Angiotensin receptor-neprilysin inhibitors: Comprehensive review and implications in hypertension treatment - Nature

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Angiotensin receptor-neprilysin inhibitors: Comprehensive review and implications in hypertension treatment - Nature
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
                                    Koichi Yamamoto1 Hiromi Rakugi1
                                                             ●

                                    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
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                                    understand the potential properties of the drug in modulating multiple factors inside and outside the cardiovascular system
                                    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
                                      kyamamoto@geriat.med.osaka-u.ac.jp
                                                                                                              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
                Renal protection
                                                     Vasodilation   pathology           31% versus 17% of patients treated with S/V versus ena-
                Glycemic control
                Lipolysis
                                                                                        lapril [43]. In contrast, plasma BNP levels were higher in
                                                                                        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 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 benefit of             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 (
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
                                                                                                                                                                                                                                        Angiotensin receptor-neprilysin inhibitors: Comprehensive review and implications in hypertension. . .

(>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
                                                                                                                                                                                                                                        1243
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 blood pressure, ARB 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] In contrast to the
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                 chronic kidney disease who had an eGFR of 20 to 60 mL/
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
are at high risk of renal insufficiency [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
was proven in patients with HFpEF in comparison to                     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
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
                                                                 the illustrations in Fig. 3.
compared to enalapril, and the incidence of AEs was similar
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
                                                                 Sankyo Co Ltd., Takeda Pharmaceutical Co Ltd., and MSD unrelated
treatment on cognitive function remains controversial, as
                                                                 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
                                                                 Pharma, Sanofi, Takeda Pharmaceutical, and Teijin Pharma unrelated
hypertension [115]. In addition, in the subanalysis of the
                                                                 to the submitted work.
Systolic Blood Pressure Intervention Trial, although inci-
dent 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
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