Pleiotropic Effects of Inhibitors of the RAAS in the Diabetic Population: Above and Beyond Blood Pressure Lowering Authors
First Online: 19 January 2010 DOI:
Cite this article as: Ismail, H., Mitchell, R., McFarlane, S.I. et al. Curr Diab Rep (2010) 10: 32. doi:10.1007/s11892-009-0081-y 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
Aliskiren Observation of Heart Failure Treatment
Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints
Aliskiren in the Evaluation of Proteinuria in Diabetes
Captopril Prevention Project
Heart Outcomes Prevention Evaluation
Microalbuminuria, Cardiovascular and Renal Outcomes
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
Dzau VJ: Theodore Cooper Lecture: tissue angiotensin and pathobiology of vascular disease: a unifying hypothesis. Hypertension 2001, 37:1047–1052.
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.
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.
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.
McFarlane SI, Banerji M, Sowers JR: Insulin resistance and cardiovascular disease. J Clin Endocrinol Metab 2001, 86:713–718.
McFarlane S: Role of angiotensin receptor blockers in diabetes: implications of recent clinical trials. Expert Rev Cardiovasc Ther 2009, 7:1363–1371.
Sowers JR, Bakris GL: Antihypertensive therapy and the risk of type 2 diabetes mellitus. N Engl J Med 2000, 342:969–970.
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.
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.
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.
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.
Kim S, Iwao H: Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol Rev 2000, 52:11–34.
•• 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
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.
• 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
• 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
Gavras H, Brunner HR: Role of angiotensin and its inhibition in hypertension, ischemic heart disease, and heart failure. Hypertension 2001, 37:342–345.
Griendling KK, Ushio-Fukai M, Lassegue B, et al.: Angiotensin II signaling in vascular smooth muscle: new concepts. Hypertension 1997, 29:366–373.
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.
Muller DN, Dechend R, Mervaala EM, et al.: NF-kappaB inhibition ameliorates angiotensin II-induced inflammatory damage in rats. Hypertension 2000, 35:193–201.
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.
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.
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.
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.
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.
Winer N, Weber MA, Sowers JR: The effect of antihypertensive drugs on vascular compliance. Curr Hypertens Rep 2001, 3:297–304.
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.
• 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
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.
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.
Agarwal R: Add-on angiotensin receptor blockade with maximized ACE inhibition. Kidney Int 2001, 59:2282–2289.
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.
Gradman AH, Kad R: Renin inhibition in hypertension. J Am Coll Cardiol 2008, 51:519–528.
• 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
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