New Drugs and Technologies
Should Angiotensin II Receptor Blockers
and Statins Be Combined?
Georg Nickenig, MD
C oronary heart disease (CHD) resulting from atheroscle-
rosis is the single largest killer in the Western world.
Approximately 40% of patients with hypertension have hy-
percholesterolemia, which is central to the pathogenesis of
atherosclerosis and cardiovascular disease (CVD).1 Con-
versely, hypertension is a significant risk factor in patients
with elevated cholesterol.2 There is strong synergy between
hypertension and hypercholesterolemia in terms of risk fac-
tors for the development of CVD.2 Both hypertension and
hypercholesterolemia result in endothelial dysfunction and
consequently the development of atherosclerosis. The recent
definition of the metabolic syndrome, characterized by hy-
pertension, elevated cholesterol and triglyceride levels, insu-
lin resistance/dyslipidemia, and central obesity, has brought
together these conditions with the notion that they are linked
and represent a cluster of factors that are synergistic for
CVD.3
The renin-angiotensin system (RAS) contributes impor-
tantly to a variety of CVDs and is the target of angiotensin-
converting enzyme (ACE) inhibitors and angiotensin receptor
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blockers (ARBs; Figure 1). RAS is an enzymatic cascade that
starts with the cleavage of angiotensinogen by renin to form
the inactive peptide angiotensin I. ACE is responsible for
converting the inactive angiotensin I to the active moiety
angiotensin II, which is the principle effector hormone of the
RAS and, through its action on angiotensin II receptors, plays
a critical role in maintaining arterial blood pressure (BP) and
fluid and electrolyte homeostasis. Although angiotensin II
binds to both type I (AT1) and type II (AT2) receptor subtypes,
the AT1 receptor mediates most of the cardiovascular effects
of angiotensin II, including oxidative stress, vasoconstriction,
aldosterone secretion, renal sodium resorption, sympathetic
stimulation, vasopressin release, cardiac and vascular cell
hypertrophy, and cell proliferation.4,5 ARBs act by blocking
the AT1 receptors with concomitant stimulation of AT2 and
thus, prevent the pathophysiological effects mediated by the
binding of angiotensin II to the AT1 receptor. In addition to
the crucial blockade of the AT1 receptor, facilitated stimula-
tion of AT2 receptors during ARB treatment could exert
additional benefit. Several experiments in animals have
shown that some of the vascular and myocardial improve-
ments seen during ARB treatment could be blocked by
Received February 24, 2004; revision received June 1, 2004; accepted June 7, 2004.
From the Department of Internal Medicine III, University Hospital of the Saarland, Homburg/Saar, Germany.
Correspondence to Prof Dr G. Nickenig, Klinik Innere Medizin III, Universitätskliniken des Saarlandes, 66421 Homburg/Saar, Germany. E-mail
nickenig@med-in.uni-saarland.de
(Circulation. 2004;110:1013-1020.)
© 2004 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
1013
additional application of an AT2 receptor inhibitor.6 Admit-
tedly, the relevance of these findings was never confirmed in
humans, because no AT2 receptor blocker is available that
could be administered in humans. The selective and potent
inhibition of angiotensin II by ARBs can prevent end-organ
damage from hypertension-associated diseases such as CHD,
atherosclerosis, and renal disease, and these effects appear to
be potentially independent of their BP-lowering effects
(VALsartan HEart Failure Trial [Val-HeFT] study group,7
Reduction in Endpoints in patients with Non–insulin-
dependent diabetes mellitus with the Angiotensin II Antago-
nist Losartan [RENAAL],8 Irbesartan in Diabetic Nephropa-
thy Trial [IDNT],9 Losartan Intervention For Endpoint
reduction in hypertension [LIFE] study group,10 Candesartan
cilexitil in Heart failure Assessment of Reduction Mortality
and morbidity [CHARM] study group,11 and VALsartan In
Acute myocardial iNfarction Trial [VALIANT]12). ARBs
have increasingly become part of the first line of treatment
against hypertensive diseases, with the more selective mode
of action of ARBs resulting in a better side-effect profile
compared with the ACE inhibitors. In addition, most of the
cited trials have revealed that ARB treatment decreases
new-onset diabetes. Besides other potential mechanisms (eg,
reduced gluconeogenesis, reduced catecholamine levels, and
increased muscle perfusion), direct, presumably AT1 recep-
tor–independent effects of ARBs leading to intracellular
activation of peroxisome proliferator–activated receptor-␥
(PPAR-␥), which is directly linked to an increase in insulin
sensitivity,13,14 could account for this well-established clinical
finding.
