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What is the role of direct renin inhibitors in the treatment of the hypertensive diabetic patient?

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Abstract

The renin-angiotensin system (RAS) is the most important mechanism leading to cardiovascular and renal damage in diabetic patients. Studies conducted until now have unequivocally demonstrated that antihypertensive treatment with RAS blockers (angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers) improve the prognosis of patients with diabetes, by reducing rates of cardiovascular events and preventing or delaying the progression of diabetic nephropathy. However, despite the benefits of such treatment, cardio-renal events are still very frequent in diabetics. Several strategies for reducing this cardiovascular and renal risk have been proposed, but among them, a more complete blockade of the RAS seems the most attractive. Direct renin inhibitors are RAS blockers with some particularities, such as their ability to reduce plasma renin activity or the possibility to modulate tissue and intracellular RAS, which could represent a theoretical advantage when treating diabetic patients. In experimental and clinical studies conducted until now, aliskiren is able to reduce blood pressure in diabetics, alone or in combination with ACE inhibitors or angiotensin-receptor blockers. Moreover, aliskiren reduces markers of cardiac and renal disease, such as left ventricular hypertrophy or post-infarction ventricular remodeling, as well as proteinuria in diabetics already treated with other RAS blockers. The translation of these promising results to the clinical arena is currently being investigated in the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE), where more than 8600 diabetic patients with chronic kidney disease and at high-risk of cardio-renal events are treated with aliskiren or placebo added to the current treatment consisting of another RAS blocker. If positive, aliskiren will be the treatment of choice in the prevention of cardiorenal disease in diabetics.

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References

  1. Dzau VJ. Theodore Cooper Lecture: tissue angiotensin and pathobiology of vascular disease: a unifying hypothesis. Hypertension. 2001;37:1047–1052.

    PubMed  CAS  Google Scholar 

  2. Touyz RM, Schiffrin EL. Signal transduction mechanisms mediating the physiological and pathophysiological actions of angiotensin II in vascular smooth muscle cells. Pharmacol Rev. 2000;52:639–672.

    PubMed  CAS  Google Scholar 

  3. Dzau V. The cardiovascular continuum and renin-angiotensin-aldosterone system blockade. J Hypertens. 2005;23(suppl. y1):S9–S17.

    Article  CAS  Google Scholar 

  4. Singh VP, Le B, Khode R, Baker KM, Kumar R. Intracellular angiotensin II production in diabetic rats is correlated with cardiomyocyte apoptosis, oxidative stress, and cardiac fribrosis. Diabetes. 2008;57:3297–3306.

    Article  PubMed  CAS  Google Scholar 

  5. Gæde P, Vedel P, Larsen N, Jensen GVH, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348:383–393.

    Article  PubMed  Google Scholar 

  6. Gæde P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358:580–591.

    Article  PubMed  Google Scholar 

  7. ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370:829–840.

    Article  Google Scholar 

  8. 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. N Engl J Med. 2000;342;145–153.

    Article  PubMed  CAS  Google Scholar 

  9. Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet. 2000;355:253–259.

    Article  Google Scholar 

  10. UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ. 1998;317:713–720.

    Google Scholar 

  11. Holman RR, Paul SK, Bethel MA, Neil HA, Matthews DR. Long-term follow-up after tight control of blood pressure in type 2 diabetes. N Engl J Med. 2008;359:1565–1576.

    Article  PubMed  CAS  Google Scholar 

  12. Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford N, Schrier RW. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med. 1998;338:645–652.

    Article  PubMed  CAS  Google Scholar 

  13. Tatti P, Pahor M, Byington RP, et al. Outcome results of the Fosinopril versus Amlodipine Cardiovascular Events Randomized Trial (FACET) in patients with hypertension and NIDDM. Diabetes Care. 1998;21:597–603.

    Article  PubMed  CAS  Google Scholar 

  14. Hansson L, Lindholm LH, Niskanen L, et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet. 1999;353:611–616.

    Article  PubMed  CAS  Google Scholar 

  15. Niskanen L, Hedner T, Hansson L, Lanke J, Niklason A. Reduced cardiovascular morbidity and mortality in hypertensive diabetic patients on first-line therapy with an ACE inhibitor compared with a diuretic/beta-blocker-based treatment regimen: a subanalysis of the Captopril Prevention Project. Diabetes Care. 2001;24:2091–2096.

    Article  PubMed  CAS  Google Scholar 

  16. Hansson L, Lindholm LH, Ekbom T, et al. Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study. Lancet. 1999;354:1751–1756.

    Article  PubMed  CAS  Google Scholar 

  17. Dahlöf B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol. Lancet. 2002;359:995–1003.

    Article  PubMed  Google Scholar 

  18. Lindholm LH, Ibsen H, Dahlöf B, et al. Cardiovascular morbidity and mortality in patients with diabetes the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol. Lancet. 2002;359:1004–1010.

    Article  PubMed  CAS  Google Scholar 

  19. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting enzyme therapy on diabetic nephropathy. N Engl J Med. 1993;329:1456–1462.

    Article  PubMed  CAS  Google Scholar 

  20. Chaturvedi N, Sjolie AK, Stephenson JM, et al. Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. The EUCLID Study Group. EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus. Lancet. 1998;351:28–31.

    Article  PubMed  CAS  Google Scholar 

  21. Ruggenenti P, Fassi A, Ilieva AP, et al. Preventing microalbuminuria in type 2 diabetes. N Engl J Med. 2004;351:1941–1951.

    Article  PubMed  CAS  Google Scholar 

  22. Haller H, Ito S, Izzo JL Jr, et al. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med. 2011;364:907–917.

    Article  PubMed  CAS  Google Scholar 

  23. Parving HH, Lehnert H, Bröchner-Mortensen J, Gomis R, Andersen S, Arner P. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Eng J Med. 2001;345:870–878.

