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      Sacubitril/valsartan increases postprandial gastrin and cholecystokinin in plasma

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          Abstract

          Aims

          Neprilysin degrades natriuretic peptides in circulation and is also suggested to degrade the gut hormones gastrin and cholecystokinin. Neprilysin inhibition has become a therapeutic strategy and thus a regimen in need of further testing in terms of other hormonal axes besides natriuretic peptides. The aim of this study was to examine whether acute inhibition of neprilysin affects meal-induced responses in gastrin and cholecystokinin concentrations in healthy individuals.

          Methods and results

          Nine healthy young men were included in an open-labelled, randomized cross-over clinical trial. The participants received a standardized meal (25 g fat, 26 g protein, 42 g carbohydrate) on two separate days with or without a one-time dosage of sacubitril ((194 mg)/valsartan (206 mg)). Blood pressure, heart rate and blood samples were measured and collected during the experiment. Statistical differences between groups were assessed using area under the curve together with an ANOVA with a Bonferroni post hoc test. Sacubitril/valsartan increased the postprandial plasma concentrations of both gastrin and cholecystokinin (80% (AUC 0-270 min, P = 0.004) and 60% (AUC 0-270 min, P = 0.003), respectively) compared with the control meal. No significant hemodynamic effects were noted (blood pressure, AUC 0-270 min, P = 0.86, heart rate, AUC 0-270 min, P = 0.96).

          Conclusion

          Our study demonstrates that sacubitril/valsartan increases the postprandial plasma concentrations of gastrin and cholecystokinin in healthy individuals. The results thus suggest that neprilysin-mediated degradation of gastrin and cholecystokinin is physiologically relevant and may have a role in heart failure patients treated with sacubitril/valsartan.

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          Most cited references28

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          Effect of sacubitril/valsartan versus enalapril on glycaemic control in patients with heart failure and diabetes: a post-hoc analysis from the PARADIGM-HF trial.

          Diabetes is an independent risk factor for heart failure progression. Sacubitril/valsartan, a combination angiotensin receptor-neprilysin inhibitor, improves morbidity and mortality in patients with heart failure with reduced ejection fraction (HFrEF), compared with the angiotensin-converting enzyme inhibitor enalapril, and improves peripheral insulin sensitivity in obese hypertensive patients. We aimed to investigate the effect of sacubitril/valsartan versus enalapril on HbA1c and time to first-time initiation of insulin or oral antihyperglycaemic drugs in patients with diabetes and HFrEF.
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            Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition.

            Heart failure affects ≈5.7 million people in the United States alone. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, and aldosterone antagonists have improved mortality in patients with heart failure and reduced ejection fraction, but mortality remains high. In July 2015, the US Food and Drug Administration approved the first of a new class of drugs for the treatment of heart failure: Valsartan/sacubitril (formerly known as LCZ696 and currently marketed by Novartis as Entresto) combines the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril in a 1:1 ratio in a sodium supramolecular complex. Sacubitril is converted by esterases to LBQ657, which inhibits neprilysin, the enzyme responsible for the degradation of the natriuretic peptides and many other vasoactive peptides. Thus, this combined angiotensin receptor antagonist and neprilysin inhibitor addresses 2 of the pathophysiological mechanisms of heart failure: activation of the renin-angiotensin-aldosterone system and decreased sensitivity to natriuretic peptides. In the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, valsartan/sacubitril significantly reduced mortality and hospitalization for heart failure, as well as blood pressure, compared with enalapril in patients with heart failure, reduced ejection fraction, and an elevated circulating level of brain natriuretic peptide or N-terminal pro-brain natriuretic peptide. Ongoing clinical trials are evaluating the role of valsartan/sacubitril in the treatment of heart failure with preserved ejection fraction and hypertension. We review here the mechanisms of action of valsartan/sacubitril, the pharmacological properties of the drug, and its efficacy and safety in the treatment of heart failure and hypertension.
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              Long-term neprilysin inhibition — implications for ARNIs

              The dual-acting angiotensin-receptor–neprilysin inhibitor (ARNI) LCZ696, approved for treatment of heart failure with reduced ejection fraction, is the first approval for chronic neprilysin inhibition. Neprilysin metabolizes many peptides, suggesting many potential consequences of chronic neprilysin inhibition, both beneficial and adverse. This Review summarizes current knowledge on neprilysin inhibitor therapy, and the possible consequences of chronic inhibition.
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                Author and article information

                Journal
                Endocr Connect
                Endocr Connect
                EC
                Endocrine Connections
                Bioscientifica Ltd (Bristol )
                2049-3614
                May 2020
                28 April 2020
                : 9
                : 5
                : 438-444
                Affiliations
                [1 ]Department of Clinical Biochemistry , Rigshospitalet, Copenhagen, Denmark
                [2 ]Institute of Biomedical Sciences , Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
                [3 ]Novo Nordisk Foundation Centre for Protein Research , Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
                [4 ]Department of Clinical Medicine , Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
                [5 ]Department of Cardiology , Rigshospitalet, Copenhagen, Denmark
                Author notes
                Correspondence should be addressed to J P Goetze: JPG@ 123456dadlnet.dk

                J P Goetze is a member of the editorial board of Endocrine Connections. He was not involved in the editorial or peer review process of this paper, on which he is listed as an author

                Article
                EC-19-0563
                10.1530/EC-19-0563
                7274559
                32348960
                4da06a32-18bf-4d83-bed9-fa8daa374551
                © 2020 The authors

                This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

                History
                : 23 April 2020
                : 28 April 2020
                Product
                Categories
                Research

                heart failure,cholecystokinin,gastrin,natriuretic peptide,sacubitril/valsartan,neprilysin

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