Angiotensin Receptor-Neprilysin Inhibitors: Comprehensive Review and Implications in Hypertension Treatment

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 modulating 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 peptides, GLP-1 glucagon-like peptide-1, VIP vasoactive intestinal treatment with S/V was also seen in the later RCT of polypeptide HFrEF, PIONEER-HF (comparison of sacubitril-valsartan versus enalapril on effect on NT-proBNP in patients stabi- lized from an acute HF episode) [6]. In this RCT, the effect Evidence of the effect on HF of S/V on the time-averaged proportional change in the NT- proBNP concentration from baseline was compared to that The apparent benefit of sacubitril/valsartan (S/V) in treating of enalapril in patients with acute decompensated HFrEF. HFrEF was first shown in a randomized clinical trial (RCT) The results showed that the reduction in the NT-proBNP named the Prospective Comparison of ARNi with ACE-I to concentration was significantly greater in the S/V group Determine Impact on Global Mortality and Morbidity in than in the enalapril group, whereas the reduction in BNP Heart Failure (PARADIGM-HF) [5]. This was a prospective did not differ between the treatment groups [6]. The sec- multicenter trial in which 8442 patients with HFrEF (EF ≤ ondary analysis of PIONEER-HF showed that S/V 40%) who were classified as New York Heart Association improved the clinical composite outcome of death from any (NYHA) class 2–4 under sufficient control with β-blockers cause, rehospitalization for HF, left ventricular assist device and an ACE inhibitor or an ARB were randomly assigned to implantation, and listing for cardiac transplantation [53]. treatment with either S/V 200 mg twice daily or an ACE These clinical benefits of S/V were observed regardless of inhibitor, enalapril, 10 mg twice daily [5]. The primary the prior use of RAS inhibitors [54]. composite outcome of death resulting from cardiovascular In contrast to the obvious benefits of S/V in HFrEF, the causes or hospitalization for HF occurred in 914 patients clinical effects of the drug on HF with preserved EF (21.8%) in the S/V group and 1117 patients (26.5%) in the (HFpEF) remain poorly established. Given the findings in enalapril group (hazard ratio in the S/V group, 0.80; 95% the phase II trial showing that S/V reduced NT-proBNP at confidence interval [CI], 0.73–0.87; p < 0.001). There was 12 weeks compared with valsartan in patients with HFpEF also a reduction in death from any cause, death from car- [55], an RCT named the Prospective Comparison of ARNI diovascular causes, hospitalization for HF, and the symp- with ARB Global Outcomes in HF with Preserved Ejection toms and physical limitations of HF in those treated with Fraction (PARAGON-HF) trial was designed to investigate S/V [5]. Subsequent subanalyses of PARDIGM-HF data the effect of ARNI on clinical outcomes in patients with have also shown that S/V was superior to enalapril in HFpEF. A total of 4822 HF patients with NYHA class 3–4, alleviating the worsening of surviving patients with HF EF of 45% or higher, elevated levels of natriuretic peptides, [34], alleviating the clinical worsening of HF treated in the and structural heart disease were randomly assigned to outpatient setting [35], hospital readmission at 30 days receive S/V 200 mg twice daily or valsartan 160 mg twice following HF hospitalization [36], recurrent hospitalizations daily [56]. S/V did not significantly reduce the primary and CV deaths [37], and quality of life [38]. The treatment composite outcome of total hospitalizations for HF and benefit of S/V over enalapril was evident irrespective of the death from cardiovascular causes (rate ratio, 0.87; 95% cause of cardiac death [39], age [40], severity of HF [41], confidence interval [CI], 0.75–1.01; p = 0.06). Regarding baseline EF [42], baseline plasma N-terminal pro BNP (NT- secondary outcomes, S/V was associated with greater proBNP) level [43], the presence of prediabetes or diabetes improvement in NYHA class and in the Kansas City Car- [44], recent hospitalization due to HF [45], baseline treat- diomyopathy Questionnaire (KCCQ) score, a patient- ment of HF [46], baseline BP [47], the presence of hypo- reported outcome of symptoms and physical limitations, tension [48], dose reduction of the treatment drugs [49], than valsartan. The prespecified subgroup analysis of the geographic variations [50], and etiology of HF [51]. primary outcome showed that S/V reduced risk in females BNP77–108 and the biologically inactive fragment NT- [56, 57] and patients with a median EF (57%) or lower [56]. proBNP1-76, both cleaved from pro-BNP1–108, serve as The combined analysis of PARADIGM-HF and 1242 K. Yamamoto, H. Rakugi

