Review Oral renin inhibitors - sepeap

Review
Oral renin inhibitors
Jan A Staessen, Yan Li, Tom Richart
Use of drugs that inhibit the renin-angiotensin system is an effective way to intervene in the pathogenesis of
cardiovascular and renal disorders. The idea of blocking the renin system at its origin by inhibition of renin has
existed for more than 30 years. Renin inhibition suppresses the generation of the active peptide angiotensin II. The
first generation of orally active renin inhibitors were never used clinically because of low bioavailability and weak
blood-pressure-lowering activity. At present, aliskiren is the first non-peptide orally active renin inhibitor to progress
to phase-III clinical trials. It might become the first renin inhibitor with indications for the treatment of hypertension
and cardiovascular and renal disorders. Novel compounds with improved oral bioavailability, specificity, and efficacy
are now in preclinical development. This Review summarises the development of oral renin inhibitors and their
pharmacokinetic and pharmacodynamic properties, with a focus on aliskiren.
Inhibition of the renin-angiotensin system is an effective
way to intervene in the pathogenesis of cardiovascular
and renal disorders. 1 Renin controls the first rate-limiting
step of the system (figure 1) and cleaves angiotensinogen
to the inactive decapeptide angiotensin I. The active
octapeptide angiotensin II is formed from angiotensin I
by the angiotensin-converting enzyme. Angiotensin II
acts via type-1 angiotensin II receptors (AT1) to increase
arterial tone, adrenal aldosterone secretion, renal sodium
reabsorption, sympathetic neurotransmission, and
cellular growth. 2
The renin system can be inhibited at various points
(figure 1). Bühler and colleagues 3 first showed that
β blockers reduce the release of renin from the
juxtaglomerular apparatus and lower blood pressure.
Inhibitors of angiotensin-converting-enzyme (ACE) reduce
the conversion of angiotensin I to angiotensin II. 4
ACE inhibitors also inhibit the inactivation of bradykinin
and substance P. These peptides mediate some of the
side-effects of ACE inhibitors, such as cough 5 and angiooedema.
6 Angiotensin-receptor blockers specifically
interfere with the interaction of angiotensin II with the
AT1 receptor, but do not oppose stimulation of the
angiotensin II type-2 receptor. 7 Inhibition of renin
activity blocks the renin system at its very origin. 8,9
ACE inhibitors, angiotensin-receptor blockers, and
renin inhibitors interrupt the normal feedback
suppression of renin secretion from the kidneys
(figure 1). The reactive rise in circulating active renin
leads to greater generation of angiotensin I (table 1),
which in turn increases the formation of angiotensin II
via pathways dependent or independent of the ACE
(figure 1). 10 Such escape processes do not occur with
β blockers (table 1). Renin inhibitors do not block
renin-like enzymes, such as cathepsin D or tonins,
which are present in the vascular wall and which
release angiotensin I from angiotensinogen (figure 1).
Renin has a unique specificity for its only known
physiological substrate, angiotensinogen. By 1957,
Skeggs 11 had already outlined the potential benefits of
specific inhibition of the renin system by diminishing
renin activity without interference with other metabolic
path ways.
Development of oral renin inhibitors
The sequence of renin differs between species, so that
preclinical studies of renin inhibitors must be done in
primates, such as marmosets, or in rat models
transgenic for human renin and angiotensinogen. 12 The
earliest attempts to block the renin system relied on
antibodies raised against renin. 13,14 Immunological
inhibition of renin reduced blood pressure in volumedepleted
normotensive marmosets 15 and provided the
proof of concept of renin inhibition.
The first synthetic renin inhibitor was pepstatin. 16
First-generation renin inhibitors were peptide analogues
of the prosegment of renin 17 or substrate analogues of
the amino-terminal sequence of angiotensinogen
containing the renin cleavage site. 18–20 They had to be
given parenterally, but were effective at inhibiting renin
activity and reducing blood pressure in animals 19 and in
people. 21 Further chemical modification led to the
development of compounds, such as CGP29287 (Ciba-
Geigy, Basel, Switzerland), that had greater stability and
longer duration of action. CGP29287 was the first renin
inhibitor to show activity when given orally; it was orally
active in marmosets at high doses. 22 In the second half
of the 1980s, several drug companies developed renin
inhibitors that had a molecular weight of a tetrapeptide.
