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Journal of the association of physicians of india • july 2013 • VOL. 61
Drug Corner
Angiotensin Receptor Blockers - Advantages of the
New Sartans
Zia Al Sabbah*, Aijaz Mansoor**, Upendra Kaul**
Abstract
Advantages of the new angiotensin receptor blockers (ARBs) include once daily dosing, an absence of significant
adverse reactions, well tolerated side effect profile and cost effectiveness. A growing realization is their beneficial
pleotropic effects. Antihypertensive agents are widely used to reduce the risk of cardiovascular events partly
beyond that of blood pressure-lowering. The RAAS, and its primary mediator Ang II, also have a direct influence
on the progression of the atherosclerotic process via effects on endothelial function, inflammation, fibrinolytic
balance, and plaque stability. For patients at high cardiovascular risk based on the results of the ONTARGET and
TRANSCEND studies, telmisartan is indicated for cardiovascular prevention. Studies have shown that olmesartan
medoxomil treatment may slow the progression of atherosclerosis and postpone albuminuria thereby potentially
improving CV outcomes.
T
he renin–angiotensin system (RAS) participates significantly
in the pathophysiology of hypertension, congestive heart
failure, myocardial infarction, and diabetic nephropathy. 1
Angiotensin (Ang) II, induces not only acute vasoconstriction
by binding mainly to the ang II type 1 receptor (AT 1) but
also promotes vascular growth and proliferation, acts as a
proinflammatory mediator and causes endothelial dysfunction,
leading to cardiovascular disease. 2 Research focused on blocking
the RAS led to the discovery of angiotensin-converting-enzyme
(ACE) inhibitors, which are effective in the treatment of
hypertension and heart failure but are associated with a high
frequency of cough and other adverse effects. AT-II-receptor
blockers (ARBs) were developed as agents that would more
completely block the RAS and decrease the adverse effects seen
with ACE inhibitors.
Although both classes of drugs (ACE inhibitors and ARBs)
block the RAS, they differ in several important aspects:
•
ACE inhibitors reduce the biosynthesis of Ang II by the
action of ACE, but do not inhibit alternative non-ACE Ang
II-generating pathways. ARBs block the actions of Ang II
via the AT1 receptor regardless of the biochemical pathway
leading to Ang II formation.
•
Unlike ACE inhibitors, ARBs allow activation of AT 2
receptors. 3 ARBs cause a several-fold increase in circulating
levels of Ang II. Because ARBs block AT1 receptors, this
increased level of Ang II is available to activate AT2
receptors. AT2 receptor activation is thought to have the
opposite effect of those mediated by the AT1 receptor, which
are beneficial to the cardiovascular system and help protect
target organs from damage.
•
ACE inhibitors increase the levels of a number of ACE
substrates, including bradykinin.
•
ACE inhibitors may increase Ang (1–7) levels more than
do ARBs. ACE is involved in the clearance of Ang (1–7), so
College of Medicine, King Khalid University, Abha Kingdom of
Saudi Arabia; **Fortis Escorts Heart Institute and Research Center,
New Delhi -110025
Received: 02.12.2011; Revised: 27.04.2012; Accepted: 28.05.2012
*
464
inhibition of ACE may increase Ang (1–7) levels more so
than do ARBs.
ACE is a relatively nonspecific enzyme that has substrates in
addition to angio I, including bradykinin and other tachykinins
and thus inhibition of ACE may result in accumulation of these
substrates. Production of angiotensin II can occur through
non-ACE pathways as well as through primary ACE pathway,
and these alternative pathways are unaffected by ACE inhibition.
