Direct Renin Inhibitors as Antihypertensive Agents

Direct Renin Inhibitors as Antihypertensive Agents

Zafar H. Israili, PhD,1* Manuel Velasco, MD, FRCP Edin,2 andValmore Bermudez, MD, MPH, PhD3

Hypertension, a serious disease affecting almost a billion people (25% of adults) worldwide, is amajor modifiable risk factor for cardiovascular (CV) and renal disease. Despite numerous advancesin the pharmacologic treatment of high blood pressure (BP) and availability of severalantihypertensive drugs to treat hypertension, a significant proportion of treated hypertensivepatients still have uncontrolled high BP, and thus, face serious morbidity and mortality. Furthermore,it is not sufficient to aim for optimum BP control, but to treat all CV risk factors, protect end-organdamage, prevent progression of disease, and prevent long-range adverse effects of the drugs.Therefore, new therapeutic modalities have to be developed to achieve the above objectives. Someyears ago, investigators identified renin inhibition as the preferred pharmacologic approach toblockade of the renin–angiotensin system. Renin is a monospecific enzyme that catalyzes the rate-limiting step in the synthesis of angiotensin II. Amplified enzymatic activity and additionalphysiologic effects occur when renin and prorenin bind to the (pro)renin receptor. Until very recently,development of clinically effective renin inhibitors remained elusive but molecular modeling wasused to develop aliskiren and other renin inhibitors that produce sustained suppression of plasmarenin activity after oral administration with a dose-dependent BP. Additional studies will ultimatelydetermine the place of renin inhibition in the treatment of hypertension and related CV disorders.

Keywords: renin, aliskiren, angiotensin II, hypertension, coronary heart disease

INTRODUCTION

Hypertension, a serious disease affecting almost abillion people (25% of adults) worldwide, is a majormodifiable risk factor for cardiovascular (CV) and renaldisease.1 Despite numerous advances in the pharma-cologic treatment of high blood pressure (BP) andavailability of 7 classes of antihypertensive drugs totreat hypertension, a significant proportion of treatedhypertensive patients still have uncontrolled high BP,and thus, face serious morbidity and mortality.Furthermore, it is not sufficient to aim for optimum

BP control, but to treat all CV risk factors, protect end-organ damage, prevent progression of disease, andprevent long-range adverse effects of the drugs, such asincrease in insulin resistance or new-onset diabetesassociated with certain classes of antihypertensiveagents. Therefore, new therapeutic modalities have tobe developed to achieve the above objectives.

RENIN–ANGIOTENSIN–ALDOSTERONE SYSTEM

The renin–angiotensin–aldosterone system (RAAS;Fig. 1) is a major physiologic regulator of body fluidvolume, electrolyte balance, arterial BP, tissue perfu-sion, and adrenal functions. Dysregulation of RAAS,such as by chronic RAAS activation, has been shown tobe a major underlying cause of hypertension, heartfailure, renal disease, and related CV disorders.Increasing evidence indicates that inhibition of theRAAS is an effective way to control high BP andintervene in the pathogenesis of CV disorders, diabetic

1Emory University School of Medicine, Department of Medicine,Atlanta, GA; 2Clinical Pharmacology Unit, Vargas MedicalSchool, Central University of Venezuela, Caracas, Venezuela;and 3The University of Zulia, Endocrine and Metabolic DiseasesResearch Center, Maracaibo, Venezuela.*Address for correspondence: Emory University School of Medi-cine, Department of Medicine, GMB, 69 Butler St, Atlanta, GA30303. E-mail: [email protected]

American Journal of Therapeutics 17, 237–254 (2010)

1075–2765 � 2010 Lippincott Williams & Wilkins www.americantherapeutics.com

kidney disease, and atherogenesis.2,3 Although, block-ade of the RAAS with angiotensin converting enzyme(ACE) inhibitors, angiotensin II AT1 receptor blockers(ARBs), or a combination of these drugs has becomeone of the most successful therapeutic approaches inmedicine,4 the ACE inhibitors and ARBs do notcompletely suppress the RAAS, because of thecompensatory rise in plasma renin activity (PRA).5