These molecules (figure 2) included enalkiren (A 64662;
Abbott, Abbott Park, IL, USA), CGP38560A (Ciba-Geigy,
Search strategy
Lancet 2006; 368: 1449–56
Published Online
September 26, 2006
DOI:10.1016/S0140-
6736(06)69442-7
Studies Coordinating Centre,
Division of Hypertension and
Cardiovascular Rehabilitation,
Department of Cardiovascular
Diseases, University of Leuven,
Leuven, Belgium
(J A Staessen MD, Y Li MD,
T Richart MD); and Centre for
Epidemiological Studies and
Clinical Trials, Ruijin Hospital,
Shanghai Institute of
Hypertension, Shanghai
Jiaotong University, Shanghai,
China (Y Li)
Correspondence to:
Dr Jan A Staessen, Studies
Coordinating Centre, Laboratory
of Hypertension, Campus
Gasthuisberg, Herestraat 49,
Box 702, B-3000 Leuven,
Belgium.
jan.staessen@med.kuleuven.be
We searched the PubMed and MEDLINE databases (1980–2005), using “renin inhibitor”
as an initial search term. We then focused our search, using the terms: “aliskiren”,
“A 62095”, “A 62918”, “A 65317”, “A 74273”, “CGP 29287”, “CGP 38560”, “CGP 44099”,
“CGP 60536”, “ciprokiren”, “CP 71362”, “CP 80794”, “CP 81282”, “CP 85339”, “enalkiren”,
“KRI 1177”, “KRI 1230”, “KRI 1314”, “SPP100”, “remikiren”, “renin inhibitory peptides”, and
“zankiren”. We preferentially selected articles published in 2000 or later, but we also
included older papers to track the historical perspective of the development of renin
inhibitors, which spans more than 20 years. We excluded from table 3 any exploratory
studies with an open design. We searched the reference lists of review articles by hand for
additional information. We visited the websites of the pharmaceutical companies known
to be active in the development of renin inhibitors. We also requested and obtained
further information from Actelion, Hoffmann-Laroche, Novartis, Pfizer, and Speedel.
www.lancet.com Vol 368 October 21, 2006 1449

Review
Tissue RAS
Kidney
β blockers
Renin
Vasoconstriction
Sodium retention
Cellular growth
Oxidative stress
Renin
inhibitors
Negative feedback via AT 1 -R
ARB
Chymase
Angiotensinogen
Cathepsin D
Tonins
Angiotensin I
ACE ACE inhibitors ACE
Angiotensin II
EP
ACE2
Angiotensin (1-7)
AT 1 -R AT 2 -R AT 1-7 -R AT 4 -R
mas
receptor
Aldosterone
Modulation of
EC function
Cough,
angio-oedema
Bradykinin
Substance P
Angiotensin (3-8)Inactive peptides
Figure 1: The renin-angiotensin-aldosterone system
Black arrows show stimulation and red arrows show inhibition. Dotted lines show alternative pathways mainly
documented in experimental studies. β blockers, renin inhibitors, inhibitors of angiotensin-converting enzyme
(ACE) and angiotensin II type-1 receptor blockers (ARB) reduce the activity of the renin-angiotensin system (RAS).
AT-R=angiotensin receptor; EP=endopeptidases; EC=endothelial cells.
Basel, Switzerland, [not shown in figure 2]), remikiren
(Ro 425892; Hoffmann-La Roche, Basel, Switzerland),
and zankiren (A 72517; Abbott). 9,23,24 When given orally,
they had a bioavailability of less than 2%, a short halflife,
and weak blood-pressure-lowering activity 9
(table 2 25–29 ).
