Current Diabetes Reports

, Volume 10, Issue 1, pp 32–36 | Cite as

Pleiotropic Effects of Inhibitors of the RAAS in the Diabetic Population: Above and Beyond Blood Pressure Lowering

  • Haisam Ismail
  • Rena Mitchell
  • Samy I. McFarlane
  • Amgad N. Makaryus
Article

Abstract

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are indispensable therapeutic agents for treating hypertension and proteinuria in patients with diabetes mellitus. Studies have shown that the renin-angiotensin-aldosterone system (RAAS) has effects on various organ systems, including the central nervous system, heart, and kidneys. Angiotensin II has major deleterious effects on vascular compliance, vascular relaxation, and plasma markers of inflammation, which are surrogate markers of cardiovascular disease. Evidence is established from major trials that ACE inhibitors and ARB therapy improve these surrogate markers and reduce cardiovascular disease, renal disease, and stroke. Accumulating evidence also supports the newer class of medication, the direct renin inhibitor aliskiren, as beneficial in hypertensive persons with diabetes mellitus. In this article, we review the mechanisms through which inhibitors of the RAAS benefit persons with hypertension and decrease the development of cardiovascular and renal disease above and beyond blood pressure lowering.

Keywords

Angiotensin-converting enzyme inhibitors Angiotensin receptor blockers Renin-angiotensin-aldosterone system Diabetes 

Clinical Trial Acronyms

ALLAY

Aliskiren Left Ventricular Assessment of Hypertrophy

ALOFT

Aliskiren Observation of Heart Failure Treatment

ALTITUDE

Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints

AVOID

Aliskiren in the Evaluation of Proteinuria in Diabetes

CAPPP

Captopril Prevention Project

HOPE

Heart Outcomes Prevention Evaluation

MICRO-HOPE

Microalbuminuria, Cardiovascular and Renal Outcomes

ONTARGET

Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial

References

Papers of particular interest, published recently, have been highlighted as: •Of importance ••Of major importance

