title: Angiotensin receptor neprilysin inhibition in heart failure: mechanistic action and clinical impact.
abstract: Heart failure (HF) is an increasingly common syndrome associated with high mortality and economic burden, and there has been a paucity over the past decade of new pharmacotherapies that improve outcomes. However, recent data from a large randomized controlled trial compared the novel agent LCZ696, a dual-acting angiotensin receptor blocker and neprilysin inhibitor (ARNi), with the well established angiotensin-converting enzyme (ACE) inhibitor enalapril and found significant reduction in mortality among the chronic reduced ejection fraction HF population. Preclinical and clinical data suggest that neprilysin inhibition provides beneficial outcomes in HF patients by preventing the degradation of natriuretic peptides and thereby promoting natriuresis and vasodilatation and counteracting the negative cardiorenal effects of the up-regulated renin-angiotensin-aldosterone system. Agents such as omapatrilat combined neprilysin and ACE inhibition but had increased rates of angioedema. Goals of an improved safety profile provided the rationale for the development of the ARNi LCZ696. Along with significant reductions in mortality and hospitalizations, clinical trials suggest that LCZ696 may improve surrogate markers of HF severity. In this paper, we review the preclinical and clinical data that led to the development of LCZ696, the understanding of the underlying mechanistic action, and the robust clinical impact that LCZ696 may have in the near future.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina. Electronic address: jonathan.buggey@duke.edu.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Buggey
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina; Department of Medicine, Duke Clinical Research Institute, Durham, North Carolina.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mentz
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina; Department of Medicine, Duke Clinical Research Institute, Durham, North Carolina.
authors.forename: Adam D
authors.initials: AD
authors.lastname: DeVore
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina; Department of Medicine, Duke Clinical Research Institute, Durham, North Carolina.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Velazquez
mesh_terms: D000613:Aminobutyrates / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D015415:Biomarkers / Q000097:blood*; D001713:Biphenyl Compounds; D004338:Drug Combinations; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D013318:Stroke Volume / Q000187:drug effects*; D013777:Tetrazoles / Q000627:therapeutic use*; D016896:Treatment Outcome; D000068756:Valsartan
chemical_list: D000613:Aminobutyrates; D000806:Angiotensin-Converting Enzyme Inhibitors; D015415:Biomarkers; D001713:Biphenyl Compounds; D004338:Drug Combinations; D013777:Tetrazoles; D000068756:Valsartan; D015260:Neprilysin; C549068:sacubitril and valsartan sodium hydrate drug combination
keywords: Angiotensin receptor neprilysin inhibition; LCZ696; heart failure