Based on studies using very high-dose ARB orcombination therapy with ACE inhibitor and ARB,it has been suggested that more complete blockadewould lead to improved clinical outcomes.6 Hence,blockade of renin, the most upstream point of RAAS,that is, at the initial, rate-limiting step in the renincascade causing also favor more complete blockade of

the system than with the existing agents, may be moreeffective in affording greater protection from hyper-tensive complications.7,8

Renin (EC 3.4.99.19; also known as angiotensinoge-nase), a circulating enzyme belonging to the asparticproteinase family (340 amino acids; molecular weight =40,000 Da), synthesized and secreted by the kidneysfrom specialized juxtaglomerular cells of the afferentarterioles, controls the first rate-limiting step of theRAAS (Fig. 1) by cleaving angiotensinogen to theinactive decapeptide angiotensin I. The enzyme ACEcleaves angiotensin I to form the active octapeptideangiotensin II, which in turn acts via angiotensin IItype 1 (AT1) receptors to increase (1) atrial tone, (2)secretion of aldosterone from adrenals, (3) renal

FIGURE 1. The RAAS and AT-R1-4 effects.

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238 Israili et al

reabsorption of sodium, (4) sympathetic neurotrans-mission, and (5) cellular growth.2 Angiotensin II playsan important physiologic role in the regulation of BP,but excessive activation of the RAAS leads to increasein BP and end-organ damage. Renin secretion is sup-pressed by b-adrenergic blockers, but the blockade isincomplete. Because neither ACE inhibitors nor ARBsalone can completely suppress RAAS activity, directinhibition of renin was attempted to completely inhibitRAAS at the first rate-limiting step. The effects ofvarious agents interrupting the RAAS at different siteson the components of the RAAS are presented in Table 1.

RENIN INHIBITORS

Early attempts included using immunologic inhibitorsof renin (antisera, monoclonal antibodies, and Fabfragments), fragments of the prorenin sequence andcompounds related to pepstatin (a potent pentapeptideinhibitor of pepsin and less potent inhibitor of renin),and angiotensinogen analogues, but none of theseattempts proved feasible for a variety of reasonsincluding poor absorption, short duration of action,and weak activity.9,10 Synthesis of compounds mim-icking the enzyme transition state, the condition ofgreatest binding affinity, has resulted in renin inhibitorswith potencies in the nanomolar range, which haveshown hypotensive activity. These compounds containat least one peptide bond and have limited oral activity.The strategy for producing orally active inhibitors ofrenin is aimed at developing compounds that aresmaller and less peptidic in nature, thus, reducingproblems of poor absorption, proteolytic degradation,and rapid biliary extraction. Such attempts have beensuccessful in the development of direct renin inhibitors,such as aliskiren.9–12

A number of low molecular weight renin inhibitors(peptidomimetic compounds and nonpeptides) havebeen synthesized, which display excellent specificity

toward human renin.8–11,13–18 Some of the renin inhi-bitors include the following:

Peptidomimetic inhibitors

Ditekren (U 71038); enalkiren (A 64662), terlakiren (CP80794); A 62198; BW 175, BW 633C; CGP 29287; CGP44099; CGP 60536; CI 992; CP 71362; CP-72,647; CP-80,794, CP 81282; EMD 51921; EMD 52297; EMD 56133;EMD 58265; ES 1005; ES 6864; ES-8891; FK 906; H-77;H-77-77; H 142; H-142-08; H-261; KR 1314, KRI 1177; L363714; PD 132002; RI 78; R-PEP-27; S 2864; SC 46944;SC 56525; SQ 32970; Pepstatin A (SR 42128); SR 43845;YM-21095; YM-26365.

