Cardiovascular Research, Research and Early Development, R&D Pharmaceuticals, Bayer AG, Wuppertal, Germany.
Cardiology and Nephrology, Clinical Development, R&D Pharmaceuticals, Bayer AG, Berlin, Germany.
Pharmacol Res. 2021 Oct;172:105859. doi: 10.1016/j.phrs.2021.105859. Epub 2021 Aug 28.
During the recent 30 years, there has been a dramatic increase in knowledge about the role of aldosterone and the mineralocorticoid receptor (MR) in the pathophysiology of cardiovascular (CV) and kidney diseases. The scientific perspective on the aldosterone/MR ensemble extended from a previously renal epithelial-centered focus on sodium-potassium exchange to a broader view as systemic modulators of extracellular matrix, inflammation and fibrosis. Spironolactone was launched as the first antagonist of aldosterone 27 years before the MR was cloned. It was classified as a potassium-sparing diuretic, based on its initial clinical characterization as a diuretic and its preferred activity to compensate for the potassium loss induced by loop diuretics when used in combination. The second steroidal MR antagonist was eplerenone which was discovered at a time when the role of aldosterone and MR in cardiac fibrosis was rediscovered. The constraint of developing potentially life-threatening hyperkalaemia when used in combination with other inhibitors of the renin-angiotensin-system (RAS) in patients with reduced kidney function initiated extensive research and development activities with the goal to identify novel nonsteroidal MR antagonists with an improved benefit-risk ratio. Here we summarize major current clinical trials with MRAs in different CV and renal diseases. Addition of the nonsteroidal MRA finerenone to optimal RAS blockade recently reduced CV and kidney outcomes in two large phase III trials in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D). We provide an outlook on further opportunities for combination therapy of nonsteroidal MRA finerenone with RAS inhibitors and sodium-glucose cotransporter-2 inhibitors (SGLT2i).
在过去的 30 年中，人们对醛固酮和盐皮质激素受体 (MR) 在心血管 (CV) 和肾脏疾病的病理生理学中的作用有了显著的认识。醛固酮/MR 集合的科学视角已经从以前的肾脏上皮细胞为中心的钠-钾交换扩展到了作为细胞外基质、炎症和纤维化的系统性调节剂的更广泛的观点。螺内酯在 MR 被克隆前 27 年被首次推出作为醛固酮的拮抗剂。它被归类为保钾利尿剂，这是基于它最初的临床特征是利尿剂，以及在与袢利尿剂联合使用时，它优先补偿钾丢失的特性。第二种甾体 MR 拮抗剂是依普利酮，它是在醛固酮和 MR 在心脏纤维化中的作用被重新发现的时候被发现的。当与肾功能降低的患者中的肾素-血管紧张素系统 (RAS) 的其他抑制剂联合使用时，会产生潜在的威胁生命的高钾血症，这一限制引发了广泛的研究和开发活动，目的是确定具有改善的获益-风险比的新型非甾体 MR 拮抗剂。在这里，我们总结了不同的 CV 和肾脏疾病中使用 MRAs 的主要临床试验。最近，在两项大型 III 期临床试验中，将非甾体 MRA 费列罗酮与最佳 RAS 阻断联合应用于慢性肾脏病 (CKD) 和 2 型糖尿病 (T2D) 患者，降低了 CV 和肾脏结局。我们对非甾体 MRA 费列罗酮与 RAS 抑制剂和钠-葡萄糖共转运蛋白-2 抑制剂 (SGLT2i) 的联合治疗的进一步机会进行了展望。
