Skip to main content

Advertisement

SpringerLink
Log in

Renin Inhibitors and Cardiovascular and Renal Protection: An Endless Quest?

  • Review Article
  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Abstract

Renin-angiotensin system (RAS) blockade with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) has become a major therapeutic approach in medicine since the end of the 1970’s. Although these molecules were the first RAS blockers to be developed, it would have been physiologically and pharmacologically more pertinent to selectively inhibit renin itself. Indeed, the reaction between renin and its unique substrate, angiotensinogen, is the highly regulated and rate-limiting step of the RAS. The development of direct renin inhibitors (DRI) has been a slow and complex process and the synthesis of the first orally active DRI, aliskiren, was only achieved in the 2000’s. Its pharmacological profile in patients with hypertension, diabetic nephropathy or heart failure, in addition to experimental evidence, suggests that aliskiren may be of value for the management of cardiovascular and renal diseases. However, the long-term, randomized, placebo-controlled, morbidity/mortality trial, ALTITUDE, which included 8,600 patients with type 2 diabetes, proteinuria and a high cardiovascular risk already treated with ACE inhibitors or ARBs was terminated in December 2011 because of futility and an increased incidence of serious adverse events in the aliskiren 300 mg arm. Other long-term studies are still ongoing to demonstrate the safety and efficacy of aliskiren to reduce cardiovascular morbidity and mortality in patients with heart failure and in elderly individuals (≥65 years) with systolic blood pressure of 130 to 159 mmHg, no overt cardiovascular disease, and a high cardiovascular risk profile. In the meantime, according to the European Medicines Agency recommendations, aliskiren should not be prescribed to diabetic patients in combination with ACE inhibitors or ARBs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Turnbull F. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet. 2003;362:1527–35.

    Article  CAS  PubMed  Google Scholar 

  2. Azizi M, Menard J. Combined blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists. Circulation. 2004;109:2492–9.

    Article  PubMed  Google Scholar 

  3. Flather MD, Yusuf S, Kober L, Pfeffer M, Hall A, Murray G, et al. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group. Lancet. 2000;355:1575–81.

    Article  CAS  PubMed  Google Scholar 

  4. Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345:1667–75.

    Article  CAS  PubMed  Google Scholar 

  5. Pfeffer MA, McMurray JJ, Velazquez EJ, Rouleau JL, Kober L, Maggioni AP, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349:1893–906.

    Article  CAS  PubMed  Google Scholar 

  6. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med. 1992;327:685–91.

    Article  Google Scholar 

  7. ACE Inhibitor Myocardial Infarction Collaborative Group. Indications for ACE inhibitors in the early treatment of acute myocardial infarction: systematic overview of individual data from 100,000 patients in randomized trials. Circulation. 1998;97:2202–12.

    Article  Google Scholar 

  8. Dickstein K, Kjekshus J. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan. Lancet. 2002;360:752–60.

    Article  CAS  PubMed  Google Scholar 

  9. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993;329:1456–62.

    Article  CAS  PubMed  Google Scholar 

  10. 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 

  11. 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 

  12. The GISEN Group. 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. Lancet. 1997;349:1857–63.

    Article  Google Scholar 

  13. Ruggenenti P, Perna A, Gherardi G, Garini G, Zoccali C, Salvadori M, et al. Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet. 1999;354:359–64.

    Article  CAS  PubMed  Google Scholar 

  14. Agodoa LY, Appel L, Bakris GL, Beck G, Bourgoignie J, Briggs JP, et al. Effect of ramipril vs. amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. Jama. 2001;285:2719–28.

    Article  CAS  PubMed  Google Scholar 

  15. Jafar TH, Schmid CH, Landa M, Giatras I, Toto R, Remuzzi G, et al. Angiotensin-converting enzyme inhibitors and progression of nondiabetic renal disease. A meta-analysis of patient-level data. Ann Intern Med. 2001;135:73–87.

    CAS  PubMed  Google Scholar 

  16. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:145–53.

    Article  CAS  PubMed  Google Scholar 

  17. Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358:1547–59.

    Article  CAS  PubMed  Google Scholar 

  18. Yusuf S, Teo K, Anderson C, Pogue J, Dyal L, Copland I, et al. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet. 2008;372:1174–83.