PARAGON-HF data showed that the treatment benefitof valsartan achieved greater ambulatory BP reductions at S/V over valsartan was modified by LVEF, and a benefit nighttime than during daytime, the reduction under S/V appeared to be present primarily in individuals with EF being greater, consistent with the notion that diuretic- below the normal range (<55%). Baseline BP and BP- induced natriuresis improves nocturnal hypertension lowering effects were not associated with the treatment [70, 71]. Nevertheless, the difference in 24-h sodium benefit of S/V in PARAGON-HF [58]. Another analysis excretion and urine excretion between the treatments dis- indicated that a treatment benefit of S/V might exist in appeared on day 28 despite the increase in urinary cGMP patients with prior HF hospitalization within 180 days of excretion with S/V [13]. The authors offered that the enrollment, but not others [59]. S/V reduced NT-proBNP vasodilatory effect of NPs [72–74] might reset sodium and compared with valsartan consistently in men and women water homeostasis and prevent sustained natriuresis and and in patients with lower or higher EF [60]. diuresis in these patients. Hypertension in the older popu- lation is characterized by isolated systolic hypertension with Evidence of the influence on hypertension increased pulse pressure caused by the physiological stif- fening of large arteries [75, 76]. Arterial stiffness is closely The BP-lowering potential of ARNI, superior to that of associated with higher central BP and left ventricular conventional RAS inhibitors, was first shown in a rando- hypertrophy, both of which could predict future cardio- mized, double-blind, placebo-controlled, active comparator vascular diseases independent of peripheral BP [77–79]. study [10]. In this study, patients aged 18–75 years with Williams et al. investigated the effects of S/V compared to mild-to-moderate hypertension were randomly assigned to olmesartan on central hemodynamics in older patients with eight groups: 100 mg (n = 156 patients), 200 mg (n = 169), systolic hypertension [12]. They found that 200 mg S/V or 400 mg (n = 172) S/V; and 80 mg (n = 163), 160 mg reduced central aortic systolic pressure, central aortic pulse (n = 166), 320 mg (n = 164) valsartan, 200 mg sacubitril pressure, mean 24-h ambulatory brachial systolic pressure, (n = 165), or placebo (n = 173). After the 8-week treatment and central aortic systolic pressure more than 20 mg olme- period, the average reduction in mean sitting diastolic BP sartan did. The superior BP reduction by S/V was more across the doses of S/V versus the comparator dose of pronounced during nighttime when 24-h ambulatory pres- valsartan showed significantly greater reductions with S/V sures were taken, suggesting that S/V contributes to the (mean reduction: −217 mm Hg, 95% CI −3.28 to −1.06; alleviation of the circadian rhythm of BP [12]. There was no p < 0.0001) [10]. The excellent BP-lowering potential of difference between treatments in the change in pulse wave S/V has been consistently replicated in numerous clinical velocity (PWV), a marker of arterial stiffness [80], while a trials for hypertension [8–15, 61, 62] and meta-analyses post hoc analysis showed a certain trend in favor of S/V [63–65]. S/V has shown a superior reduction of ambulatory [12]. Schmieder et al. used magnetic resonance imaging BP as well as clinic siting BP compared with comparable (MRI) scans to investigate the effect of S/V compared to doses of valsartan [10, 13, 14] or an ARB, olmesartan olmesartan on cardiovascular remodeling in patients with [8, 9, 11, 12, 15] (Table 1). The mechanisms by which S/V essential hypertension [15]. LV mass index, as a measure of induces additional BP-lowering effects have also been LVH, was decreased from baseline to a greater extent by investigated. Consistent with the findings in RCTs on HF, S/V than valsartan at 12 (−6.36 vs. −2.32 g/m2, p = 0.039) S/V reduced plasma NT-proBNP [12, 13] and