(Figure1). Conversion of AT-I to AT-II is not the only pathway
for AT-II generation. AT-II is also formed via pathways involving
cathepsin G, elastase, tissue plasminogen activator, chymostatinsensitive AT-II-generating enzyme, and chymase.4 Thus, ACE
inhibition only partially reduces the formation of AT-II. Agents
that can specifically and selectively inhibit the action of AT-II
could completely block the RAS. Currently, two classes of
drugs have the mechanistic potential to completely block the
RAS: renin inhibitors and AT-II-receptor antagonists. ARBs
displace angiotensin II from the angiotensin I receptor and
produce their blood pressure lowering effects by antagonizing
angiotensin II actions (vasoconstriction, aldosterone release,
catecholamine release, arginine vasopressin release, water
intake and hypertrophic response. 5 ARBs down regulate
sympathetic adrenergic activity by blocking the effects of AT-II
on sympathetic nerve release and re-uptake of norepinephrine.
Although the ARBs have some structural and pharmacokinetic
differences, few pharmacological differences separate these
agents from one another. Two subtypes of AT-II receptors have
been identified. Type 1 receptors are predominantly found
on vascular endothelium and are linked to all the known
physiological and pharmacologic actions of AT-II. Stimulation of
type 1 receptors by AT-II induces vasoconstriction, renal tubular
sodium reabsorption, aldosterone release, vascular smooth
muscle remodeling, and stimulation of central and peripheral
sympathetic activity, thus leading to increases in blood volume
and blood pressure. Antagonism of type 1 receptors lowers
blood pressure by inhibiting these actions. Type II receptors are
predominantly found in the adrenal medulla, uterus, and fetal
tissue and may play a role in fetal growth and differentiation,
although the exact function of these receptors has not been
identified.6
© JAPI • july 2013 • VOL. 61
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Journal of the association of physicians of india • july 2013 • VOL. 61 There are eight ARBs currently on the market for hypertension
and in different cardiovascular indications, ie, losartan, valsartan,
candesartan, eprosartan, irbesartan telmisartan, olmesartan,
and azilsartan, All ARBs are approved for the treatment of
hypertension. In addition, irbesartan and losartan are approved
for diabetic nephropathy, losartan is approved for stroke
prophylaxis, and valsartan and candesartan are approved for
heart failure and to reduce cardiovascular mortality in clinically
stable patients with left ventricular failure or left ventricular
dysfunction following myocardial infarction. ARBs also
demonstrated effectiveness in preventing atheromas, decreasing
endothelial dysfunction, increasing fibrinolysis, reducing
proteinuria, and preserving kidney function in diabetic patients.7
Pharmacokinetics of various ARBs are depicted in Table 1. A
succinct discussion of the newer ARBs follows.
Telmisartan
Telmisartan is licensed for the treatment of essential
hypertension. Telmisartan, a nonpeptide AT-II-receptor
antagonist, gained FDA approval for use in the treatment of
hypertension in 1998. Peak plasma levels are obtained 0.5-1
hour after oral administration, and the plasma t1/2 is ~24 hours.
Oral bioavailability of ARBs generally is low (<50%, except for
irbesartan, with 70% available), and protein binding is high
(>90%). Telmisartan is cleared from the circulation mainly
by biliary secretion of intact drug. The plasma clearance of
telmisartan is affected by hepatic but not renal insufficiency.8 The
recommended oral dosage of telmisartan is 40-80 mg once daily.
