TcattthtdctmRdtiiAaTdtA

CI

s

C

0d

Renin–Angiotensin System Blockade and Cardiovascular andRenal Protection

Byron J. Hoogwerf, MD

The renin–angiotensin–aldosterone system (RAAS) plays an important role in the patho-genesis of a variety of clinical conditions, including atherosclerosis, hypertension, leftventricular hypertrophy, myocardial infarction, and heart failure. Inhibition of the RAASwith either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers(ARBs) has been shown to be effective in lowering blood pressure and reducing cardio-vascular mortality and morbidity in various at-risk patient populations. A number ofstudies have shown that these 2 classes are effective in reducing the rate of renal diseaseprogression in patients with diabetic nephropathy, although more long-term vascularoutcome studies are needed in patients with chronic kidney disease. The Ongoing Telm-isartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET)was the first study to show comparable reno- and cardioprotective effects between anARB (telmisartan) and ramipril in a broad section of at-risk patients, on top of usualstandard care. However, telmisartan showed better tolerability than ramipril in ONTAR-GET, with less cough and angioedema. This difference was obtained despite patientshaving been selected for tolerability to both drugs at study entry. © 2010 Elsevier Inc.

All rights reserved. (Am J Cardiol 2010;105[suppl]:30A–35A)

pathiEti

R

TvlpDwc5�(tc0wwpcaw

he renin–angiotensin–aldosterone system (RAAS) plays aentral role in the control of blood pressure, fluid volume,nd sodium balance, and overactivity of this system con-ributes to the pathogenesis of a variety of clinical condi-ions, including atherosclerosis, hypertension, left ven-ricular hypertrophy, myocardial infarction (MI), andeart failure.1 As a result, the RAAS represents a logicalherapeutic target in the management of hypertension, renalisease, and cardiovascular disease (CVD). Currently, 3lasses of RAAS-modulating drugs are available: (1) angio-ensin-converting enzyme (ACE) inhibitors block the for-ation of angiotensin II, the principal effector peptide of theAAS, (2) angiotensin receptor blockers (ARBs) block theeleterious effects of angiotensin II at the angiotensin IIype 1 receptor; and (3) aliskiren inhibits renin. ACE inhib-tors, ARBs, and aliskiren have been shown to be effectiven lowering elevated blood pressure.2–7 ACE inhibitors andRBs reduce renal disease risk and cardiovascular mortality

nd morbidity in various at-risk patient populations.1,4–7

he ACE inhibitor ramipril has been shown to reduce car-iovascular risk in the Heart Outcomes Prevention Evalua-ion (HOPE) study.8 However, it was not known whether anRB could match the cardioprotective profile of ramipril,

Department of Endocrinology, Diabetes, and Metabolism, Clevelandlinic, Cleveland, Ohio, USA; and Lilly USA, LLC, (Endocrinology),

ndianapolis, Indiana, USA.Statement of author disclosure: Please see the Author Disclosures

ection at the end of this article.This work was supported by Boehringer Ingelheim GmbH.Address for reprints: Byron J. Hoogwerf, MD, 2237 Demington Drive,

leveland Heights, Ohio 44106-3320.

mE-mail address: byronhoogwerf@gmail.com.

002-9149/10/$ – see front matter © 2010 Elsevier Inc. All rights reserved.oi:10.1016/j.amjcard.2009.10.009

articularly in high-risk patients, including those with renalnd heart disease. This article examines the cardioprotec-ive and renal protective effects of ARBs and ACE in-ibitors and considers the impact of the Ongoing Telm-sartan Alone and in Combination with Ramipril Globalndpoint Trial (ONTARGET), which compared the ARB

elmisartan with ramipril, on top of usual standard care,ncluding antihypertensive agents and statins.9

enal DiseaseDiabetic nephropathy as a cardiovascular risk factor:

he importance of diabetic nephropathy as a major cardio-ascular risk factor has been established by a number ofarge epidemiologic and interventional studies. For exam-le, in an analysis from the United Kingdom Prospectiveiabetes Study (UKPDS), which included 5,097 patientsith type 2 diabetes mellitus, the 10-year prevalence of mi-

