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Novel antihypertensive agents for resistant hypertension: what does the future hold?

Abstract

Finding complementary compelling novel therapeutic agents for better control of blood pressure in people with resistant hypertension is moving into unchartered territory. The latest therapeutic developments explore approaches in the clinical arena that were either not examined or could only be examined in animal models two decades ago. Four main mechanisms have now been explored and operationalized in drug development: (a) mineralocorticoid receptor blockade using a nonsteroidal structure with many fewer side effects, (b) an aminopeptidase A inhibitor that has central effects on vasopressin, (c) a combined endothelin A and B receptor blocker and (d) an aldosterone synthase inhibitor devoid of glucocorticoid activity. All these agents are either completing Phase II development and starting Phase III or are involved in the ongoing recruitment of Phase III trials. Additionally, novel agents use antisense inhibition to block angiotensinogen development in the liver. These agents are discussed only for completeness, as they are still in Phase II trial development. Last, another agent that was initially being developed as an antihypertensive and once the data were reviewed by the company clearly showed efficacy as a heart failure agent was sacubitril/valsartan, which was ultimately approved. However, there are some discussions about reinvigorating the quest for an indication for hypertension, although no such steps have been formally initiated.

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References

  1. Harrison DG, Coffman TM, Wilcox CS. Pathophysiology of hypertension: The Mosaic Theory and Beyond. Circ Res. 2021;128:847–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Carey RM, Calhoun DA, Bakris GL, Brook RD, Daugherty SL, Dennison-Himmelfarb CR, et al. Resistant hypertension: detection, evaluation, and management: a scientific statement from the American Heart Association. Hypertension. 2018;72:e53–90.

    Article  CAS  PubMed  Google Scholar 

  3. Weber MA, Schiffrin EL, White WB, Mann S, Lindholm LH, Kenerson JG, et al. Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. J Clin Hypertens (Greenwich). 2014;16:14–26.

    Article  Google Scholar 

  4. Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018;39:3021–104.

    Article  PubMed  Google Scholar 

  5. Oparil S, Acelajado MC, Bakris GL, Berlowitz DR, Cífková R, Dominiczak AF, et al. Hypertension. Nat Rev Dis Prim. 2018;4:18014.

    Article  PubMed  Google Scholar 

  6. Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. Bmj. 2003;326:1427.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gradman AH, Basile JN, Carter BL, Bakris GL. Combination therapy in hypertension. J Clin Hypertens (Greenwich). 2011;13:146–54.

    Article  Google Scholar 

  8. Jamerson K, Weber MA, Bakris GL, Dahlöf B, Pitt B, Shi V, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N. Engl J Med. 2008;359:2417–28.

    Article  CAS  PubMed  Google Scholar 

  9. Bakris GL, Sarafidis PA, Weir MR, Dahlöf B, Pitt B, Jamerson K, et al. Renal outcomes with different fixed-dose combination therapies in patients with hypertension at high risk for cardiovascular events (ACCOMPLISH): a prespecified secondary analysis of a randomised controlled trial. Lancet. 2010;375:1173–81.

    Article  CAS  PubMed  Google Scholar 

  10. Rahman M, Pressel S, Davis BR, Nwachuku C, Wright JT Jr., Whelton PK, et al. Renal outcomes in high-risk hypertensive patients treated with an angiotensin-converting enzyme inhibitor or a calcium channel blocker vs a diuretic: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med. 2005;165:936–46.

    Article  CAS  PubMed  Google Scholar 

  11. Wright JT Jr., Bakris G, Greene T, Agodoa LY, Appel LJ, Charleston J, et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. Jama. 2002;288:2421–31.

    Article  CAS  PubMed  Google Scholar 

  12. Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Lancet. 1997;349:1857–63.

  13. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N. Engl J Med. 2001;345:851–60.

    Article  CAS  PubMed  Google Scholar 

  14. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N. Engl J Med. 2001;345:861–9.

    Article  CAS  PubMed  Google Scholar 

  15. Kintscher U, Bakris GL, Kolkhof P. Novel non-steroidal mineralocorticoid receptor antagonists in cardiorenal disease. Br J Pharmacol. 2021. https://doi.org/10.1111/bph.15747.