When further blood pressure reduction is needed (beyond that
achieved with 80 mg/day), the addition of hydrochlorothiazide
has been found to produce incremental reductions. 9 Telmisartan
lowers systolic/diastolic blood pressure in patients with
hypertension by up to 12/9 mm Hg at 40 mg once daily, and
up to 13/10 mm Hg at 80 mg once daily. It is at least as effective
Fig. 1 : Renin-angiotensin-aldosterone system
Table 1 : Pharmacokinetic properties of the angiotensin II receptor blockers
F (%)
(bioavailability
Active
metabolite
Tmax (hr)
t ½ (hr)
Metabolism
(primary
pathway)
Elimination (%)
Food
interactions
Losartan
Valsartan
Irbesartan
Candesartan
Eprosartan
Telmisartan
33
10-35
60-80
15
13
42-58
Olmesartn
Medosomil
26
Yes
No
No
Yes
No
No
Yes
I (metabolite,3-4)
I (metabolite, 6-9)
2-4
6
1.5-2
11-15
3-4
3.5-4 (metabolite,
3-11)
1-2
5-9
No
Only 11%
biotransformed
CYP-2C9 and
3A4
Unknown
CYP 2C9
O-demethylation
Glucoronide
conjugation
Conjugation
1-3
12-18
(metabolite,
8-13)
De-eserifictation
20 renal,
80 biliary
No
33 renal,
67 biliary
No
35 renal,
10 renal,
60 bilary
>80 bilary
10%decrease in ~50% decrease in
bioavailability
AUC (NS)
7 renal,
>97 biliary
90 biliary
Delayed
6%-20% decrease
absorption (NS)
in
Bioavailability
None
Digoxin
8-12 renal,
biliary
No
Drug
Rifampin,
None
None
None
None
Interactions
fluconazole
(significant)
No change in
No change in
No change in Use with caution No change in
Dose in hepatic
Initial dosage
No change in
dose*
does*
does
does
impairment
dose*
Dose in renal
No change in
No change in
No change in
No change in
No change in
No change in
No change in
impairment
does
does
does
does
does
does
does
*
No change in dosage for mild to moderate hepatic dysfunction; exercise care in severe disease (no data available); No dosage adjustment necessary
unless the patient is volume-depleted. No change in dosage for mild to moderate renal dysfunction; exercise care in severe disease (no data available).
AUC= area under the curve; CYP = cytochrome P-450; F= bioavailability; t½ =elimination half-life; T max=time of maximum plasma concentration.
© JAPI • july 2013 • VOL. 61 465
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Journal of the association of physicians of india • july 2013 • VOL. 61
Table 2 : Important clinical trials of Telmisartan
Clinical Trial
Patient population
Design
Outcomes
Patients aged 35–80 years, with T2DM,
Telmisartan or enalapril on a background Equivalent reduction in the primary
DETAIL38
mild to moderate hypertension and early of antihypertensive treatment; mean/
endpoint of the change in the GFR from
nephropathy; n = 250
median follow-up not available
baseline during 5 years of treatment with
telmisartan vs enalapril
Patients aged 21–80 years, with T2DM,
Telmisartan or losartan on a background Significant reduction in the primary
AMADEO46
hypertension, or on antihypertensive
of antihypertensive treatment mean
endpoint of the difference in the urinary
drugs and overt nephropathy; n 860
follow-up 0.89 years
albumin to creatinine ratio from baseline
to week 52 with telmisartan vs losartan
despite similar BP reductions in the 2
groups
Patients aged 30–80 years, with T2DM,
Telmisartan or valsartan on a background Equivalent reductions in the primary
VIVALDI47
hypertension and overt nephropathy; n
of antihypertensive treatment mean/
endpoint of the change from baseline in
= 885
median follow-up not available
the 24-hour proteinuria after 12 months
for telmisartan and valsartan. Greater
renoprotection was seen in those patients
with better BP control
High-risk patients aged $55 years, with
Telmisartan-, ramipril- or telmisartan plus Telmisartan was equivalent to ramipril
ONTARGET39
coronary, peripheral, or cerebrovascular ramipril-based antihypertensive regimens; for the primary composite endpoint of
disease or diabetes with end-organ
median follow-up 4.7 years
CV death, MI, stroke, or hospitalization
damage; n 25,620
due to HF, but it was associated with
less angioedema and better treatment
adherence. The combination was
associated with more adverse events
without an increase in efficacy
Telmisartan regimen or placebo based
Equivalent reduction in the primary
TRANSCEND40 High-risk patients aged $55 years, with
coronary, peripheral, or cerebrovascular regimen (on a background of other
composite endpoint of CV death, MI,
disease or diabetes with end-organ
antihypertensive agents); median
stroke, or hospitalization for HF with
damage, and intolerant to ACE inhibitors; follow-up 4.7 years
telmisartan vs placebo. Significant
n 5926
reduction in the secondary composite
endpoint of CV death, MI, or stroke with
telmisartan (13%; HR 0.87) vs placebo
(14.8%)
as enalapril, lisinopril, and losartan in the treatment of mild to
moderate hypertension. Important clinical studies of telmisartan
are shown in Table 2.