Hypercholesterolemia is recognized as a major risk factor
for the development and progression of CVDs.15 The
3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) re-
ductase inhibitors (statins) exert both direct and indirect
(cholesterol-lowering) effects on the vasculature. Statins have
been shown to significantly reduce cardiovascular mortality
and morbidity in patients at risk for CVD.16,17 Recent data
also suggest that statins may have direct effects on plaque
stability, nitric oxide (NO) metabolism, inflammation, endo-
thelial function, oxidative stress (Figure 2), thrombosis, and
stroke.17,18 Statins are increasingly prescribed as preventive
medicine for various cardiovascular risk factors, and more
DOI: 10.1161/01.CIR.0000139857.85424.45
 1014 Circulation August 24, 2004
Figure 1. Diagrammatic representation of RAS, showing site of
intervention with ARBs and ACE inhibitors. Abbreviations are as
defined in text.
recently, the metabolic syndrome has been identified as a
secondary target for lipid-lowering therapy by the National
Cholesterol Education Program Adult Treatment Panel
(NCEP ATP) III guidelines in the United States.
This article reviews the available evidence that pharmaco-
therapies targeting several risk factors can simultaneously
improve cardiovascular outcomes. The combination of ARBs
and statins as primary treatment may therefore provide a
greater degree of protection and control of these risk factors,
improving the vascular and general health of the patient.
The Link Between Hypercholesterolemia
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and Hypertension
Recent evidence points to the interplay between hypercholes-
terolemia and hypertension, acting through the RAS, to
increase cardiovascular risk.2,4,5 Both hypertension and hy-
percholesterolemia result in endothelial dysfunction and the
development of atherosclerosis. Increased levels of angioten-
sin II are correlated with hypertension, which is a major
trigger for endothelial dysfunction. ACE expression and
activity have been demonstrated to increase during athero-
Figure 2. Summary of role of cholesterol and hypercholesterol-
emia in hypertension and atherosclerosis. HMG-CoA reductase
inhibitors (statins) exert both direct and indirect (cholesterol-
lowering) effects on vasculature. Abbreviations are as defined
in text.
Figure 3. Hypercholesterolemia, diabetes, hypertension, and
heart failure result in release of angiotensin II, which acts on AT1
receptors. Activation of AT1 receptors stimulates NADH oxidase
in endothelial cells, resulting in generation of reactive oxygen
species in vascular cells and eventually, endothelial dysfunction.
Reactive oxygen species result in activation of redox-sensitive
genes that are proinflammatory and play critical roles in initia-
tion and progression of atherosclerosis, as well as reduced bio-
availability of NO in vascular wall, which appears to result from
increased oxygen free-radical generation and decreased NO
production.
sclerosis and hyperlipidemia.19 Oxidative stress has been
implicated in many pathophysiological conditions in the
cardiovascular system, including hypercholesterolemia, hy-
pertension, diabetes, and heart failure.20,21 Angiotensin II and
AT1 receptor activation stimulate NADPH oxidase, resulting
in the generation of reactive oxygen species in vascular cells
and eventually, endothelial dysfunction.4,5 Oxidative stress
results in activation of redox-sensitive genes that are proin-
flammatory and play a critical role in the initiation and
progression of atherosclerosis.4,5,21 Another potential mecha-
nism resulting in oxidative damage and endothelial dysfunc-
tion in both hypertension and hypercholesterolemia22 is
reduced bioavailability of NO in the vascular wall, which
appears to result from increased oxygen free-radical genera-
tion and decreased NO production.21 The bioavailability of
NO is probably impaired by mechanisms affecting both the
synthesis and breakdown of NO itself. The reduced bioavail-
ability of NO impairs endothelium-dependent vasodilation
and activates other mechanisms that play a role in the
pathogenesis of atherosclerosis.21 Blockade of AT1 receptors
by ARBs results in reduced oxidative stress and decreased
breakdown of NO, and conversely, increased bioavailability
of NO (see Figure 3).4,5 ARBs increase basal NO production
and release, independent of BP reduction, in essential hyper-
tension, suggesting that they can have favorable effects on
endothelial dysfunction,22–24 and have been shown to inhibit
the development of atherosclerotic lesions.
