Angiotensin–neprilysin inhibition confers renoprotection in rats with diabetes and hypertension by limiting podocyte injury
Estrellita UijlDaan C. ‘t HartLodi C.W. RoksnoerMarian C. Clahsen‐van GroningenRichard van VeghelIngrid M. GarreldsRené de VriesJohan van der VlagRobert ZietseTom NijenhuisJaap A. JolesEwout J. HoornA.H. Jan Danser
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Combined angiotensin receptor--neprilysin inhibition (ARNI) reduces glomerulosclerosis better than single angiotensin receptor blockade (ARB) in diabetic, hypertensive rats. The renoprotective mechanism remains unknown, but may depend on superior blood pressure control, improved renal hemodynamics, suppressed renal inflammation or prevention of podocyte loss.To address this, TGR(mREN2)27 rats (a model of angiotensin II-dependent hypertension) were made diabetic for 12 weeks and treated with vehicle (n = 10), valsartan (ARB; n = 7) or sacubitril/valsartan (ARNI; n = 8) for the final 3 weeks. Arterial pressure was measured via radiotelemetry.Sacubitril/valsartan lowered mean arterial pressure by -50 ± 4 mmHg and valsartan by -43 ± 4 mmHg (P = 0.3). Both treatments lowered albuminuria, but only sacubitril/valsartan maintained high urinary atrial natriuretic peptide, improved glycemic control and protected podocyte integrity, reflected by increased nephrin expression and suppression of transient receptor potential canonical 6 and regulator of calcineurin 1. This resulted in markedly reduced glomerulosclerosis (P < 0.05 vs. control and valsartan). Despite higher effective renal plasma flow and glomerular filtration rates, sacubitril/valsartan did neither improve filtration fraction nor renal immune cell infiltration.Sacubitril/valsartan offers drug-class-specific renoprotection in a preclinical model of diabetes and hypertension. Renoprotection is unrelated to antihypertensive efficacy, renal hemodynamics or inflammation, but may be related to protective effects of natriuretic peptides on podocyte integrity.Keywords:
Sacubitril
Sacubitril, Valsartan
Filtration fraction
Albuminuria
Glomerulosclerosis
Chronic heart failure (CHF) is currently a common disease and the search for new approaches to the treatment of various forms of CHF remains relevant. Sacubitril/valsartan is a member of a new class of angiotensin-neprilysin receptor inhibitors (ARNIs) that act on key neurohormonal mechanisms, including the RAAS and natriuretic peptides. Simultaneous inhibition of RAAS and neprilysin provides more effective neurohormonal modulation, preventing clinical deterioration in patients with CHF. New mechanisms of action of sacubitril/valsartan associated with the inhibition of several targets involved in cardiac hypertrophy, fibrosis, cardiac remodeling and apoptosis have been disclosed. Sacubitril/valsartan is recommended for CHF with low ejection fraction (EF) in addition to traditional therapy with ACE inhibitors, mineralocorticoid receptor antagonists, beta-blockers, and also has an independent effect. A number of studies have shown the effect of sacubitril/valsartan on heart remodeling, a decrease in the level of the NT-proBNP biomarker and an improvement in EF, and according to the PARADIGM-HF study, the drug significantly reduced the risk of cardiovascular mortality by 20% and hospitalizations for CHF by 21%, which found confirmation in three meta-analyses. The use of sacubitril/valsartan in CHF with preserved and intermediate EF showed a beneficial therapeutic effect and a decrease in the level of biomarkers, as well as a significant decrease in the frequency of hospitalizations due to CHF by 15–22%, but without a significant advantage in terms of the effect on mortality, which supported by several meta-analyses of studies. A number of large meta-analyses of studies of sacubitril/valsartan in CHF have shown reverse cardiac remodeling and a reduced risk of atrial fibrillation. Thus, the accumulated data substantiate and expand the possibilities of using sacu-bitril/valsartan in CHF.
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In 2015, sacubitril–valsartan was approved in Europe and the United States as a new therapeutic agent for heart failure with reduced ejection fraction. Approval was based primarily on the results of the PARADIGM-HF trial.1 In that trial, sacubitril–valsartan was compared with enalapril in clinically stable patients with heart failure. At a median follow-up of 27 months, there was a significantly lower rate of the primary outcome of death from cardiovascular causes or hospitalization for heart failure with sacubitril–valsartan than with enalapril. Despite the robust evidence of benefit seen in the PARADIGM-HF trial, the adoption of sacubitril–valsartan in clinical practice has . . .