Drug interactions : No interactions with drugs that inhibit
or are metabolized by CYP isoenzymes would be expected,
given that CYP isoenzymes are not involved in telmisartan’s
metabolism, with the possible exception of interference with
the metabolism of drugs metabolized by CYP2C19. When
telmisartan is administered with digoxin, peak and trough
plasma concentrations of digoxin are increased 49% and 20%,
respectively. When telmisartan is given with warfarin there is no
evidence of any change in the International Normalized Ratio.
Adverse events : The overall frequency of adverse events with
telmisartan 20-160 mg/ day was reported to be similar to that
with placebo. Rates of upper-respiratory-tract infection (7%),
dizziness (5%), back pain (3%), sinusitis (3%), and diarrhea (3%)
were similar to the rates for placebo (6%, 6%, 1%, 3%, and 2%,
respectively). The rate of cough with telmisartan (15.6%) was
comparable to that with placebo (9.6%) and significantly less
than with lisinopril (60%).9
Olmesartan Medoximil
In April 2002 the FDA approved Olmesartan medoxomil for
the treatment of hypertension. Olmesartan medoxomil, which is
administered as a prodrug, is rapidly and completely desterified
to the active metabolite olmesartan during absorption from the
gastrointestinal tract. Following the conversion of olmesartan
medoxomil to olmesartan, virtually no further metabolism
occurs. The bioavailability of olmesartan is approximately
26%, similar to that of losartan and valsartan. Following oral
466
administration, the peak plasma concentration (Cmax) of
olmesartan is reached after one to two hours. The bioavailability
of olmesartan is not affected by food.10,11 The plasma t1/2 is
between 10 and 15 hours. Plasma clearance of olmesartan is due
to both renal elimination and biliary excretion. Although renal
impairment and hepatic disease decrease the plasma clearance
of olmesartan, no dose adjustment is required in patients with
mild-to-moderate renal or hepatic impairment. The oral dosage
of olmesartan medoxomil is 20-40 mg once daily. If BP is not
controlled by olmesartan medoxomil alone, a diuretic may be
added.
Adverse Effects : Based on data from a number of studies,
patients have tolerated the drug well, and the incidence of
adverse events was similar to that for placebo (42.2% and 42.7%,
respectively.12-15 The most commonly reported side effects were
headache, upper respiratory tract infections, and influenza-like
symptoms. Dizziness was also frequently noted. Oparil et al16
found that the rate of dizziness associated with olmesartan
medoxomil (1.4%) was similar to the rates for losartan (0.7%),
valsartan (1.4%), and irbesartan (3.4%).. In clinical trials, the
incidence of cough was similar for olmesartan medoxomil (0.9%)
and placebo (0.7%).17 This rate is much lower than that reported
in users of the ACE inhibitors; in those patients, cough has been
noted to occur in up to 39% of cases.18 Angioedema has rarely
occurred with ARB therapy, although facial edema has been
reported in five patients receiving olmesartan medoxomil.17
Drug Interactions : Olmesartan medoxomil does not
appear to have any clinically relevant drug interactions. The
co-administration of antacids does not significantly alter its
bioavailability19 and no clinically significant drug interactions
have been reported with the co-administration of digoxin or
© JAPI • july 2013 • VOL. 61
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Journal of the association of physicians of india • july 2013 • VOL. 61 to 8 mm Hg. A higher dose of azilsartan (80 mg) was superior
to valsartan 320 mg or olmesartan 40 mg in lowering systolic
blood pressure in short-term studies. Additional blood pressure
reduction is expected when Azilsartan is used adjunctively
with a diuretic. Findings from recent studies suggest that
azilsartan medoxomil can lower 24-hour blood pressure more
effectively than maximally recommended doses of other ARBs.