By means of crystallography and computational
molecular modelling starting from a corporate
compound library, Hoffmann-La Roche subsequently
developed and optimised substituted piperidine renin
inhibitors, which were abandoned after tests in
preclinical studies. 30 At about the same time, Ciba-Geigy
(now Novartis, Basel, Switzerland) discovered the orally
active compound aliskiren (CGP 60536B, figure 2). 31
However, the pathway for its synthesis, patented in
1995, had many steps and was not suitable for industrial
manufacture. In 1999, aliskiren was out-licensed to
Speedel AG (Basel, Switzerland), who succeeded in
designing a cost-effective method of production. 23,32
After successful preclinical and clinical testing of
aliskiren (SPP 100) by Speedel, Novartis exercised its
call-back option for the further development of aliskiren
in phase-III clinical trials. 33
In 2001, Hoffmann-La Roche copied this strategy by
out-licensing to Speedel a new subclass of renin
inhibitors, which are known as the SPP 600 series and
are now under preclinical investigation. 23 In April, 2003,
Speedel joined forces with Locus Pharmaceuticals (Blue
Bell, PA, USA), who used their proprietary computational
technologies to identify novel leads. In June, 2005,
Speedel announced the discovery of new compounds
(SSP 800 series), which have entered pharmacological
profiling in animal models, with the goal of selecting a
preclinical candidate in 2006.
Studies of the first generation of oral renin
inhibitors
Haemodynamic and endocrine effects
In normotensive primates 24,34–38 and human beings, 29,39–51
renin inhibitors given intravenously or orally lead to
acute and dose-dependent decreases in plasma renin
activity, plasma concentrations of angiotensin I and
angiotensin II, (table 1) and blood pressure, without
inducing reflex tachycardia.
Table 3 summarises the effects of oral remikiren 28,41,43–48
and zankiren 29,42 on blood pressure and plasma renin
activity in randomised clinical trials, excluding two
exploratory studies with an open design. 26,52 In general,
the blood-pressure-lowering activity has been small.
Because normal feedback inhibition is interrupted by
angiotensin II (table 1), renin inhibition consistently
elicits a rise in circulating active renin. This escape
process, which also occurs during treatment with ACE
inhibitors and angiotensin-receptor blockers, explains
why these three drug classes behave as incomplete
Enzymes Substrates End-products
PRA PRC Angiotensinogen Angiotensin I Bradykinin Angiotensin II Aldosterone
β blockers ↓ ↓ NA NA NA NA NA
Renin inhibitors ↓ ↑ NA ↓ NA ↓ ↓
ACE inhibitors ↑ ↑ ↓ ↑ ↑ ↓ ↓
ARB ↑ ↑ ↓ ↑ NA ↑ ↓
ACE inhibitors plus ARB ↑↑ ↑↑ ↓↓ ↑↑ ↑ NA ↓
Renin inhibitors plus ARB ↓ ↑↑ NA NA NA NA ↓↓
PRA=enzymatic activity of plasma renin—ie, the rate of generation of angiotensin I. PRC=the plasma concentration of renin, not including prorenin; PRC is also referred to as
circulating active renin. NA=data not available.
Table 1: Effects of inhibitors of the renin system on enzymes, substrates, and end-products
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Review
blockers of the renin system. Whether renin inhibitors
also improve insulin sensitivity, as ACE inhibitors and
angiotensin-receptor blockers do, needs to be clarified.
In most studies (table 3), the time course of the bloodpressure-lowering
activity paralleled the inhibition of
plasma renin activity and the fall in plasma levels of
angiotensin I and II. 53 However, some investigators
showed desynchronisation between the haemodynamic
and endocrine effects attributable to an in vitro artefact
in the assay for plasma renin activity that leads to an
overestimation of renin inhibition. 54
Kleinert and co-workers 55 infused enalkiren in doses
of 0·1 mg/kg, 1·0 mg/kg, and 10·0 mg/kg to anephric
monkeys, human-renin-infused anephric monkeys, and
normal control monkeys. The lowest dose of enalkiren
was inactive in anephric animals, but decreased blood
pressure during infusion of human renin. The highest
dose consistently reduced blood pressure in all three
models. These findings suggest that the blood-pressurelowering
activity of renin inhibitors must be due, at
least partly, to the inhibition of plasma renin activity,
but that at higher doses, renin inhibitors might also act
via other mechanisms, such as the inhibition of tissue
renin (figure 1). Further studies should clarify the role
of tissue renin in the blood-pressure-lowering activity of
renin inhibitors.