Nonpeptide inhibitors

Aliskiren (SPP-100; formerly CGP-60536; CGP 60536B,Tekturna, Resilez); ciprokiren (Ro 44-9375); remikiren(Ro 42-5892); zankiren (A 72517); Ro 44-9378; A 65317;A 74273; BILA 2157 BS; BW 175; CGP 38560A; H 189; S2864; SQ 33800.

Cyclic analogues

Cyclothiazomycin (macrocyclic thiopeptide antibiotic)and other cyclic analogues, such as PD-129,541.

Renin-binding protein

N-acetyl-d-glucosamine-2-epimerase enzyme, renininhibitory peptide, statins, and pepstatins.

MECHANISM OF ACTION OF RENININHIBITORS

The direct renin inhibitors bind to the active site of therenin molecule resulting in the blockade of the con-version of angiotensinogen to angiotensin I (Fig. 1).Angiotensin I suppression decreases the formation ofthe pharmacologically active angiotensin II and, ineffect inhibits the actions of angiotensin II (Fig. 1).Because angiotensin II also functions within the RAAS

Table 1. Effect of blockers of RAAS on the components of RAAS.

RAASblocker

Ang Ilevel

Ang IIlevel

Plasmarenin conc. PRA

Plasma/tissuebradykinin

Non-ACE Ang IIproduction Aldosterone

ACE-I [ Y [ [ [ Not blocked YARB [ [ [ [ NC Blocked YRenin I Y Y [ Y NC Not blocked YACE-I+ ARB [[ Y/NC [[ [[ [ — YRenin I+ ACE-I Y/NC YY [[ Y [ — YYRenin I+ ARB Y/NC Y/NC [[ Y NC — YY

Ang I, angiotensin I; Ang II, angiotensin II; ACE-I, angiotensin converting enzyme inhibitor; renin I, renin inhibitor; NC, no change.Adapted from Azizi,10 Shafiq et al,8 and Staessen et al.12

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Renin Inhibitors 239

as a negative inhibitory feedback mediator in the renalparenchyma to suppress the additional release of renin,the reduction in angiotensin II levels suppresses thisfeedback loop, leading to further increase in plasmarenin concentration (PRC) and subsequent activity(PRA). This disinhibitory effect can be potentially pro-blematic for ACE inhibitor and ARB therapy becauseincreased PRA could partially overcome the pharma-cologic inhibition of the RAAS. But for direct renininhibitors, blunting of PRA despite the increased PRC(from loss of the negative feedback) may be clinicallyadvantageous. The biochemical consequences of renininhibition differ from those of ACE inhibition and AT1

receptor antagonism, particularly in terms of angio-tensin profile (Table 1) and interactions with the brady-kinin–nitric oxide–cyclic guanosine monophosphatepathway and possibly the (pro)renin receptor (see below).

A prorenin/renin receptor has been identified inmesangial cells, to which prorenin/renin binds withhigh affinity (Kd = 400 pmol/L); the receptor, acting asa cofactor, mediates the intracellular effects of renin andprorenin by increasing their enzymatic activity on thecell surface.18 It is not known whether the binding ofprorenin to its receptor is attenuated by the addition ofa renin inhibitor. The binding of renin to this receptoralso elicits an increase in plasminogen activatorinhibitor-1 antigen and an increase in [3H]-thymidineincorporation, without cell proliferation. Renin bindingto the receptor in mesangial cells is not attenuated bythe addition of a renin inhibitor, indicating that therenin catalytic site is distinct from the receptor-bindingsite. Once bound, renin induces a series of intracellularevents, including the activation of the mitogen-activatedextracellular signal-regulated protein kinases, ERK1 andERK2, and19 these effects which are not attributable tothe generation of angiotensin II, are not blocked by therenin inhibitor aliskiren.20 Renin inhibitors cause com-pensatory increase in both prorenin and renin, but theangiotensin-independent actions of these molecules atthe renin receptor are not known.