Experimental studies in animals have revealed the pleotropic
effects of Azilsartan. like improvement in insulin sensitivity and
activation of PPAR gamma resulting in a favourable metabolic
profile. Azilsartan is well tolerated; the most common side effects
are headache and diarrhea. No cases of hyperkalemia have been
reported in 6-week clinical trials. Worsening of renal function
and hypotension should be monitored, particularly in those with
baseline risk factors. There is a lack of human data supporting the
use of Azilsartan for improvement in cardiovascular outcomes;
therefore, Azilsartan is not approved for indications other than
the treatment of hypertension.
warfarin.20 Because olmesartan medoxomil is not metabolized
by the cytochrome P-450 system, drugs that induce, inhibit, or
are metabolized by this enzyme do not appear to interact with it.
Clinical Efficacy : Seven placebo-controlled studies involved
2,693 patients with essential hypertension; 2,145 patients
received olmesartan medoxomil, and 548 patients received
placebo. Doses ranged from 2.5 to 80 mg once daily for six to12
weeks. Patient responses to olmesartan medoxomil were doserelated; doses of 20 mg daily produced an overall reduction
of sitting trough BP (the lowest measured BP with the patient
sitting) of about –10/6 mm Hg over placebo, and doses of 40 mg
daily produced an overall sitting trough BP reduction of about
–12/7 mm Hg over placebo. Doses greater than 40 mg did not
offer any additional effects. Various published and unpublished
comparative studies have also reported on the antihypertensive
efficacy of olmesartan medoxomil.21-25
Clinical trials of Olmesartan
Results from clinical trials suggest that olmesartan medoxomil
can be as effective as atenolol (Van Mieghem et al,26 Püchler et
al)27 and more effective than captopril (Williams et al),28 losartan
(Ball et al),29 valsartan and irbesartan (Oparil et al)30 in reducing
systolic or diastolic BP. Olmesartan for the Delay or Prevention
of Microalbuminuria in Type 2 Diabetes. (ROADMAP) is the
first large outcomes trial with olmesartan;31 it was conducted in
4447 patients with type 2 diabetes and one or more additional
cardiovascular risk factors, but no evidence of microalbuminuria.
Participants could have normal blood pressure or well-controlled
hypertension. The primary end point was a renal one, time to
onset of albuminuria. Patients were randomized to either 40 mg
of olmesartan (n=2232) or placebo (n=2215) daily and were all
allowed to take additional non-renin-angiotensin system (RAS)
antihypertensive medications to reach target BP (≤130/80 mm Hg),
until the predefined number of adjudicated microalbuminuria
events occurred at a median follow-up of 3.2 years. The average
baseline BP of participants was 137/80 mm Hg. The results show
there was a cumulative incidence of microalbuminuria of 8.2%
with olmesartan and 9.8% with placebo; the primary end point,
time to onset of microalbuminuria, was delayed by 23% with
olmesartan (hazard ratio 0.77, p=0.01), with the majority of this
effect being BP. The higher rate of fatal cardiovascular events
with olmesartan among patients with preexisting coronary heart
disease was noted (15 patients (0.7%) in the olmesartan group as
compared with 3 patients (0.1%) (P=0.01) in the placebo group.
This excess mortality in the olmesartan group prompted an FDA
safety review which is ongoing, and so far, FDA has determined
that the benefits of olmesartan continue to outweigh its potential
risks when used for the treatment of patients with high blood
pressure according to the drug label.
Advantages of the Newer ‘Sartans’
Advantages of these drugs include once daily dosing, an
absence of significant adverse reactions, well tolerated side
effect profile and cost effectiveness. A growing realization is
their beneficial pleotropic effects. ARBs are better tolerated
than ACE inhibitors and other antihypertensive agents in both
the short term and the long term. This is an important benefit,
because hypertension is often asymptomatic, making long-term
treatment adherence a challenge. None of the ARBs interact with
food, which makes oral administration very easy.