roalbuminuria (defined as a urine albumin concentration of0–299 mg/L and a plasma creatinine concentration �175mol/L) was 24.9%, whereas that of macroalbuminuria

urine albumin �300 mg/L and plasma creatinine concen-ration �175 �mol/L) was 5.3% and that of elevated plasmareatinine (�175 �mol/L) or renal replacement therapy was.8%.10 The annual mortality rate increased progressivelyith the degree of nephropathy, from 1.4% in patientsithout nephropathy to 19.2% in those with elevatedlasma creatinine or renal replacement therapy, largely be-ause of an increasing risk of cardiovascular death. Thennual incidence of deaths from CVD was 0.7% in patientsithout nephropathy compared with 2.0% in those with

icroalbuminuria, 3.5% in those with macroalbuminuria,

www.AJConline.org

arpcim

vofcvmdadfTwqrt1rivfchc1n

toi

aiubtr5

dwEissptuRcr(

dictpw0h

tstr

Ff bumin-

31AHoogwerf/Renin–Angiotensin System Blockade and Cardiovascular and Renal Protection

nd 12.1% in those with elevated plasma creatinine or renaleplacement therapy (p �0.0001 for trend). Similarly, theroportion of all deaths that were attributable to CVD in-reased from 51% in patients without nephropathy to 66%n those with microalbuminuria and 75% in those withacroalbuminuria.10

An analysis of data from the HOPE study, which in-olved 3,498 patients with and 5,545 without diabetes, withbjective evidence of vascular disease, plus �1 other riskactor, showed that the relation between albuminuria andardiovascular risk is continuous and graded, both in indi-iduals with and without diabetes (Figure 1).11 After adjust-ent for other risk factors, the relative risk of major car-

iovascular events (cardiovascular death, MI, or stroke)ssociated with microalbuminuria was 1.83 (95% confi-ence interval [CI], 1.64–2.05), and that for hospitalizationor congestive heart failure was 3.23 (95% CI, 2.54–4.10).he relative risk of major cardiovascular events increasedith the degree of nephropathy. Compared with the lowestuartile of urinary albumin-to-creatinine ratio (UACR), theelative risks of major cardiovascular events in the second,hird, and fourth quartiles were 1.11 (95% CI, 0.95–1.30),.38 (95% CI, 1.19–1.60), and 1.97 (95% CI, 1.73–2.25),espectively (p �0.001 for trend); for every 0.4-mg/mmolncrease in the UACR, the adjusted risk of major cardio-ascular events increased by 5.9% (95% CI, 4.9–7.0%). Aurther analysis showed that the cumulative incidence ofardiovascular death, MI, or stroke was significantlyigher in patients with mild renal insufficiency (serumreatinine �124 �mol/L) than in those without (22.2% vs5.1%, p �0.001), and increased with the serum creati-ine concentration.12

Effects of RAAS inhibition on diabetic nephropa-hy: In a landmark study, Lewis et al13 compared the effectsf the ACE inhibitor captopril and placebo on renal function

igure 1. Incidence of cardiovascular events (cardiovascular death, myocailure) according to degree of albuminuria, expressed as deciles of the al

n 409 patients with type 1 diabetes and diabetic nephrop- �

thy (urinary protein excretion �500 mg/day; serum creat-nine �221 �mol/L). During a median of 3 years’ follow-p, the risk of a doubling of serum creatinine was reducedy 48% (95% CI, 16–69%; p � 0.007) among captopril-reated patients compared with the placebo group, and theisk of death, dialysis, or transplantation was reduced by0% (95% CI, 18–70%, p � 0.006).

In a further study, 94 normotensive patients with type 2iabetes and microalbuminuria (30–300 mg per 24 hours)ere treated with enalapril 10 mg or placebo for 5 years.14

nalapril treatment was associated with an initial decreasen albuminuria, which was followed by a slow increase,uch that urine albumin concentrations after 5 years wereimilar to those at the start of the study. By contrast, inlacebo-treated patients, albuminuria progressed throughouthe study, resulting in a significant (p �0.005) difference inrine albumin concentrations between the groups at 5 years.enal function, expressed as the mean reciprocal of serumreatinine, decreased by 13% in the placebo group andemained stable (mean change – 1%) in the enalapril groupp �0.05).

