Is there a place for a dual angiotensin receptor-neprilysin inhibitor in the treatment of hypertension?

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In the last 20 years, no new drug with an innovative mechanism of action has been developed and reached the market for the treatment of hypertension. Innovation in antihypertensive therapy has been characterized essentially by the development of single pill combinations associating angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) with calcium channel blockers or diuretics or both [1]. In the 1990s, the concept of vasopeptidase inhibition was elaborated [2]. It involved the simultaneous inhibition of two important enzymatic cascades implicated in blood pressure (BP) regulation, that is the renin–angiotensin system by inhibiting ACE and the natriuretic peptide system by inhibiting the neutral endopeptidase EC 24.11 (neprilysin) leading to an increase in the vasodilatatory, natriuretic and antiproliferative properties of these peptides. This very interesting concept was put in concrete form with omapatrilat, a compound which had the capacity to inhibit both enzymes and which was found to have a superior antihypertensive efficacy compared with other classes to provide target organ protection in humans and to reduce morbidity and mortality from cardiovascular events in animal models. On the contrary, this drug was withdrawn before it actually reached the market because of an increased incidence of life-threatening angioedema due to the double enzymatic inhibition leading to significant increases in vasoactive peptides among which bradykinin that contributes to the pathophysiology of angioedema [3,4]. Moreover, per se, neprilysin inhibition was not found to have sufficient BP-lowering effects to be developed as a new antihypertensive agent [5].

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