  16. Barrera-Chimal J, Jaisser F, Anders HJ. The mineralocorticoid receptor in chronic kidney disease. Br J Pharmacol. 2021. https://doi.org/10.1111/bph.15734.

  17. Barrera-Chimal J, Kolkhof P, Lima-Posada I, Joachim A, Rossignol P, Jaisser F. Differentiation between emerging non-steroidal and established steroidal mineralocorticoid receptor antagonists: head-to-head comparisons of pharmacological and clinical characteristics. Expert Opin Investig Drugs. 2021;30:1141–57.

    Article  CAS  PubMed  Google Scholar 

  18. Chow CPLJ, Tan XJ, Huang ZH. Pharmacological Profile of Kbp-5074, a novel nonsteroidal mineralocorticoid receptor antagonist for the treatment of cardiorenal diseases. J Drug Res Dev. 2017;3:67–75.

    Google Scholar 

  19. Pitt B, Jaisser F, Bakris G. An evaluation of KBP-5074 in advanced chronic kidney disease with uncontrolled hypertension. Expert Opin Investig Drugs. 2021;30:1017–23.

    Article  CAS  PubMed  Google Scholar 

  20. Jaisser F, Tan X, Chi S, Liu J, Wang P, Bush M, et al. The non-steroidal mineralocorticoid receptor antagonist KBP-5074 limits Albuminuria and has improved therapeutic index compared with Eplerenone in a Rat Model With mineralocorticoid-induced renal injury. Front Pharm. 2021;12:604928.

    Article  CAS  Google Scholar 

  21. Zhang B, Tan X, Ni S. Pharmacokinetics and safety of KBP-5074 in phase 1 single and multiple ascending dose studies. Paper presented at: Poster presented at American Society of Nephrology Kidney Week meeting 2016.

  22. Zhang BCP, Smith WB, Lasseter K, Yang F, Tan X, Pelka P. Safety, tolerability and pharmacokinetics of KBP-5074 in patients with mild-to-moderate chronic kidney disease [Abstract PUB116]. J Am Soc Nephrol. 2016;27:931A.

    Google Scholar 

  23. Bakris G, Yang YF, Pitt B. Mineralocorticoid receptor antagonists for Hypertension management in advanced Chronic Kidney Disease: BLOCK-CKD Trial. Hypertension. 2020;76:144–9.

    Article  CAS  PubMed  Google Scholar 

  24. Bakris G, Pergola PE, Delgado B, Genov D, Doliashvili T, Vo N, et al. Effect of KBP-5074 on Blood Pressure in Advanced Chronic Kidney Disease: Results of the BLOCK-CKD Study. Hypertension. 2021;78:74–81.

    Article  CAS  PubMed  Google Scholar 

  25. Lazich I, Bakris GL. Prediction and management of hyperkalemia across the spectrum of chronic kidney disease. Semin Nephrol. 2014;34:333–9.

    Article  CAS  PubMed  Google Scholar 

  26. Trensz F, Bortolamiol C, Kramberg M, Wanner D, Hadana H, Rey M, et al. Pharmacological characterization of Aprocitentan, a dual Endothelin receptor antagonist, alone and in combination with blockers of the Renin Angiotensin System, in two models of experimental Hypertension. J Pharm Exp Ther. 2019;368:462–73.

    Article  CAS  Google Scholar 

  27. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332:411–5.

    Article  CAS  PubMed  Google Scholar 

  28. Schiffrin EL, Deng LY, Sventek P, Day R. Enhanced expression of endothelin-1 gene in resistance arteries in severe human essential hypertension. J Hypertens. 1997;15:57–63.

    Article  CAS  PubMed  Google Scholar 

  29. Gueneau de Mussy P, Sidharta PN, Wuerzner G, Maillard MP, Guérard N, Iglarz M, et al. Effects of the dual Endothelin receptor antagonist aprocitentan on body weight and fluid homeostasis in healthy subjects on a high Sodium diet. Clin Pharm Ther. 2021;109:746–53.