The newer agents, Telmisartan, and Olmesartan have longer
half-lives and durations of action than the older agents losartan
and Valsartan. Twenty-four–hour blood pressure control could
be more readily achievable with the newer agents. ARBs are
often used in patients who are intolerant of ACE inhibitors
due to the development of cough or angioedema, or in those
who are at a high risk of developing either of these side effects.
Patients over 60 years, females, those of east-Asian ethnicity and
smokers are at increased risk of cough, and patients of AfricanAmerican ethnicity, smokers, or those patients with a history
of ACE inhibitor cough are at increased risk of angioedema.33
Studies in hypertensive patients have shown consistently that
Telmisartan improves insulin sensitivity and lipid profiles.34
Telmisartan has been demonstrated to improve markers of
glycemic control, such as glycosylated hemoglobin, in patients
with type 2 diabetes.35 Telmisartan is the only ARB shown to be
able to activate PPAR (peroxisome proliferator-activated receptor
gamma) at therapeutic dosages,36 and in general, Telmisartan
produces greater beneficial effects on glucose metabolism than
the other ARBs.
Azilsartan
Clinical evidence for improvements in endothelial function
with Telmisartan is provided by the Telmisartan versus
Ramipril in renal ENdothelial DYsfunction (TRENDY) study.37
In the TRENDY® study, Telmisartan not only improved renal
endothelial function in patients with type 2 diabetes but
also preserved renal function. In comparison with Ramipril,
Telmisartan significantly improved resting renal plasma
flow, renal vascular resistance, and lowered albuminuria. The
Diabetics Exposed to Telmisartan And enalaprIL (DETAIL)
study38 showed the long-term benefit of Telmisartan in patients
with type 2 diabetes and either micro- or macroalbuminuria. GR
rate of decline was markedly reduced.
It is the latest ARB to be approved for hypertension.32 The
key points of Azilsartan are its potency, its ability of sustained
blood pressure control over a 24- hour period, and experimental
evidence of favorable pleotropic cardioprotective effects.
azilsartan medoxomil at a dose of 40 mg or 80 mg once daily
showed greater efficacy (about 10% in absolute rate) than a
320 mg dose of valsartan, the highest approved dose for this
drug. Azilsartan is a prodrug that is quickly hydrolyzed to
the active moiety azilsartan, a potent and highly selective ARB
with estimated bioavailability of 60% and elimination half-life
of 12 hours. At the approved dosage, it reduces systolic blood
pressure by 12 to 15 mm Hg and diastolic blood pressure by 7
© JAPI • july 2013 • VOL. 61 On the basis of the ONTARGET results, 39 Telmisartan
467
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Journal of the association of physicians of india • july 2013 • VOL. 61
is proven to have cardiovascular protective effects. The
ONTARGET study in patients at high risk of cardiovascular
events showed that Telmisartan was non-inferior, as defined by
pre-specified boundaries, to the ACEi ramipril given at the same
dose as had been proven to be beneficial in the HOPE study. It
is as effective as ramipril but is associated with less angioedema
and cough. In the TRANSCEND40 study, Telmisartan was well
tolerated among patients who were unable to tolerate ACE
inhibitors and their was a significant reduction in the risk of
the composite outcomes of cardiovascular death, myocardial
infarction, or stroke by 13%.
There is substantial evidence supporting the hypothesis that
Ang II plays a significant role in the initiation and progression of
atherogenesis,41 with endothelial dysfunction a hallmark of early
event in atherogenesis. Data from the Olmesartan medoxomil
clinical trials OLIVUS,42 EUTOPIA,43 VIOS,44 and MORE45 have
demonstrated the specific utility of RAAS suppression in reducing
atherosclerotic plaque volume, improving plaque composition
and stability, and in improving endothelial dysfunction. These
studies have shown that Olmesartan medoxomil treatment may
slow the progression of atherosclerosis, thereby potentially
improving CV outcomes.