increased and 52 weeks (−6.83 vs. −3.55 g/m2, p = 0.029), and the plasma ANP concentrations [10] in patients with hyper- difference remained significant after adjusting for changes tension. Urinary cGMP secretion continuously increased in SBP [15]. In contrast, they did not find a treatment dif- with S/V treatment, suggesting that restoration of the ference in the change in MRI-based local aortic dis- bioavailability of NPs is physiologically relevant in hyper- tensibility assessed by PWV, while central BP was reduced tensive patients treated with S/V [12, 13]. Natriuresis is by S/V greater than by valsartan. S/V was also shown to considered a key mechanism of the BP-lowering effect of have no additional effect on aortic characteristic impedance, NPs [27, 66–69]. In this context, Wang et al. conducted a a measure of central aortic stiffness, compared to enalapril clinical trial to investigate the mechanisms of action of S/V in patients with HFrEF [81]. Taken together, the data show in lowering BP in patients with salt-sensitive hypertension that this ARNI has the ability to lower BP more than con- (SSH) [13]. In this crossover study, patients with SSH, ventional RAS inhibitors, primarily attributed to the defined by a 10% BP increase after switching from a low- natriuretic and potential vasodilating effects of NPs. The sodium diet (50 mmol/d) to a high-sodium diet (320 mmol/ benefit of the ARNI compared to conventional RAS inhi- d) were consecutively administered 400 mg S/V and 320 mg bitors involves the alleviation of hypertension-induced valsartan or vice versa. They found that cumulative 6- and cardiac remodeling along with its excellent potency in 24-h sodium excretion and urine excretion increased with S/ reducing central BP, although the effect on arterial stiffness V on day 1 of treatment. They also found that both S/V and is uncertain (Table 2). nitni eetrnpiyi niios opeesv eiwadipiain nhpreso...1243 . . hypertension. in implications and review Comprehensive inhibitors: receptor-neprilysin Angiotensin Table 1 The summary of randomized clinical trials of sacubitril/valsartan versus ARBs in patients with hypertension

Patient background S/V Comparator Duration for evaluation BP lowering effect Speciﬁc ﬁndings besides BP lowering effect Ref.

Patients with mild to 200 mg (n = 188) Olmesartan 20 mg (n = 8 weeks 24‐h mean ambulatory SBP were observed in the S/V group N/A [8] moderate essential 187) vs. the olmesartan group (−4.3 mmHg vs. −1.1 mmHg, hypertension P < 0.001). Reductions in 24‐h mean ambulatory diastolic BP (>18 years) and PP and office SBP and DBP were significantly greater with S/V vs. olmesartan. Asian patients with 200 mg (n = 479) Olmesartan 20 mg (n = 8 weeks S/V 200 and 400 mg provided a significantly greater N/A [9] mild-to-moderate 400 mg 486) reduction in sitting SBP than olmesartan 20 mg at week 8 hypertension (n = 473) (between-treatment difference: −2.33 mmHg or −3.52 mmHg, respectively) Greater reductions in sitting SBP with S/V were observed in elderly patients, and those with ISH. Both doses of sacubitril/valsartan provided significantly greater reductions from baseline in nighttime mean ambulatory BP vs. Patients aged 18–75 100 mg (n = 156) Valsartan 80 mg (n = 8 weeks The average reduction in mean sitting DBP across the doses Plasma ANP concentrations increased with all three doses of [10] years with mild-to- 200 mg 163) of S/V versus the comparator dose of valsartan showed S/V compared with the comparator dose of valsartan moderate (n = 169) 400 mg 160 mg (n = 166) 320 significantly greater reductions with S/V. hypertension (n = 172) mg (n = 164) Scubitril 200 mg (n = 165) Placebo (n = 173) Asian patients (65 100 mg titrated to Olmeartan 10 mg titrated 14 weeks S/V provided superior sitting SBP reductions vs. olmesartan N/A [11] years) with systolic 200 mg after to (22.71 vs. 16.11 mmHg, respectively); similarly, reductions hypertension 4 weeks. Up-titrated 20 mg after 4 weeks. from baseline in other BP and PP assessments were to 400 mg for Up-titrated to 40 mg for significantly greater with sacubitril/valsartan. At week 14, patients with patients with BP > 140/ despite more patients requiring up-titration in the olmesartan BP > 140/90 mm Hg 90 mm Hg at 10 weeks group, sitting BP and sitting PP reductions from baseline at 10 weeks (n = (n = 292) were significantly greater