Hypercholesterolemia and elevated plasma concentrations
of LDL cholesterol are involved in the pathogeneses of
atherosclerosis,25,26 and hypercholesterolemic patients often
have hypertension. Angiotensin II increases lipid uptake in
cells and lipid accumulation in the vessel wall. LDL upregu-
lates expression of the AT1 receptor in cultured vascular
smooth muscle cells and in hypercholesterolemic rabbits.27–30
 Nickenig Rationale for Combining Sartans and Statins 1015

TABLE 1. Summary of Major Clinical Trials With ARBs

ARB Name of Trial No. of Subjects BP on Enrollment Duration of Trial Primary End Points
Losartan LIFE 9193 160–200/95–115 mm Hg 4 years Cardiovascular morbidity and death10
Losartan RENAAL 1513 152/82 mm Hg 3.4 years Composite end point of doubling serum creatinine
level, end-stage renal disease, or death8
Losartan ELITE II 3152 134/78 mm Hg 1.5 years All-cause mortality. (ELITE II)80
Valsartan Val-HeFT 5010 123⫾18/76⫾10 mm Hg 23 months All-cause mortality and a composite of mortality
and morbidity after congestive heart failure7
Valsartan MARVAL 332 ⬍180/105 mm Hg 24 weeks Percent change in elevated urine albumin excretion
from baseline to week 2446
Valsartan VALIANT 14500 Systolic ⬎100 mm Hg 6 years Survival after myocardial infarction and reduction
in cardiovascular events12
Irbesartan IDNT 1715 ⬍160/95 mm Hg 2.6 years Doubling of baseline serum creatinine
concentration, development of end-stage renal
disease, or death from any cause9
Candesartan CHARM 7601 131/77 mm Hg 2 years Cardiovascular mortality and a composite of
cardiovascular mortality and morbidity after
congestive heart failure11
ELITE II indicates Losartan Heart Failure Survival Study. Other acronyms as in text.

Angiotensin II–induced vasoconstriction and vascular oxygen
free-radical production were increased in these animals, and
this was associated with changes in endothelium-dependent
vasodilation. These changes were reversed by an ARB
without any concomitant changes in BP or LDL levels. The
increases in AT1 receptor expression in vascular smooth
muscles cells, demonstrated both in vivo and in vitro, could
be attenuated by statin treatment.28 Conversion of LDL to
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inflammatory cells into atheromatous areas.5,37 Inflammation
appears to play an important role in the pathogenesis of
hypertension and atherosclerosis via angiotensin II.40 There-
fore, the benefits seen in recent trials with ARBs may, at least
in part, be the result of their effect on arterial inflammation,
and the reduction in CVD morbidity and mortality may also
be the result of decreasing proinflammatory processes present
in patients with hypertension, atherosclerosis, or heart

oxidized LDL by reactive oxygen species is a key step in the
pathogenesis of atherosclerosis,31 and the different statins on
the market have been demonstrated to reduce the susceptibil-
ity of LDL to oxidation.32 Furthermore, upregulation of the
AT1 receptor has also been reported in hypercholesterolemic
men.28 These findings may also explain why hypercholester-
olemia is frequently associated with hypertension. Thus,
these studies suggest a strong link between hypercholesterol-
emia and hypertension mediated by stimulation of AT1
receptors and production of reactive oxygen species and
endothelial dysfunction.