    Article  CAS  PubMed  Google Scholar 

  19. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001;358:1033–41.

    Article  Google Scholar 

  20. Yusuf S, Diener HC, Sacco RL, Cotton D, Ounpuu S, Lawton WA, et al. Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med. 2008;359:1225–37.

    Article  CAS  PubMed  Google Scholar 

  21. Juillerat L, Nussberger J, Ménard J, Mooser V, Christen Y, Waeber B, et al. Determinants of angiotensin II generation during converting enzyme inhibition. Hypertension. 1990;16:564–72.

    Article  CAS  PubMed  Google Scholar 

  22. Fisher ND, Hollenberg NK. Renin inhibition: what are the therapeutic opportunities? J Am Soc Nephrol. 2005;16:592–9.

    Article  CAS  PubMed  Google Scholar 

  23. Rongen GA, Lenders JW, Smits P, Thien T. Clinical pharmacokinetics and efficacy of renin inhibitors. Clin Pharmacokinet. 1995;29:6–14.

    Article  CAS  PubMed  Google Scholar 

  24. Rahuel J, Rasetti V, Maibaum J, Rueger H, Goschke R, Cohen NC, et al. Structure-based drug design: the discovery of novel nonpeptide orally active inhibitors of human renin. Chem Biol. 2000;7:493–504.

    Article  CAS  PubMed  Google Scholar 

  25. Wood JM, Maibaum J, Rahuel J, Grutter MG, Cohen NC, Rasetti V, et al. Structure-based design of aliskiren, a novel orally effective renin inhibitor. Biochem Biophys Res Commun. 2003;308:698–705.

    Article  CAS  PubMed  Google Scholar 

  26. Nussberger J, Wuerzner G, Jensen C, Brunner HR. Angiotensin II suppression in humans by the orally active renin inhibitor Aliskiren (SPP100): comparison with enalapril. Hypertension. 2002;39:E1–8.

    Article  CAS  PubMed  Google Scholar 

  27. Vaidyanathan S, Jarugula V, Dieterich HA, Howard D, Dole WP. Clinical pharmacokinetics and pharmacodynamics of aliskiren. Clin Pharmacokinet. 2008;47:515–31.

    Article  CAS  PubMed  Google Scholar 

  28. Azizi M, Webb R, Nussberger J, Hollenberg NK. Renin inhibition with aliskiren: where are we now, and where are we going? J Hypertens. 2006;24:243–56.

    Article  CAS  PubMed  Google Scholar 

  29. Feldman DL, Jin L, Xuan H, Contrepas A, Zhou Y, Webb RL, et al. Effects of aliskiren on blood pressure, albuminuria, and (pro)renin receptor expression in diabetic TG(mRen-2)27 rats. Hypertension. 2008;52:130–6.

    Article  CAS  PubMed  Google Scholar 

  30. Krop M, Garrelds IM, de Bruin RJ, van Gool JM, Fisher ND, Hollenberg NK, Jan Danser AH. Aliskiren accumulates in Renin secretory granules and binds plasma prorenin. Hypertension. 2008;52:1076–83.

    Article  CAS  PubMed  Google Scholar 

  31. Azizi M, Menard J, Bissery A, Guyenne TT, Bura-Riviere A, Vaidyanathan S, Camisasca RP. Pharmacologic demonstration of the synergistic effects of a combination of the renin inhibitor aliskiren and the AT1 receptor antagonist valsartan on the angiotensin II-renin feedback interruption. J Am Soc Nephrol. 2004;15:3126–33.

    Article  PubMed  Google Scholar 

  32. Okunishi H, Miyazaki M, Toda N. Evidence for a putatively new angiotensin II-generating enzyme in the vascular wall. J Hypertens. 1984;2:277–84.

    Article  CAS  PubMed  Google Scholar 

  33. Urata H, Kinoshita A, Misono KS, Bumpus FM, Husain A. Identification of a highly specific chymase as the major angiotensin II-forming enzyme in the human heart. J Biol Chem. 1990;265:22348–57.

