Uijl Estrellita, Roksnoer Lodi C W, Hoorn Ewout J, Danser A H Jan
Division of Pharmacology and Vascular Medicine Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
Curr Hypertens Rep. 2016 Dec;18(12):86. doi: 10.1007/s11906-016-0694-x.
Coexistence of hypertension, diabetes mellitus and chronic kidney disease synergistically aggravates the risk of cardiovascular and renal morbidity and mortality. These high-risk, multi-morbid patient populations benefit less from currently available anti-hypertensive treatment. Simultaneous angiotensin II type 1 receptor blockade and neprilysin inhibition ('ARNI') with valsartan/sacubitril (LCZ696) might potentiate the beneficial effects of renin-angiotensin-aldosterone inhibition by reinforcing its endogenous counterbalance, the natriuretic peptide system. This review discusses effects obtained with this approach in animals and humans. In animal models of hypertension, either alone or in combination with myocardial infarction or diabetes, ARNI consistently reduced heart weight and cardiac fibrosis in a blood pressure-independent manner. Additionally, LCZ696 treatment reduced proteinuria, focal segmental glomerulosclerosis and retinopathy, thus simultaneously demonstrating favourable effects on microvascular complications. These results were confirmed in patient populations. Besides blood pressure reductions in hypertensive patients and greatly improved (cardiovascular) mortality in heart failure patients, ventricular wall stress and albuminuria were reduced particularly in diabetic patients. The exact underlying mechanism remains unknown, but may involve improved renal haemodynamics and reduced glomerulosclerosis, e.g. related to a rise in natriuretic peptide levels. However, the assays of these peptides are hampered by methodological artefacts. Moreover, since sacubitrilat is largely renally cleared, drug accumulation may occur in patients with impaired renal function and thus hypotension is a potential side effect in patients with chronic kidney disease. Further caution is warranted since neprilysin also degrades endothelin-1 and amyloid beta in animal models. Accumulation of the latter may increase the risk of Alzheimer's disease.
高血压、糖尿病和慢性肾脏病并存会协同加剧心血管和肾脏发病及死亡风险。这些高危、多病共存的患者群体从目前可用的抗高血压治疗中获益较少。缬沙坦/沙库巴曲（LCZ696）同时进行1型血管紧张素II受体阻断和中性肽链内切酶抑制（“ARNI”），可能通过增强其内源平衡——利钠肽系统，来增强肾素-血管紧张素-醛固酮抑制的有益作用。本综述讨论了这种方法在动物和人类中的效果。在高血压动物模型中，单独使用或与心肌梗死或糖尿病联合使用时，ARNI均以血压非依赖性方式持续减轻心脏重量和心肌纤维化。此外，LCZ696治疗可减少蛋白尿、局灶节段性肾小球硬化和视网膜病变，从而同时显示出对微血管并发症的有利影响。这些结果在患者群体中得到了证实。除了降低高血压患者的血压以及显著改善心力衰竭患者的（心血管）死亡率外，特别是在糖尿病患者中，心室壁应力和蛋白尿也有所降低。确切的潜在机制尚不清楚，但可能涉及改善肾脏血流动力学和减少肾小球硬化症，例如与利钠肽水平升高有关。然而，这些肽的检测受到方法学假象的阻碍。此外，由于沙库巴曲缬沙坦主要经肾脏清除，肾功能受损患者可能会发生药物蓄积，因此低血压是慢性肾脏病患者的潜在副作用。由于在动物模型中中性肽链内切酶也会降解内皮素-1和β-淀粉样蛋白，因此需要进一步谨慎。后者的蓄积可能会增加患阿尔茨海默病的风险。