with S/V. 296) Older patients with 200 mg titrated to Olmeartan 20 mg titrated 12 weeks for titration At week 12, reductions were significantly greater with S/V in The reduction in the mean plasma NT-proBNP from baseline [12] systolic hypertension 400 mg after 4 weeks to 40 mg after 4 weeks 12 weeks to 52 weeks for central aortic systolic pressure (−3.7 mmHg), central aortic to week 12 was greater in patients treated with S/V (34%) and pulse pressure (n = 229) (n = 225) add-on treatment with PP (−2.4 mmHg), mean 24-h ambulatory brachial systolic compared with olmesartan (20%). An increase in the urine >60 mm Hg amlodipine and pressure (−4.1 mmHg) and central aortic systolic pressure cGMP/creatinine ratio was observed at week 52 but not at (60 years) hydrochlorothiazide (−3.6 mmHg). Differences in 24-h ambulatory pressures week 12 in the S/V-treated patients. were pronounced during sleep. After 52 weeks, more patients required add-on antihypertensive therapy with olmesartan (47%) versus S/V (32%) Asian patients with 400 mg Valsartan 320 mg Double-blind crossover Compared with valsartan, S/V was associated with greater Compared with valsartan, S/V was associated with a [13] salt sensitive treatment for 28 days reductions in office and ambulatory BP on day 28 significant increase in natriuresis and diuresis on day 1, but hypertension not on day 28. Compared with valsartan, S/V significantly (>18years) (n = 70) reduced plasma NT-proBNP on day 28. Patients with mild-to- 400 mg Valsartan (320 mg) 8 weeks There were greater reductions in sitting office SBP and 24-h N/A [14] moderate systolic alone or valsartan with ambulatory SBP with S/V than with valsartan (−5.7 and hypertension placebo or 50, 100, 200, −3.4 mmHg, respectively). The SBP reduction with S/V was or 400 mg sacubitril similar to co-administered free valsartan and sacubitril 200 mg. Patients with essential 200 mg titrated to Olmeartan 20 mg titrated 12 weeks for single Reductions in SBP were significantly greater with S/V at MRI-based LVMI decreased to a greater extent in the S/V [15] hypertension stage 1 400 mg after 2 weeks to 40 mg after 2 weeks treatment period 52 weeks but not at 12 weeks. Reduction in Central SBP and group compared to the olmesartan group from baseline to 12 and 2 and elevated (n = 57) (n = 57) 12–52 weeks for add- DBP were not different between S/V and olmesartan at and 52 weeks after adjustment for SBP. The change in aortic brachial PP on period 12 weeks and 52 weeks. Reductions in central PP was local distensibility and PWV were not different between the (50 mmHg) significantly greater with S/V at 52 weeks but not at two groups. 12 weeks. S/V sacubitril/valsartan, BP blood pressure, SBP systolic BP, DBP diastolic BP, ANP atrial natriuretic peptide, BNP brain natriuretic peptide, PP pulse pressure, LVMI left ventricular mass index, PWV pulse wave velocity 1244 K. Yamamoto, H. Rakugi

Table 2 The influence of sacubitril/valsartan on cardiovascular increase in eGFR and UACR following treatment with structures and hemodynamics in patients with hypertension S/V can be explained by the molecular mechanism of the Peripheral BP Superior to ARB inhibition of the RAS and the activation of NPs in mod- 24 h-amubulatory BP Superior to ARB (particularly at night) ulating renal hemodynamics [92, 93]. Inhibition of the Central BP Superior to ARB RAS by valsartan induces dilation of efferent arterioles, Left ventricular hypertrophy Superior to ARB leading to decreased intraglomerular pressure and GFR. In Arterial stiffness Equivalent to ARB contrast, NPs predominantly induce dilation of afferent arterioles, leading to increases in renal perfusion flow and BP ARB blood pressure, angiotensin II type1 blocker GFR [94]. Therefore, the increase in the bioavailability of NPs by sacubitril would contribute to the increase in GFR Evidence of an influence on renal function along with the increased glomerular filtration of albumin in patients treated with S/V [92, 93](Fig.3). The direct Renal impairment and hypertension are closely inter- effect of NPs on kidney function, including increased related, and the protection of renal function is one of the glomerular permeability and blockade of tubular protein expected roles of antihypertensive medications [82]. It is reabsorption, might also contribute to the increased of interest to clarify whether ARNIs