In the HOPE study, ramipril treatment significantly re-uced the high cardiovascular risk associated with renalmpairment.12 The hazard ratio for the combined risk ofardiovascular death, MI, or stroke in ramipril-treated pa-ients with renal insufficiency compared to placebo-treatedatients was 0.80 (95% CI, 0.59–1.09), whereas in patientsithout renal impairment, the corresponding figure was.79 (95% CI, 0.70–0.88, p �0.2 for heterogeneity ofazard ratios).12

Several studies have also investigated the effects of ARBherapy in patients with diabetic nephropathy. In the Irbe-artan Diabetic Nephropathy Trial (IDNT),15 1,715 hyper-ensive patients with type 2 diabetes and nephropathy (se-um creatinine, 106–265 �mol/L in men and 88–265

nfarction, stroke, all-cause mortality, hospitalization for congestive heartto-creatinine ratio. (Reprinted with permission from JAMA.11)

ardial i

mol/L in women) were randomized to receive irbesartan

3mocf0ohipep

ttpe�wAoc(SavatpTi3ttdssC

i(bsutTcgrI2mitso

sAVP5([tgp

trddboitet1fii

H

SpiPItdeac

tawtsrccw0pmctcg

32A The American Journal of Cardiology (www.AJConline.org) Vol 105 (1A) January 4, 2010

00 mg, amlodipine 10 mg, or placebo, and studied for aean of 2.6 years. Irbesartan significantly reduced the risk

f the primary end point (a composite of doubling of serumreatinine, development of end-stage renal disease, or deathrom any cause) compared with both amlodipine (p �.006) and placebo (p � 0.02), but had no effect on the riskf cardiovascular events (cardiovascular death, nonfatal MI,ospitalization for heart failure, permanent neurologic def-cit result from cerebrovascular disease, or lower limb am-utation above the ankle); however, the study was not ad-quately powered to detect significant changes in these endoints.

The Reduction of Endpoints in NIDDM with the Angio-ensin II Antagonist Losartan (RENAAL) study16 comparedhe effects of losartan 50–100 mg and placebo in 1,513atients with type 2 diabetes and nephropathy (defined as anarly morning UACR �300, or a urinary albumin excretion0.5 g/day and serum creatinine of 115–265 �mol/L) whoere already receiving standard antihypertensive therapy.gain, ARB therapy significantly reduced the progressionf nephropathy compared with placebo but had no signifi-ant effect on cardiovascular outcomes, except for a 32%p � 0.005) reduction in hospitalizations for heart failure.imilarly, in the Irbesartan in Patients with Type 2 Diabetesnd MicroAlbuminuria–2 (IRMA-2) study,17 which in-olved 590 patients with hypertension with type 2 diabetesnd microalbuminuria, ARB therapy significantly delayedhe development of diabetic nephropathy compared withlacebo, but it had no effect on cardiovascular outcomes.he incidence of nonfatal cardiovascular events was higher

n the placebo group than in the group receiving irbesartan00 mg (8.7% vs 4.5%), but the difference was not statis-ically significant (p � 0.11). It should be noted that none ofhese nephropathy trials using ARB therapy showed a re-uction in cardiovascular risk; however, none of them hadufficient numbers of subjects or study duration to haveufficient statistical power to demonstrate any benefit onVD outcomes.