    Article  CAS  Google Scholar 

  30. Iglarz M, Clozel M. At the heart of tissue: endothelin system and end-organ damage. Clin Sci (Lond). 2010;119:453–63.

    Article  CAS  Google Scholar 

  31. Amiri F, Virdis A, Neves MF, Iglarz M, Seidah NG, Touyz RM, et al. Endothelium-restricted overexpression of human endothelin-1 causes vascular remodeling and endothelial dysfunction. Circulation. 2004;110:2233–40.

    Article  CAS  PubMed  Google Scholar 

  32. Sen S, Chen S, Feng B, Iglarz M, Chakrabarti S. Renal, retinal and cardiac changes in type 2 diabetes are attenuated by macitentan, a dual endothelin receptor antagonist. Life Sci. 2012;91:658–68.

    Article  CAS  PubMed  Google Scholar 

  33. McCoy EK, Lisenby KM. Aprocitentan (a Dual Endothelin-Receptor Antagonist) for Treatment-Resistant Hypertension. J Cardiovasc Pharm. 2021;77:699–706.

    Article  CAS  Google Scholar 

  34. Dhaun N, Goddard J, Kohan DE, Pollock DM, Schiffrin EL, Webb DJ. Role of endothelin-1 in clinical hypertension: 20 years on. Hypertension. 2008;52:452–9.

    Article  CAS  PubMed  Google Scholar 

  35. Angeli F, Verdecchia P, Reboldi G. Aprocitentan, A Dual Endothelin Receptor Antagonist Under Development for the Treatment of Resistant Hypertension. Cardiol Ther. 2021;10:397–406.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Angeli F, Reboldi G, Verdecchia P. Interpretation of ambulatory blood pressure profile: a prognostic approach for clinical practice. J Hypertens. 2015;33:454–7.

    Article  CAS  PubMed  Google Scholar 

  37. Sidharta PN, Ulč I, Dingemanse J. Single-Dose Pharmacokinetics and Tolerability of Aprocitentan, a Dual Endothelin Receptor Antagonist, in Subjects with Severe Renal Function Impairment. Clin Drug Investig. 2019;39:1117–23.

    Article  CAS  PubMed  Google Scholar 

  38. Verweij P, Danaietash P, Flamion B, Ménard J, Bellet M. Randomized Dose-Response Study of the New Dual Endothelin Receptor Antagonist Aprocitentan in Hypertension. Hypertension. 2020;75:956–65.

    Article  CAS  PubMed  Google Scholar 

  39. Kohan DE, Pollock DM. Endothelin antagonists for diabetic and non-diabetic chronic kidney disease. Br J Clin Pharm. 2013;76:573–9.

    CAS  Google Scholar 

  40. Mann JF, Green D, Jamerson K, Ruilope LM, Kuranoff SJ, Littke T, et al. Avosentan for overt diabetic nephropathy. J Am Soc Nephrol. 2010;21:527–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Black HR, Bakris GL, Weber MA, Weiss R, Shahawy ME, Marple R, et al. Efficacy and safety of darusentan in patients with resistant hypertension: results from a randomized, double-blind, placebo-controlled dose-ranging study. J Clin Hypertens (Greenwich). 2007;9:760–9.

    Article  CAS  Google Scholar 

  42. Burnier M. Update on Endothelin Receptor Antagonists in Hypertension. Curr Hypertens Rep. 2018;20:51.

    Article  PubMed  Google Scholar 

  43. Georgianos PI, Agarwal R. Endothelin A receptor antagonists in diabetic kidney disease. Curr Opin Nephrol Hypertens. 2017;26:338–44.

    Article  CAS  PubMed  Google Scholar 

  44. Smeijer JD, Kohan DE, Webb DJ, Dhaun N, Heerspink HJL. Endothelin receptor antagonists for the treatment of diabetic and nondiabetic chronic kidney disease. Curr Opin Nephrol Hypertens. 2021;30:456–65.

