From ARB to ARNI in Cardiovascular Control

Abstract

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.

Keywords: Angiotensin; Chronic kidney disease; Diabetes; Natriuretic peptide; Neprilysin.

Fig. 1

Opposing effects of neprilysin (NEP) inhibition. NEP degrades vasodilators (e.g. A-type (atrial) natriuretic peptide (ANP) produced by atrial myocytes, B-type (brain) natriuretic peptide (BNP) produced by ventricular myocytes and urodilatin produced by the distal convoluted tubule and the collecting duct) as well as vasoconstrictors (e.g. angiotensin II (Ang II) and endothelin-1 produced by endothelial cells) into inactive metabolites. The effect of NEP inhibition with LCZ696 may be unpredictable as it depends on the relative dominance of either vasodilators or vasoconstrictors

Fig. 2

Effect of LCZ696 on BNP and NT-proBNP production. LCZ696 lowers blood pressure by simultaneous blockade of angiotensin II type 1 receptors (AT1R) and inhibition of neprilysin (NEP). Relative dominance of either effect determines BNP levels. NT-proBNP represents effects on ventricular wall stretch, as it is not degraded by neprilysin