Statins have also been demonstrated to have antioxidative
effects. Although the beneficial effects of statins have been
mainly attributed to their cholesterol-lowering properties,
there is growing evidence that some advantageous effects of
these agents are independent of plasma cholesterol levels.17,33
Recent studies have demonstrated that statins may prevent
angiotensin II–induced cellular and organ damage, such as
the production of oxygen free radicals in vascular smooth
muscle cells, cardiac hypertrophy, and end-organ
damage.18,34 –37
Recent studies have also suggested that angiotensin II may
act as a proinflammatory stimulus in addition to its vasocon-
strictive action. Angiotensin II has been shown to induce
profound inflammation in animal models, and this influence
is independent of the effect on BP.38 Angiotensin II and the
resulting oxidative stress activate stress genes and enzyme
pathways in vascular smooth muscle cells and monocytes.5,39
These result in an increase in the expression of adhesion
molecules, which in turn are involved in the movement of
failure.7,10 –12
Clinical Evidence for Combining ARBs
and Statins
Benefits of ARBs
Because angiotensin II is also synthesized in some tissues via
alternative pathways that do not involve ACE,41 inhibition of
the actions of the AT1 receptor by ARBs may result in a more
complete RAS blockade than by ACE inhibitors: Because
“ACE escape” is not allowed, there is a slow return of
angiotensin II to pretreatment levels seen with long-term use
of ACE inhibitors.6
The pharmacology of the ARBs has demonstrated that they
are highly selective, orally active AT1 receptor antagonists.
The sartans are as effective as other antihypertensive agents,
such as diuretics, calcium channel blockers, ␤-blockers, and
ACE inhibitors, but have a superior side-effect profile com-
pared with these other drugs.42,43 Numerous clinical trials
with ARBs have shown their effectiveness, not only in BP
control but also across the entire cardiovascular continuum
(see the summary [Table 1] of the major trials). Losartan was
shown to improve cardiovascular morbidity and mortality in
patients with isolated systolic hypertension and left ventric-
ular hypertrophy. In that study, losartan was compared with
atenolol and was shown to have better efficacy as well as
tolerability (LIFE study group),10 and a decrease in the onset
of diabetes in losartan-treated individuals compared with the
atenolol-treated group10 also was demonstrated. The superi-
ority of the ARB was especially evident in patients with
isolated systolic hypertension or diabetes.44,45 The heart
 1016 Circulation August 24, 2004

TABLE 2. Summary of Major Clinical Trials With Statins

Name of No. of Cholesterol Duration of Reduction
Statin Trial Subjects Level, mmol/L Trial in LDL Primary End Points
Simvastatin 4S 4444 5.5–8.0 5.4 years 35% Major coronary events, coronary mortality, and
total mortality49
Pravastatin WOSCOPS 6595 7.03 4.9 years 26% Coronary events leading to hospitalization and
cardiovascular mortality33
Pravastatin CARE 4159 5.4 5 years 28% Coronary death or nonfatal myocardial infarction50
Pravastatin LIPID 9014 4.0–7.0 6.1 years 25% Mortality from coronary heart disease, overall
mortality, myocardial infarction, stroke (LIPID
study group)51
Lovastatin AFCAPS/TexCAPS 6605 5.71 5.2 years 25% Major coronary event: myocardial infarction,
unstable angina, or sudden death53
Atorvastatin MIRACL 3086 3.2 16 weeks 40% Death, nonfatal myocardial infarction, cardiac
arrest, or recurrent symptomatic myocardial
ischemia55
Simvastatin HPS 20 536 3–5 5.5 years 29% Mortality and fatal or nonfatal vascular events56
Atorvastatin ASCOT 10 297 5.5 5 years 36% Nonfatal myocardial infarction and fatal coronary
heart disease61
WOSCOPS indicates West of Scotland COronary Prevention Study; CARE, Cholesterol And Recurrent Events; and LIPID, Long-term Intervention with Pravastatin in
Ischemic Disease. Other acronyms as in text.

failure trials (Val-HeFT7 and CHARM11) demonstrated a
reduction in the combined end point of mortality and mor-
bidity in patients with heart failure when an ARB was added
to their conventional therapy. Sartans have been shown to
have positive effects on left ventricular hypertrophy, endo-
thelial dysfunction, and atherosclerosis,10,22–24 suggesting that
ARBs not only protect target organs but also are very
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patients with ischemic heart disease (IHD), although with the
advent of many large clinical trials during the past 10 years,
their use has been extended to preventive treatment for a
variety of CVDs.
