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Current Hypertension Reports
Published in: Current Hypertension Reports 4/2011

01-08-2011

Antihypertensive Therapy in Diabetes: The Legacy Effect and RAAS Blockade

Authors: Massimo Volpe, Francesco Cosentino, Giuliano Tocci, Francesca Palano, Francesco Paneni

Published in: Current Hypertension Reports | Issue 4/2011

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Abstract

Two recently published post-monitoring follow-up studies of the United Kingdom Prospective Diabetes Study (UKPDS) have shown that although early and intensive treatment of hyperglycemia provides benefits for cardiovascular mortality that extend over time, the effects of a tight antihypertensive strategy in patients with diabetes did not seem to last during the following years. The authors concluded that blood pressure control is of crucial importance in patients with diabetes but is not protective against cardiovascular events when it is not sustained. Several lines of evidence suggest, however, that early and intensive antihypertensive treatment with some classes of drugs exerts benefits that may persist during the following years. Particularly, blockade of the renin-angiotensin-aldosterone system (RAAS) may interrupt the molecular and cellular mechanisms underlying cardiac and vascular remodeling and the maintenance of high blood pressure values. This review article critically discusses current evidence and explores the rationale for a legacy effect of RAAS blockade in hypertensive patients with diabetes.
Literature
1.
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837–853.
2.
••Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577–89. This is a post-trial monitoring follow-up of the UKPDS study, showing for the first time that early and intensive treatment of hyperglycemia provides sustained benefits in patients with type 2 diabetes. PubMedCrossRef
3.
•• 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;359:1565–76. This substudy of the UKPDS trial is a post-monitoring follow-up aimed at assessing whether benefits of an intensive blood pressure lowering strategy were maintained during the following years in hypertensive patients with type 2 diabetes. The authors found that intensive blood pressure lowering does not confer cardiovascular protection after switching to a conventional antihypertensive regimen. PubMedCrossRef
4.
Nathan DM, Cleary PA, Backlund JY, et al. Diabetes control and complications trial/epidemiology of diabetes interventions and complications (DCCT/EDIC) study research group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353:2643–53.PubMedCrossRef
5.
Cowie CC, Rust KF, Ford ES, et al. Full accounting of diabetes and pre-diabetes in the U.S. population in 1988–1994 and 2005–2006. Diabetes Care. 2009;32:287–94.PubMedCrossRef
6.
Hypertension in Diabetes Study (HDS). II. Increased risk of cardiovascular complications in hypertensive type 2 diabetic patients. J Hypertens. 1993;11:319–25.
7.
Ball SG. Benefits of blood pressure reduction in diabetic patients. J Hypertens Suppl. 2003;21:S31–6.PubMedCrossRef
8.
Vijan S, Hayward RA. Treatment of hypertension in type 2 diabetes mellitus: blood pressure goals, choice of agents, and setting priorities in diabetes care. Ann Intern Med. 2003;138:593–602.PubMed
9.
Sciarretta S, Paneni F, Palano F, et al. Role of the renin-angiotensin-aldosterone system and inflammatory processes in the development and progression of diastolic dysfunction. Clin Sci. 2009;116:467–77.PubMedCrossRef
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;342:145–53.PubMedCrossRef
11.
Sleight P, Redon J, Verdecchia P, et al. ONTARGET investigators. Prognostic value of blood pressure in patients with high vascular risk in the Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial study. J Hypertens. 2009;27:1360–9.PubMedCrossRef
12.
Patel A. 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;370:829–40.PubMedCrossRef
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.PubMedCrossRef
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;353:611–6.PubMedCrossRef
15.
Estacio RO, Jeffers BW, Hiatt WR, et al. 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;338:645–52.PubMedCrossRef
16.
