1. Renin–Angiotensin System Blockade and Cardiovascular and
Renal 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, left
ventricular hypertrophy, myocardial infarction, and heart failure. Inhibition of the RAAS
with 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 of
studies have shown that these 2 classes are effective in reducing the rate of renal disease
progression in patients with diabetic nephropathy, although more long-term vascular
outcome 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 an
ARB (telmisartan) and ramipril in a broad section of at-risk patients, on top of usual
standard care. However, telmisartan showed better tolerability than ramipril in ONTAR-
GET, with less cough and angioedema. This difference was obtained despite patients
having been selected for tolerability to both drugs at study entry. © 2010 Elsevier Inc.
All rights reserved. (Am J Cardiol 2010;105[suppl]:30A–35A)
The renin–angiotensin–aldosterone system (RAAS) plays a particularly in high-risk patients, including those with renal
central role in the control of blood pressure, fluid volume, and heart disease. This article examines the cardioprotec-
and sodium balance, and overactivity of this system con- tive and renal protective effects of ARBs and ACE in-
tributes to the pathogenesis of a variety of clinical condi- hibitors and considers the impact of the Ongoing Telm-
tions, including atherosclerosis, hypertension, left ven- isartan Alone and in Combination with Ramipril Global
tricular hypertrophy, myocardial infarction (MI), and Endpoint Trial (ONTARGET), which compared the ARB
heart failure.1 As a result, the RAAS represents a logical telmisartan with ramipril, on top of usual standard care,
therapeutic target in the management of hypertension, renal including antihypertensive agents and statins.9
disease, and cardiovascular disease (CVD). Currently, 3
classes of RAAS-modulating drugs are available: (1) angio-
tensin-converting enzyme (ACE) inhibitors block the for- Renal Disease
mation of angiotensin II, the principal effector peptide of the Diabetic nephropathy as a cardiovascular risk factor:
RAAS, (2) angiotensin receptor blockers (ARBs) block the The importance of diabetic nephropathy as a major cardio-
deleterious effects of angiotensin II at the angiotensin II vascular risk factor has been established by a number of
type 1 receptor; and (3) aliskiren inhibits renin. ACE inhib- large epidemiologic and interventional studies. For exam-
itors, ARBs, and aliskiren have been shown to be effective ple, in an analysis from the United Kingdom Prospective
in lowering elevated blood pressure.2–7 ACE inhibitors and Diabetes Study (UKPDS), which included 5,097 patients
ARBs reduce renal disease risk and cardiovascular mortality with type 2 diabetes mellitus, the 10-year prevalence of mi-
and morbidity in various at-risk patient populations.1,4 –7 croalbuminuria (defined as a urine albumin concentration of
The ACE inhibitor ramipril has been shown to reduce car- 50 –299 mg/L and a plasma creatinine concentration 175
diovascular risk in the Heart Outcomes Prevention Evalua- mol/L) was 24.9%, whereas that of macroalbuminuria
tion (HOPE) study.8 However, it was not known whether an (urine albumin 300 mg/L and plasma creatinine concen-
ARB could match the cardioprotective profile of ramipril, tration 175 mol/L) was 5.3% and that of elevated plasma
creatinine ( 175 mol/L) or renal replacement therapy was
Department of Endocrinology, Diabetes, and Metabolism, Cleveland 0.8%.10 The annual mortality rate increased progressively
Clinic, Cleveland, Ohio, USA; and Lilly USA, LLC, (Endocrinology), with the degree of nephropathy, from 1.4% in patients
Indianapolis, Indiana, USA. without nephropathy to 19.2% in those with elevated
Statement of author disclosure: Please see the Author Disclosures plasma creatinine or renal replacement therapy, largely be-
section at the end of this article. cause of an increasing risk of cardiovascular death. The
This work was supported by Boehringer Ingelheim GmbH.