Results from the major clinical trials on statins are sum-
marized in Table 2. The megatrials on hypolipidemic therapy
demonstrated instances wherein there was an ⬇30% reduc-

effective in other areas of the cardiovascular system, such as
in blood vessels. ARBs have been shown to have protective
effects on the kidney (MicroAlbuminuria Reduction with
VALsartan [MARVAL], RENAAL, and IDNT).8,9,46 These
findings have led to the recommendation that ARBs should
be included in first-line therapy for the treatment of hyper-
tension in patients with type 2 diabetes and renal insuffi-
ciency. Thus, ARBs have been demonstrated to be highly
effective in slowing the progression of renal disease and
importantly, in preventing new-onset diabetes. These large-
scale, randomized, controlled clinical trials have demon-
strated that ARBs offer cardiovascular and renal protective
benefits in addition to their favorable effects on systemic BP.
ARBs are also associated with placebo-like tolerability and
long-term compliance. ARBs show a greater drug compliance
pattern at 1 year than any other class of antihypertensive
drug.47 An ongoing trial has been designed to show whether
ARBs evoke atheroprotective effects, as has been observed
with ACE inhibitors (ONgoing Telmisartan Alone and in
combination with Ramipril Global Endpoint Trial
[ONTARGET]).
Benefits of Statins
Statins reduce cholesterol synthesis by competitively inhibit-
ing the enzyme HMG-CoA reductase, which is responsible
for converting HMG-CoA to mevalonate, the rate-limiting
step in cholesterol biosynthesis.48 These lipid-lowering drugs
are most effective at decreasing LDL levels but also provide
some improvements in HDL cholesterol values. The statins
are usually used to treat hypercholesterolemia and to manage
tion in major coronary events, reduced coronary mortality,
and reduced total mortality, thus establishing without a doubt
that hypolipidemic therapy is safe and reduces morbidity and
mortality in hypercholesterolemic patients.33,49 –51 These stud-
ies also demonstrated that statin treatment could be used as
secondary preventive therapy in patients at risk of myocardial
infarction but with normal cholesterol levels. These 3 trials
demonstrated that statin therapy, besides showing excellent
benefit, was very well tolerated: Discontinuation rates due to
intolerable adverse effects were only ⬇1%.52 Primary pre-
vention trials such as the Air Force Coronary Atherosclerosis
Prevention Study/TEXas Coronary Atherosclerosis Preven-
tion Study (AFCAPS/TexCAPS)53 showed that statins could
reduce adverse cardiovascular events in patients with normal
or elevated cholesterol levels. Statins have been given to
⬎50 000 patients in clinical trials, and the conclusion is that
statin therapy is safe, with the most frequently observed
adverse effect being gastrointestinal disturbances. Occurrence
of myopathy and rhabdomyolysis with statins as mono-
therapy is uncommon, although with cerivastatin these prob-
lems did surface, but the important lesson was that careful
patient monitoring is always required with new formulations
and when drugs are combined.54
Besides lowering cholesterol levels, statins are known to
modify endothelial function and atherogenesis, stabilize ath-
erosclerotic plaques, and reduce inflammation and thrombus
formation. These pleiotropic properties of statins may have
important clinical implications in addition to lowering serum
cholesterol.17,18 The Myocardial Ischemia Reduction with
 Nickenig
Aggressive Cholesterol Lowering (MIRACL)55 trial demon-
strated a decrease in death, nonfatal myocardial infarction,
cardiac arrest, or recurrent symptomatic ischemia. The re-
cently conducted Heart Protection Study (HPS)56 demon-
strated reduced (by 18%) coronary mortality and a highly
significant reduction in total mortality. The ongoing trials
such as the Treating to New Targets (TNT) trial, Incremental
Decrease in Endpoints through Aggressive Lipid lowering
(IDEAL) trial, and Anglo-Scandinavian Cardiac Outcome
Trial (ASCOT) (see below) will test the hypothesis that
lowering LDL to ⬍2.6 mmol/L, which is the current guide-
line value for low risk, will provide additional benefits for
CHD risk reduction.57
Evidence for Combination Therapy
