The Renin-Angiotensin–Aldosterone System (RAAS) is central to blood pressure (BP) control. Chronic overactivation of the RAAS occurs in a majority of cardiovascular disorders including hypertension and heart failure, leading to damage of internal organs (e.g., the heart, kidneys, brain and vasculature), thereby sustaining the effect of BP elevation [1]. Over the past decades, pharmacological inhibition of the RAAS with angiotensin-converting enzyme inhibitors (ACEI), angiotensin-II receptor blockers (ARB) and mineral corticoid receptor antagonists (MRA) has contributed significantly to the success of cardiovascular pharmacotherapy [1]. Despite these major breakthroughs, clinical event rates in hypertension and heart failure remain high.

The search to enhance the clinical benefits of RAAS blockade in order to improve BP lowering and protect hypertension mediated organ damage is ongoing. Dual-acting RAAS and neprilysin inhibitors augment the benefits of RAAS blockade with complementary beneficial actions of the natriuretic peptides [1,2]. Neprilysin (NEP), a metallopeptidase, degrades biologically active atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and C-type natriuretic peptide. Endogenous natriuretic peptides have powerful diuretic, natriuretic, sympatholytic, antihypertrophic, antifibrotic and BP lowering effects. Increased NEP activity in the setting of heart failure and hypertension induces a state of relative deficiency of natriuretic peptides, providing the rationale for dual-acting compounds that both inhibit NEP and block the maladaptive effects of the RAAS.

Omapatrilat, a dual ACE-NEP inhibitor (a class of drugs termed vasopeptidase inhibitors) was the first agent to be evaluated in clinical trials of hypertension and heart failure treatment [2]. Omapatrilat lowered BP more than stand-alone ACE inhibitor treatment in hypertension. In the OCTAVE study, the efficacy of omapatrilat versus enalapril to reduce clinical events was evaluated in approximately 25,000 untreated or uncontrolled hypertensives. Participants randomized to omapatrilat exhibited improved systolic BP control compared to enalapril. However, further development of omapatrilat was discontinued because of an increased risk of angioedema in OCTAVE, possibly explained by excessive accumulation of bradykinin which normally would be hydrolysed by NEP, ACE and also (potentially) aminopeptidase-P and dipeptidyl peptidase-4. Substance P, which is also hydrolyzed by these enzymes, has also been coupled with angioedema.

Novel angiotensin-receptor neprilysin-inhibitors (ARNi) seek to exploit clinical efficacy of combined RAAS antagonism and NEP inhibition-mediated natriuretic peptide augmentation while circumventing the potential clinical safety issues related to bradykinin excess, and occurrence of angioedema seen with vasopetidase inhibitors [1,2]. LCZ696, comprised of equal molecular moieties of the NEP inhibitor prodrug AHU377 (sacubitril) and the ARB valsartan combined in one compound, is the first-in-class ARNi. After oral intake, sacubitril is metabolised by enzymatic cleavage to LBQ657, an active NEP inhibitor. In a clinical trial in patients with hypertension LCZ696 (sacubitril/valsartan) was shown to have greater BP lowering capacity and similar tolerability compared with stand-alone valsartan treatment [3]. Supported by a strong body of preclinical evidence, more recent clinical studies have demonstrated additional favourable effects of LCZ696 on deleterious cardiovascular remodelling compared to single RAAS blockade [4]. Despite these encouraging data, no adequately powered clinical outcome trial of LCZ696 for the treatment of uncomplicated hypertension is currently being conducted or planned. The medical community is left with a striking gap in evidence for the putative safety and benefit of LCZ696 in hypertension.

LCZ696 lowers mortality and morbidity compared to enalapril in patients with heart failure with reduced ejection fraction (HFrEF) by mechanisms that appear to be independent of BP lowering [5]. Moreover, in a phase-II trial in patients with HF with preserved ejection fraction (HFpEF) LCZ696 reduced the primary endpoint of NT-proBNP, a surrogate of cardiac wall stress, to a greater extent than valsartan [6]. Interestingly, in that study BP reduction was greater in the LCZ696 group than in the valsartan group after 12 weeks of treatment. Whether or not these effects may translate into improved outcomes in HFpEF is currently being tested in the Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction (PARAGON-HF) Trial [7].

Why then is LCZ696 being neglected by the hypertension community? One reason may be real or perceived fear of unforeseen off-target effects related to inhibition of degradation of the large number of NEP substrates outside the natriuretic peptide family [8]. For example, it has been suggested that LCZ696 may inhibit degradation of amyloid-β peptides in the brain, predisposing to Alzheimer disease, age-related macular degeneration, and cerebral amyloid angiopathy [8]. The clinical relevance of these theoretical considerations is unclear. Other theoretical off-target effects of NEP inhibition include inflammation, bronchoconstriction, and even promotion of cancer by inhibiting the degradation of neoangiogenic and mitogenic peptides [8]. None of these have thus far been shown to be relevant in humans. In contrast, beneficial effects beyond RAAS blockade have been attributed to dual-acting RAAS and NEP inhibition. For example, renal dysfunction and failure are frequent in hypertension and in heart failure and often limit initiation and up-titration of RAAS blockers. A recent meta-analysis of studies in patients with heart failure that included data from PARADIGM-HF reported better renal preservation with concomitant RAAS-NEP inhibition than with RAAS inhibition alone [9]. Moreover, NEP inhibition acts as a “natural” diuretic without impact on serum potassium and serum uric acid. In light of the documented BP-lowering effect, more potent than that of the ARB alone [3,6], and safety of LCZ696 [3,4], the lack of clinical outcome studies, and underutilization of the novel ARNi drug class in hypertension is a major lost opportunity. The BP lowering effects of LCZ696 would likely be further enhanced in combination with a thiazide diuretic, as has been shown with other RAAS-inhibitors, further enhancing its potential utility for the treatment of difficult to manage hypertension.

A LCZ696-thiazide diuretic combination therapy might have the ability to control severe or even treatment-resistant hypertension. Approximately 10–20% of patients with hypertension have apparent treatment resistant hypertension, defined as failure to achieve BP targets despite three or more antihypertensive drugs including a diuretic in highest tolerable dose. With the projected ageing of populations and rise in the prevalence of CV disease, controlling hypertension in this population is ever more critical. Controlling hypertension is the key to the prevention of heart failure, ischemic heart disease, stroke and renal failure. It is unfortunate that LCZ696, originally developed for and possibly a very potent tool to lower BP [3], is not registered for this indication and does appear destined for further development as an antihypertensive agent.

In our opinion, ARNi and LCZ696 should be further developed for the treatment of hypertension. With the spotlight currently on ARNi as treatment for HF, hypertension is becoming the neglected child in CV pharmacotherapy [10]. More effective treatment of hypertension, including ARNi, may prevent or delay the onset of HF and reduce the overall tremendous burden of CV disease. Taken together, our statement is a call for action addressed to the pharmaceutical industry to enable physicians to expand their therapeutic armamentarium in hypertension, as the most common CV disorder, which continues to take its toll in millions of people worldwide. Besides, ARNIs should be highlighted in the future guidelines as a recommended treatment for patients with hypertension and heart failure.