Address for reprints: Byron J. Hoogwerf, MD, 2237 Demington Drive, annual incidence of deaths from CVD was 0.7% in patients
Cleveland Heights, Ohio 44106-3320. without nephropathy compared with 2.0% in those with
E-mail address: byronhoogwerf@gmail.com. microalbuminuria, 3.5% in those with macroalbuminuria,
0002-9149/10/$ – see front matter © 2010 Elsevier Inc. All rights reserved. www.AJConline.org
doi:10.1016/j.amjcard.2009.10.009

2. Hoogwerf/Renin–Angiotensin System Blockade and Cardiovascular and Renal Protection 31A
Figure 1. Incidence of cardiovascular events (cardiovascular death, myocardial infarction, stroke, all-cause mortality, hospitalization for congestive heart
failure) according to degree of albuminuria, expressed as deciles of the albumin-to-creatinine ratio. (Reprinted with permission from JAMA.11)
and 12.1% in those with elevated plasma creatinine or renal athy (urinary protein excretion 500 mg/day; serum creat-
replacement therapy (p 0.0001 for trend). Similarly, the inine 221 mol/L). During a median of 3 years’ follow-
proportion of all deaths that were attributable to CVD in- up, the risk of a doubling of serum creatinine was reduced
creased from 51% in patients without nephropathy to 66% by 48% (95% CI, 16 – 69%; p 0.007) among captopril-
in those with microalbuminuria and 75% in those with treated patients compared with the placebo group, and the
macroalbuminuria.10 risk of death, dialysis, or transplantation was reduced by
An analysis of data from the HOPE study, which in- 50% (95% CI, 18 –70%, p 0.006).
volved 3,498 patients with and 5,545 without diabetes, with In a further study, 94 normotensive patients with type 2
objective evidence of vascular disease, plus 1 other risk diabetes and microalbuminuria (30 –300 mg per 24 hours)
factor, showed that the relation between albuminuria and were treated with enalapril 10 mg or placebo for 5 years.14
cardiovascular risk is continuous and graded, both in indi- Enalapril treatment was associated with an initial decrease
viduals with and without diabetes (Figure 1).11 After adjust- in albuminuria, which was followed by a slow increase,
ment for other risk factors, the relative risk of major car- such that urine albumin concentrations after 5 years were
diovascular events (cardiovascular death, MI, or stroke) similar to those at the start of the study. By contrast, in
associated with microalbuminuria was 1.83 (95% confi- placebo-treated patients, albuminuria progressed throughout
dence interval [CI], 1.64 –2.05), and that for hospitalization the study, resulting in a significant (p 0.005) difference in
for congestive heart failure was 3.23 (95% CI, 2.54 – 4.10). urine albumin concentrations between the groups at 5 years.
The relative risk of major cardiovascular events increased Renal function, expressed as the mean reciprocal of serum
with the degree of nephropathy. Compared with the lowest creatinine, decreased by 13% in the placebo group and
quartile of urinary albumin-to-creatinine ratio (UACR), the remained stable (mean change – 1%) in the enalapril group
relative risks of major cardiovascular events in the second, (p 0.05).