There is a strong rationale for combining an ARB with a
statin from the preclinical studies discussed earlier in this
article. More recently, Horiuchi et al58 tested whether statins
may enhance the effect of an ARB to improve vascular
remodeling in a mouse vascular injury model. They demon-
strated that a combination of low-dose valsartan and low-dose
fluvastatin acted synergistically to attenuate neointimal for-
mation at doses that were without effect when administered
alone and were devoid of any effects on BP or cholesterol
levels. There is also a limited clinical study demonstrating an
increase in AT1 receptor expression in hypercholesterolemic
men.28 In a comparison of 20 hypercholesterolemic versus 19
normocholesterolemic men, angiotensin II infusion produced
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a 2-fold increase in BP and a concomitant increase in AT1
receptor expression. Both of these effects could be blocked
with statin therapy. Hussein et al59 have also reported a
synergistic antioxidative effect of valsartan and fluvastatin
against LDL oxidation in a small group (n⫽21) of hypercho-
lesterolemic and hypertensive men. Statins have been dem-
onstrated to directly downregulate AT1 receptor expression in
isolated vascular smooth muscle cells and animal models.36,37
This mechanism may explain some of the cholesterol-
independent beneficial effects of statins and also answer why
giving a statin and an ARB could produce synergistic effects
against CVDs.
Nazzaro and coworkers60 studied 30 hypercholesterolemic
hypertensive subjects at rest and during stress to investigate
the effects of statins and ACE inhibition on vascular reactiv-
ity and vasodilative capacity. Simvastatin reduced total and
LDL cholesterol as expected. The ACE inhibitor enalapril
also reduced total cholesterol and LDL cholesterol, but there
was a greater lowering with combination therapy in both
cases. Thus, combination of a statin with antihypertensive
therapy demonstrated a significant additive effect on hyper-
cholesterolemia, structural vascular damage, BP, and vascular
resistance. These findings also suggest that ACE inhibitors
improve vascular reactivity and reduce structural damage in
hypercholesterolemic hypertensive subjects. Additional infor-
mation has been derived from a subgroup analysis of the
Heart Outcomes Prevention Evaluation (HOPE) study, indi-
cating that the beneficial effect of ACE inhibition was also
evident in patients with concomitant statin therapy.61 On the
other hand, a subgroup analysis from the HPS suggested that
Rationale for Combining Sartans and Statins 1017
the end-point reduction by statin therapy was equally detect-
able in patients treated with ACE inhibitors or not.61
At present, no trials have tested a combination of ARBs
with statins. However, post hoc analysis of the OPtimal Trial
In Myocardial infarction with the Angiotensin II Antagonist
Losartan (OPTIMAAL), in which patients after myocardial
infarction were treated with either captopril or losartan,
revealed that additional treatment with a statin resulted in a
marked reduction of death and subsequent myocardial infarc-
tion.62 One ongoing trial is testing the hypothesis that
reducing cholesterol (with statins) and BP (with ACE inhib-
itors plus calcium channel blockers vs ␤-blocker plus a
diuretic) may have a CVD preventive effect, regardless of
cholesterol diagnosis (ASCOT).63 The ASCOT is a multi-
center international trial that involves 2 treatment compari-
sons in a factorial design: a prospective, randomized, open,
blinded end-point design comparing 2 antihypertensive regi-
mens and a double-blind, placebo-controlled trial of a lipid-
lowering agent in a subsample of those hypertensive patients
(the lipid-lowering arm). The results from the lipid-lowering
arm of the ASCOT demonstrated that patients (n⫽10 297)
with high BP but moderate cholesterol levels (5.5 mmol/L)
who were taking atorvastatin had 36% fewer nonfatal myo-
cardial infarction and fatal CHD events compared with the
placebo group. The benefit of this treatment emerged almost
immediately, and other clinical end points that were signifi-
cantly reduced were fatal and nonfatal stroke (27%), total
coronary events (29%), and total cardiovascular events
(38%).