The Incipient to Overt: Angiotensin II Blocker, Telm-sartan, Investigation on Type 2 Diabetic NephropathyINNOVATION) study was a randomized, multicenter, dou-le-blind, placebo-controlled study in which 527 normoten-ive and hypertensive Japanese patients with microalbumin-ria (UACR of 100�300 mg/g creatinine) were randomizedo telmisartan 40 mg or telmisartan 80 mg for 52 weeks.18

he transition to overt diabetic nephropathy was signifi-antly lower in the telmisartan 80 mg and telmisartan 40 mgroups compared with placebo (16.7% and 22.6% vs 49.9%,espectively; p �0.0001) over a 30-month follow-up period.n addition, 12.8% of the telmisartan 40 mg group and1.2% of the telmisartan 80 mg group also had microalbu-inuria remission (UACR �30 mg/g) compared with 1.2%

n the placebo group (p �0.001). In a post hoc analysis ofhe INNOVATION study, telmisartan 40 or 80 mg was alsohown to reduce the transition from microalbuminuria to

vert nephropathy compared with placebo in the normoten- i

ive patients (n � 163).19 Similar findings were observed inTrial to Compare Telmisartan 40 mg Titrated to 80 mg

ersus Losartan 100 mg in Hypertensive Type 2 Diabeticatients with Overt Nephropathy (AMADEO); a larger,2-week study of 860 patients with diabetic nephropathyserum creatinine �3 mg/dL [women] and �3.2 mg/dLmen]) and blood pressure �130/80 mm Hg.20 In this study,he reduction in the UACR from baseline was significantlyreater for telmisartan than losartan (Figure 2), despite com-arable reductions in blood pressure.

More recently, the ONTARGET trial, which was amonghe first large-scale trials to compare an ACE inhibitor withamipril in 25,620 high-risk patients, showed that the inci-ence of the primary renal outcome (a composite of dialysis,oubling of serum creatinine, and death) was comparableetween telmisartan and ramipril during a median follow-upf 56 months (13.4% vs 13.5%, respectively).20 The increasen urinary albumin excretion rate was significantly less withelmisartan than ramipril (p � 0.04) but the decrease in thestimated glomerular filtration rate was lower for ramipril thanelmisartan (�2.82 mL/min per 1.73 m2 vs �4.12 mL/min per.73 m2). However, the overall yearly estimated glomerularltration rate decrease in ONTARGET was �1 mL/yr, which

s the level observed in a healthy, age-matched population.21

eart Disease Risk

everal large trials, including the HOPE study,8 the Euro-ean Trial on Reduction of Cardiac Events with Perindopriln Stable Coronary Artery Disease (EUROPA),22 and therevention of Events with Angiotensin Converting Enzymenhibitors (PEACE) study,23 have shown that ACE inhibitorherapy significantly reduces the risk of coronary arteryisease (CAD) in various at-risk patient populations. How-ver, the available evidence suggests that combination ther-py with ACE inhibitors and ARBs may not offer signifi-ant benefits in this setting.

For example, the Valsartan in Acute Myocardial Infarc-ion Trial (VALIANT) compared the effects of captoprillone and in combination with valsartan in 14,703 patientsith acute MI.24 Although there were some questions about

he dosages of interventions used in the trial, there was noignificant difference in overall mortality between patientseceiving valsartan or captopril monotherapy and those re-eiving combination treatment. The hazard ratio for all-ause mortality in the combination therapy group comparedith the captopril monotherapy group was 0.98 (97.5% CI,.89–1.09; p � 0.73). Valsartan and captopril monothera-ies were found to be comparable in terms of all-causeortality and a composite end point of fatal and nonfatal

ardiovascular events. A subsequent analysis25 showed thathe incidence of MI was slightly lower in patients receivingombination therapy than in either of the monotherapyroups, although the difference was not statistically signif-

cant (p � 0.187 vs captopril).

swvwtichae(td

P

Psra1rp

CSatwopgiemdr0H

Rt5cnm0d

F( Kidney

33AHoogwerf/Renin–Angiotensin System Blockade and Cardiovascular and Renal Protection

Until ONTARGET was published, there were no largetudies on the effects of ARBs on CAD risk in patientsithout heart failure. In this trial, 25,620 patients withascular disease or high-risk diabetes without heart failureere randomized to treatment with telmisartan, ramipril, or

he combination.9 At a median follow-up of 56 months, thencidence of the primary composite end point (death fromardiovascular causes, MI, stroke, or hospitalization foreart failure) was comparable between telmisartan (16.7%)nd ramipril (16.5%). The occurrence of any heart failurevent was also comparable between telmisartan and ramipril6.7% vs 6.9%, respectively). ONTARGET also showed thathe combination of telmisartan and ramipril did not offer ad-itional benefits in terms of cardiovascular protection.

