Angiotensin receptor neprilysin inhibition for the treatment of hypertension: the neglected child in cardiovascular pharmacotherapy

The Renin–Angiotensin–Aldosterone System (RAAS) is central to blood pressure (BP) control, and chronic overactivation of the RAAS occurs in the vast majority of cardiovascular (CV) disorders including hypertension and heart failure (HF) leading to damage of target organs (e.g. the heart, kidneys, and vasculature), thereby perpetuating BP elevation.¹ Over the past decades, pharmacological inhibition of the RAAS with angiotensin II receptor blockers (ARB), angiotensin-converting enzyme inhibitors (ACEI), 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 HF have remained unacceptably high.

The search to further enhance the clinical benefits of RAAS blockade in order to improve BP lowering and end organ protection is ongoing. Dual-acting RAAS and neprilysin (NEP) inhibitors concomitantly exploit RAAS blockade with augmentation of natriuretic peptides’ salutary actions.^2,3 NEP, a metallopeptidase, degrades biologically active atrial natriuretic peptide, B-type natriuretic peptide (BNP), and C-type natriuretic peptide. Endogenous natriuretic peptides exert powerful diuretic, natriuretic, sympatholytic, antihypertrophic, antifibrotic, and BP-lowering effects; unfortunately, excessive NEP activity in HF and hypertension induces a state of relative deficiency of these beneficial peptides, thus 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.³ In hypertension, omapatrilat lowered BP more than stand-alone ACE inhibition. In the landmark OCTAVE trial, the efficacy of omapatrilat vs. enalapril to reduce clinical events was evaluated in 25 302 untreated or uncontrolled hypertensives. Subjects 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 hydrolyzed by NEP, ACE, and also potentially aminopeptidase-P and dipeptidyl peptidase-4.

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 relating to bradykinin and occurrence of angioedema seen with vasopetidase inhibitors.^2,3 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 metabolized by enzymatic cleavage to LBQ657, an active NEP inhibitor. In a landmark clinical trial in patients with hypertension, LCZ696 (sacubitril/valsartan) has been shown to have greater BP-lowering capacities compared with stand-alone valsartan with similar tolerability.⁴ In addition, backed by a strong body of preclinical evidence, recent clinical studies have demonstrated additional favourable effects on deleterious cardiovascular remodelling beyond single RAAS blockade.⁵ Despite these encouraging data, it is noteworthy that no adequately powered definitive clinical outcome trial is currently being conducted or even planned. Therefore, the medical community is left with a striking gap in evidence on the putative safety and benefit of sacubitril/valsartan in hypertension.

LCZ696 lowers mortality and morbidity compared to enalapril in patients with heart failure with reduced ejection fraction.⁶ These benefits appear to have been achieved independently of BP-lowering effects. Moreover, in a phase-II trial in patients with heart failure with preserved ejection fraction (HFpEF) LCZ696 reduced the primary endpoint of NT-proBNP, a surrogate of cardiac wall stress to a greater extent than did valsartan.⁷ Interestingly, in that study BP was reduced more substantially 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 prospectively in a large outcome trial.⁸

Why then is LCZ696 only reluctantly adopted or even neglected by the hypertension community? One reason may be real or perceived fear for unforeseen off-target effects, mechanistically based on the large number of NEP substrates beyond the natriuretic peptide family.⁹ This is exemplified by the debate on LCZ696 potentially inhibiting degradation of amyloid-β peptides in the brain predisposing to Alzheimer disease, age-related macular degeneration, and cerebral amyloid angiopathy.⁹ 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.⁹ None of these have thus far been shown to be relevant in human beings. On the contrary, specific 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 HF and often limit initiation and uptitration of RAAS blockers. A recent meta-analysis in patients with HF including data from PARADIGM-HF reported better renal preservation with concomitant RAAS-NEP inhibition.¹⁰ In light of the potent BP-lowering effect and safety of LCZ696^4,5 the lack of clinical outcome studies, treatment guidelines, and underutilization of the novel drug class of ARNi in hypertension constitutes a major lost opportunity. Conceptually the BP-lowering abilities of LCZ696 might be even further enhanced in combination with hydrochlorothiazide (HCTZ) as has been shown with other RAAS-inhibitors.

Perhaps LCZ696-HCTZ combination therapy may have the ability to normalize 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, prevention employing the most effective contemporary pharmacotherapy is mandated. Accordingly, controlling hypertension is the key to the prevention of HF, ischaemic heart disease, stroke, and renal failure. Therefore, it is a shame that LCZ696, originally developed for and quite possibly the most potent tool to lower BP,⁴ is not registered for this indication nor do its owners appear to commit to further development as an antihypertensive agent.

The potential of novel expensive drugs to capture relevant shares in markets saturated with affordable effective pharmacological agents will, understandably always be a concern for the pharmaceutical industry. While these concerns in some cases may underlie purely business-motivated decisions to abandon further development of even the most promising drugs for a certain indication, it is the opinion of the authors that the clinical community is morally obliged to explore and establish clinical utility when a huge opportunity presents itself. The drug class of ARNi with its currently only protagonist drug, LCZ696 is such a major opportunity in hypertension. ARNi and LCZ696 should be further developed towards the treatment of hypertension. With the spotlight currently on ARNi as treatment for HF, hypertension is becoming the neglected child in CV pharmacotherapy. 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 disease which continues to take its toll in millions of people worldwide.

Conflict of interest: S.E.K. has within the past 3 years received modest honoraria for consultancy and lecturing from Bayer, Merck KGaA, Merck & Co., Inc., and Takeda. D.A. has within the past 3 years received modest consultancy and lecturing fees from Novartis, Astra-Zeneca, Merck (MSD), Bayer, Boehringer-Ingelheim, BMS/Pfizer, Sanofi-Regeneron and Amgen, and research grants from Medtronic and BMS/Pfizer. T.v.L. reports modest lecture and consultancy honoraria for Pfizer, Vifor, Novartis, St Jude Medical, Astra Zeneca, and Pharmacosmos.

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