Renal renin accounts for cardiac and vascular renin,
but certainly not for that in other organs, such as the
brain and the testes. 2 Renin inhibitors probably pass the
blood-testicular barrier. AT1 receptors are present in
both the female and male reproductive tract 56 and
angiotensin II stimulates sperm motility. 56 Although
phase-I studies of aliskiren 32 did not suggest any toxicity,
the possible long-term influence of renin inhibition on
reproduction needs further investigation.
Vascular effects
Most renin in blood-vessel walls is taken up from the
plasma. 9 Experimental studies showed that renin
inhibitors, like ACE inhibitors, suppress vascular angiotensin
II 57 and reduce neointima formation after vascular
injury. 58 Compared with placebo, ACE inhibitors reduce
the rate of progression of thickening in the carotid
intima media, 59 but the possible effects of renin
inhibitors on atherogenesis in human beings is
unknown.
Renal effects
The intrarenal renin system has a pivotal role in the
regulation of blood flow within the kidney. In dogs, the
renin inhibitor ciprokiren (RO 449375, Hoffman-La
Roche, Basel, Switzerland) prevented the reduction of
renal blood flow and the elevation of renal arterial
resistance in response to a decrease in perfusion
pressure. 60 Similarly, in sodium-depleted monkeys 61 and
normotensive guinea pigs, 62 enalapril and the renin
inhibitors enalkiren and remikiren consistently reduced
H 3 CO
H 3 C
H 3 C
O
H 3 CO
H 3 C
O
S
O
H
O
Aliskiren
H 2 N
Remikiren
H
N
OH
N H
N
O
renal vascular resistance and increased renal blood flow
with or without an increase in glomerular filtration rate
and fractional sodium excretion.
Fisher and colleagues 63 investigated in healthy and
hypertensive sodium-depleted men the responsiveness
of the renal circulation to angiotensin II in the presence
of placebo, enalkiren, or captopril. Compared with
placebo, both active drugs increased renal blood flow
during the infusion of angiotensin II. In a study of
14 hypertensive patients with normal or impaired renal
function, remikiren given once daily at a dose of 600 mg
reduced mean arterial pressure from baseline by 11·2%
at peak plasma concentration and by 6·0% at trough. 64
Renal vascular resistance and filtration fraction fell by
15% and 10%, respectively, without change in glomerular
filtration rate. In six patients with renal dysfunction,
remikiren also reduced proteinuria by 27% from
baseline. 64 The apparent renoprotective effect of the
8-day course of remikiren contrasted with its weak
blood-pressure-lowering activity and probably reflected
specific uptake of the drug by the kidney. 65
Cardiac effects
In dogs, 66 rats, 67 and sheep 68 with left-ventricular failure,
renin inhibitors had beneficial haemodynamic effects,
Bioavailability,
%
H H
OH
IC 50 (nmol/L)
Plasma half life,
h (SD)
Aliskiren 25 2·7 0·6 23·7 (7·6)
CGP 38560 26

Review
Renin inhibitor study
Remikiren
Characteristics of study
Design Number
total
(women)
Mean age (range),
years
Blood
pressure class
Sodium intake
in mmol/day
Dose
mg/day
Days
Main results on maximum dose
Change in SBP/DBP,
mm Hg
Change in PRA, %
Peak Trough Peak Trough
Camenzind 43 SB, PC 24 (0) NA (21–30) NT U 100–1200 1 ~0/~0 ~0/~0 –76 +37
Kleinbloesem 28 DB, PC, CO 55 (0) 26 (NA) NT U 100–1600 1 ~0/~0 ~0/~0 –81 –17
Kobrin 44 DB, PC 24 (0) 55 (20–65) HT U 600 8 NA/–9·8 NA/–8·6 –100 –40