Parving HH, Lehnert H, Bröchner-Mortensen J, Gomis R, Andersen S, Arner P. Irbesartan in patients with Type 2 diabetes and microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345:870–8.PubMedCrossRef
17.
Viberti G, Wheeldon NM. MicroAlbuminuria reduction with VALsartan (MARVAL) study investigators. Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressure-independent effect. Circulation. 2002;106:672–8.PubMedCrossRef
18.
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. RENAAL Study Investigators. N Engl J Med. 2001;345:861–9.PubMedCrossRef
19.
Heinig RE. What should the role of ACE inhibitors be in the treatment of diabetes? Lessons from HOPE and MICRO-HOPE. Diab Obes Metab. 2002;4 Suppl 1:S19–25.CrossRef
20.
Ruggenenti P, Fassi A, Ilieva AP, et al. Preventing microalbuminuria in type 2 diabetes. Bergamo nephrologic diabetes complications trial (BENEDICT) investigators. N Engl J Med. 2004;351:1941–51.PubMedCrossRef
21.
• Haller H, Ito S, Izzo JL, et al. Prevention of microalbuminuria in type 2 diabetes (Roadmap Trial): 6A.02. Oral presentation at the annual meeting of the European Society of Hypertension (Oslo, Norway, June 18–21, 2010). J Hypertens 2010;28:e233. The ROADMAP trial is a very recent study designed to ascertain whether treatment with olmesartan can prevent or delay the occurrence of microalbuminuria in patients with type 2 diabetes. The authors found that olmesartan was able to reduce microalbuminuria by 23% in 5,000 patients with hypertension and type 2 diabetes.
22.
Mancia G, De Backer G, Dominiczak A, et al. ESH-ESC practice guidelines for the management of arterial hypertension: ESH-ESC task force on the management of arterial hypertension. J Hypertens. 2007;25:1751–62.PubMedCrossRef
23.
Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Eur Heart J. 2007;28:88–136.
24.
Frustaci A, Kajstura J, Chimenti C, Jakoniuk I, Leri A, Maseri A, et al. Myocardial cell death in human diabetes. Circ Res. 2000;87:1123–32.PubMed
25.
Savoia C, Schiffrin EL. Vascular inflammation in hypertension and diabetes: molecular mechanisms and therapeutic interventions. Clin Sci. 2007;112:375–84.PubMedCrossRef
26.
Singh VP, Baker KM, Kumar R. Activation of the intracellular renin-angiotensin system in cardiac fibroblasts by high glucose: role in extracellular matrix production. Am J Physiol Heart Circ Physiol. 2008;294:H1675–84.PubMedCrossRef
27.
• McMurray JJ, Holman RR, Haffner SM, et al. NAVIGATOR Study Group. Effect of valsartan on the incidence of diabetes and cardiovascular events. N Engl J Med. 2010;362:1477–90. This trial clearly shows that RAAS antagonism prevents the development of diabetes in patients with impaired glucose tolerance and cardiovascular risk factors. These findings are in line with experimental evidence showing that RAAS hyperactivation impairs glucose metabolism and insulin sensitivity. PubMedCrossRef
28.
Elliott WJ, Meyer PM. Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis. Lancet. 2007;369:201–7.PubMedCrossRef
29.
Tocci G, Paneni F, Palano F, et al. Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and diabetes: a meta-analysis of placebo-controlled clinical trials. Am J Hypertens. 2011 Feb 17 (Epub ahead of print).
30.
Hsieh TJ, Fustier P, Zhang SL, et al. High glucose stimulates angiotensinogen gene expression and cell hypertrophy via activation of the hexosamine biosynthesis pathway in rat kidney proximal tubular cells. Endocrinology. 2003;144:4338–49.PubMedCrossRef
31.
Choi KC, Kim NH, An MR, Kang DG, Kim SW, Lee J. Alterations of intrarenal renin-angiotensin and nitric oxide systems in streptozotocin-induced diabetic rats. Kidney Int Suppl. 1997;60:S23–7.PubMed
32.
• Toma I, Kang JJ, Sipos A, et al. Succinate receptor GPR91 provides a direct link between high glucose levels and renin release in murine and rabbit kidney. J Clin Invest. 2008;118:2526–34. This study provide an additional mechanism by which hyperglycemia upregulates RAAS activity. In this investigation, the authors found that accumulation of succinate, a citric cycle intermediate, binds and activates the G-protein-coupled receptor GPR91, directly triggering the release of renin. PubMed
33.
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 fibrosis. Diabetes. 2008;57:3297–306.PubMedCrossRef
34.
Parving HH, Persson F, Lewis JB, Lewis EJ. AVOID Study Investigators. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med. 2008;358:2433–46.PubMedCrossRef
