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

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)

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

“…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.…”

Cardiovascular Actions of Incretin-Based Therapies

“…8 These findings have been corroborated independently in rats by the detection of Glp1r mRNA transcripts in RNA from isolated islets and the lung, but not in RNA isolated from ventricular cardiomyocytes and whole myocardial tissue extracts. 16 Complementary studies analyzing transgenic expression of a yellow fluorescent reporter protein under the control of endogenous mouse Glp1r regulatory sequences failed to detect reporter expression in murine ventricular myocardium; however, cells positive for yellow fluorescence were scattered throughout the atrial myocardium. 10 A novel mouse monoclonal antibody localized immunohistochemical GLP-1R expression to the atria, but not the ventricle, predominantly within the sinoatrial node, in monkey and human heart tissue.…”

“…Furthermore, lixisenatide (0.3 nmol/L), a structurally related, DPP-4-resistant exendin-4 derivative, decreased infarct size in rats after LAD coronary artery occlusion ex vivo for 45 minutes followed by 2 hours of reperfusion, but did not increase coronary flow or LV contractility. 16 …”

Liraglutide can reverse memory impairment, synaptic loss and reduce plaque load in aged APP/PS1 mice, a model of Alzheimer's disease

“…Currently, the GLP-1 receptor agonists exendin-4 (Exenatide, Byetta Ò ), liraglutide (Victoza Ò ) and lixisenatide (Lyxumia Ò ) are approved for treatment of T2DM (Lovshin and Drucker, 2009;Wohlfart et al, 2013). These analogues are injected subcutaneously and are well tolerated.…”