MacFadyen 41 DB, PC, CO 12 (0) 28 (NA) NT 40 30–1000 1 –12·7/–14·1 –1·0/–4·7 –100 –82
Rongen 45 DB, PC 49 (23) 54 (20–68) HT U 300–600 8 –11·0/–3·1 –5·9/+1·2 –72 ~0
van den
SB, AC*, CO 8 (1) 52 (28–63) HT U 600 8 –8·2/–5·4
Meiracker 46 +4·0/+3·0†
–5·1/–3·5
+8·8/+4·1†
–83 ~0
van Paassen 47 DB, PC, CO 16 (3) 54 (37–67) HT 50 600 1 –10·0/–7·0 NA/NA –87 NA
Viskoper 48 DB, PC 25 (2) 55 (NA) HT U 100 8 NA/–6·0 NA/–2·7 NA NA
Zankiren
Fisher 42 Open, CO 12 (0) 37 (27–47) NT 10 5–250 1 –4·6‡ NA –95 –90
Ménard 29 DB, PC 24 (0) 29 (23–29) NT 100 10–250 1 –6·4/–7·7 +5·3/+2·3 –100 –80
Aliskiren
Azizi 49 DB, PAC*, CO 12 (0) NA (18–35) NT 30 300 1 –4·6‡
+1·7†
+0·1‡
+1·2†
–96 –39
Gradman 51 DB, PAC* 652 (325) 56 (≥18) HT U 150–600 56 NA/NA –10·4/–5·2 NA NA
–3·2/–2·6†
Nussberger 25 DB,PAC*, CO 18 (0) NA (20–34) NT 100 40–640 8 ~0/~0 ~0/~0 –75 –58
Stanton 50 DB, AC* 197 (67) 52 (21–70) HT U 37·5–300 28 –1·8/~0 –4·0/~0 NA –83
SB=single-blind trial; PC=placebo-controlled trial; NT=normotensive; U=diet unrestricted for sodium; DB=double-blind trial; CO=cross-over trial; HT=hypertensive patients; AC=actively controlled trial;
PAC=placebo and actively controlled trial; SBP/DBP=systolic/diastolic blood pressure; PRA=plasma renin activity; *active comparator: enalapril 20 mg/day in studies 46 and 25; valsartan 160 mg/day in study 49;
irbesartan 150 mg/day in study 51; and losartan 100 mg/day in study 50. †Difference versus active comparator. ‡ Mean arterial pressure in mm Hg. NA=data not available.
Table 3: Effects of oral renin inhibitors on blood pressure and plasma renin activity in randomised clinical trials
as exemplified by the decline in the left-ventricular enddiastolic
pressure and systolic afterload. In spontaneously
hypertensive rats, a specific inhibitor of rat renin
reduced blood pressure and caused similar regression
of left-ventricular hypertrophy, as compared with an
ACE inhibitor or an angio tensin-receptor blocker. 69
In a double-blind trial by Kiowski and co-workers, 70
36 patients with chronic heart failure (New York Heart
Association Class 2 or 3) were randomly assigned to
intravenous remikiren, enalaprilat, or their combination.
Remikiren and enalaprilat were associated with similar
rapid reductions in systemic vascular resistance and
blood pressure. These haemodynamic changes were
proportional to the baseline plasma renin activity. Both
drugs also equally lowered blood pressure in the right
atrium and pulmonary artery as well as the pulmonarycapillary
wedge pressure. During exercise, remikiren
and enalaprilat similarly increased the stroke volume
index and reduced pulmonary-capillary wedge pressure.
The combination of both drugs did not induce additive
haemodynamic changes. Neuberg and colleagues 71
reported similar haemodynamic results in nine patients
with chronic heart failure treated with intravenous
enalkiren at rest.
Limitations of the first oral renin inhibitors
Clinical development of orally active renin inhibitors has
been far more challenging than originally expected. Major
hurdles were low bioavailability attributable to poor
gastrointestinal absorption with large variability between
individuals and substantial first-pass metabolism, 27 short
duration of action, weak blood-pressure-lowering activity,
and the successful marketing of ACE inhibitors and
angiotensin-receptor blockers in the 1990s. None of the
first-generation renin inhibitors successfully completed
clinical testing.