have an additional UACR induced by S/V [92, 93, 95, 96]Incontrasttothe benefit on renal function beyond that provided by classical clear evidence of the renal effect of S/V in HF patients, RAS inhibitors that are positioned as a first-line therapy in the effect in non-HF patients is not clearly supported by hypertensive patients with diabetic kidney disease or clinical studies. In the United Kingdom Heart and Renal nondiabetic kidney disease with proteinuria [83–87]. The Protection (UK HARP)‐III trial, 414 participants with analysis of RCTs has consistently revealed the specific chronickidneydiseasewhohadaneGFRof20to60mL/ effect of S/V on renal function in patients with HF who min/1.73 m2 were randomly assigned to S/V 200 mg twice areathighriskofrenalinsufficiency [88]. In the daily and irbesartan 300 mg once daily. As a result, there PARADIGM-HF trial, the decrease in eGFR during was no difference in measured GFR at 12 months of 48 months’ follow-up was less under S/V compared with treatment: 29.8 [SE, 0.5] among participants assigned S/V enalapril (−1.61 ml/min/1.73 m2/year vs. −2.04 ml/min/ versus 29.9 [SE, 0.5] mL/min/1.73 m2 among those 1.73 m2/year, p < 0.001) despite a modest but greater assigned irbesartan. There was also no significant differ- increase in urinary albumin/creatinine ratio (UACR) ence in estimated GFR at 3, 6, 9, or 12 months and no under S/V than enalapril (1.20 mg/mmol vs. 0.90 mg/ clear difference in UACR between treatment arms despite mmol, p < 0.001) in patients with HFrEF [89]. This see- the greater decline of BP in S/V patients [97]. Never- mingly paradoxical effect of S/V on eGFR and UACR theless, it should be noted that the relatively short was consistent with the findings of an RCT named the observation period in this study compared to the clinical Prospective Comparison of ARNI with ARB on Man- trials for HF might have affected the results [97]. There is agement Of heart failUre with preserved ejectioN fracTion no previous or ongoing clinical trial to measure the effect (PARAMOUNT) trial [55]. In this phase II clinical trial of S/V vs. other antihypertensive drugs on long-term renal where the efficacy of S/V on the reduction of NT-proBNP function in hypertensive patients. It was reported that wasproveninpatientswithHFpEFincomparisonto 8 weeks of treatment with S/V effectively reduced BP, valsartan, eGFR declined less under S/V than under val- with no clinically meaningful changes in creatinine, sartan (−1.5 vs. −5.2 mL/min per 1.73 m2; p = 0.002); potassium, blood urea nitrogen, or eGFR, in Japanese however, UACR increased in the S/V group (2.4–2.9 mg/ patients with hypertension and renal dysfunction (eGFR ≥ mmol), whereas it remained stable in the valsartan group 15 and <60 mL/min/1.73 m2)[98]. Collectively, the stu- (2.1–2.0 mg/mmol; p = 0.016) over 36 weeks of the study dies have shown that S/V can be safely used in hyper- period [90]. In the PARAGON-HF trial, the prespecified tensive patients with CKD, while the additive effect of composite renal outcome made up of the time to first neprilysin inhibition on renal function is not clear in occurrence of a ≥50% reduction in estimated glomerular patients without HF. filtration rate (eGFR), end-stage renal disease, and death from renal causes, was analyzed [91]. In 4882 patients, the composite renal outcome occurred in 33 patients Evidence of an influence on metabolic (1.4%) assigned to S/V and 64 patients (2.7%) assigned to parameters valsartan (hazard ratio, 0.50 [95% CI, 0.33-0.77]; p = 0.001) [91]. The decline in eGFR was less under sacubi- Given the metabolic effects of NPs and other peptides tril/valsartan than under valsartan. Changes in UACR cleaved by neprilysin, clinical interest in ARNIs has also were not evaluated in this trial [91]. The concomitant resulted from its potential to improve metabolic profiles. In Angiotensin receptor-neprilysin inhibitors: Comprehensive review and implications in hypertension. . . 1245

Fig. 3 The inﬂuence of ARBs or Baseline ARB ARNI ARNIs on renal hemodynamics vasodilation Intraglomerular Intraglomerular and function. ARB angiotensin pressure pressure II receptor blocker, ARNI Efferent artery Afferent artery angiotensin receptor-neprilysin inhibitor

glomerular permeability

Albumin Albumin excretion excretion

