Dual neurohormonal intervention in CV disease: angiotensin receptor and Neprilysin inhibition

Segura, Julián; Salazar, Jorge Brenes; Ruilope, Luís M.

doi:10.1517/13543784.2013.797962

Cited by 25 publications

(24 citation statements)

References 53 publications

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“…16,17 Blockade of the angiotensin receptor reduces sodium and water retention and inhibits cardiac hypertrophy and remodeling (arterial stiffness). 18,19 Considering the age-related changes to arteries underlying …”

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confidence: 99%

Efficacy and Safety of Sacubitril/Valsartan (LCZ696) Compared With Olmesartan in Elderly Asian Patients (≥65 Years) With Systolic Hypertension

Supasyndh

Wang

Hafeez

et al. 2017

American Journal of Hypertension

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Hypertension is a very common disease in the elderly (aged ≥65 years). 1 More than 50% of the elderly population has hypertension, 2 especially systolic hypertension, which arises primarily due to age-related changes in the arterial structure of large arteries, contributing to the large artery stiffness. 3 These changes lead to loss of arterial elasticity, 4 resulting in elevated systolic blood pressure (SBP) and widened pulse pressure (PP; difference between SBP and diastolic blood pressure [DBP]). 1 Studies have shown that elevated SBP has a stronger association with adverse cardiovascular (CV) outcomes than elevated DBP in the elderly. 1,5,6 Furthermore, lowering of SBP has been shown to reduce the risk of CV events in elderly patients. 7 A strong association between hypertension and CV events has been reported in Asian population. 8 Olmesartan is one of the most widely prescribed angiotensin II receptor blockers (ARBs) for the treatment of systolic hypertension in elderly patients, 10 including Asians. 11 Despite the available antihypertensive treatments, blood pressure (BP) control is poor in Asian patients. 12 In addition, SBP is considered more difficult to control than DBP, particularly in elderly patients, 13,14 which further suggests the need to develop more effective treatments to target the underlying causes of systolic hypertension in this population.BP is modulated by counter-regulatory neurohormonal interactions between natriuretic peptides, the sympathetic nervous system, and the renin-angiotensin-aldosterone system. 15 Natriuretic peptide levels can be enhanced by inhibiting the enzyme neprilysin, which catalyzes the degradation of multiple vasoactive peptides in the CV system, including natriuretic peptides. 16,17 Blockade of the angiotensin receptor reduces sodium and water retention and inhibits cardiac hypertrophy and remodeling (arterial stiffness). 18,19 Considering the age-related changes to arteries underlying OBJECTIVESystolic hypertension is common in elderly patients and remains a challenge to treat effectively. The efficacy and safety of sacubitril/valsartan (LCZ696), a first-in-class angiotensin receptor neprilysin inhibitor, vs. olmesartan was evaluated in elderly Asian patients (≥65 years) with systolic hypertension. METHODSIn this randomized, double-blind, 14-week study, patients initially received once-daily sacubitril/valsartan 100 mg or olmesartan 10 mg, increased to sacubitril/valsartan 200 mg or olmesartan 20 mg at week 4. At week 10, for patients with blood pressure (BP) >140/90 mm Hg, the doses were up-titrated to sacubitril/valsartan 400 mg or olmesartan 40 mg. The primary assessment was superiority of sacubitril/valsartan vs. olmesartan in reducing office mean sitting (ms) systolic BP (msSBP) from baseline at week 10. Secondary efficacy assessments included changes from baseline in ms diastolic BP (msDBP), ms pulse pressure (msPP), 24-hour mean ambulatory (ma) BP (maBP), and maPP at week 10; msBP and msPP at weeks 4 and 14. RESULTSOverall, 588 patients were randomized (...

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confidence: 99%

Efficacy and Safety of Sacubitril/Valsartan (LCZ696) Compared With Olmesartan in Elderly Asian Patients (≥65 Years) With Systolic Hypertension

Supasyndh

Wang

Hafeez

et al. 2017

American Journal of Hypertension

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“…Sacubitril is then rapidly metabolized by non‐specific esterases to the active neprilysin inhibitor LBQ657. Neprilysin inhibition enhances the circulating levels of natriuretic peptides, which have natriuretic, diuretic, and vasodilatory properties, lower the sympathetic tone, exert anti‐proliferative and anti‐hypertrophic effects on cardiovascular tissues, and modulate metabolic parameters . AT 1 ‐receptor blockade suppresses the renin‐angiotensin‐aldosterone system (RAAS), thereby attenuating vasoconstriction, reducing sodium and water retention, and inhibiting cardiac hypertrophy and adverse remodeling of cardiovascular tissues .…”