Aliskiren
Pharmacokinetic properties
Aliskiren is the only orally active renin inhibitor that
progressed to phase-III clinical trials. 33 In marmosets,
aliskiren reached peak plasma concentrations 1–2 h after
a single oral dose of 10 mg/kg. 72 The mean half-life was
2·3 h and the calculated bioavailability was 16·3%. 72 In
healthy volunteers, after oral aliskiren in doses of
40–640 mg/day, the plasma concentration dosedependently
increased, with peak concentrations after
3–6 h. The plasma half-life averaged 23·7 h (range
20–45 h), 25 making the compound suitable for once-daily
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Review
administration. The oral bioavailability was 2·7%
(table 2). Plasma steady-state concentrations were reached
after 5–8 days of treatment. The main elimination route
of aliskiren is via biliary excretion as unmetabolised
drug. Less than 1% of aliskiren given orally is excreted in
the urine. 25 Compared with other orally active renin
inhibitors, such as remikiren or enalkiren, 27 aliskiren is
one of the most potent compounds yet identified with
high specificity for primate renin (table 2). 33 Aliskiren is
not metabolised by cytochrome P450, does not interfere
with the action of warfarin, 73 and shows no clinically
relevant pharmacokinetic interactions with lovastatin,
atenolol, celecoxib, or cimetidine. 74
Pharmacodynamic properties
In sodium-depleted marmosets, aliskiren at doses of
1 mg/kg and 3 mg/kg caused complete inhibition of
plasma renin activity for 6 h and 24 h, respectively. 72 Single
oral doses (1–30 mg/kg) dose-dependently lowered blood
pressure. At a dose of 3 mg/kg, mean arterial pressure fell
by a maximum of 30 mm Hg 1 h after intake and this
reduction persisted for more than 24 h. A single dose of
3 mg/kg aliskiren was more effective than the same dose
of remikiren or zankiren. Aliskiren at 10 mg/kg was as
effective as 10 mg/kg valsartan or benazepril. 72
Pilz and colleagues 12 compared the effects of aliskiren
(0·3 mg/kg/day and 3 mg/kg/day), valsartan (1 mg/kg/day
and 10 mg/kg/day), with no treatment in relation to
target-organ damage in hypertensive rats transgenic for
human renin and angiotensinogen. Both aliskiren doses
and the high valsartan dose lowered blood pressure and
albuminuria more effectively than the low valsartan dose.
After 3 weeks, none of the untreated rats had survived
compared with 74% of the low-dose valsartan group, and
100% in all other groups. In this animal model, renin
inhibition therefore compared favourably with AT1-
receptor blockade in reversing target-organ damage.
In a double-blind and randomised crossover study,
18 male normotensive volunteers on a constant sodium
diet (100 mmol/day) received two oral doses of aliskiren
(either 40 mg and 80 mg or 160 mg and 640 mg once
daily), enalapril 20 mg/day, or placebo. 25 Aliskiren dose
dependently decreased plasma renin activity and plasma
concentrations of angiotensin I and II. Compared with
placebo, the highest dose of aliskiren reduced plasma
angiotensin II by about 80%, although the plasma
concentration of renin rose by more than ten times.
Enalapril 20 mg/day and aliskiren 160 mg/day produced
similar reductions in plasma angiotensin II. Aliskiren at
daily doses of 80 mg or more but not at 40 mg lowered
plasma and urinary aldosterone by 40–50%. Blood
pressure and heart rate were unchanged on aliskiren and
enalapril, possibly as a result of the reactive increase in
circulating active renin. 25
In a small pilot trial with a four-period randomised
crossover design, Azizi and colleagues 49 gave single doses
of 300 mg aliskiren, 160 mg valsartan, the combination of
150 mg aliskiren plus 80 mg valsartan, or placebo to
12 male volunteers with mild sodium depletion. Aliskiren
reduced plasma renin activity and plasma levels of
angiotensin I and II for 48 h. Compared with valsartan,
aliskiren more strongly stimulated the release of active
renin into the circulation (about 10 times compared with
about 15 times) while inhibiting plasma renin activity,
and reduced the urinary aldosterone excretion for a longer
period (8 vs 48 h). The effects of the combination of the
lower doses of aliskiren and valsartan were similar to
those of 300 mg aliskiren and larger than those of 160 mg
valsartan. These findings suggest that, at lower doses,
renin inhibitors and angiotensin-receptor blockers might
have synergistic effects on the renin system. Aliskiren
also blunted the valsartan-induced rise in plasma renin
activity and in plasma concentration of angiotensin I and
II. The active drugs reduced mean arterial pressure 4 h
after intake by about 5–7 mm Hg, but these bloodpressure
responses were no longer apparent at 24 h
(table 3).