A recent article published by Wald and Law64 suggested
that taking a single combination pill (statin, thiazide,
␤-blocker, ACE inhibitor, folic acid, and aspirin) could
reduce the risk of CVD and the risk of stroke by ⬎80%. They
suggested that such a pill should be given to people with
vascular disease and all people older than 55 years, which is
a very bold claim, but their conclusion was based on a
systematic review and meta-analysis of 750 trials and
400 000 participants. Lowering cholesterol concentrations
that are ⬎4.0 mmol/L and of BP values that are ⬎140/
90 mm Hg will provide significant benefit as shown in the
ASCOT.63 Thus, these exciting conclusions suggest that the
combination of an ARB and a statin would potentially have
profound beneficial effects against CVD.
Who Would Benefit From Combined Therapy of
ARBs and Statins?
Accumulating evidence suggests that preventive medications
are a future trend in a growing population in whom longevity
is increasing. Thus, one can envisage that combination
therapy of an ARB and a statin would find utilization in
people with cardiovascular risk factors and provocatively,
also in people without symptomatic disease but who are ⬎55
years old, as age also becomes a risk factor for CVDs.
Patients presenting with 2 or more linked risk factors for
CVD would benefit from the combination of cholesterol
lowering and antihypertensive drug therapy (ie, patients with
hypertension, moderate cholesterol levels, the metabolic syn-
drome, type 2 diabetes, and a previous cardiovascular event
such as stroke or myocardial infarction). The patients in the
 1018 Circulation August 24, 2004
lipid-lowering arm of the ASCOT63 all had hypertension and
ⱖ3 other risk factors for CHD. Therefore, one could specu-
late that the combination of an ARB and a statin could be
given to any patient at risk of developing CVD. Some of the
important patient groups who may benefit from this therapy
are summarized below.
The Metabolic Syndrome
Type 2 diabetes and CVD have many risk factors in common,
and many of these risk factors are highly correlated with 1
another.65 The clustering of several of the metabolic and CVD
risk factors has been termed the metabolic syndrome. Meta-
bolic syndrome arises from a number of causes, including
predetermined genetic factors such as insulin resistance, as
well as acquired or lifestyle characteristics such as obesity,
physical inactivity, and high-carbohydrate diets (⬎60% total
calories). Dyslipidemia, which includes hypercholesterolemia
and hypertriglyceridemia, is associated with hypertension and
central obesity, all of which, together with insulin resistance,
constitute the metabolic syndrome.66 The components of the
metabolic syndrome are associated with insulin resistance,
disturbances of coagulation and fibrinolysis, endothelial dys-
function, and elevated markers of subclinical inflammation.
This syndrome is presumably a powerful determinant of
diabetes and CVD. The end product of the metabolic syn-
drome is atherosclerosis leading to CVD, myocardial infarc-
tion, stroke, peripheral arterial disease, and endothelial dys-
function. The prevalence of the metabolic syndrome is
increasing worldwide, with an estimated 20% to 25% of
American adults being affected.67 Their identification war-
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rants aggressive intervention to prevent type 2 diabetes,
progression of atherosclerosis, and CVD. Recently, the NCEP
ATP III recommended that statins be first-line therapy for
patients with high LDL levels, but this group also recognized
the need for combination therapy to treat total lipid profiles.
They also recommended aggressive treatment of any hyper-
tension present.68 The Joint National Committee VII recom-
mended appropriate drug therapy for each of the constituents
of the metabolic syndrome, including cholesterol-lowering
drugs and antihypertensive agents.69 Thus, combination of an
ARB and a statin would have great potential for use in the
metabolic syndrome.
Type 2 Diabetes
Type 2 diabetes increases the risk for hypertension and
associated CVDs. The worldwide prevalence of type 2
diabetes has exploded in recent years.70 The frequent associ-
ation of diabetes with dyslipidemia, hypertension, and endo-
thelial and metabolic abnormalities also aggravates the un-
derlying vascular disease process in patients who possess
these comorbid conditions. Diabetes is a predictor of athero-
sclerosis, and this is the main cause of morbidity and
mortality in these patients.71 Insulin induces AT1 receptor
overexpression.72 Clinical trials have shown that ARBs ef-
fectively reduce cardiovascular end points in hypertensive
diabetics and preserve renal function in diabetics with neph-
ropathy (LIFE,10 RENAAL,8 IDNT,9 and MARVAL46). The
American Diabetes Association recommends the use of st-
atins to treat dyslipidemia in patients with type 2 diabetes, as
well as the use of antihypertensives to a target BP goal of
130/80 mm Hg. Therefore, a combination of an ARB and a
statin could have beneficial effects in type 2 diabetes.
