Sanofi R&D Diabetes Division, Industriepark Hoechst, H825, 65926, Frankfurt/Main, Germany.
J Transl Med. 2013 Mar 28;11:84. doi: 10.1186/1479-5876-11-84.
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.
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.
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.
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.
(ELIXA, ClinicalTrials.gov Identifier: NCT01147250).
利西那肽是一种胰高血糖素样肽-1 类似物，可刺激胰岛素分泌，抑制胰高血糖素分泌和胃排空。我们研究了利西那肽在反映临床情况的啮齿动物模型中的心脏保护作用。
在经历短暂缺血和再灌注的离体大鼠心脏中，研究了利西那肽的急性心脏作用。在仅短暂冠状动脉阻塞后进行长期再灌注的改良大鼠心力衰竭模型中，评估了利西那肽慢性治疗对心脏功能的影响。使用新鲜分离的心肌细胞研究利西那肽作用的细胞类型特异性机制。
在缺血再灌注的急性情况下，利西那肽将梗死面积/危险区的比例减少了 36%，而对冠脉流量、左心室压力和心率没有影响。与安慰剂相比，在心脏缺血再灌注后开始治疗 10 周的利西那肽治疗可改善左心室舒张末期压力和舒张时间，并预防肺充血。未观察到抗纤维化作用。基因表达分析显示，与 ACE 抑制剂雷米普利相比，重塑基因发生了变化。在分离的心肌细胞中，利西那肽减少了细胞凋亡并增加了分数缩短。在大鼠心脏样本或分离的心肌细胞中均无法检测到胰高血糖素样肽-1 受体（GLP1R）mRNA 表达。令人惊讶的是，从 GLP-1 受体敲除小鼠中分离出的心肌细胞仍对利西那肽有反应。
在啮齿动物模型中，利西那肽在急性缺血后减少梗死面积，并在缺血再灌注损伤后长期给予时改善心脏功能。GLP-1 受体非依赖性机制有助于描述利西那肽的心脏保护作用。基于这些临床前发现，目前正在招募心脏功能障碍患者参加一项随机、双盲、安慰剂对照、多中心的利西那肽研究。
（ELIXA，ClinicalTrials.gov 标识符：NCT01147250）。