    CAS  PubMed  Google Scholar 

  34. Carey RM, Wang ZQ, Siragy HM. Role of the angiotensin type 2 receptor in the regulation of blood pressure and renal function. Hypertension. 2000;35:155–63.

    Article  CAS  PubMed  Google Scholar 

  35. Levy BI. Can angiotensin II type 2 receptors have deleterious effects in cardiovascular disease? implications for therapeutic blockade of the renin-angiotensin system. Circulation. 2004;109:8–13.

    Article  PubMed  Google Scholar 

  36. Reudelhuber TL. The continuing saga of the AT2 receptor: a case of the good, the bad, and the innocuous. Hypertension. 2005;46:1261–2.

    Article  CAS  PubMed  Google Scholar 

  37. Erdös EG, Angiotensin I. converting enzyme and the changes in our concepts through the years. Hypertension. 1990;16:363–70.

    Article  PubMed  Google Scholar 

  38. Iyer SN, Ferrario CM, Chappell MC. Angiotensin-(1–7) contributes to the antihypertensive effects of blockade of the renin-angiotensin system. Hypertension. 1998;31:356–61.

    Article  CAS  PubMed  Google Scholar 

  39. Azizi M, Rousseau A, Ezan E, Guyene TT, Michelet S, Grognet JM, et al. Acute angiotensin-converting enzyme inhibition increases the plasma level of the natural stem-cell regulator N-Acetyl-Seryl-Aspartyl-Lysyl-Proline. J Clin Invest. 1996;97:839–44.

    Article  CAS  PubMed  Google Scholar 

  40. Linz W, Wiemer G, Gohlke P, Unger T, Scholkens BA. Contribution of kinins to the cardiovascular actions of angiotensin-converting enzyme inhibitors. Pharmacol Rev. 1995;47:25–49.

    CAS  PubMed  Google Scholar 

  41. Israili ZH, Hall WD. Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy. A review of the literature and pathophysiology. Ann Intern Med. 1992;117:234–42.

    CAS  PubMed  Google Scholar 

  42. Nussberger J, Cugno M, Amstutz C, Cicardi M, Pellacani A, Agostoni A. Plasma bradykinin in angio-oedema. Lancet. 1998;351:1693–7.

    Article  CAS  PubMed  Google Scholar 

  43. Nguyen G, Delarue F, Berrou J, Rondeau E, Sraer JD. Specific receptor binding of renin on human mesangial cells in culture increases plasminogen activator inhibitor-1 antigen. Kidney Int. 1996;50:1897–903.

    Article  CAS  PubMed  Google Scholar 

  44. Nguyen G, Delarue F, Burckle C, Bouzhir L, Giller T, Sraer JD. Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest. 2002;109:1417–27.

    CAS  PubMed  Google Scholar 

  45. Ichihara A, Kaneshiro Y, Suzuki F. Prorenin receptor blockers: effects on cardiovascular complications of diabetes and hypertension. Expet Opin Investig Drugs. 2006;15:1137–9.

    Article  CAS  Google Scholar 

  46. Feldt S, Batenburg WW, Mazak I, Maschke U, Wellner M, Kvakan H, et al. Prorenin and renin-induced extracellular signal-regulated kinase 1/2 activation in monocytes is not blocked by aliskiren or the handle-region peptide. Hypertension. 2008;51:682–8.

    Article  CAS  PubMed  Google Scholar 

  47. Oh BH, Mitchell J, Herron JR, Chung J, Khan M, Keefe DL. Aliskiren, an oral renin inhibitor, provides dose-dependent efficacy and sustained 24-hour blood pressure control in patients with hypertension. J Am Coll Cardiol. 2007;49:1157–63.

    Article  CAS  PubMed  Google Scholar 

  48. Palatini P, Jung W, Shlyakhto E, Botha J, Bush C, Keefe DL. Maintenance of blood-pressure-lowering effect following a missed dose of aliskiren, irbesartan or ramipril: results of a randomized, double-blind study. J Hum Hypertens. 2010;24:93–103.

    Article  CAS  PubMed  Google Scholar 

  49. Wuerzner G, Azizi M. Renin inhibition with aliskiren. Clin Exp Pharmacol Physiol. 2008;35:426–30.

    Article  CAS  PubMed  Google Scholar 

  50. Jensen C, Herold P, Brunner HR. Aliskiren: the first renin inhibitor for clinical treatment. Nat Rev Drug Discov. 2008;7:399–410.