Stroke
Stroke is the third leading cause of death in the United States,
with ⬇750 000 new cases and 158 000 deaths each year, and
stroke is the leading cause of neurological disability in adults.
Hypertension is a major risk factor for stroke, and epidemi-
ological studies have confirmed a relation between hyperten-
sion and stroke.73 A meta-analysis of studies of antihyperten-
sives reported that a modest 5- to 6-mm Hg decrease in BP
resulted in a 42% reduction in stroke incidence.74 There is
convincing evidence that ACE inhibitors and especially
ARBs can significantly reduce the risk of stroke.10,75 The
LIFE trial was a primary stroke prevention study of losartan
in high-risk patients, and the investigators were able to
demonstrate a significant decrease in stroke (Table 1). Re-
cently, another ARB, candesartan, was demonstrated to
reduce stroke by 28% in the Study on COgnition and
Prognosis in the Elderly (SCOPE).76 This study focused on
elderly patients (70 to 89 years) with mild hypertension: A
significant reduction in stroke and a trend toward reduced
rates of new-onset diabetes were seen.
There is not a strong correlation between the risk of stroke
and cholesterol levels. However, clinical trials of statins in
patients with coronary artery disease have shown significant
stroke-preventive effects.77 Law et al77 performed a system-
atic review and meta-analysis of the statin trials and were able
to show that statins can lower LDL cholesterol concentrations
by an average of 1.8 mmol/L, which translates into a 60%
decrease in the risk of IHD and a 17% reduction in the risk of
stroke. Therefore, combination of an ARB and a statin may
have tremendous potential for the prevention of first stroke as
well as in poststroke patients.
Heart Failure
Recent studies have demonstrated a beneficial effect of ARBs
in heart failure.7,11,78 There is also evidence that statins are
beneficial in heart failure, as shown in a subgroup analysis
from the Scandinavian Simvastatin Survival Study (4S)
trial,49 and further ongoing trials are examining the effects of
statins in heart failure. Recent studies79,80 have demonstrated
direct effects of statins on the myocardium. Therefore,
patients at risk from heart failure would probably be ideal
candidates for combination therapy with an ARB and a statin.
Controlled Rosuvastatin Multinational Study in Heart Failure
(CORONA) is a long-term, randomized, double-blind,
placebo-controlled, multinational study that is evaluating the
effects of rosuvastatin on cardiovascular mortality and mor-
bidity and overall survival in 4950 patients aged 60 years or
greater with chronic symptomatic systolic heart failure
(NYHA class II–IV) of ischemic etiology who are receiving
standard treatment.80
Conclusions
Treatment of the multiple risk factors associated with ele-
vated BP and cholesterol with therapy that minimizes exces-
sive oxidative stress is critical to the maintenance of normal
endothelial cell function and a reduction in cardiovascular
morbidity and mortality.
 Nickenig
Statins reduce cholesterol, are atheroprotective, and im-
prove endothelial function. ARBs are effective in controlling
hypertension and associated CVD risks beyond BP lowering
by blocking the binding of angiotensin II to the AT1 receptor.
Therefore, further studies are warranted to confirm the
beneficial impact of ARBs and statins through their poten-
tially synergistic mode of action, which could represent a
potent and effective combination in a variety of patient
populations.
In this light, a combination of statins and ARBs in one pill
not only would be appealing with respect to the efficient
prevention of cardiovascular end points but also would
potentially increase treatment adherence in patients who have
been prescribed long-term polymedication therapy.
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KEY WORDS: receptors, angiotensin 䡲 statins 䡲 heart failure 䡲 cardiovascular
diseases 䡲 syndrome X