The currently available ARBs have demonstrated their
differential efficacy along the cardiovascular and renal disease
continua. For patients at high cardiovascular risk based on
the results of the ONTARGET and TRANSCEND studies,
Telmisartan is indicated for cardiovascular prevention beyond
that of blood pressure-lowering alone.
Combination Therapy
Combination therapy is an effective strategy to increase
antihypertensive efficacy in those patients with poor blood
pressure (BP) control. A calcium channel blocker (CCB)/
angiotensin receptor blocker (ARB) combination is a rational
approach for such an antihypertensive strategy. The ARBs
confer stroke protection, renal protection, and tolerability similar
to placebo, without dose-related symptomatic and metabolic
AEs, while CCBs are beneficial in reducing stroke and treating
angina and cardiac ischemia. The antihypertensive efficacy
of combinations of once-daily oral amlodipine and valsartan
(administered as separate agents or as amlodipine/valsartan)
has been demonstrated in several large, randomized, doubleblind clinical trials of 8-16 weeks’ duration; BP reductions were
maintained for approximately 1 year in open-label extensions of
some of these studies. Combination therapy was more effective
than amlodipine or valsartan monotherapy in reducing BP in
patients with mild to moderate hypertension, and more effective
than amlodipine monotherapy in reducing BP in patients with
moderate to severe (stage 2) hypertension.
CREATE (Heart Institute of Japan Candesartan Randomized Trial
for Evaluation in Coronary Artery Disease) was a randomized,
double-blind, placebo-controlled study; data from 1025 patients
with CAD and hypertension and an eCrCl less than 60 ml/min
were included in the subanalysis.46 Patients were randomized to
candesartan 4 mg to 12 mg daily or placebo and followed for an
average of 4.2 years. The primary CV outcome was the composite
of CV death, nonfatal MI, unstable angina, heart failure, stroke,
and CV events requiring hospitalization. An 11% lower rate
in the composite CV outcome was observed with candesartan
versus placebo. There was also a lower rate of hospitalization
for unstable angina in patients with CKD given candesartan
compared with those given placebo. In IDNT study, irbesartan
was renoprotective independently of its BP lowering effect in
patients with NIDDM and microalbuminuria.47 In RENAAL
study 48 (losartan vs placebo) losartan conferred significant renal
benefits in patients with NIDDM and nephropathy, benefit not
attributable to changes in BP. Telmisartan has also demonstrated
renal protective effects. The beneficial effects on vascular growth
and fibrosis in the kidney via blockade of the AT1 receptor as
well as the stimulation of PPAR-γ make telmisartan useful in
the prevention of hypertensive renal disease. In the VIVALDI49
(inVestIgate the efficacy of telmisartan versus VALsartan in
hypertensive type 2 DIabetic) trial, Telmisartan 80 mg/day
and Valsartan 160 mg/day produced similar reductions in
24-hour urinary protein excretion rates by 33% after 12 months
of treatment in diabetic patients with hypertension and overt
nephropathy.10 It is thought that their renoprotective benefit
in VIVALDI, was solely due to the antihypertensive effect.
However, in the AMADEO50 (A comparison of telMisartan
versus losArtan in hypertensive type 2 DiabEtic patients with
Overt nephropathy) trial, Telmisartan 80 mg/day was superior
to losartan 100 mg/day in terms of renoprotective properties.
JNC 8 guidelines are anticipated this year and it is expected that
there will be specific recommendations on hypertension in the
CKD population.
Central Aortic Pressure
Activation of the RAAS plays an important role in the
progression of CKD regardless of the initial nephropathy, and
its blockade remains the most important goal in achieving
preservation of renal function.
The level of augmentation of central systolic blood pressure
(SBP) or the central augmentation index (cAI) is caused by
reflection of pulse waves in the periphery. Increased pulse
wave velocity from stiff large arteries and increased peripheral
vascular resistance are two major causes for an earlier return,
and higher amplitude of the reflected pulse wave, respectively.