Endocrine effects of renin inhibitors

In normotensive human beings, renin inhibitors givenintravenously or orally lead to acute and dose-dependent decreases in PRA, angiotensin I, angiotensinII, aldosterone (Table 1), and BP, without inducingreflex tachycardia.8–12,21,22 The natriuretic response torenin inhibitors is dependent on pretreatment renaltone, because the effect of single and multiple doses ofremikiren significantly correlated with pretreatmentrenal vascular tone (estimated from free fraction andrenal vascular resistance), but not with remikiren-induced changes in renal hemodynamics or hormonalparameters.23

Effect of renin inhibitors on plasma renin levels

The in vitro inhibition (IC50 values) of human renin byvarious renin inhibitors is shown in Table 2. The IC50

values are higher in plasma than in buffer because ofthe binding of the renin inhibitors to plasma proteins.In humans, renin inhibitors, such as aliskiren,suppress PRA (dose dependently) when given eitheras monotherapy or in combination with ARBs or ACEinhibitors.24–27 Actually, aliskiren suppresses thecompensatory rise in PRA stimulated by a diuretic,an ACE inhibitor, or an ARB, when given in com-bination.28 However, it causes much greater reactiverise in PRC than does any other antihypertensive classof drugs tested.29 The renin inhibitors, similar to ACEinhibitors and ARBs, only block 90%–95% of plasmarenin, but the pressor consequences of the greaterreactive rise in PRC seem to offset the net ability ofrenin inhibitors to lower BP, especially at higherdoses.29

Effect of renin inhibitors on the variation and normalcircadian rhythm of BP

Aliskiren has no effect on the variation and circadianrhythm of BP.24–28

Table 2. Inhibition of human renin by some renininhibitors IC50 (nmol/L).*

Aliskiren(P100)

0.6 CP-81,198 10.0

Ciprokiren(Ro 44-9375)

0.07–0.65 CP-81,282 5.0

Enalkiren(A 64662)

0.6–14.0 ES-8891 0.7

Remikiren(Ro 42-5892)

0.8–1.7 FK-906 0.6

Terlakiren(CP 80794)

1.1 H-141/H-142 10.0

Zankiren(A 72517)

0.6–1.1 PD 133,450 0.1

SQ 33800 0.35A-74273 3.1–4.3BW-175 3.3 SR 42128 0.03–0.35CGP-29,287 1.0 Ditekren (U 71038) 0.4CGP 38560 0.7–1.0 KR1-1314 4.7CGP-44099A 0.3 GR 70982 6.9CP-72,647 5.0 RO 42-5892 0.5ES 6864 7.3 H-77 1.0SR 43845 0.1 YM-21095 0.47YM-26365 2.9 CI-992 0.58

IC50 is the concentration needed for 50% inhibition of humanrenin.*The renin inhibitors show higher potency in inhibiting renin inin vitro (at pH 7.4 buffer) than in plasma because of proteinbinding in the latter.


240 Israili et al

POTENTIAL ADVANTAGES ANDDISADVANTAGES OF RENININHIBITORS

The advantages of direct renin inhibitors includepossible greater protection from hypertensive compli-cations, additional BP reduction when used in combi-nation therapy, a placebo-like side-effect profile, avidrenal concentration, and long duration of action forsome compounds (eg, aliskiren).27,29 The renin inhib-itors may prevent end-organ damage, especially in thekidney and heart, or at least slow the progression of thedamage. Because PRA is a risk factor for myocardialinfarction,30 and renin inhibitors decrease it, theseagents may be cardioprotective. The Aliskiren Obser-vation of Heart Failure Treatment trial showed that theaddition of the aliskiren to an ACE inhibitor or an ARBand a b-blocker leads to favorable effects on neuro-hormonal actions (reduction in plasma brain natriureticpeptide) in heart failure.31 Compared with the ACEinhibitors, the renin inhibitors have fewer sideeffects.6,13,27,29 The renin inhibitors may find a placeas adjunctive therapy, in combinations with ACEinhibitors or ARBs, or in patients intolerant to thesedrugs.32