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Sacubitril/valsartan is a first-in-class angiotensin receptor-neprilysin inhibitor (ARNI) that has been recommended in clinical practice guidelines to reduce morbidity and mortality in patients with chronic, symptomatic heart failure (HF) with reduced ejection fraction (HFrEF). This review provides an overview of ARNI therapy, proposes strategies to improve the implementation of sacubitril/valsartan in clinical practice, and provides clinicians with evidence-based, practical guidance on the use of sacubitril/valsartan in patients with HFrEF. Despite evidence demonstrating the benefits of ARNI therapy over standard of care, only a fraction of eligible patients takes sacubitril/valsartan. Barriers preventing the prescription of sacubitril/valsartan in eligible patients may include practitioners' unfamiliarity with ARNIs, safety concerns, and payer reimbursement issues. The optimal implementation of sacubitril/valsartan in clinical practice has the potential to reduce the overall burden of HF. Throughout this review, we describe our experience with sacubitril/valsartan, including strategies for the management of adverse events and common patient concerns. In addition, a strategy for the gradual introduction of sacubitril/valsartan using a treatment sequence scheme is proposed.
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Sacubitril with valsartan (sacubitril/valsartan) is a relatively novel compound that has become a milestone in the treatment of patients with chronic heart failure (HF) with reduced ejection fraction (HFrEF) in the last decade. Contemporary data suggest that sacubitril/valsartan is associated with improved outcomes compared with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, and has a greater beneficial effect on myocardial reverse remodelling. Additionally, two recent trials have shown that sacubitril/valsartan is well-tolerated even in the acute HF setting, thus enabling a continuum of use in the patient’s journey with HFrEF. This article summarises available data on the effectiveness and tolerability of sacubitril/valsartan in patients with HFrEF, and provides the clinician with practical insights to facilitate the use of this drug in every setting, with an emphasis on acute HF, hypotension, electrolyte imbalance and renal insufficiency.
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Heart failure (HF) is one of the leading causes of morbidity and mortality worldwide. Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor, has been approved for the treatment of HF. At present, there have been few systematic and detailed reviews discussing the efficacy and safety of sacubitril/valsartan in HF. In this review, we first introduced the pharmacological mechanisms of sacubitril/valsartan, including the reduction in the degradation of natriuretic peptides in the natriuretic peptide system and inhibition of the renin-angiotensin system. Then, we summarized the efficacy of sacubitril/valsartan in HF patients with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF) including the reduction in risks of mortality and hospitalization, reversal of cardiac remodeling, regulation of biomarkers of HF, improvement of the quality of life, antiarrhythmia, improving renal dysfunction and regulation of metabolism. Finally, we discussed the safety and tolerability of sacubitril/valsartan in the treatment of HFrEF or HFpEF. Compared with ACEIs/ARBs or placebo, sacubitril/valsartan showed good safety and tolerability, although the risk of hypotension might be high. In conclusion, the overwhelming majority of studies show that sacubitril/valsartan is effective and safe in the treatment of HFrEF patients but that it has little benefit in HFpEF patients. Sacubitril/valsartan will probably be a promising anti-HF drug in the near future.
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Sacubitril/valsartan (LCZ696), a compound composed of sacubitril and valsartan, plays a role by targeting on renin-angiotensin aldosterone system and natriuretic peptide system, which represents a breakthrough in the treatment of heart failure (HF) recently. PARADIGM-HF trial showed that LCZ696 can significantly reduce death from cardiovascular causes, death from any causes and hospitalization for HF, and improve the symptoms and physical strength in patients with HF with reduced ejection fraction (HFrEF). Therefore, the updated European, American and Chinese guidelines for HF all recommended LCZ696 for patients with HFrEF. However, as a new drug, LCZ696 still has many problems to be addressed in the treatment of HF. This paper will summarize the clinical efficacy and existing problems of LCZ696 in the treatment of HF.
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Sacubitril/valsartan; Heart failure
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The PARADIGM-HF trial demonstrated that sacubitril/valsartan had an advantage in improving mortality and morbidity over enalapril in patients with systolic heart failure.1 However, not many patients can achieve the target dose as recommended in the PARADIGM-HF trial in the real-world practice dominantly due to hypotension. Pandey et al. demonstrated that even the lower than the standard dose of sacubitril/valsartan reduced NT-proBNP maintaining serum potassium and creatinine levels.2 Several concerns should improve their findings. Although statistically not significant, there are numerically several differences in baseline characteristics, including systolic blood pressure, diuretic dose, and beta-blocker dose, among the three groups stratified by the dose of sacubitril/valsartan.2 It would be required to adjust for these differences to investigate the independent impact of very low dose sacubitril/valsartan, although a small sample size would not permit such an adjustment. Although the patients with very low dose sacubitril/valsartan enjoyed significant improvement in NT-proBNP, there was no control group,2 which might also have achieved similar improvement without sacubitril/valsartan. It would be better to compare their endpoint with a control group without sacubitril/valsartan. The doses of diuretics could not be reduced and the dose of mineralocorticoid was rather reduced in the patients with very low dose sacubitril/valsartan.2 In addition to the decrease in NT-proBNP level, longer-term outcomes including cardiac reverse remodeling in such a cohort remain the future concerns. None.
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