Role of neprilysin inhibitor combinations in hypertension: insights from hypertension and heart failure trials

Abstract

Neprilysin is a neutral endopeptidase and its inhibition increases bioavailability of natriuretic peptides, bradykinin, and substance P, resulting in natriuretic, vasodilatatory, and anti-proliferative effects. In concert, these effects are prone to produce a powerful ventricular unloading and antihypertensive response. LCZ696 (Valsartan/sacubitril) is a first-in-class angiotensin II-receptor neprilysin inhibitor. LCZ696 is a novel drug not only for the treatment of heart failure but it is also likely to be a useful antihypertensive drug and may have a preferential effect on systolic pressure. This review discusses (i) the mechanism of action, pharmacokinetics, and pharmacodynamics of this novel drug, (ii) the efficacy, safety, and tolerability of LCZ696 in treatment of hypertension from the available trials, (iii) evidence from other contemporary trials on combined Neprilysin inhibitors, (iv) future trials and areas of research to identify hypertensive patient populations that would most benefit from LCZ696.

Sacubitril/valsartan: An important piece in the therapeutic puzzle of heart failure

“…In a dose escalation study in healthy participants there was a maximal 40% increase in mean cGMP levels at 4 h and significant increases at 12 h post-dose, with return to baseline levels at 24 h after administration of LCZ696. 23,31 In the same study, significant dose-dependent effects of the valsartan moiety led to increases in renin concentration, plasma renin activity and angiotensin II, which were still observed 24 h after dosing. This also implies that BNP is not a viable biomarker in HF patients treated with sacubitril/valsartan, whereas NT-proBNP remains so, since it is not a substrate for NEP.…”

Sacubitril/valsartan for chronic heart failure: its future potential

“…25 The authors of this review speculate that sacubitril/valsartan may offer greater efficacy and a similar safety profile compared with established antihypertensive drugs.…”

Sacubitril/Valsartan

“…The fact that all biomarkers were increased at the same time suggests that the pharmacodynamic effects of both sacubitril and valsartan occur in parallel, which may contribute to the overall efficacy of the combination. 8,21 This is unlike the delayed neprilysin inhibition that occurred in relation to ACE inhibition with omapatrilat. 21 In patients with hypertension, sacubitril/valsartan and sacubitril alone increased concentrations of ANP and cGMP, whereas valsartan alone lowered concentrations of these substances.…”

“…8,21 This is unlike the delayed neprilysin inhibition that occurred in relation to ACE inhibition with omapatrilat. 21 In patients with hypertension, sacubitril/valsartan and sacubitril alone increased concentrations of ANP and cGMP, whereas valsartan alone lowered concentrations of these substances. 22 The increases in ANP and cGMP were numerically greater with sacubitril alone compared with sacubitril/valsartan but were not dose dependent with the combination.…”