    Article  CAS  PubMed  Google Scholar 

  51. Gradman AH, Schmieder RE, Lins RL, Nussberger J, Chiang Y, Bedigian MP. Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. Circulation. 2005;111:1012–8.

    Article  CAS  PubMed  Google Scholar 

  52. Oparil S, Yarows SA, Patel S, Fang H, Zhang J, Satlin A. Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomised, double-blind trial. Lancet. 2007;370:221–9.

    Article  CAS  PubMed  Google Scholar 

  53. Pool JL, Schmieder RE, Azizi M, Aldigier JC, Januszewicz A, Zidek W, et al. Aliskiren, an orally effective Renin inhibitor, provides antihypertensive efficacy alone and in combination with valsartan. Am J Hypertens. 2007;20:11–20.

    Article  CAS  PubMed  Google Scholar 

  54. Andersen K, Weinberger MH, Egan B, Constance CM, Ali MA, Jin J, Keefe DL. Comparative efficacy and safety of aliskiren, an oral direct renin inhibitor, and ramipril in hypertension: a 6-month, randomized, double-blind trial. J Hypertens. 2008;26:589–99.

    Article  CAS  PubMed  Google Scholar 

  55. Schmieder RE, Philipp T, Guerediaga J, Gorostidi M, Smith B, Weissbach N, et al. Long-term antihypertensive efficacy and safety of the oral direct renin inhibitor aliskiren: a 12-month randomized, double-blind comparator trial with hydrochlorothiazide. Circulation. 2009;119:417–25.

    Article  CAS  PubMed  Google Scholar 

  56. Musini VM, Fortin PM, Bassett K, Wright JM. Blood pressure lowering efficacy of renin inhibitors for primary hypertension: a Cochrane systematic review. J Hum Hypertens. 2009;23:495–502.

    Article  CAS  PubMed  Google Scholar 

  57. Gao D, Ning N, Niu X, Wei J, Sun P, Hao G. Aliskiren vs. angiotensin receptor blockers in hypertension: meta-analysis of randomized controlled trials. Am J Hypertens. 2011;24:613–21.

    Article  CAS  PubMed  Google Scholar 

  58. Zhenfeng Z, Huilan S, Junya J, Dong L, Shan L. A systematic review and meta-analysis of aliskiren and angiotension receptor blockers in the management of essential hypertension. J Renin Angiotensin Aldosterone Syst. 2011;12:102–12.

    Article  CAS  Google Scholar 

  59. Villamil A, Chrysant SG, Calhoun D, Schober B, Hsu H, Matrisciano-Dimichino L, Zhang J. Renin inhibition with aliskiren provides additive antihypertensive efficacy when used in combination with hydrochlorothiazide. J Hypertens. 2007;25:217–26.

    Article  CAS  PubMed  Google Scholar 

  60. Brown MJ, McInnes GT, Papst CC, Zhang J, MacDonald TM. Aliskiren and the calcium channel blocker amlodipine combination as an initial treatment strategy for hypertension control (ACCELERATE): a randomised, parallel-group trial. Lancet. 2011;377:312–20.

    Article  CAS  PubMed  Google Scholar 

  61. Jordan J, Engeli S, Boye SW, Le Breton S, Keefe DL. Direct Renin inhibition with aliskiren in obese patients with arterial hypertension. Hypertension. 2007;49:1047–55.

    Article  CAS  PubMed  Google Scholar 

  62. Littlejohn 3rd TW, Trenkwalder P, Hollanders G, Zhao Y, Liao W. Long-term safety, tolerability and efficacy of combination therapy with aliskiren and amlodipine in patients with hypertension. Curr Med Res Opin. 2009;25:951–9.

    Article  CAS  PubMed  Google Scholar 

  63. Fogari R, Zoppi A, Mugellini A, Maffioli P, Lazzari P, Monti C, Derosa G. Effect of aliskiren addition to amlodipine on ankle edema in hypertensive patients: a three-way crossover study. Expert Opin Pharmacother. 2011;12:1351–8.

