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Open Access Highly Accessed Research

Cardioprotective effects of lixisenatide in rat myocardial ischemia-reperfusion injury studies

Paulus Wohlfart1*, Wolfgang Linz1, Thomas Hübschle1, Dominik Linz2, Jochen Huber13, Sibylle Hess1, Daniel Crowther1, Ulrich Werner1 and Hartmut Ruetten1

Author Affiliations

1 Sanofi R&D Diabetes Division, Industriepark Hoechst, H825, 65926, Frankfurt/Main, Germany

2 Faculty of Medicine, Saarland University, Saarbrücken, Homburg/Saar, Germany

3 Current Adress: Boehringer-Ingelheim Pharma GmbH, CMDR, Biberach a.d.R., Germany

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Journal of Translational Medicine 2013, 11:84  doi:10.1186/1479-5876-11-84

Published: 28 March 2013

Abstract

Background

Lixisenatide is a glucagon-like peptide-1 analog which stimulates insulin secretion and inhibits glucagon secretion and gastric emptying. We investigated cardioprotective effects of lixisenatide in rodent models reflecting the clinical situation.

Methods

The acute cardiac effects of lixisenatide were investigated in isolated rat hearts subjected to brief ischemia and reperfusion. Effects of chronic treatment with lixisenatide on cardiac function were assessed in a modified rat heart failure model after only transient coronary occlusion followed by long-term reperfusion. Freshly isolated cardiomyocytes were used to investigate cell-type specific mechanisms of lixisenatide action.

Results

In the acute setting of ischemia-reperfusion, lixisenatide reduced the infarct-size/area at risk by 36% ratio without changes on coronary flow, left-ventricular pressure and heart rate. Treatment with lixisenatide for 10 weeks, starting after cardiac ischemia and reperfusion, improved left ventricular end-diastolic pressure and relaxation time and prevented lung congestion in comparison to placebo. No anti-fibrotic effect was observed. Gene expression analysis revealed a change in remodeling genes comparable to the ACE inhibitor ramipril. In isolated cardiomyocytes lixisenatide reduced apoptosis and increased fractional shortening. Glucagon-like peptide-1 receptor (GLP1R) mRNA expression could not be detected in rat heart samples or isolated cardiomyocytes. Surprisingly, cardiomyocytes isolated from GLP-1 receptor knockout mice still responded to lixisenatide.

Conclusions

In rodent models, lixisenatide reduced in an acute setting infarct-size and improved cardiac function when administered long-term after ischemia-reperfusion injury. GLP-1 receptor independent mechanisms contribute to the described cardioprotective effect of lixisenatide. Based in part on these preclinical findings patients with cardiac dysfunction are currently being recruited for a randomized, double-blind, placebo-controlled, multicenter study with lixisenatide.

Trial registration

(ELIXA, ClinicalTrials.gov Identifier: NCT01147250)

Keywords:
Lixisenatide; GLP1-receptor agonist; Diabetes; Macrovascular risk; Cardioprotection; Myocardial ischemia-reperfusion; Cardiac dysfunction; Pre-clinical models