Earlier return of the reflected pulse wave shifts central BP
augmentation from diastole into late systole, and therefore leads
to augmentation of central SBP and hence cardiac after load.
In addition to detrimental effects on the heart, elevated central
SBP is also thought to be a major determinant of the risk for
stroke. Studies51 have shown that ARBs (irbisartan) reduce cAI
whereas atenolol increases it. Furthermore, central to peripheral
pulse pressure (PP) amplification is unaffected by treatment
with irbesartan, but decreases with atenolol. This could partly
explain the reported differential effects of ARB versus β-blocker
treatment on cardiovascular mortality in patients with essential
hypertension.
In 2007, the AHA developed a scientific statement on treating
hypertension and designated the CKD population as a high
coronary artery disease (CAD) risk group and recommended
a blood pressure goal of less than 130/80 mm Hg. Angiotensinconverting enzyme inhibitors (ACEIs) or angiotensin receptor
blockers (ARBs) are preferred antihypertensive agents in patients
with CKD as per the NKF KDOQI and JNC 7 guidelines. HIJ-
A meta-analysis published in Lancet Oncology (2010)52 raised
the possibility that angiotensin receptor blockers (ARBs) might
increase the risk of malignancy. This generated a significant
debate until the publication of two further meta-analyses,53,54
neither of which demonstrated an increased risk of new cancer
ARBs and CKD
468
ARBs and Cancer Risk
© JAPI • july 2013 • VOL. 61
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Journal of the association of physicians of india • july 2013 • VOL. 61 occurrence or cancer-related death with the use of ARBs in
patients with hypertension, heart failure, and/or nephropathy.
Overall, the bulk of evidence today indicates that ARBs are not
associated with increased cancer risk, as endorsed by the FDA.54
14. Püchler K, Laeis P, Stumpe KO. A comparison of the efficacy and
safety of the oral angiotensin II antagonist olmesartan medoxomil
with those of atenolol in patients with moderate to severe
hypertension under continuous treatment with hydrochlorothiazide
[Abstract No. P2.175]. J Hypertens 2001;19(Suppl 2):153.
Individual Differences Among ARBs
15. Neutel JM. Clinical studies of CS-866, the newest angiotensin II
receptor antagonist. Am J Cardiol 2001;87:37–43.
Telmisartan vs. others
16. Oparil S, Williams D, Chrysant SG, et al. Comparative efficacy of
olmesartan, losartan, valsartan, and irbesartan in the control of
essential hypertension. J Clin Hypertens 2001;3:283–291.
Ambulatory blood pressure monitoring (ABPM) has shown
that Telmisartan 80 mg confers significantly greater blood
pressure lowering than several other ARBs. When compared
with Valsartan 160 mg, Telmisartan provided sustained
antihypertensive efficacy and superior control of blood pressure
during the early morning period.55 3 ABPM studies comparing
Telmisartan 40 or 80 mg with losartan 50 or 100 mg demonstrated
that Telmisartan provided greater reductions than losartan in
both the 24-hour mean SBP and DBP and in the in last 6 hours
of the dosing interval.56
17. Benicar® package insert. Sankyo Pharma, Inc, New York.
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19. Kawaratani T, Laeis P, Püchler K, et al. The effect of an antacid
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ABPM provides more clinical data and is a better predictor
of target- organ damage than other BP monitoring methods.
Considerable focus was placed on the use of ABPM in the clinical
program of Telmisartan, providing the largest ABPM database
for a single ARB. Studies using ABPM showed that differences
in efficacy and duration of action exist within the ARB class. A
meta-analysis of trials using ABPM showed that Telmisartan
was the most efficacious and exhibited the longest duration of
action.57 In clinical practice, these qualities of ARBs may optimize
24-hour BP control, including the critical early morning period.
20. Püchler K, Laeis P, Kawaratani T, et al. The effect of the combination
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