    Article  CAS  PubMed  Google Scholar 

  45. Heerspink HJL, Parving HH, Andress DL, Bakris G, Correa-Rotter R, Hou FF, et al. Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial. Lancet. 2019;393:1937–47.

    Article  CAS  PubMed  Google Scholar 

  46. Reaux A, Fournie-Zaluski MC, David C, Zini S, Roques BP, Corvol P, et al. Aminopeptidase A inhibitors as potential central antihypertensive agents. Proc Natl Acad Sci USA. 1999;96:13415–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Bodineau L, Frugiere A, Marc Y, Inguimbert N, Fassot C, Balavoine F, et al. Orally active aminopeptidase A inhibitors reduce blood pressure: a new strategy for treating hypertension. Hypertension. 2008;51:1318–25.

    Article  CAS  PubMed  Google Scholar 

  48. Basting T, Lazartigues E. DOCA-Salt Hypertension: an Update. Curr Hypertens Rep. 2017;19:32.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Balavoine F, Azizi M, Bergerot D, De Mota N, Patouret R, Roques BP, et al. Randomised, double-blind, placebo-controlled, dose-escalating phase I study of QGC001, a centrally acting aminopeptidase a inhibitor prodrug. Clin Pharmacokinet. 2014;53:385–95.

    Article  CAS  PubMed  Google Scholar 

  50. Azizi M, Courand PY, Denolle T, Delsart P, Zhygalina V, Amar L, et al. A pilot double-blind randomized placebo-controlled crossover pharmacodynamic study of the centrally active aminopeptidase A inhibitor, firibastat, in hypertension. J Hypertens. 2019;37:1722–8.

    Article  CAS  PubMed  Google Scholar 

  51. Ferdinand KC, Balavoine F, Besse B, Black HR, Desbrandes S, Dittrich HC, et al. Efficacy and Safety of Firibastat, A First-in-Class Brain Aminopeptidase A Inhibitor, in Hypertensive Overweight Patients of Multiple Ethnic Origins. Circulation. 2019;140:138–46.

    Article  CAS  PubMed  Google Scholar 

  52. Lenzini L, Zanotti G, Bonchio M, Rossi GP. Aldosterone synthase inhibitors for cardiovascular diseases: A comprehensive review of preclinical, clinical and in silico data. Pharm Res. 2021;163:105332.

    Article  CAS  Google Scholar 

  53. Ren L, Colafella KMM, Bovée DM, Uijl E, Danser AHJ. Targeting angiotensinogen with RNA-based therapeutics. Curr Opin Nephrol Hypertens. 2020;29:180–9.

    Article  PubMed  Google Scholar 

  54. Setten RL, Rossi JJ, Han SP. The current state and future directions of RNAi-based therapeutics. Nat Rev Drug Disco. 2019;18:421–46.

    Article  CAS  Google Scholar 

  55. Liang XH, Sun H, Nichols JG, Crooke ST. RNase H1-Dependent Antisense Oligonucleotides Are Robustly Active in Directing RNA Cleavage in Both the Cytoplasm and the Nucleus. Mol Ther. 2017;25:2075–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Bertrand JR, Pottier M, Vekris A, Opolon P, Maksimenko A, Malvy C. Comparison of antisense oligonucleotides and siRNAs in cell culture and in vivo. Biochem Biophys Res Commun. 2002;296:1000–4.