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confidence: 99%

Pharmacokinetic drug–drug interaction assessment of LCZ696 (an angiotensin receptor neprilysin inhibitor) with omeprazole, metformin or levonorgestrel‐ethinyl estradiol in healthy subjects

Gan

Jiang

Mendonza

et al. 2015

Clinical Pharm in Drug Dev

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LCZ696 is a novel angiotensin receptor neprilysin inhibitor in development for the treatment of cardiovascular diseases. Here, we assessed the potential for pharmacokinetic drug-drug interaction of LCZ696 (400 mg, single dose or once daily [q.d.]) when co-administered with omeprazole 40 mg q.d. (n = 28) or metformin 1000 mg q.d. (n = 27) or levonorgestrel-ethinyl estradiol 150/30 μg single dose (n = 24) in three separate open-label, single-sequence studies in healthy subjects. Pharmacokinetic parameters of LCZ696 analytes (sacubitril, LBQ657, and valsartan), metformin, and levonorgestrel-ethinyl estradiol were assessed. Omeprazole did not alter the AUCinf of sacubitril and pharmacokinetics of LBQ657; however, 7% decrease in the Cmax of sacubitril, and 11% and 13% decreases in AUCinf and Cmax of valsartan were observed. Co-administration of LCZ696 with metformin had no significant effect on the pharmacokinetics of LBQ657 and valsartan; however, AUCtau,ss and Cmax,ss of metformin were decreased by 23%. Co-administration of LCZ696 with levonorgestrel-ethinyl estradiol had no effect on the pharmacokinetics of ethinyl estradiol and LBQ657 or AUCinf of levonorgestrel. The Cmax of levonorgestrel decreased by 15%, and AUCtau,ss and Cmax,ss of valsartan decreased by 14% and 16%, respectively. Co-administration of LCZ696 with omeprazole, metformin, or levonorgestrel-ethinyl estradiol was not associated with any clinically relevant pharmacokinetic drug interactions.

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“…RAS underlies cardiac hypertrophy and heart failure in several cardiovascular disorders, and thus ACE inhibition or angiotensin II receptor antagonists are generally prescribed to treat these patients (Escobar and Barrios 2013; Ferrari and Boersma 2013; Segura et al 2013). Several lines of evidence indicate that in adults, taurine supplementation also improves the cardiac ischemia/reperfusion and heart failure by inhibiting RAS activation (Ito et al 2014).…”

Section: 4 Discussionmentioning

confidence: 99%

The Effect of Perinatal Taurine on Adult Renal Function Does Not Appear to Be Mediated by Taurine’s Inhibition of the Renin-Angiotensin System

2015

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This study tests the hypothesis that perinatal taurine supplementation alters adult renal function by inhibition of the renin-angiotensin system. Female Sprague-Dawley rats were fed normal rat chow and given water alone (Control) or water containing an angiotensin converting enzyme inhibitor (captopril, 400 mg/ml) from conception until delivery (FD) or from delivery until weaning (LD). After weaning, the rats received normal rat chow and tap water. At 7–8 weeks of age, renal function at rest and after acute saline load was studied in conscious, restrained male rats. Body weight, mean arterial pressure, heart rate, effective renal blood flow, and renal vascular resistance were not significantly different among the three groups. Compared to Control, glomerular filtration rate, but not filtration fraction, significantly increased after saline load in both FD and LD groups. Water excretion significantly increased only in FD compared to Control, while fractional water excretion was significantly increased after saline load in both FD and LD groups. Sodium excretion significantly increased after saline load only in FD, while both captopril-treated groups significantly decreased fractional sodium excretion. Potassium excretion significantly increased in both FD and LD groups, while fractional potassium excretion significantly increased at rest in FD and decreased in LD groups after saline load. These effects of perinatal RAS inhibition on adult renal function contrast sharply, and are opposite in many cases to, the effects of perinatal taurine supplementation. Thus, these data suggest that perinatal taurine supplementation does not alter adult renal function through its ability to inhibit the perinatal RAS.

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Dual neurohormonal intervention in CV disease: angiotensin receptor and Neprilysin inhibition

Cited by 25 publications

References 53 publications

Efficacy and Safety of Sacubitril/Valsartan (LCZ696) Compared With Olmesartan in Elderly Asian Patients (≥65 Years) With Systolic Hypertension

Efficacy and Safety of Sacubitril/Valsartan (LCZ696) Compared With Olmesartan in Elderly Asian Patients (≥65 Years) With Systolic Hypertension

Pharmacokinetic drug–drug interaction assessment of LCZ696 (an angiotensin receptor neprilysin inhibitor) with omeprazole, metformin or levonorgestrel‐ethinyl estradiol in healthy subjects

The Effect of Perinatal Taurine on Adult Renal Function Does Not Appear to Be Mediated by Taurine’s Inhibition of the Renin-Angiotensin System

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