  1. 1.
    Dzau VJ: Theodore Cooper Lecture: tissue angiotensin and pathobiology of vascular disease: a unifying hypothesis. Hypertension 2001, 37:1047–1052.PubMedGoogle Scholar
  2. 2.
    Ushio-Fukai M, Zafari AM, Fukui T, et al.: p22phox is a critical component of the superoxide-generating NADH/NADPH oxidase system and regulates angiotensin II-induced hypertrophy in vascular smooth muscle cells. J Biol Chem 1996, 271:23317–23321.CrossRefPubMedGoogle Scholar
  3. 3.
    Laursen JB, Rajagopalan S, Galis Z, et al.: Role of superoxide in angiotensin II-induced but not catecholamine-induced hypertension. Circulation 1997, 95:588–593.PubMedGoogle Scholar
  4. 4.
    McFarlane SI, Kumar A, Sowers JR: Mechanisms by which angiotensin converting enzyme inhibitors prevent diabetes and cardiovascular disease. Am J Cardiol 2003, 91:30H–37H.CrossRefPubMedGoogle Scholar
  5. 5.
    McFarlane SI, Banerji M, Sowers JR: Insulin resistance and cardiovascular disease. J Clin Endocrinol Metab 2001, 86:713–718.CrossRefPubMedGoogle Scholar
  6. 6.
    McFarlane S: Role of angiotensin receptor blockers in diabetes: implications of recent clinical trials. Expert Rev Cardiovasc Ther 2009, 7:1363–1371.CrossRefPubMedGoogle Scholar
  7. 7.
    Sowers JR, Bakris GL: Antihypertensive therapy and the risk of type 2 diabetes mellitus. N Engl J Med 2000, 342:969–970.CrossRefPubMedGoogle Scholar
  8. 8.
    Tuomilehto J, Lindstrom J, Eriksson JG, et al.: Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001, 344:1343–1350.CrossRefPubMedGoogle Scholar
  9. 9.
    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.CrossRefPubMedGoogle Scholar
  10. 10.
    Yusuf S, Sleight P, Pogue J, et al.: 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, 342:145–153.CrossRefPubMedGoogle Scholar
  11. 11.
    Lindholm LH, Ibsen H, Dahlof B, et al.: Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002, 359:1004–1010.CrossRefPubMedGoogle Scholar
  12. 12.
    Kim S, Iwao H: Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol Rev 2000, 52:11–34.PubMedGoogle Scholar
  13. 13.
    •• Makaryus AN, McFarlane SI: Treatment of hypertension in the diabetic patient. Therapy 2009, 6:497–505. This is an up-to-date review article on the different medications used to treat hypertension.CrossRefGoogle Scholar
  14. 14.
    Chobanian AV, Bakris GL, Black HR, et al.: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003, 289:2560–2572.CrossRefPubMedGoogle Scholar
  15. 15.
    • Mancia G, DeBaker G, Dominiczak A, et al.: 2007 Guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2007, 28:1462–1536. This is an up-to-date guideline statement on the treatment of hypertension from the European Society of Cardiology.PubMedGoogle Scholar
  16. 16.
    • Pimenta E, Oparil S: Role of aliskiren in cardio-renal protection and use in hypertensives with multiple risk factors. Ther Clin Risk Manag 2009, 5:459–464. This is a recent review article outlining recent studies on the benefits of aliskiren.PubMedGoogle Scholar
  17. 17.
    Gavras H, Brunner HR: Role of angiotensin and its inhibition in hypertension, ischemic heart disease, and heart failure. Hypertension 2001, 37:342–345.PubMedGoogle Scholar
  18. 18.
    Griendling KK, Ushio-Fukai M, Lassegue B, et al.: Angiotensin II signaling in vascular smooth muscle: new concepts. Hypertension 1997, 29:366–373.PubMedGoogle Scholar
  19. 19.
    Muller DN, Mervaala EM, Dechend R, et al.: Angiotensin II (AT(1)) receptor blockade reduces vascular tissue factor in angiotensin II-induced cardiac vasculopathy. Am J Pathol 2000, 157:111–122.PubMedGoogle Scholar
  20. 20.
    Muller DN, Dechend R, Mervaala EM, et al.: NF-kappaB inhibition ameliorates angiotensin II-induced inflammatory damage in rats. Hypertension 2000, 35:193–201.PubMedGoogle Scholar
  21. 21.
    Vaughan DE, Lazos SA, Tong K: Angiotensin II regulates the expression of plasminogen activator inhibitor-1 in cultured endothelial cells: a potential link between the renin-angiotensin system and thrombosis. J Clin Invest 1995, 95:995–1001.CrossRefPubMedGoogle Scholar
  22. 22.
    Chen YQ, Su M, Walia RR, et al.: Sp1 sites mediate activation of the plasminogen activator inhibitor-1 promoter by glucose in vascular smooth muscle cells. J Biol Chem 1998, 273:8225–8231.CrossRefPubMedGoogle Scholar
  23. 23.
    Schneiderman J, Sawdey MS, Keeton MR, et al.: Increased type plasminogen activator inhibitor gene expression in atherosclerotic human arteries. Proc Natl Acad Sci U S A 1992, 89:6998–7002. CrossRefPubMedGoogle Scholar
  24. 24.
    Hamsten A, de Faire U, Walldius G, et al.: Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 1987, 2:3–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Oikawa T, Freeman M, Lo W, et al.: Modulation of plasminogen activator inhibitor-1 in vivo: new mechanism for the anti-fibrotic effect of renin-angiotensin inhibition. Kidney Int 1997, 51:164–172.CrossRefPubMedGoogle Scholar
  26. 26.
    Winer N, Weber MA, Sowers JR: The effect of antihypertensive drugs on vascular compliance. Curr Hypertens Rep 2001, 3:297–304.CrossRefPubMedGoogle Scholar
  27. 27.
    London GM, Pannier B, Guerin AP, et al.: Cardiac hypertrophy, aortic compliance, peripheral resistance, and wave reflection in end-stage renal disease: comparative effects of ACE inhibition and calcium channel blockade. Circulation 1994, 90:2786–2796.PubMedGoogle Scholar
  28. 28.
    • Natali A, Pucci G, Boldrini B, et al.: Metabolic syndrome: at the crossroads of cardiorenal risk. J Nephrol 2009, 22:29–38. This is a recent article describing the effects of the cardiometabolic syndrome.PubMedGoogle Scholar
  29. 29.
    Lewis EJ, Hunsicker LG, Clarke WR, et al.: Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001, 345:851–860.CrossRefPubMedGoogle Scholar
  30. 30.
    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 Engl J Med 2001, 345:861–869.CrossRefPubMedGoogle Scholar
  31. 31.
    Agarwal R: Add-on angiotensin receptor blockade with maximized ACE inhibition. Kidney Int 2001, 59:2282–2289.PubMedGoogle Scholar
  32. 32.
    Mogensen CE, Neldam S, Tikkanen I, et al.: Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study. BMJ 2000, 321:1440–1444.CrossRefPubMedGoogle Scholar
  33. 33.
    Gradman AH, Kad R: Renin inhibition in hypertension. J Am Coll Cardiol 2008, 51:519–528.CrossRefPubMedGoogle Scholar
  34. 34.
    • Sanoski CA. Aliskiren: An oral direct renin inhibitor for the treatment of hypertension. Pharmacotherapy 2009, 29:193–212. This is a recent article outlining the pharmacotherapy of aliskiren.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Haisam Ismail
    • 1
  • Rena Mitchell
    • 2
  • Samy I. McFarlane
    • 2
  • Amgad N. Makaryus
    • 1
  1. 1.Department of CardiologyNorth Shore University HospitalManhassetUSA
  2. 2.State University of New York-Downstate Medical CenterBrooklynUSA

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