the PARADIGM-HF trial, S/V did not reduce the pre- Interestingly, Jordan et al. indicated that S/V modestly specified exploratory outcome of new-onset diabetes that increased abdominal subcutaneous adipose tissue lipolysis occurred in 84 patients during the course of the assessed by glycerol concentration in obese patients with PARADIGM-HF trial [5, 99]. However, a post hoc analysis hypertension in the above-mentioned study [100], con- in 3778 patients with known diabetes or an HbA1c ≥ 65% sistent with the findings that NPs promote lipid mobiliza- at screening showed a certain benefit of S/V on glycemic tion and oxidation in humans [103, 104]. In contrast, the control [99]. HbA1c levels were lower in the S/V group same group reported that S/V did not affect exercise- than in the enalapril group over the 3-year follow-up induced lipolysis or substrate oxidation compared to (between-group reduction 0.14%, 95% CI 0.06–0.23, p = amlodipine in obese patients with hypertension [105]. They 0.0055), while the degree of the reduction was modest in also reported that S/V treatment for 8 weeks did not alter both groups (0.16% (SD 1.40) in the enalapril group and the abdominal subcutaneous adipose tissue transcriptome 0.26% (SD 1.25) in the S/V group during the first year of or the expression of proteins involved in lipolysis, NP follow-up). The new use of insulin was 29% lower in signaling, or oxidative metabolism in obese hypertensive patients receiving S/V (114 [7%] patients) than in patients patients [106]. Therefore, further investigation is required receiving enalapril (153 [10%]; hazard ratio 0.71, 95% CI to elucidate whether and how S/V mediates clinically 0.56–0.90, p = 0.0052) [99]. The effect of S/V on glycemic relevant adipose tissue lipolysis. NP-independent pathways control was not assessed in other large-scale RCTs in could involve the restoration of other neprilysin-targeted patients with HF. Jordan et al. reported that S/V improved peptides, including glucagon-like peptide-1 (GLP-1), bra- insulin sensitivity compared to amlodipine in patients with dykinin, insulin-B chain, and vasoactive intestinal poly- obesity and hypertension [100]. In this study, 8 weeks of peptide (VIP), which potentially contribute to improved treatment with 400 mg S/V (n = 50) but not amlodipine glycemic control [102](Fig.2). Indeed, it was reported that (n = 48) increased the insulin sensitivity index, as assessed S/V increased plasma GLP-1 concentrations in patients by the hyperinsulinemic euglycemic glucose clamp without with HF [107, 108]. any alteration in body weight. The molecular mechanisms Moreover, S/V was reported to decrease plasma uric acid by which neprilysin inhibition improves glucose metabo- concentration in patients with HF in the PARADIGM-HF lism could involve NP-dependent and independent path- and PARAGON-HF trials [109, 110]. Nevertheless, it is ways, though clinical data to directly support this remains conceivable that the favorable influence of S/V on uric acid insufficient (Fig. 2). Epidemiological studies have shown is attributed not to the direct effect on uric acid but to the that increased levels of NPs or genetic variants associated indirect effect via the improvement of HF control with the increased production of NPs are associated with a [109, 110]. There is no evidence that S/V alters the plasma reduced risk of new-onset diabetes [101, 102]. Although uric acid concentration in hypertensive patients. Regarding the molecular mechanisms that could directly explain the the effect of ARNIs on plasma lipid profile, little evidence is favorable relationship between NPs and glycemic control available except from the PARAGIGM-HF trial, in which remain to be elucidated, basic studies have suggested that S/V modestly increased HDL cholesterol by 0.02 mmol/L NPs have various metabolic actions in organs, including compared with enalapril without alterations in LDL or tri- the liver, skeletal muscles, and adipose tissues [101]. glyceride levels. 1246 K. Yamamoto, H. Rakugi

