Steroidal and Novel Non-steroidal Mineralocorticoid Receptor Antagonists in Heart Failure and Cardiorenal Diseases: Comparison at Bench and Bedside
Steroidal and Novel Non-steroidal Mineralocorticoid Receptor Antagonists in Heart Failure and Cardiorenal Diseases: Comparison at Bench and Bedside
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DOI：
10.1007/164_2016_76
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发表时间：
2017-01-01
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影响因子：
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通讯作者：
Pitt, Bertram
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文献类型：
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作者：
Kolkhof, Peter;Jaisser, Frederic;Pitt, Bertram
对具有细胞特异性缺失或过表达的盐皮质激素受体(MR)的小鼠的表征为其在健康和疾病中的作用提供了新的线索。MR的病理生理激活在慢性肾脏疾病(CKD)和心力衰竭(HF)等心肾疾病的发生发展中起到了过多的有害分子机制的作用。因此，现有的类固醇MR拮抗剂(MRAs)、螺内酯(第一代MRA)和依普利酮(第二代MRA)已被证明能有效降低慢性心力衰竭患者的心血管(CV)死亡率和发病率，并降低左心室射血分数(HFrEF)。然而，它们仍未得到充分利用，很大程度上是因为存在引发严重不良事件的风险，包括高钾血症和肾功能恶化，特别是在肾素血管紧张素系统(RAS)抑制剂的基础上给予伴有肾功能障碍的患者。在药物发现活动中发现了新的、有效的和选择性的非类固醇MRA(第三代)，最近一些药物进入了临床开发。其中之一是与类固醇MRAs相比，具有不同的物理化学、药代动力学和药理性质的FINERENONE。在2,000多名心力衰竭和其他慢性肾脏病和/或糖尿病患者以及糖尿病肾病患者中使用非那瑞酮进行的5项II期临床试验的现有数据表明，高血钾和肾功能下降都不是限制其使用的因素。此外，在一项IIb期试验中，与Eplerenone相比，在1066名患有HFrEF和伴随的2型糖尿病(T2 DM)和/或CKD的患者中，非涅瑞酮显示出名义上比依普利诺酮更好的结果。
Characterization of mice with cell-specific deletion or overexpression of the mineralocorticoid receptor (MR) shed a new light on its role in health and disease. Pathophysiological MR activation contributes to a plethora of deleterious molecular mechanisms in the development of cardiorenal diseases like chronic kidney disease (CKD) and heart failure (HF). Accordingly, the available steroidal MR antagonists (MRAs) spironolactone (first generation MRA) and eplerenone (second generation MRA) have been shown to be effective in reducing cardiovascular (CV) mortality and morbidity in patients with chronic HF and a reduced left ventricular ejection fraction (HFrEF). However, they remain underutilized, in large part owing to the risk inducing severe adverse events including hyperkalemia and worsening of kidney function, particularly when given on top of inhibitors of the renin angiotensin system (RAS) to patients with concomitant kidney dysfunction. Novel, potent, and selective non-steroidal MRAs (third generation) were identified in drug discovery campaigns and a few entered clinical development recently. One of these is finerenone with different physicochemical, pharmacokinetics, and pharmacological properties in comparison with the steroidal MRAs. Available data from five clinical phase II trials with finerenone in more than 2,000 patients with HF and additional CKD and/or diabetes as well as in patients with diabetic kidney disease demonstrated that neither hyperkalemia nor reductions in kidney function were limiting factors to its use. Moreover, finerenone demonstrated a nominally improved outcome compared to eplerenone in a phase IIb trial with 1,066 patients with HFrEF and concomitant type 2 diabetes mellitus (T2DM) and/or CKD.