with placebo); pancreatic cancer (less than 0.1% vs. 0.3%); severe symptomatic hypoglycemia (0.3 events per 100 patient-years vs. 0.6 events per 100 patient-years); malignancy (2.9% vs. 2.6%); and drug-related allergic reactions (0.2% for both lixisenatide and placebo).

Lixisenatide is a once-daily prandial GLP-1 RA for the treatment of adult patients with T2DM. GLP-1 is a naturally occurring peptide hormone that is released within minutes after eating a meal. It is known to suppress glucagon secretion from pancreatic alpha cells and to stimulate glucose-dependent insulin secretion by pancreatic beta cells.

Lixisenatide is currently approved for the treatment of adults with T2DM in more than 50 countries outside the U.S. Its proprietary name in Europe is Lyxumia. The proprietary name in the U.S. is under consideration.

Source: PipelineReview; June 8, 2015.

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