The Glitazars Paradox: Cardiotoxicity of the Metabolically Beneficial Dual PPARα and PPARγ Activation.
The Glitazars Paradox: Cardiotoxicity of the Metabolically Beneficial Dual PPARα and PPARγ Activation.
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DOI：
10.1097/fjc.0000000000000891
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发表时间：
2020-11
影响因子：
3
通讯作者：
Drosatos K
中科院分区：
文献类型：
--
作者：
Kalliora C;Drosatos K
2型糖尿病患者最常见的并发症是高血糖和高脂血症，这可能会导致心血管疾病。减轻这些并发症是治疗糖尿病的主要治疗方法。过氧化物酶体增殖物激活受体激动剂α和γ分别用于治疗高脂血症和高血糖。PPAR属于核受体超家族，调节脂肪酸代谢。PPARα配体，如贝特类，可降低循环中的甘油三酯水平，而PPARγ激动剂，如噻唑烷二酮类，可提高胰岛素敏感性。双PPARα/γ激动剂(格列氮)是为了结合PPARα和PPARγ激动剂的有益作用而开发的。尽管它们改善了代谢参数，但它们通过仍然难以捉摸的机制，矛盾地加剧了2型糖尿病患者的充血性心力衰竭。在III期临床试验中，许多格列氮，如Muraglitazar、Tesaglitazar和Aleglitazar被放弃。这篇综述文章的目的在于了解PPARα和PPARγ的联合激活是如何导致心功能障碍的。此外，它的目的是提出干预措施，以维持双重PPARα/γ激动剂的有益效果，并减轻糖尿病患者的不良心脏后果。
The most common complications in patients with type-2 diabetes are hyperglycemia and hyperlipidemia that can lead to cardiovascular disease. Alleviation of these complications constitutes the major therapeutic approach for the treatment of diabetes mellitus. Agonists of peroxisome proliferator-activated receptor (PPAR) alpha and PPARγ are used for the treatment of hyperlipidemia and hyperglycemia, respectively. PPARs belong to the nuclear receptors super-family and regulate fatty acid metabolism. PPARα ligands, such as fibrates, reduce circulating triglyceride levels, and PPARγ agonists, such as thiazolidinediones, improve insulin sensitivity. Dual-PPARα/γ agonists (glitazars) were developed to combine the beneficial effects of PPARα and PPARγ agonism. Although they improved metabolic parameters, they paradoxically aggravated congestive heart failure in patients with type-2 diabetes via mechanisms that remain elusive. Many of the glitazars, such as muraglitazar, tesaglitazar, and aleglitazar, were abandoned in phase-III clinical trials. The objective of this review article pertains to the understanding of how combined PPARα and PPARγ activation, which successfully targets the major complications of diabetes, causes cardiac dysfunction. Furthermore, it aims to suggest interventions that will maintain the beneficial effects of dual PPARα/γ agonism and alleviate adverse cardiac outcomes in diabetes.