Evidence of a potential influence on reduce BP and ameliorate cardiac remodeling raises the cognitive function possibility of utilizing ARNIs in the treatment of patients with hypertension in real-world clinical practice. The excel- Finally, it should be noted that amyloid β (Aβ) peptides are lent antihypertensive effect of the ARNI over conventional substrates of neprilysin, and neprilysin inhibitors theoreti- RAS inhibitors is attributed to the NP-induced natriuretic cally increase Aβ concentrations, raising the concern that effect that could also contribute to normalization of the cir- long-term neprilysin inhibition might induce Aβ accumu- cadian rhythm of BP in hypertensive patients. Nevertheless, lation, a central etiology of Alzheimer’s disease (AD) [25] it is desirable to discover the superior clinical benefits of (Fig. 2). In a human study, 14 days of treatment with S/V in ARNI over pre-existing antihypertensive drug classes in healthy volunteers increased nonpathologic, soluble Aβ treating hypertension beyond its effect on lowering BP. In 1–38 by 42%, but not aggregable, pathologic Aβ forms Aβ this context, the potential BP-independent effects of NPs and 1–40 and Aβ 1–42 in cerebrospinal fluid (CSF) compared to other substrates modulated by neprilysin inhibition on organ placebo [111]. Schoenfeld et al. reported that S/V impaired protection have been suggested by a variety of basic studies the clearance of Aβ1–42, Aβ1–40, and Aβ1–38 compared to and clinical trials of HF. Particularly, it is important to clarify valsartan on day 1 but not on day 15 of consecutive oral whether the beneficial effects of ARNIs on renal function and administration in cynomolgus monkeys, whereas S/V glycemic control in patients with HF are clinically relevant in increased newly generated Aβ forms in CSF on days 1 and the treatment of hypertension. Finally, given the lifelong 15 [112]. They also showed that 39 weeks of treatment with duration of hypertension treatment, further investigations are S/V revealed no evidence of brain Aβ deposition in the necessary to eliminate the possibility that ARNIs contribute cynomolgus monkey [112]. to the development of dementia. In the PARADIGM-HF trial, there was no evidence that S/V increased dementia-related adverse effects (AEs) Acknowledgements We thank Hiroko Yamamoto for the creation of compared to enalapril, and the incidence of AEs was similar the illustrations in Fig. 3. to that in other recent trials on HFrEF [113]. An ongoing Author contributions KY wrote the manuscript. HR gave advice on clinical trial is planned to investigate the effect of S/V writing the manuscript. compared to valsartan on cognitive function in patients with HFpEF for 3 years using a comprehensive battery of tests Compliance with ethical standards that evaluate longitudinal changes in cognitive domains, including memory, executive function, and attention [114]. Conflict of interest KY received lecture fees from Daiichi Sankyo In terms of hypertension, the effect of antihypertensive unrelated to the submitted work. HR received lecture fees from Daiichi treatment on cognitive function remains controversial, as Sankyo Co Ltd., Takeda Pharmaceutical Co Ltd., and MSD unrelated to the submitted work. KY and HR received grants from Astellas suggested by the study where active treatment modestly Pharma, Bayer Yakuhin, Daiichi Sankyo, Dainippon Sumitomo decreased incident dementia not in an independent analysis Pharma, Kyowa Hakko Kirin, Mitsubishi Tanabe Pharma, Mochida but in a meta-analysis of placebo-controlled RCTs of Pharmaceutical, MSD, Nippon Boehringer Ingelheim, Novartis fi hypertension [115]. In addition, in the subanalysis of the Pharma, Sano , Takeda Pharmaceutical, and Teijin Pharma unrelated to the submitted work. Systolic Blood Pressure Intervention Trial, although incident dementia did not significantly differ between intensive Publisher’s note Springer Nature remains neutral with regard to (target systolic BP < 120 mmHg) and standard anti- jurisdictional claims in published maps and institutional affiliations. hypertensive treatment arms (target systolic BP < 140 mmHg), the incidence of mild cognitive impairment was References more frequently observed in patients given the standard treatment [116]. Therefore, the long-term effect of ARNIs 1. Shimokawa H, Miura M, Nochioka K, Sakata Y. Heart c fi failure as a general pandemic in Asia. Eur J Heart Fail. 2015; on ognitive function needs to be clari ed by carefully – fl 17:884 92. considering several factors that could potentially in uence 2. Savarese G, Lund LH. Global public health burden of heart cognitive function in hypertensive patients. failure. Card Fail Rev. 2017;3:7–11. 3. 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