Abstract
BackgroundLixisenatide 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.MethodsThe 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.ResultsIn 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.ConclusionsIn 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)
Highlights
Lixisenatide is a glucagon-like peptide-1 analog which stimulates insulin secretion and inhibits glucagon secretion and gastric emptying
New therapies based on the incretin hormone glucagonlike peptide-1 (GLP-1) are currently tested in clinical studies on their ability to improve the metabolic dysfunction in type 2 diabetes mellitus (T2DM) patients and to reduce cardiovascular risk
Acute ischemia reperfusion injury in isolated rat hearts The left anterior descending artery (LAD) coronary artery was occluded for 45 minutes followed by reperfusion for 120 minutes
Summary
Lixisenatide is a glucagon-like peptide-1 analog which stimulates insulin secretion and inhibits glucagon secretion and gastric emptying. New therapies based on the incretin hormone glucagonlike peptide-1 (GLP-1) are currently tested in clinical studies on their ability to improve the metabolic dysfunction in T2DM patients and to reduce cardiovascular risk. When added to standard therapy in patients with acute myocardial infarction and successful angioplasty, a 3d long infusion of GLP-1 was safe, well-tolerated and improved regional and global left ventricular function [6]. Chronic infusion of GLP-1 significantly improved left ventricular function, functional status, and quality of life in patients with severe heart failure [7]. Despite these promising cardiovascular effects, the therapeutic potential of GLP-1 is limited mainly because of its short half-life by rapid breakdown through dipeptidylpeptidase-4 [8]
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