    Article  CAS  Google Scholar 

  24. Viberti G, Wheeldon NM. Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressure-independent effect. Circulation. 2002;106:672–678.

    Article  PubMed  CAS  Google Scholar 

  25. Brenner BM, Cooper ME, De Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Eng J Med. 2001;345:861–869.

    Article  CAS  Google Scholar 

  26. Lewis ED, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Eng J Med. 2001;345:851–860.

    Article  CAS  Google Scholar 

  27. The ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358:1547–1559.

    Article  Google Scholar 

  28. Turnbull F, Neal B, Algert C, et al. Effects of different blood pressure-lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively designed overviews of randomized trials. Arch Intern Med. 2005;165:1410–1419.

    Article  PubMed  Google Scholar 

  29. The ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362:1575–1585.

    Article  Google Scholar 

  30. Dahlöf B, Sever PS, Poulter NR, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet. 2005;366:895–906.

    Article  PubMed  Google Scholar 

  31. Ostergren J, Poulter NR, Sever PS, et al. The Anglo-Scandinavian Cardiac Outcomes Trial: blood pressure-lowering limb: effects in patients with type II diabetes. J Hypertens. 2008;26:2103–2111.

    Article  PubMed  Google Scholar 

  32. Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008;359:2417–2428.

    Article  PubMed  CAS  Google Scholar 

  33. Bakris GL, Sarafidis PA, Weir MR, 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;375:1173–1181.

    Article  PubMed  CAS  Google Scholar 

  34. Weber MA, Bakris GL, Jamerson K, et al. Cardiovascular events during differing hypertension therapies in patients with diabetes. J Am Coll Cardiol. 2010;56:77–85.

    Article  PubMed  CAS  Google Scholar 

  35. Krop M, Garrelds IM, de Bruin RJ, et al. Aliskiren accumulates in renin secretory granules and binds plasma prorenin. Hypertension. 2008;52:1076–1083.

    Article  PubMed  CAS  Google Scholar 

  36. Masson S, Solomon S, Angelici L, et al. Elevated plasma renin activity predicts adverse outcome in chronic heart failure, independently of pharmacologic therapy: data from the Valsartan Heart Failure Trial (Val-HeFT). J Card Fail. 2010;16:964–970.

    Article  PubMed  CAS  Google Scholar 

  37. Verma S, Gupta M, Holmes DT, et al. Plasma renin activity predicts cardiovascular mortality in the Heart Outcomes Prevention Evaluation (HOPE) study. Eur Heart J. 2011; Mar 17 [Epub ahead of print].

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

    Article  PubMed  CAS  Google Scholar 

  39. Taylor AA, Anderson DR, Arora V, et al. Antihypertensive efficacy of the direct renin inhibitor aliskiren in patients with diabetes: a pooled analysis of 10 randomized trials. Diabetes Care. 2007;30(suppl.):A 129

    Google Scholar 

  40. Doulton TWR, He FJ, MacGregor GA. Systematic review of combined angiotensin-converting enzyme inhibition and angiotensin receptor blockade in hypertension. Hypertension. 2005;45:880–886.

    Article  PubMed  CAS  Google Scholar 

  41. Kunz R, Friedrich C, Wolbers M, Mann JF. Metaanalysis: effect of monotherapy and combination therapy with inhibitors of the renin angiotensin system on proteinuria in renal disease. Ann Intern Med. 2008;148:30–48.

    PubMed  Google Scholar 

  42. Mann JF, Schmieder RE, McQueen M, et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet. 2008;372:547–553.

    Article  PubMed  CAS  Google Scholar 

  43. Uresin Y, Taylor AA, Kilo C, et al. Efficacy and safety of the direct renin inhibitor aliskiren and ramipril alone or in combination in patients with diabetes and hypertension. J Renin Angiotensin Aldosterone Syst. 2007;8:190–198.

    Article  PubMed  CAS  Google Scholar 

  44. 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;370:221–229.

    Article  PubMed  CAS  Google Scholar 

  45. Solomon SD, Appelbaum E, Manning WJ, 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;119:530–537.

    Article  PubMed  CAS  Google Scholar 

  46. Solomon SD, Shin SH, Shah H, et al. Effect of the direct renin inhibitor aliskiren on left ventricular remodelling following myocardial infarctions with systolic dysfunction. Eur Heart J. 2011;32:1227–1234.

    Article  PubMed  CAS  Google Scholar 

  47. 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;358:2433–2446.

    Article  PubMed  CAS  Google Scholar 

  48. Persson F, Rossing P, Reinhardt H, 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;32:1873–1879.

    Article  PubMed  CAS  Google Scholar 

  49. 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;33:2304–2309.

    Article  PubMed  Google Scholar 

  50. Parving HH, Brenner BM, McMurray JJ, et al. Aliskiren trial in type 2 diabetes using cardio-renal endpoints (ALTITUDE): rationale and study design. Nephrol Dial Transplant. 2009;24:1663–1669.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Hypertension Unit, Department of Internal Medicine, Hospital Mutua Terrassa, University of Barcelona, Plaza Dr. Robert, 5, 08021, Terrassa, Spain

    Alejandro de la Sierra

  2. Medical Affairs, Novartis Farmaceutica SA, Barcelona, Spain

    Jorge Salazar

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  1. Alejandro de la Sierra
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  2. Jorge Salazar
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Correspondence to Alejandro de la Sierra.

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de la Sierra, A., Salazar, J. What is the role of direct renin inhibitors in the treatment of the hypertensive diabetic patient?. Adv Therapy 28, 716–727 (2011). https://doi.org/10.1007/s12325-011-0049-6

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