    Article  CAS  PubMed  Google Scholar 

  64. O'Brien E, Barton J, Nussberger J, Mulcahy D, Jensen C, Dicker P, Stanton A. Aliskiren reduces blood pressure and suppresses plasma renin activity in combination with a thiazide diuretic, an angiotensin-converting enzyme inhibitor, or an angiotensin receptor blocker. Hypertension. 2007;49:276–84.

    Article  PubMed  CAS  Google Scholar 

  65. Stergiou GS, Makris T, Papavasiliou M, Efstathiou S, Manolis A. Comparison of antihypertensive effects of an angiotensin-converting enzyme inhibitor, a calcium antagonist and a diuretic in patients with hypertension not controlled by angiotensin receptor blocker monotherapy. J Hypertens. 2005;23:883–9.

    Article  CAS  PubMed  Google Scholar 

  66. Doulton TW, He FJ, MacGregor GA. Systematic review of combined angiotensin-converting enzyme inhibition and angiotensin receptor blockade in hypertension. Hypertension. 2005;45:880–6.

    Article  CAS  PubMed  Google Scholar 

  67. Birkenhager WH, Staessen JA. Dual inhibition of the renin system by aliskiren and valsartan. Lancet. 2007;370:195–6.

    Article  PubMed  Google Scholar 

  68. Messerli FH. The sudden demise of dual renin-angiotensin system blockade or the soft science of the surrogate end point. J Am Coll Cardiol. 2009;53:468–70.

    Article  CAS  PubMed  Google Scholar 

  69. Hollenberg NK. Direct renin inhibition and the kidney. Nat Rev Nephrol. 2010;6:49–55.

    Article  CAS  PubMed  Google Scholar 

  70. Fisher ND, Allan D, Kifor I, Gaboury CL, Williams GH, Moore TJ, Hollenberg NK. Responses to converting enzyme and renin inhibition. Role of angiotensin II in humans. Hypertension. 1994;23:44–51.

    Article  CAS  PubMed  Google Scholar 

  71. Fisher ND, Hollenberg N. Renal vascular responses to renin inhibition with zankiren in men. Clin Pharmacol Ther. 1995;57:342–8.

    Article  CAS  PubMed  Google Scholar 

  72. Fisher ND, Jan Danser AH, Nussberger J, Dole WP, Hollenberg NK. Renal and hormonal responses to direct renin inhibition with aliskiren in healthy humans. Circulation. 2008;117:3199–205.

    Article  CAS  PubMed  Google Scholar 

  73. Menard J, Campbell DJ, Azizi M, Gonzales MF. Synergistic effects of ACE inhibition and Ang II antagonism on blood pressure, cardiac weight and renin in spontaneously hypertensive rats. Circulation. 1997;96:3072–8.

    Article  CAS  PubMed  Google Scholar 

  74. Griffiths CD, Morgan TO, Delbridge LM. Effects of combined administration of ACE inhibitor and angiotensin II receptor antagonist are prevented by a high NaCl intake. J Hypertens. 2001;19:2087–95.

    Article  CAS  PubMed  Google Scholar 

  75. Richer-Giudicelli C, Domergue V, Gonzalez MF, Messadi E, Azizi M, Giudicelli JF, Menard J. Haemodynamic effects of dual blockade of the renin-angiotensin system in spontaneously hypertensive rats: influence of salt. J Hypertens. 2004;22:619–27.

    Article  CAS  PubMed  Google Scholar 

  76. Cherney DZ, Lai V, Scholey JW, Miller JA, Zinman B, Reich HN. Effect of direct renin inhibition on renal hemodynamic function, arterial stiffness, and endothelial function in humans with uncomplicated type 1 diabetes: a pilot study. Diabetes Care. 2010;33:361–5.

    Article  CAS  PubMed  Google Scholar 

  77. Persson F, Rossing P, Reinhard H, Juhl T, Stehouwer CD, Schalkwijk C, et al. Renal effects of aliskiren compared with and in combination with irbesartan in patients with type 2 diabetes, hypertension, and albuminuria. Diabetes Care. 2009;32:1873–9.