third, and fourth quartiles were 1.11 (95% CI, 0.95–1.30), In the HOPE study, ramipril treatment significantly re-
1.38 (95% CI, 1.19 –1.60), and 1.97 (95% CI, 1.73–2.25), duced the high cardiovascular risk associated with renal
respectively (p 0.001 for trend); for every 0.4-mg/mmol impairment.12 The hazard ratio for the combined risk of
increase in the UACR, the adjusted risk of major cardio- cardiovascular death, MI, or stroke in ramipril-treated pa-
vascular events increased by 5.9% (95% CI, 4.9 –7.0%). A
tients with renal insufficiency compared to placebo-treated
further analysis showed that the cumulative incidence of
patients was 0.80 (95% CI, 0.59 –1.09), whereas in patients
cardiovascular death, MI, or stroke was significantly
without renal impairment, the corresponding figure was
higher in patients with mild renal insufficiency (serum
0.79 (95% CI, 0.70 – 0.88, p 0.2 for heterogeneity of
creatinine 124 mol/L) than in those without (22.2% vs
hazard ratios).12
15.1%, p 0.001), and increased with the serum creati-
Several studies have also investigated the effects of ARB
nine concentration.12
therapy in patients with diabetic nephropathy. In the Irbe-
Effects of RAAS inhibition on diabetic nephropa- sartan Diabetic Nephropathy Trial (IDNT),15 1,715 hyper-
thy: In a landmark study, Lewis et al13 compared the effects tensive patients with type 2 diabetes and nephropathy (se-
of the ACE inhibitor captopril and placebo on renal function rum creatinine, 106 –265 mol/L in men and 88 –265
in 409 patients with type 1 diabetes and diabetic nephrop- mol/L in women) were randomized to receive irbesartan

3. 32A The American Journal of Cardiology (www.AJConline.org) Vol 105 (1A) January 4, 2010
300 mg, amlodipine 10 mg, or placebo, and studied for a sive patients (n 163).19 Similar findings were observed in
mean of 2.6 years. Irbesartan significantly reduced the risk A Trial to Compare Telmisartan 40 mg Titrated to 80 mg
of the primary end point (a composite of doubling of serum Versus Losartan 100 mg in Hypertensive Type 2 Diabetic
creatinine, development of end-stage renal disease, or death Patients with Overt Nephropathy (AMADEO); a larger,
from any cause) compared with both amlodipine (p 52-week study of 860 patients with diabetic nephropathy
0.006) and placebo (p 0.02), but had no effect on the risk (serum creatinine 3 mg/dL [women] and 3.2 mg/dL
of cardiovascular events (cardiovascular death, nonfatal MI, [men]) and blood pressure 130/80 mm Hg.20 In this study,
hospitalization for heart failure, permanent neurologic def- the reduction in the UACR from baseline was significantly
icit result from cerebrovascular disease, or lower limb am- greater for telmisartan than losartan (Figure 2), despite com-
putation above the ankle); however, the study was not ad- parable reductions in blood pressure.
equately powered to detect significant changes in these end More recently, the ONTARGET trial, which was among
points. the first large-scale trials to compare an ACE inhibitor with
The Reduction of Endpoints in NIDDM with the Angio- ramipril in 25,620 high-risk patients, showed that the inci-
tensin II Antagonist Losartan (RENAAL) study16 compared dence of the primary renal outcome (a composite of dialysis,
the effects of losartan 50 –100 mg and placebo in 1,513 doubling of serum creatinine, and death) was comparable
patients with type 2 diabetes and nephropathy (defined as an between telmisartan and ramipril during a median follow-up
early morning UACR 300, or a urinary albumin excretion of 56 months (13.4% vs 13.5%, respectively).20 The increase
0.5 g/day and serum creatinine of 115–265 mol/L) who in urinary albumin excretion rate was significantly less with
were already receiving standard antihypertensive therapy. telmisartan than ramipril (p 0.04) but the decrease in the
Again, ARB therapy significantly reduced the progression estimated glomerular filtration rate was lower for ramipril than
of nephropathy compared with placebo but had no signifi- telmisartan ( 2.82 mL/min per 1.73 m2 vs 4.12 mL/min per
cant effect on cardiovascular outcomes, except for a 32% 1.73 m2). However, the overall yearly estimated glomerular
(p 0.005) reduction in hospitalizations for heart failure. filtration rate decrease in ONTARGET was 1 mL/yr, which
Similarly, in the Irbesartan in Patients with Type 2 Diabetes is the level observed in a healthy, age-matched population.21
and MicroAlbuminuria–2 (IRMA-2) study,17 which in-
volved 590 patients with hypertension with type 2 diabetes
and microalbuminuria, ARB therapy significantly delayed Heart Disease Risk
the development of diabetic nephropathy compared with
placebo, but it had no effect on cardiovascular outcomes. Several large trials, including the HOPE study,8 the Euro-
The incidence of nonfatal cardiovascular events was higher pean Trial on Reduction of Cardiac Events with Perindopril
in the placebo group than in the group receiving irbesartan in Stable Coronary Artery Disease (EUROPA),22 and the
300 mg (8.7% vs 4.5%), but the difference was not statis- Prevention of Events with Angiotensin Converting Enzyme
tically significant (p 0.11). It should be noted that none of Inhibitors (PEACE) study,23 have shown that ACE inhibitor
these nephropathy trials using ARB therapy showed a re- therapy significantly reduces the risk of coronary artery
duction in cardiovascular risk; however, none of them had disease (CAD) in various at-risk patient populations. How-
sufficient numbers of subjects or study duration to have ever, the available evidence suggests that combination ther-
sufficient statistical power to demonstrate any benefit on apy with ACE inhibitors and ARBs may not offer signifi-
CVD outcomes. cant benefits in this setting.
