Hypertension Research (2021) 44:1239–1250 https://doi.org/10.1038/s41440-021-00706-1 REVIEW ARTICLE Review series - New Horizons in the Treatment of Hypertension Angiotensin receptor-neprilysin inhibitors: Comprehensive review and implications in hypertension treatment 1 1 Koichi Yamamoto ● Hiromi Rakugi Received: 30 April 2021 / Revised: 16 June 2021 / Accepted: 21 June 2021 / Published online: 21 July 2021 © The Japanese Society of Hypertension 2021 Abstract Angiotensin receptor-neprilysin inhibitors (ARNIs) are a new class of cardiovascular agents characterized by their dual action on the major regulators of the cardiovascular system, including the renin–angiotensin system (RAS) and the natriuretic peptide (NP) system. The apparent clinical benefit of one ARNI, sacubitril/valsartan, as shown in clinical trials, has positioned the drug class as a first-line therapy in patients with heart failure, particularly with reduced ejection fraction. Accumulating evidence also suggests that sacubitril/valsartan is superior to conventional RAS blockers in lowering blood pressure in patients with hypertension. To decide whether to apply an ARNI to treat hypertension clinically, it is important to understand the potential properties of the drug in modulating multiple factors inside and outside the cardiovascular system 1234567890();,: 1234567890();,: beyond its effect on reducing peripheral blood pressure. In this context, ARNIs are distinct from preexisting antihypertensive medications in terms of the multiple actions of NPs in various organs and the pharmacological potential of neprilysin inhibitors to modulate multiple cardiac and noncardiac peptides. In particular, analysis of the clinical trials of sacubitril/ valsartan implies that ARNIs can provide additional clinical benefits independent of their original purpose, including alleviation of glycemic control and renal impairment in patients with heart failure. Understanding the potential mechanisms of action of ARNIs will help interpret the relevance of their additional benefits beyond lowering blood pressure in hypertension. This review summarizes the comprehensive clinical evidence and relevance of ARNIs by specifically focusing on the potential properties of this new drug class in treating patients with hypertension. Keywords ARNI ● Heart failure ● Hypertension ● Natriuretic peptides Introduction system (RAS) and the natriuretic peptide (NP) system. In addition to the clinically promising benefit of inhibition of In both developing and developed countries, heart failure the angiotensin II type 1 receptor (AT1), a robust increase in (HF) has been increasingly prevalent and is now a large cardioprotective NPs by the inhibition of the degrading social and medical burden, referred to as the HF pandemic enzyme neprilysin by sacubitril/valsartan, the only clinically [1, 2]. Recently, the clinical application of new classes of applied ARNI, has been shown to be beneficial in patients cardiovascular agents has rapidly advanced the treatment of with HF, particularly those with reduced ejection fraction HF, including sodium–glucose cotransporter-2 (SGLT2) (EF), in recent clinical trials [5–7]. Several clinical trials inhibitors [3], hyperpolarization-activated cyclic nucleotide- have also shown that sacubitril/valsartan is superior to gated (HCN) channel blockers [4], and angiotensin preexisting RAS inhibitors in reducing blood pressure (BP) receptor-neprilysin inhibitors (ARNIs). ARNIs are char- in hypertensive patients [8–15]. To consider the clinical acterized by their dual action on the major regulators of the application of ARNI to treat hypertension, it is important to cardiovascular system, including the renin–angiotensin understand the potential properties of the drug in modulat- ing multiple factors inside and outside the cardiovascular system beyond its effect on reducing peripheral BP. In this context, ARNIs are distinct from preexisting anti- * Koichi Yamamoto hypertensive medications in terms of the multiple actions of [email protected] NPs in various organs and the pharmacological potential of 1 The Department of Geriatric and General Medicine, Osaka neprilysin inhibitors to modulate multiple cardiac and university Graduate School of Medicine, Suita, Osaka, Japan noncardiac peptides. 