Phase-II clinical trials in hypertensive patients
Stanton and colleagues 50 enrolled 226 patients, aged
21–70 years, with mild to moderate hypertension in a
randomised, double-blind dose-finding 4 week study of
aliskiren with losartan 100 mg/day as active comparator.
The daytime systolic blood pressure measured by
ambulatory monitoring was the primary endpoint; it
gradually fell with higher doses of aliskiren (37·5 mg,
75 mg, 150 mg, and 300 mg daily). The reductions in the
daytime systolic pressure were similar for the two highest
doses of aliskiren and for losartan, averaging about
8–11 mm Hg. The blood-pressure-lowering activity of the
300 mg dose persisted for 24 h (figure 3). With aliskiren,
plasma renin activity fell dose-dependently by 50–80%,
whereas it doubled with losartan. Of note, two patients
allocated aliskiren 300 mg/day had severe hypotension or
Systolic blood pressure (mm Hg)
160
150
140
130
120
110
Baseline
Losartan 100 mg (n=36)
Aliskiren 150 mg (n=41)
Aliskiren 300 mg (n=40)
0
08·00 12·00 16·00 20·00 00·00
Time of day
04·00 08·00
Figure 3: The 24-hour systolic pressure at baseline and after inhibition of the
renin system with either aliskiren or losartan
Aliskiren and losartan were given for 4 weeks in once daily doses. of 150 mg
(n=41), 300 mg (n=40) and 100 mg (n=36), respectively. Adapted from
reference 50 with permission from Lippincott Williams and Wilkins.
www.lancet.com Vol 368 October 21, 2006 1453

Review
chest tightness with electrocardiographic signs of
ischaemia. However, such severe side-effects did not
occur in other trials that tested aliskiren at daily doses of
300 mg or higher (table 3).
In a double-blind, randomised parallel-group trial,
Gradman and colleagues 51 assigned 652 hypertensive
patients once-daily doses of 150 mg, 300 mg, or 600 mg
aliskiren, 150 mg irbesartan, or placebo. The reductions in
blood pressure (systolic/diastolic) measured at trough
after 8 weeks of follow-up and adjusted for baseline values
and the difference from placebo averaged 6·1/2·9 mm Hg,
10·5/5·4 mm Hg, 10·4/5·2 mm Hg, and 7·2/2·5 mm Hg
on the increasing doses of aliskiren and irbesartan,
respectively (table 3). The two highest aliskiren doses
lowered diastolic blood pressure significantly more than
irbesartan p=0·01. The frequency of adverse effects was
similar for placebo and aliskiren with the exception of
diarrhoea associated with the 600 mg/day dose
(1·5 vs 6·9%).
Further development
Novartis is now doing phase-III trials of aliskiren to test
its effects on intermediate markers of target-organ
damage. In the Aliskiren in Left-Ventricular Hypertrophy
trial (ALLAY, registration number [http://clinicaltrial.gov]
NCT00219141), hypertensive patients with left-ventricular
hypertrophy are randomly assigned aliskiren, losartan, or
the combination. The primary endpoint is left-ventricular
mass and geometry as measured by MRI. Furthermore,
in the Aliskiren Observation of Heart Failure Treatment
trial (ALOFT, NCT00219011), aliskiren is being compared
with placebo given in addition to optimum standard
treatment. The primary endpoint is the fall in plasma
concentration of brain natriuretic peptide. Finally, in the
Aliskiren in the Evaluation of Proteinuria In Diabetes
trial (AVOID, NCT00219206), aliskiren or placebo will be
added to treatment with losartan to study the reduction
in the urinary albumin-to-creatinine ratio. Each of these
three trials will enrol 300–500 patients.