35.
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;24:1663–71.PubMedCrossRef
36.
Ichihara A, Sakoda M, Kurauchi-Mito A, et al. Possible roles of human (pro)renin receptor suggested by recent clinical and experimental findings. Hypertens Res. 2010;33:177–80.PubMedCrossRef
37.
Lavrentyev EN, Malik KU. High glucose-induced Nox1-derived superoxides downregulate PKC-betaII, which subsequently decreases ACE2 expression and ANG(1–7) formation in rat VSMCs. Am J Physiol Heart Circ Physiol. 2009;296:H106–18.PubMedCrossRef
38.
Reinemund J, Seidel K, Steckelings UM, et al. Poly(ADP-ribose) polymerase-1 (PARP-1) transcriptionally regulates angiotensin AT2 receptor (AT2R) and AT2R binding protein (ATBP) genes. Biochem Pharmacol. 2009;77:1795–805.PubMedCrossRef
39.
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 fibrosis. Diabetes. 2008;57:3297–306.PubMedCrossRef
40.
Creager MA, Lüscher TF, Cosentino F, Beckman JA. Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: Part I. Circulation. 2003;108:1527–32.PubMedCrossRef
41.
Rizzoni D, Porteri E, Boari GE, et al. Prognostic significance of small-artery structure in hypertension. Circulation. 2003;108:2230–5.PubMedCrossRef
42.
Izzard AS, Rizzoni D, Agabiti-Rosei E, Heagerty AM. Small artery structure and hypertension: adaptive changes and target organ damage. J Hypertens. 2005;23:247–50.PubMedCrossRef
43.
Rizzoni D, Porteri E, De Ciuceis C, et al. Effect of treatment with candesartan or enalapril on subcutaneous small artery structure in hypertensive patients with noninsulin-dependent diabetes mellitus. Hypertension. 2005;45:659–65.PubMedCrossRef
44.
Savoia C, Touyz RM, Endemann DH, et al. Angiotensin receptor blocker added to previous antihypertensive agents on arteries of diabetic hypertensive patients. Hypertension. 2006;48:271–7.PubMedCrossRef
45.
Kim SM, Chen L, Faulhaber-Walter R, et al. Regulation of renin secretion and expression in mice deficient in beta1- and beta2-adrenergic receptors. Hypertension. 2007;50:103–9.PubMedCrossRef
46.
• Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358:580–91. This trial demonstrates that in patients with type 2 diabetes, intensive intervention with multiple drug combinations and behavior modification has sustained beneficial effects on vascular complications and rates of death from any cause and from cardiovascular causes. These results highlight the importance of lifestyle changes and global cardiovascular risk reduction in the diabetic population. PubMedCrossRef
47.
• Lind M, Odén A, Fahlén M, Eliasson B. The shape of the metabolic memory of HbA1c: re-analysing the DCCT with respect to time-dependent effects. Diabetologia. 2010;53:1093–8. In this report, Lind et al. analyzed the impact of glycosylated hemoglobin and found that HbA1c still had an important impact on the development of microvascular complications for up to 8 years. In other words, this study demonstrates that initially high levels of HbA1c are a strong predictor of events even if normalization of such values is achieved in ensuing years. PubMedCrossRef
48.
• ACCORD Study Group, Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362:1575–85. In the ACCORD trial, diabetic patients achieving a BP target less than 120 mm Hg had an increased rate of myocardial infarction. These findings suggest that an intensive BP-lowering strategy may prove detrimental in diabetic patients. PubMedCrossRef
49.
Sleight P, Redon J, Verdecchia P, et al. ONTARGET investigators. Prognostic value of blood pressure in patients with high vascular risk in the Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial study. J Hypertens. 2009;27:1360–9.PubMedCrossRef
50.
Jamerson K, Weber MA, Bakris GL, et al. ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008;359:2417–28.PubMedCrossRef
Metadata
Title
Antihypertensive Therapy in Diabetes: The Legacy Effect and RAAS Blockade
Authors
Massimo Volpe
Francesco Cosentino
Giuliano Tocci
Francesca Palano
Francesco Paneni
Publication date
01-08-2011
Publisher
Current Science Inc.
Published in
Current Hypertension Reports / Issue 4/2011
Print ISSN: 1522-6417
Electronic ISSN: 1534-3111
DOI
https://doi.org/10.1007/s11906-011-0205-z

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