    Article  CAS  PubMed  Google Scholar 

  78. Persson F, Rossing P, Reinhard H, Juhl T, Stehouwer CD, Schalkwijk C, et al. Optimal antiproteinuric dose of aliskiren in type 2 diabetes mellitus: a randomised crossover trial. Diabetologia. 2010;53:1576–80.

    Article  CAS  PubMed  Google Scholar 

  79. Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med. 2008;358:2433–46.

    Article  CAS  PubMed  Google Scholar 

  80. Persson F, Lewis JB, Lewis EJ, Rossing P, Hollenberg NK, Parving HH. Aliskiren in combination with losartan reduces albuminuria independent of baseline blood pressure in patients with type 2 diabetes and nephropathy. Clin J Am Soc Nephrol. 2011;6:1025–31.

    Article  CAS  PubMed  Google Scholar 

  81. Persson F, Lewis JB, Lewis EJ, Rossing P, Hollenberg NK, Parving HH. Impact of baseline renal function on the efficacy and safety of aliskiren added to losartan in patients with type 2 diabetes and nephropathy. Diabetes Care. 2010:Aug 6; epub ahead of print.

  82. Stevens LA, Greene T, Levey AS. Surrogate end points for clinical trials of kidney disease progression. Clin J Am Soc Nephrol. 2006;1:874–84.

    Article  PubMed  Google Scholar 

  83. Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, Haffner SM, Solomon SD, et al. Aliskiren trial in type 2 diabetes using cardio-renal endpoints (ALTITUDE): rationale and study design. Nephrol Dial Transplant. 2009;24:1663–71.

    Article  CAS  PubMed  Google Scholar 

  84. European Medicines Agency starts review of aliskiren-containing medicines following termination of ALTITUDE study. http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2011/12/WC500119982.pdf. Accessed 8 Feb 2012.

  85. Palmer BF. Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system. N Engl J Med. 2004;351:585–92.

    Article  CAS  PubMed  Google Scholar 

  86. Azizi M, Menard J, Bissery A, Guyene TT, Bura-Riviere A. Hormonal and hemodynamic effects of aliskiren and valsartan and their combination in sodium-replete normotensive individuals. Clin J Am Soc Nephrol. 2007;2:947–55.

    Article  CAS  PubMed  Google Scholar 

  87. McMurray JJV, Pitt B, Latini R, Maggioni AP, Solomon SD, Keefe DK, et al. Effects of the oral direct renin inhibitor aliskiren in patients with symptomatic heart failure. Circ Heart Fail. 2008;1:17–24.

    Article  CAS  PubMed  Google Scholar 

  88. Persson F, Lewis JB, Lewis EJ, Rossing P, Hollenberg NK, Parving HH. Impact of aliskiren treatment on urinary aldosterone levels in patients with type 2 diabetes and nephropathy: an AVOID substudy. J Renin Angiotensin Aldosterone Syst. 2011.

  89. Lakhdar R, Al-Mallah MH, Lanfear DE. Safety and tolerability of angiotensin-converting enzyme inhibitor versus the combination of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker in patients with left ventricular dysfunction: a systematic review and meta-analysis of randomized controlled trials. J Card Fail. 2008;14:181–8.

    Article  CAS  PubMed  Google Scholar 

  90. Solomon SD, Shin SH, Shah A, Skali H, Desai A, Kober L, et al. Effect of the direct renin inhibitor aliskiren on left ventricular remodelling following myocardial infarction with systolic dysfunction. Eur Heart J. 2011;32:1227–34.

    Article  CAS  PubMed  Google Scholar 

  91. Harel Z, Gilbert C, Wald R, Bell C, Perl J, Juurlink D, et al. The effect of combination treatment with aliskiren and blockers of the renin-angiotensin system on hyperkalaemia and acute kidney injury: systematic review and meta-analysis. BMJ. 2012;344:e42.

    Article  PubMed  CAS  Google Scholar 

  92. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341:709–17.

    Article  CAS  PubMed  Google Scholar 

  93. Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364:11–21.

    Article  CAS  PubMed  Google Scholar 

  94. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309–21.

    Article  CAS  PubMed  Google Scholar 

  95. Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A, Redelmeier DA. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med. 2004;351:543–51.