revention of Diabetes Mellitus

ost hoc analyses of both ACE inhibitor and ARB trialstrongly suggest that RAAS blockade is associated with aeduction in the incidence of new-onset diabetes. For ex-mple, in a recent systematic review that included data from3 studies involving approximately 67,000 patients, theelative risks for the development of new-onset diabetes in

igure 2. The change in the urinary protein-to-creatinine (UPC) ratio for tSD) at each time point over 52 weeks. (Reprinted with permission from

atients receiving ACE inhibitors or ARBs were 0.79 (95% s

I, 0.74–0.85) and 0.78 (95% CI, 0.73–0.84), respectively.imilar findings were obtained when the data were stratifiedccording to the antihypertensive therapy received by pa-ients in the control groups.26 In the HOPE study, ramiprilas associated with a 34% reduction in the risk of new-nset diabetes (relative risk, 0.66; 95% CI, 0.51–0.85;

�0.001) compared with placebo in all patient sub-roups.27 Importantly, a follow-up trial, HOPE–The Ongo-ng Outcomes (HOPE-TOO), showed that this protectiveffect was maintained during long-term follow-up for aean of 7.2 years (Figure 3).28 The relative risk for the

evelopment of new-onset diabetes among patients in theamipril group during this period was 0.66 (95% CI, 0.46–.95); the overall relative risk during both HOPE andOPE-TOO was 0.69 (95% CI, 0.56–0.86; p � 0.0006).The Diabetes Reduction Assessment with Ramipril and

osiglitazone Medication (DREAM) study29 investigatedhe effect of ramipril on the development of diabetes in,269 patients without CVD but with impaired fasting glu-ose or impaired glucose tolerance. Ramipril treatment hado significant impact on the risk of death or the develop-ent of diabetes, compared with placebo (hazard ratio,

.91; 95% CI, 0.81–1.03; p � 0.15) The DREAM study isiscussed in more detail in an article elsewhere in this

tan- and losartan-treated patients (p � 0.027). The values represent meanInt.20)

elmisar

upplement.30 In the ONTARGET trial, the development of

nt6wsatdpOadon

C

CAsopitrpfit

saotsis

A

WSBcCfwam

A

Tf

FO ed with

34A The American Journal of Cardiology (www.AJConline.org) Vol 105 (1A) January 4, 2010

ew-onset diabetes was largely comparable among the 3reatment groups: 6.7% (ramipril), 7.5% (telmisartan), and.1% (combination therapy).9 It is difficult to determinehether treatment in ONTARGET was associated with a

ignificant reduction in the risk of diabetes, given the lack ofplacebo arm. Further analysis of the baseline characteris-

ics may help to predict the likelihood of progression toiabetes and other overt conditions in such a high-riskopulation if aggressive treatment was not administered.NTARGET also indicates that the combination of an ARB

nd an ACE inhibitor was not associated with further re-uction in new-onset diabetes. Further studies of the effectsf ARBs and combination therapy on the development ofew-onset diabetes are currently under way.

onclusion

ardiovascular and renal benefits have been shown in bothRB and ACE inhibitor trials. A number of studies have

hown that these 2 classes are effective in reducing the ratef renal disease progression in patients with diabetic ne-hropathy, although more long-term vascular outcome stud-es are needed in patients with chronic kidney disease. Bothhe INNOVATION and AMADEO studies showed that theenoprotective effects achieved with telmisartan were inde-endent of blood pressure. ONTARGET is also among therst studies to show comparable renoprotective effects be-

igure 3. Kaplan-Meier plot of the risk of new-onset diabetes mellitus duringoing Outcomes (HOPE-TOO) extension study (p � 0.0006). (Reprint

ween an ARB (telmisartan) and ramipril on top of usual B

tandard care in a broad section of at-risk patients. Bothgents had a comparable effect on the composite primaryutcome, which is indicative of comparative cardioprotec-ive benefits, even in at-risk patients without heart failure attudy inclusion. However, further studies of ARBs and ACEnhibitors are still warranted in patients with metabolicyndrome and in the development of new-onset diabetes.

