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Review series - New Horizons in the Treatment of Hypertension

Angiotensin receptor-neprilysin inhibitors: Comprehensive review and implications in hypertension treatment

Abstract

Angiotensin receptor-neprilysin inhibitors (ARNIs) are a new class of cardiovascular agents characterized by their dual action on the major regulators of the cardiovascular system, including the renin–angiotensin system (RAS) and the natriuretic peptide (NP) system. The apparent clinical benefit of one ARNI, sacubitril/valsartan, as shown in clinical trials, has positioned the drug class as a first-line therapy in patients with heart failure, particularly with reduced ejection fraction. Accumulating evidence also suggests that sacubitril/valsartan is superior to conventional RAS blockers in lowering blood pressure in patients with hypertension. To decide whether to apply an ARNI to treat hypertension clinically, it is important to understand the potential properties of the drug in modulating multiple factors inside and outside the cardiovascular system beyond its effect on reducing peripheral blood pressure. In this context, ARNIs are distinct from preexisting antihypertensive medications in terms of the multiple actions of NPs in various organs and the pharmacological potential of neprilysin inhibitors to modulate multiple cardiac and noncardiac peptides. In particular, analysis of the clinical trials of sacubitril/valsartan implies that ARNIs can provide additional clinical benefits independent of their original purpose, including alleviation of glycemic control and renal impairment in patients with heart failure. Understanding the potential mechanisms of action of ARNIs will help interpret the relevance of their additional benefits beyond lowering blood pressure in hypertension. This review summarizes the comprehensive clinical evidence and relevance of ARNIs by specifically focusing on the potential properties of this new drug class in treating patients with hypertension.

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Acknowledgements

We thank Hiroko Yamamoto for the creation of the illustrations in Fig. 3.

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KY wrote the manuscript. HR gave advice on writing the manuscript.

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Correspondence to Koichi Yamamoto.

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KY received lecture fees from Daiichi Sankyo unrelated to the submitted work. HR received lecture fees from Daiichi Sankyo Co Ltd., Takeda Pharmaceutical Co Ltd., and MSD unrelated to the submitted work. KY and HR received grants from Astellas Pharma, Bayer Yakuhin, Daiichi Sankyo, Dainippon Sumitomo Pharma, Kyowa Hakko Kirin, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, MSD, Nippon Boehringer Ingelheim, Novartis Pharma, Sanofi, Takeda Pharmaceutical, and Teijin Pharma unrelated to the submitted work.

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Yamamoto, K., Rakugi, H. Angiotensin receptor-neprilysin inhibitors: Comprehensive review and implications in hypertension treatment. Hypertens Res 44, 1239–1250 (2021). https://doi.org/10.1038/s41440-021-00706-1

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Keywords

  • ARNI
  • Heart failure
  • Hypertension
  • Natriuretic peptides

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