The nephroprotective effect of sacubitril/valsartan in heart failure: insights from the real-life clinical setting

Excerpt

Sacubitril/valsartan represents the first agent in a new class of drugs developed for heart failure (HF) treatment and termed angiotensin receptor neprilysin (NEP) inhibitors (ARNIs). It is a fixed-dose combination compound containing molecular moieties of valsartan, an angiotensin-type I receptor (AT1)-inhibitor, and the NEP inhibitor sacubitril in a 1:1 molar ratio [1]. Sacubitril is a prodrug that, following oral administration, is rapidly metabolized to the biologically active molecule sacubitrilat. This inhibits the NEP, which is a ubiquitous endopeptidase that is responsible for the breakdown of many vasoactive peptides, including the biologically active natriuretic peptides (NPs), adrenomedullin, substance P, bradykinin, vasoactive intestinal polypeptide, calcitonin gene-related peptide, and enkephalins. Inhibition of NEP increases the levels of these substances, countering the neurohormonal overactivation that contributes to vasoconstriction, sodium retention, and maladaptive remodeling in patients with HF [1]. The NPs are structurally related but genetically different hormones or paracrine factors, that protect the cardiovascular (CV) system from volume overload. The mammalian NP system comprises of mainly 3 NPs: atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). In the kidney, more specifically distal tubular cells, expression of ANP precursor produces a subtype called urodilatin, which helps ANP to regulate renal sodium and water excretion through inhibition of antidiuretic hormone and, Angiotensin II/aldosterone-dependent sodium and water re-absorption [2]. In addition, NPs are known to oppose RAS and have anti-proliferative and anti-hypertrophic effects. As the clinical stage of HF progresses, the responsiveness to NPs, in particular ANP and BNP, decreases. This can be due to downregulation of NPs receptors, increased clearance of BNP by NEP or the NPR-C receptor, or decreased downstream signaling. Blocking NEP with sacubitril/valsartan (S/V) results in greater level of NPs and in increased generation of myocardial cGMP. In this way it is possible to overcome natriuretic resistance, resulting from any one of the previously described mechanisms, thus producing favourable clinical outcomes in patients with HF [2]. Indeed, S/V is the most remarkable pharmacological innovation concerning the treatment of patients with chronic HF and reduced ejection fraction (HFrEF) [3]. In “The Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure” (PARADIGM-HF) trial, this drug was studied in 8442 patients with HFrEF, clearly showing superiority above treatment with ACE-inhibitor enalapril [4]. The outcomes of the trial were so overwhelmingly positive that it was stopped early by its data monitoring committee. With a median follow-up of 27 months, the investigators demonstrated a 20% relative risk reduction in the composite of CV death or hospitalization for HF and a 16% relative risk improvement in all-cause mortality, with a number needed-to-treat of 35 [4]. Additionally, S/V is also promising in HF with preserved ejection fraction (HFpEF), because it leads to improvement in ventricular diastolic function. …