1240 K. Yamamoto, H. Rakugi In this review, we will summarize the comprehensive and NPRC, which have distinct roles in the signaling and clinical evidence and relevance of ARNIs, focusing parti- metabolism of NPs. NPRA, the receptors for ANP and BNP, cularly on the potential properties of this new drug class in and NPRB, the receptor for CNP, trigger biologically and treating patients with hypertension. physiologically potent cellular signaling, primarily through the generation of cyclic guanosine monophosphate (cGMP) (Fig. 1)[26–29]. By increasing cellular cGMP levels, NPs Pharmacological property of ARNIs contribute to the regulation of systemic homeostasis and metabolism, including vasodilation, increased renal perfu- Sacubitril/valsartan (formerly called LCZ696) consists of an sion, natriuresis, antihypertrophic and antifibrotic actions, ARB, valsartan, and a neprilysin inhibitor, sacubitril reduced water and salt intake, and lipolysis (Fig. 1)[26–30]. (AHU377), in a 1:1 molecular ratio [16–18]. AHU377 is In contrast, NPRC serves as a clearance receptor for NPs by converted by enzymatic cleavage of its ethyl ester into the proteolyzing the peptides after internalization. Therefore, the active neprilysin-inhibiting metabolite LBQ657. Given the net effect of the NP system is determined by the balance extensive clinical use of ARBs, with abundant evidence of between the production and enzymatic degradation of NPs their benefit, the pharmacological novelty of this ARNI and their signal transduction and degradation via their primarily depends on the inhibition of neprilysin, a mem- receptors (Fig. 1). Among the other substrates of neprilysin, brane metallo-endopeptidase. Neprilysin cleaves peptides at bradykinin, and substance P are associated with a clinically the amino side of hydrophobic residues, and its diverse relevant symptom of neprilysin inhibition, angioedema, targets include not only NPs but also glucagon, glucagon- when combined with another enzyme inhibitor class of these like peptide-1 (GLP-1), bradykinin, substance P, neuro- peptides, the angiotensin-converting enzyme (ACE) inhibi- tensin, oxytocin, enkephalins, angiotensin I, endothelin-1, tors [21] (Fig. 2). The development of omapatrilat, which is adrenomedullin, amyloid β, and others [19]. Basic and an inhibitor of both ACE and neprilysin, was terminated clinical studies have indicated the many modulating effects because of the high incidence of angioedema [31] despite the of neprilysin inhibitors on its substrates GLP-1 [20], bra- potential benefit shown in the clinical trials for HF with dykinin, substance P [21], angiotensin I [22], endothelin-1 reduced EF (HFrEF) [32, 33]. Neprilysin also catalyzes the [23], adrenomedullin [24], and amyloid β [25]. Nevertheless, conversion of angiotensin I into angiotensin 1–7, and a the protective effect of neprilysin inhibitors on HF is pri- theoretical increase in the cascade from angiotensin I to marily attributed to the inhibition of the degradation of NPs, angiotensin II by neprilysin inhibitors implies the potential which consist of atrial NP (ANP), brain NP (BNP), and benefit of the combination of these drugs with ARBs C-type NP (CNP) (Fig. 1). ANP and BNP, which are called (Fig. 2). Other substrates of neprilysin, including GLP-1 and cardiac NPs, are released from the atrial and ventricular amyloid β, can be potentially associated with the clinical walls, respectively, primarily triggered by wall stretching effect of ARNIs, and this issue will be discussed in later [26, 27]. In contrast, the primary sources of CNP are the sections (Fig. 2). vascular endothelium and brain [28, 29]. There are three types of receptors for NPs: NP receptor A (NPRA), NPRB, Fig. 1 The signaling network of natriuretic peptides (NPs) and neprilysin. ANP atrial natriuretic peptide, BNP brain natriuretic peptide, CNP C-type natriuretic peptide, NPRA NP receptor A, NPRB NP receptor A, NPRC NP receptor C, GC guanylate cyclase, GTP guanosine triphosphate, cGMP cyclic guanosine monophosphate Angiotensin receptor-neprilysin inhibitors: Comprehensive review and implications in hypertension. 1241 Neprilysin sensitive plasma biomarkers of HF [52]. In response to treatment with S/V, alterations in these biomarkers reflect a unique signature of pharmacological and therapeutic effects Angiotensin I NPs GLP-1 Bradykinin Amyloidβ Insulin-B chain Substance P of the drug. In PARDIGM-HF, median plasma NT-proBNP VIP levels in patients treated with S/V were significantly lower 1 month after randomization than in those treated with ≤ BP elevation Cardio protection Glycemic control Angioedema Alzheimer disease enalapril, and NT-proBNP decreased to 1000 pg/ml in BP reduction Vasodilation pathology Renal protection 31% versus 17% of patients treated with S/V versus ena- Glycemic control lapril [43]. In contrast, plasma BNP levels were higher in Lipolysis patients given S/V after randomization than in those given Fig. 2 Theoretical relationship between major substrates of neprilysin enalapril. This paradoxical response of these biomarkers to and clinical manifestations. BP blood pressure, NPs natriuretic pep- tides, GLP-1 glucagon-like peptide-1, VIP vasoactive intestinal treatment with S/V was also seen in the later