Current role of neprilysin inhibitors in hypertension and heart failure.
Cardiovascular diseases (CVD) continue to represent the major cause of death, morbidity and healthcare expenditure worldwide. Current medical therapy fails to effectively halt disease progression and to reduce adverse clinical outcomes, reflecting incomplete understanding of pathomechanisms as well as the need to expand current pharmacotherapeutic strategies. Hypertension and heart failure, the most important CVD entities, are associated with imbalance in neurohormonal systems activity such as the renin-angiotensin-aldosterone system (RAAS), the sympathetic nervous system and the endothelin system. Blockade of the RAAS constitutes the most successful pharmacotherapeutic concept in hypertension and heart failure to date. The RAAS-opposing natriuretic peptide system constitutes the body's own BP-lowering system, and mediates a multitude of beneficial actions within cardiovascular tissues. The metallopeptidase neprilysin (NEP) hydrolyzes natriuretic peptides. Conceptually, NEP inhibition would increase salutary natriuretic peptide actions in CVD. However, stand-alone NEP inhibitors (NEPi) lacked efficacy beyond standard pharmacotherapy. Combined blockers of NEP and the endothelin system demonstrated efficacy in preclinical studies but have not been evaluated in clinical trials. A decade ago, omapatrilat and other dual-acting NEPi-ACEi (vasopeptidase-inhibitors) were promising agents for hypertension and heart failure. Despite greater efficacy, development of vasopeptidase-inhibitors was halted due to significant off-target effects in some cohorts, most notably increased frequency of angioedema in hypertensive subjects. Novel angiotensin-receptor-neprilysin-inhibitors (ARNi) seek to fully exploit clinical efficacy of combined RAAS-blockade and NEPi-mediated natriuretic peptide augmentation, and hopefully do so with improved clinical safety. We herein review current knowledge of NEPi as stand-alone and combined pharmacotherapeutic agents in hypertension and heart failure.
Monash Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Alfred Hospital, Melbourne, VIC 3004, Australia; Department of Cardiology B, Oslo University Hospital Ullevål, Norway; Faculty of Medicine, University of Oslo, Norway.
Thomas G
TG
von Lueder
Department of Cardiology B, Oslo University Hospital Ullevål, Norway; Faculty of Medicine, University of Oslo, Norway.
Dan
D
Atar
Monash Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Alfred Hospital, Melbourne, VIC 3004, Australia. Electronic address: henry.krum@med.monash.edu.au.
Henry
H
Krum
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000503:physiopathology; D015195:Drug Design; D004359:Drug Therapy, Combination; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology
D002317:Cardiovascular Agents; D015260:Neprilysin
Heart failure; Hypertension; Natriuretic peptide; Neprilysin; RAAS