cknowledgment

riting and editorial assistance was provided by Michaelhaw, PhD, of PAREXEL MMS, which was contracted byoehringer Ingelheim for these services. The author(s) meetriteria for authorship as recommended by the Internationalommittee of Medical Journal Editors (ICMJE) and were

ully responsible for all content and editorial decisions, andere involved at all stages of manuscript development. The

uthors received no compensation related to the develop-ent of the manuscript.

uthor Disclosures

he author who contributed to this article has disclosed theollowing industry relationship:

Byron J. Hoogwerf, MD, has served as a consultant for

eart Outcomes Prevention Evaluation (HOPE) study and the HOPE–Thepermission from Circulation.29)

ng the H

oehringer Ingelheim.

1

1

1

1

1

1

1

1

1

1

2

2

2

2

2

2

2

2

2

2

3

35AHoogwerf/Renin–Angiotensin System Blockade and Cardiovascular and Renal Protection

1. Ferrario CM, Strawn WB. Role of the renin-angiotensin-aldosteronesystem and proinflammatory mediators in cardiovascular disease. Am JCardiol 2006;98:121–128.

2. Weir M, Bush C, Anderson D, Zhang J, Keefe D, Satlin A. Antihy-pertensive efficacy, safety, and tolerability of the oral direct renininhibitor aliskiren in patients with hypertension: a pooled analysis.J Am Soc Hypertens 2007;1:264–277.

3. Williams B, Poulter NR, Brown MJ, Davis M, McInnes GT, Potter JF,Sever PS, McG Thom S. Guidelines for the management of hyperten-sion: report of the fourth working party of the British HypertensionSociety, 2004 – BHS-IV. J Hum Hypertens 2004;18:139–185.

4. Pitt B. Clinical trials of angiotensin receptor blockers in heart failure:what do we know and what will we learn? Am J Hypertens 2002;15:22S–27S.

5. Kjeldsen SE, Julius S. Hypertension mega-trials with cardiovascularend points: effect of angiotensin-converting enzyme inhibitors andangiotensin receptor blockers. Am Heart J 2004;148:747–754.

6. Schmieder RE, Hilgers KF, Schlaich MP, Schmidt BM. Renin-angio-tensin system and cardiovascular risk. Lancet 2007;369:1208–1219.

7. Giles T. Renin-angiotensin system modulation for treatment and pre-vention of cardiovascular diseases: toward an optimal therapeuticstrategy. Rev Cardiovasc Med 2007;8(suppl 2):S14–S21.

8. The Heart Outcomes Prevention Evaluation Study Investigators. Ef-fects of an angiotensin-converting-enzyme inhibitor, ramipril, on car-diovascular events in high-risk patients. N Engl J Med 2000;342:145–153.

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

0. Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holma RR.Development and progression of nephropathy in type 2 diabetes: theUnited Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int2003;63:225–232.

1. Gerstein HC, Mann JFE, Yi Q, Zinman B, Dinneen SF, Hoogwerf B,Hallé JP, Young J, Rashkow A, Joyce C, Nawaz S, Yusuf S. Albu-minuria and risk of cardiovascular events, death, and heart failure indiabetic and nondiabetic individuals. JAMA 2001;286:421–426.

2. Mann JF, Gerstein HC, Pogue J, Bosch J, Yusuf S. Renal insufficiencyas a predictor of cardiovascular outcomes and the impact of ramipril:the HOPE randomized trial. Ann Intern Med 2001;134:629–636.

3. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angio-tensin-converting-enzyme inhibition on diabetic nephropathy. N EnglJ Med 1993;329:1456–1462.

4. Ravid M, Savin H, Jutrin I, Bental T, Lang R, Lishner M. Long-termeffect of ACE inhibition on development of nephropathy in diabetesmellitus type II. Kidney Int Suppl 1994;45:S161–S164.

5. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, RitzE, Atkins RC, Rohde R, Raz I. Renoprotective effect of the angioten-sin-receptor antagonist irbesartan in patients with nephropathy due totype 2 diabetes. N Engl J Med 2001;345:851–860.

6. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE,Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S. Effectsof losartan on renal and cardiovascular outcomes in patients with type2 diabetes and nephropathy. N Engl J Med 2001;345:861–869.

7. 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 Engl J Med2001;345:870–878.

8. Makino H, Haneda M, Babazono T, Moriya T, Ito S, Iwamoto Y,Kawamori R, Takeuchi M, Katayama S, for the INNOVATION StudyGroup. Prevention of transition from incipient to overt nephropathywith telmisartan in patients with type 2 diabetes. Diabetes Care 2007;30:1577–1578.

9. Makino H, Haneda M, Babazono T, Moriya T, Ito S, Iwamoto Y,Kawamori R, Takeuchi M, Katayama S, for the INNOVATION StudyGroup. Microalbuminuria reduction with telmisartan in normotensiveand hypertensive Japanese patients with type 2 diabetes: a post-hocanalysis of The Incipient to Overt: Angiotensin II Blocker, Telmisar-tan, Investigation on Type 2 Diabetic Nephropathy (INNOVATION)study. Hypertension Res 2008;31:657–664.

0. Bakris G, Burgess E, Weir M, Davidai G, Koval S, on behalf of theAMADEO Study Investigators. Telmisartan is more effective thanlosartan in reducing proteinuria in patients with diabetic nephropathy.Kidney Int 2008;74:364–369.

1. Mann JFE, Schmieder RE, McQueen M, Dyal L, Schumacher H, PoqueJ, Wang X, Maggioni A, Budaj A, Chaithiraphan S, et al, on behalf of theONTARGET investigators. Renal outcomes with telmisartan, ramipril, orboth, in people at high vascular risk (the ONTARGET study): a multi-centre, randomized, double-blind, controlled trial. Lancet 2008;372:547–553.

2. The EURopean trial On reduction of cardiac events with Perindopril instable coronary Artery disease Investigators. Efficacy of perindopril inreduction of cardiovascular events among patients with stable coronaryartery disease: randomised, double-blind, placebo-controlled, multi-centre trial (the EUROPA study). Lancet 2003;362:782–788.

3. The PEACE Trial Investigators. Angiotensin-converting-enzyme inhi-bition in stable coronary artery disease. N Engl J Med 2004;351:2058–2068.

4. Pfeffer MA, McMurray JJV, Velazquez EJ, Rouleau JL, Køber L,Maggioni AP, Solomon SD, Swedberg K, Van de Werf F, White H,et al. Valsartan, captopril, or both in myocardial infarction compli-cated by heart failure, left ventricular dysfunction, or both. N EnglJ Med 2003;349:1893–1906.

5. McMurray J, Solomon S, Pieper K, Reed S, Rouleau J, Velazquez E,White H, Howlett J, Swedberg K, Maggioni A, et al. The effect ofvalsartan, captopril, or both on atherosclerotic events after acute myo-cardial infarction: an analysis of the Valsartan in Acute MyocardialInfarction Trial (VALIANT). J Am Coll Cardiol 2006;47:726–733.

6. McCall KL, Craddock D, Edwards K. Effect of angiotensin-convertingenzyme inhibitors and angiotensin II type 1 receptor blockers on therate of new-onset diabetes mellitus: a review and pooled analysis.Pharmacotherapy 2006;26:1297–1306.

7. Yusuf S, Gerstein H, Hoogwerf B, Pogue J, Bosch J, WolffenbuttelBH, Zinman B. Ramipril and the development of diabetes. JAMA2001;286:1882–1885.

8. HOPE/HOPE-TOO Study Investigators. Long-term effects of ramiprilon cardiovascular events and on diabetes: results of the HOPE Studyextension. Circulation 2005;112:1339–1346.

9. The DREAM Trial Investigators. Effect of ramipril on the incidence ofdiabetes. N Engl J Med 2006;355:1551–1562.

0. Probstfield JL, O’Brien KD. Progression of cardiovascular damage:the role of renin–angiotensin system blockade. Am J Cardiol 2010;

(suppl 1A):10A–20A.