The Incipient to Overt: Angiotensin II Blocker, Telm- For example, the Valsartan in Acute Myocardial Infarc-
isartan, Investigation on Type 2 Diabetic Nephropathy tion Trial (VALIANT) compared the effects of captopril
(INNOVATION) study was a randomized, multicenter, dou- alone and in combination with valsartan in 14,703 patients
ble-blind, placebo-controlled study in which 527 normoten- with acute MI.24 Although there were some questions about
sive and hypertensive Japanese patients with microalbumin- the dosages of interventions used in the trial, there was no
uria (UACR of 100 300 mg/g creatinine) were randomized significant difference in overall mortality between patients
to telmisartan 40 mg or telmisartan 80 mg for 52 weeks.18 receiving valsartan or captopril monotherapy and those re-
The transition to overt diabetic nephropathy was signifi- ceiving combination treatment. The hazard ratio for all-
cantly lower in the telmisartan 80 mg and telmisartan 40 mg cause mortality in the combination therapy group compared
groups compared with placebo (16.7% and 22.6% vs 49.9%, with the captopril monotherapy group was 0.98 (97.5% CI,
respectively; p 0.0001) over a 30-month follow-up period. 0.89 –1.09; p 0.73). Valsartan and captopril monothera-
In addition, 12.8% of the telmisartan 40 mg group and pies were found to be comparable in terms of all-cause
21.2% of the telmisartan 80 mg group also had microalbu- mortality and a composite end point of fatal and nonfatal
minuria remission (UACR 30 mg/g) compared with 1.2% cardiovascular events. A subsequent analysis25 showed that
in the placebo group (p 0.001). In a post hoc analysis of the incidence of MI was slightly lower in patients receiving
the INNOVATION study, telmisartan 40 or 80 mg was also combination therapy than in either of the monotherapy
shown to reduce the transition from microalbuminuria to groups, although the difference was not statistically signif-
overt nephropathy compared with placebo in the normoten- icant (p 0.187 vs captopril).

4. Hoogwerf/Renin–Angiotensin System Blockade and Cardiovascular and Renal Protection 33A
Figure 2. The change in the urinary protein-to-creatinine (UPC) ratio for telmisartan- and losartan-treated patients (p 0.027). The values represent mean
(SD) at each time point over 52 weeks. (Reprinted with permission from Kidney Int.20)
Until ONTARGET was published, there were no large CI, 0.74 – 0.85) and 0.78 (95% CI, 0.73– 0.84), respectively.
studies on the effects of ARBs on CAD risk in patients Similar findings were obtained when the data were stratified
without heart failure. In this trial, 25,620 patients with according to the antihypertensive therapy received by pa-
vascular disease or high-risk diabetes without heart failure tients in the control groups.26 In the HOPE study, ramipril
were randomized to treatment with telmisartan, ramipril, or was associated with a 34% reduction in the risk of new-
the combination.9 At a median follow-up of 56 months, the onset diabetes (relative risk, 0.66; 95% CI, 0.51– 0.85;
incidence of the primary composite end point (death from p 0.001) compared with placebo in all patient sub-
cardiovascular causes, MI, stroke, or hospitalization for groups.27 Importantly, a follow-up trial, HOPE–The Ongo-
heart failure) was comparable between telmisartan (16.7%) ing Outcomes (HOPE-TOO), showed that this protective
and ramipril (16.5%). The occurrence of any heart failure effect was maintained during long-term follow-up for a
event was also comparable between telmisartan and ramipril mean of 7.2 years (Figure 3).28 The relative risk for the
(6.7% vs 6.9%, respectively). ONTARGET also showed that development of new-onset diabetes among patients in the
the combination of telmisartan and ramipril did not offer ad- ramipril group during this period was 0.66 (95% CI, 0.46 –
ditional benefits in terms of cardiovascular protection. 0.95); the overall relative risk during both HOPE and
HOPE-TOO was 0.69 (95% CI, 0.56 – 0.86; p 0.0006).