In a meta-analysis of 127 clinical trials, Casas and
colleagues 75 showed that the renoprotective effects of
ACE inhibitors and angiotensin-receptor blockers beyond
blood-pressure lowering are questionable in patients
with diabetes as well as those without. Similarly,
metaregression highlighted that small differences in the
achieved systolic blood pressure were the major
determinant of cardio vascular outcomes in primary and
secondary prevention trials. 76,77 The interpretation of the
continuing aliskiren trials will therefore not be easy.
There are likely to be small between-group differences in
blood pressure in the placebo-controlled ALOFT and
AVOID studies as well as in the ALLAY trial between the
monotherapy and combination-therapy groups. Alternatively,
to achieve the same blood-pressure effect in the
groups randomised in the aliskiren trials will imply that
the background treatment will differ in intensity and
thereby confound the results. Furthermore, showing
regres sion of intermediate endpoints versus placebo or
the standard of care is a useful step in the development
of aliskiren. However, to establish a new drug class as a
valuable addition to available therapeutic options requires
proof of beneficial effects on morbidity and mortality. For
aliskiren, this challenging mission might take another
7 or 8 years.
Conclusions
For almost 20 years, the development of oral renin
inhibitors met huge problems. The clinical development
of aliskiren signifies a breakthrough. However, the search
for agents with improved oral bioavailability, specificity
for human renin, and efficacy will continue. 23,78
Compared with ACE inhibitors, renin inhibitors have
fewer side-effects, 23,78 but as with angiotensin-receptor
blockers, they might be less powerful in reducing blood
pressure, because they do not block the degradation of
bradykinin (figure 1). Renin inhibitors might be clinically
indicated in combination therapy with drugs that lead to a
reactive increase in the plasma renin activity, such as
diuretics, ACE inhibitors and angiotensin-receptor
blockers. Renin inhibitors might be useful in younger and
white patients, who have a more active renin system than
older and non-white people. Renin inhibitors might also
be useful in patients intolerant of ACE inhibitors, for the
treatment of disorders in which angiotensin II contributes
to the pathogenesis, 2 and for secondary prevention of
cardiovascular diseases. Moreover, renin inhibitors offer
additional safety for patients with cardio vascular disease
and concomitant renal dysfunction, because they are
preferentially eliminated via the liver 25 without much
interference with other drugs. 70,71 Like ACE inhibitors,
renin inhibitors behave as vasodilators with the potential
to improve the elasticity of the large arteries. 79 Conversely,
they are likely to be subject to the same contraindications
as ACE inhibitors and angiotensin-receptor blockers, such
as pregnancy and bilateral renal-artery stenoses.
Contributors
J A Staessen and T Richart did the literature search. JA Staessen and
Y Li drafted and revised the report. T Richart planned the figures. Y Li
checked the accuracy of the references. All authors approved the final
version of the report.
Conflict of interest statement
J A Staessen has been an ad-hoc consultant for pharmaceutical companies
with commercial interests in cardiovascular medicine and has received
funding for studies, seminars, and travel from such companies. Y Li and
T Richart declare that they have no conflict of interest.
Acknowledgments
We thank Professor Willem H Birkenhäger (Erasmus University,
Rotterdam, Netherlands) for his critical comments; Sandra Covens for
help with the literature searches and maintenance of the reference
manager database; Katrin zur Nieden (MediSign, Pulheim, Germany)
for production of illustrations; and Hein van Ingen (Novartis, Basel,
Switzerland) for reviewing the factual information on aliskiren for
accuracy.
Role of the funding source
The authors did not receive any funding for writing this Review. The
corresponding author had full access to all data and had final
responsibility for the decision to submit the manuscript for publication.
1454 www.lancet.com Vol 368 October 21, 2006

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