    Article  CAS  PubMed  Google Scholar 

  96. Palmer BF. Renal dysfunction complicating the treatment of hypertension. N Engl J Med. 2002;347:1256–61.

    Article  PubMed  Google Scholar 

  97. Cushman WC, Evans GW, Byington RP, Goff Jr DC, Grimm Jr RH, Cutler JA, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362:1575–85.

    Article  PubMed  CAS  Google Scholar 

  98. Andersen K, Weinberger MH, Constance CM, Ali MA, Jin J, Prescott MF, Keefe DL. Comparative effects of aliskiren-based and ramipril-based therapy on the renin system during long-term (6 months) treatment and withdrawal in patients with hypertension. J Renin Angiotensin Aldosterone Syst. 2009;10:157–67.

    Article  CAS  PubMed  Google Scholar 

  99. Vaidyanathan S, Bigler H, Yeh C, Bizot MN, Dieterich HA, Howard D, Dole WP. Pharmacokinetics of the oral direct renin inhibitor aliskiren alone and in combination with irbesartan in renal impairment. Clin Pharmacokinet. 2007;46:661–75.

    Article  CAS  PubMed  Google Scholar 

  100. Vaidyanathan S, Reynolds C, Yeh CM, Bizot MN, Dieterich HA, Howard D, Dole WP. Pharmacokinetics, safety, and tolerability of the novel oral direct renin inhibitor aliskiren in elderly healthy subjects. J Clin Pharmacol. 2007;47:453–60.

    Article  CAS  PubMed  Google Scholar 

  101. Vaidyanathan S, Camenisch G, Schuetz H, Reynolds C, Yeh CM, Bizot MN, et al. Pharmacokinetics of the oral direct renin inhibitor aliskiren in combination with digoxin, atorvastatin, and ketoconazole in healthy subjects: the role of P-glycoprotein in the disposition of aliskiren. J Clin Pharmacol. 2008;48:1323–38.

    Article  CAS  PubMed  Google Scholar 

  102. Sever PS, Gradman AH, Azizi M. Managing cardiovascular and renal risk: the potential of direct renin inhibition. J Renin Angiotensin Aldosterone Syst. 2009;10:65–76.

    Article  CAS  PubMed  Google Scholar 

  103. Solomon SD, Appelbaum E, Manning WJ, Verma A, Berglund T, Lukashevich V, et al. Effect of the direct Renin inhibitor aliskiren, the Angiotensin receptor blocker losartan, or both on left ventricular mass in patients with hypertension and left ventricular hypertrophy. Circulation. 2009;119:530–7.

    Article  CAS  PubMed  Google Scholar 

  104. von Lutterotti N, Catanzaro DF, Sealey JE, Laragh JH. Renin is not synthesized by cardiac and extrarenal vascular tissues. A review of experimental evidenc. Circulation. 1994;89:458–70.

    Article  Google Scholar 

  105. Dzau VJ, Re R. Tissue angiotensin system in cardiovascular medicine. A paradigm shift? Circulation. 1994;89:458–70.

    Article  Google Scholar 

Download references

Conflicts of interest

MA: Occasional interventions and consultant activities: Novartis, Sanofi-Aventis, Actelion. Clinical trials, as principal investigator: Novartis.

JM: Consultant activities: Novartis and member of the scientific Council of Actelion since 2001.

Author information

Authors and Affiliations

  1. Université Paris Descartes, Faculté de Médecine, Paris, 75006, France

    Michel Azizi & Joël Ménard

  2. Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, 75015, France

    Michel Azizi & Joël Ménard

  3. INSERM, CIC 9201, Paris, 75015, France

    Michel Azizi & Joël Ménard

  4. Service d’Hypertension Artérielle et de Médecine Vasculaire, Centre d’Investigation Clinique, Hôpital Européen Georges Pompidou, 20-40 rue Leblanc, 75015, Paris, France

    Michel Azizi

Authors
  1. Michel Azizi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joël Ménard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michel Azizi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Azizi, M., Ménard, J. Renin Inhibitors and Cardiovascular and Renal Protection: An Endless Quest?. Cardiovasc Drugs Ther 27, 145–153 (2013). https://doi.org/10.1007/s10557-012-6380-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10557-012-6380-6

Key words

Search

Navigation