The Diabetes Reduction Assessment with Ramipril and
Prevention of Diabetes Mellitus Rosiglitazone Medication (DREAM) study29 investigated
the effect of ramipril on the development of diabetes in
Post hoc analyses of both ACE inhibitor and ARB trials 5,269 patients without CVD but with impaired fasting glu-
strongly suggest that RAAS blockade is associated with a cose or impaired glucose tolerance. Ramipril treatment had
reduction in the incidence of new-onset diabetes. For ex- no significant impact on the risk of death or the develop-
ample, in a recent systematic review that included data from ment of diabetes, compared with placebo (hazard ratio,
13 studies involving approximately 67,000 patients, the 0.91; 95% CI, 0.81–1.03; p 0.15) The DREAM study is
relative risks for the development of new-onset diabetes in discussed in more detail in an article elsewhere in this
patients receiving ACE inhibitors or ARBs were 0.79 (95% supplement.30 In the ONTARGET trial, the development of

5. 34A The American Journal of Cardiology (www.AJConline.org) Vol 105 (1A) January 4, 2010
Figure 3. Kaplan-Meier plot of the risk of new-onset diabetes mellitus during the Heart Outcomes Prevention Evaluation (HOPE) study and the HOPE–The
Ongoing Outcomes (HOPE-TOO) extension study (p 0.0006). (Reprinted with permission from Circulation.29)
new-onset diabetes was largely comparable among the 3 standard care in a broad section of at-risk patients. Both
treatment groups: 6.7% (ramipril), 7.5% (telmisartan), and agents had a comparable effect on the composite primary
6.1% (combination therapy).9 It is difficult to determine outcome, which is indicative of comparative cardioprotec-
whether treatment in ONTARGET was associated with a tive benefits, even in at-risk patients without heart failure at
significant reduction in the risk of diabetes, given the lack of study inclusion. However, further studies of ARBs and ACE
a placebo arm. Further analysis of the baseline characteris- inhibitors are still warranted in patients with metabolic
tics may help to predict the likelihood of progression to syndrome and in the development of new-onset diabetes.
diabetes and other overt conditions in such a high-risk
population if aggressive treatment was not administered.
ONTARGET also indicates that the combination of an ARB
Acknowledgment
and an ACE inhibitor was not associated with further re-
duction in new-onset diabetes. Further studies of the effects
Writing and editorial assistance was provided by Michael
of ARBs and combination therapy on the development of
new-onset diabetes are currently under way. Shaw, PhD, of PAREXEL MMS, which was contracted by
Boehringer Ingelheim for these services. The author(s) meet
criteria for authorship as recommended by the International
Committee of Medical Journal Editors (ICMJE) and were
Conclusion
fully responsible for all content and editorial decisions, and
were involved at all stages of manuscript development. The
Cardiovascular and renal benefits have been shown in both
authors received no compensation related to the develop-
ARB and ACE inhibitor trials. A number of studies have
ment of the manuscript.
shown that these 2 classes are effective in reducing the rate
of renal disease progression in patients with diabetic ne-
phropathy, although more long-term vascular outcome stud-
ies are needed in patients with chronic kidney disease. Both Author Disclosures
the INNOVATION and AMADEO studies showed that the
renoprotective effects achieved with telmisartan were inde- The author who contributed to this article has disclosed the
pendent of blood pressure. ONTARGET is also among the following industry relationship:
first studies to show comparable renoprotective effects be- Byron J. Hoogwerf, MD, has served as a consultant for
tween an ARB (telmisartan) and ramipril on top of usual Boehringer Ingelheim.

6. Hoogwerf/Renin–Angiotensin System Blockade and Cardiovascular and Renal Protection 35A
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