    Article  CAS  PubMed  Google Scholar 

  57. Levin AA. Treating Disease at the RNA Level with Oligonucleotides. N. Engl J Med. 2019;380:57–70.

    Article  PubMed  Google Scholar 

  58. Springer AD, Dowdy SF. GalNAc-siRNA Conjugates: Leading the Way for Delivery of RNAi Therapeutics. Nucleic Acid Ther. 2018;28:109–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Prakash TP, Graham MJ, Yu J, Carty R, Low A, Chappell A, et al. Targeted delivery of antisense oligonucleotides to hepatocytes using triantennary N-acetyl galactosamine improves potency 10-fold in mice. Nucleic Acids Res. 2014;42:8796–807.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Morgan ES, Tami Y, Hu K, Brambatti M, Mullick AE, Geary RS, et al. Antisense Inhibition of Angiotensinogen With IONIS-AGT-L(Rx): Results of Phase 1 and Phase 2 Studies. JACC Basic Transl Sci. 2021;6:485–96.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Huang STJ, Casey S, Leung PM, Webb DJ, Desai AS, Cheng Y, et al. Durable Reductions in Circulating Angiotensinogen and Blood Pressure Six Months After Single Doses of ALN-AGT, an RNA Interference Therapeutic Targeting Hepatic Angiotensinogen Synthesis, in Hypertensive Patients. Circulation. 2021;144:A10974 https://doi.org/10.1161/circ.144.suppl_1.10974.

    Article  Google Scholar 

  62. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N. Engl J Med. 2014;371:993–1004.

    Article  PubMed  Google Scholar 

  63. De Vecchis R, Soreca S, Ariano C. Anti-Hypertensive Effect of Sacubitril/Valsartan: A Meta-Analysis of Randomized Controlled Trials. Cardiol Res. 2019;10:24–33.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Zhao Y, Yu H, Zhao X, Ma R, Li N, Yu J. The Effects of LCZ696 in Patients With Hypertension Compared With Angiotensin Receptor Blockers: A Meta-Analysis of Randomized Controlled Trials. J Cardiovasc Pharm Ther. 2017;22:447–57.

    Article  CAS  Google Scholar 

  65. Wang JG, Yukisada K, Sibulo A Jr., Hafeez K, Jia Y, Zhang J. Efficacy and safety of sacubitril/valsartan (LCZ696) add-on to amlodipine in Asian patients with systolic hypertension uncontrolled with amlodipine monotherapy. J Hypertens. 2017;35:877–85.

    Article  CAS  PubMed  Google Scholar 

  66. Kostis JB, Packer M, Black HR, Schmieder R, Henry D, Levy E. Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens. 2004;17:103–11.

    Article  CAS  PubMed  Google Scholar 

  67. Bavishi C, Messerli FH, Kadosh B, Ruilope LM, Kario K. Role of neprilysin inhibitor combinations in hypertension: insights from hypertension and heart failure trials. Eur Heart J. 2015;36:1967–73.

    Article  CAS  PubMed  Google Scholar 

  68. Gu J, Noe A, Chandra P, Al-Fayoumi S, Ligueros-Saylan M, Sarangapani R, et al. Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi). J Clin Pharm. 2010;50:401–14.

    Article  CAS  Google Scholar 

  69. Segura J, Ruilope LM. Dual-acting angiotensin receptor-neprilysin inhibition. Curr Hypertens Rep. 2011;13:74–8.

    Article  CAS  PubMed  Google Scholar 

  70. Chrysant SG. Benefits and pitfalls of sacubitril/valsartan treatment in patients with hypertension. J Clin Hypertens (Greenwich). 2018;20:351–5.

    Article  Google Scholar 

  71. Ruilope LM, Dukat A, Böhm M, Lacourcière Y, Gong J, Lefkowitz MP. Blood-pressure reduction with LCZ696, a novel dual-acting inhibitor of the angiotensin II receptor and neprilysin: a randomised, double-blind, placebo-controlled, active comparator study. Lancet. 2010;375:1255–66.

    Article  CAS  PubMed  Google Scholar 

  72. Perkovic V, Huxley R, Wu Y, Prabhakaran D, MacMahon S. The burden of blood pressure-related disease: a neglected priority for global health. Hypertension. 2007;50:991–7.

    Article  CAS  PubMed  Google Scholar 

  73. Kario K, Sun N, Chiang FT, Supasyndh O, Baek SH, Inubushi-Molessa A, et al. Efficacy and safety of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in Asian patients with hypertension: a randomized, double-blind, placebo-controlled study. Hypertension. 2014;63:698–705.

    Article  CAS  PubMed  Google Scholar 

  74. Kario K, Tamaki Y, Okino N, Gotou H, Zhu M, Zhang J. LCZ696, a First-in-Class Angiotensin Receptor-Neprilysin Inhibitor: The First Clinical Experience in Patients With Severe Hypertension. J Clin Hypertens (Greenwich). 2016;18:308–14.

    Article  CAS  Google Scholar 

  75. Stamler J. The INTERSALT Study: background, methods, findings, and implications. Am J Clin Nutr. 1997;65:626s–42s.

    Article  CAS  PubMed  Google Scholar 

  76. Katsuya T, Ishikawa K, Sugimoto K, Rakugi H, Ogihara T. Salt sensitivity of Japanese from the viewpoint of gene polymorphism. Hypertens Res. 2003;26:521–5.

    Article  PubMed  Google Scholar 

  77. Wang TD, Tan RS, Lee HY, Ihm SH, Rhee MY, Tomlinson B, et al. Effects of Sacubitril/Valsartan (LCZ696) on Natriuresis, Diuresis, Blood Pressures, and NT-proBNP in Salt-Sensitive Hypertension. Hypertension. 2017;69:32–41.

    Article  CAS  PubMed  Google Scholar 

  78. Volpe M, Gallo G. Sacubitril/valsartan for heart failure with preserved ejection fraction and resistant hypertension: one shot for a double strike? Eur Heart J. 2021;42:3753–5.

    Article  PubMed  Google Scholar 

  79. Solomon SD, Zile M, Pieske B, Voors A, Shah A, Kraigher-Krainer E, et al. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet. 2012;380:1387–95.

    Article  CAS  PubMed  Google Scholar 

  80. Jackson AM, Jhund PS, Anand IS, Düngen HD, Lam CSP, Lefkowitz MP, et al. Sacubitril-valsartan as a treatment for apparent resistant hypertension in patients with heart failure and preserved ejection fraction. Eur Heart J. 2021;42:3741–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Anderson AH, Yang W, Townsend RR, Pan Q, Chertow GM, Kusek JW, et al. Time-updated systolic blood pressure and the progression of chronic kidney disease: a cohort study. Ann Intern Med. 2015;162:258–65.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Williams B, Cockcroft JR, Kario K, Zappe DH, Brunel PC, Wang Q, et al. Effects of Sacubitril/Valsartan Versus Olmesartan on Central Hemodynamics in the Elderly With Systolic Hypertension: The PARAMETER Study. Hypertension. 2017;69:411–20.

    Article  CAS  PubMed  Google Scholar 

  83. Williams B. Hypertension and the “J-curve”. J Am Coll Cardiol. 2009;54:1835–6.

    Article  PubMed  Google Scholar 

  84. Ruiz-Hurtado G, Ruilope LM. Advantages of sacubitril/valsartan beyond blood pressure control in arterial hypertension. Eur Heart J. 2017;38:3318–20.

    Article  CAS  PubMed  Google Scholar 

  85. Iwata N, Tsubuki S, Takaki Y, Shirotani K, Lu B, Gerard NP, et al. Metabolic regulation of brain Abeta by neprilysin. Science. 2001;292:1550–2.

    Article  CAS  PubMed  Google Scholar 

  86. Hüttenrauch M, Baches S, Gerth J, Bayer TA, Weggen S, Wirths O. Neprilysin deficiency alters the neuropathological and behavioral phenotype in the 5XFAD mouse model of Alzheimer’s disease. J Alzheimers Dis. 2015;44:1291–302.

    Article  PubMed  Google Scholar 

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Correspondence to George L. Bakris.

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VDS—None; GLB is supported by T32 NIH grant DK07011 and is a consultant to Bayer, KBP Biosciences, Ionis, Alnylam, Astra Zeneca, Quantum Genomics, Horizon, Novo Nordisk, Dia Medica Therapeutics, and InRegen.

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Salvador, V.D., Bakris, G.L. Novel antihypertensive agents for resistant hypertension: what does the future hold?. Hypertens Res 45, 1918–1928 (2022). https://doi.org/10.1038/s41440-022-01025-9

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Keywords

  • Hypertension
  • Neprilysin
  • Resistant hypertension
  • Kidney
  • Nephropathy

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