Potential limitations include modest levels of BPreduction that are not greater than that produced byARBs or ACE inhibitors,33–35 reduced gastrointestinalabsorption with a high-fat meal, considerable first-pass

effect limiting oral bioavailability, short plasma T1/2

and duration of action (for some renin inhibitors), andlarge reactive increases in renin secretion. The BP doesnot fall, especially in patients with low PRA and a largeincrease in reactive renin secretion, following theadministration of the renin inhibitor.35 Furthermore,development of tolerance may result in the reduction inthe antihypertensive effect of some renin inhibitors,such as remikiren, in salt-replete hypertensive patientsby repeated administration.36 In addition, combinationtherapy (renin inhibitors with ARBs or ACE inhibitors)is expected to increase the incidence of side effects, suchas hyperkalemia and acute renal insufficiency.

PHARMACOKINETICS OF RENININHIBITORS

Some of the pharmacokinetic parameters of renininhibitors are presented in Table 3. The oral bio-availability of most of the renin inhibitors is very low.The T1/2 is rather short, except for aliskiren. Maximumplasma levels (Cmax) achieved after oral administrationis usually dose related, however, there is considerablevariation in the reported values between studies.

Aliskiren

Aliskiren has good water solubility and low lip-ophilicity, but its bioavailability after oral administra-tion is quite low (2.6%). Peak plasma levels (Cmax) are

Table 3. Pharmacokinetic parameters of some renin inhibitors after oral administration.

DrugDose(mg)

Bioavailability(%)

Cmax

ng/mLPlasma t1/2 hours

(6SD)Plasma

Binding (%) References

Aliskiren 150–300 2.7 23–36 24 (16–40) 50 Sureshkumar37

CGP 38560 200 ,1.0 ;9 ;1 de Gasparo et al39

Ciprokiren 0.07–0.65Enalkiren 1.6 6 0.4 89–94 Glassman et al40

Enalkiren 40 0.5 37 Kleinert et al41

ES-8891 240 42 Kokubu et al42

Remikiren 200 ,1.0 4–6 9.4 6 4.1 Weber et al43

Remikiren 300 23–27 Weber et al43

Remikiren 400 0.2 4 Kleinbloesem et al44


Remikiren 600 83 Weber et al43

Remikiren 600 68 McFadyen et al45




Remikiren 1000 137 McFadyen et al45

Zankiren 50 29 Menard et al46





achieved in 1–4 hours (tmax) after oral administration.In healthy volunteers, single oral doses of aliskiren (160mg) produced Cmax (24.2 6 6.79 ng/mL) greater than50 times the reported IC50 values for inhibition of renin(Table 3). Administration of aliskiren (150 mg) withfood reduces Cmax by 81% and area under the plasmalevel time curve (AUC) by 62%, but inhibition of PRA isnot affected.37,38 Absorption is further reduced by high-fat meal. Aliskiren binds moderately strongly toplasma proteins: the mean protein binding is 49.5%,which is independent of concentration over the range10–500 ng/mL.38 The extent of metabolism of aliskirenis not known, but a small fraction of the dose ismetabolized by cytochrome P450CYP3A4; hepaticmetabolism is not significantly affected by changes inCYP450 activity. After oral administration of radioac-tively labeled drug, 91% of aliskiren was eliminatedunchanged in the feces, 1.4% as oxidized metabolites,and 0.6% (one-fourth of the absorbed dose) waseliminated in the urine,47 suggesting a significantinvolvement of hepatobiliary clearance. The terminalT1/2 aliskiren is about 24 hours (range 16–40 hours),suggesting a 2- to 3-fold accumulation in steady-stateplasma concentration, achieved after 7 days of once-daily dosing. In one study, the reported aliskirentrough/peak ratio was 64% and 98% with once-dailydoses of 150 and 300 mg, respectively, indicating thataliskiren maintains significant plasma concentrationsthroughout the 24-hour dosing interval.48

In healthy male volunteers, single and multiple-dosepharmacokinetic studies of oral aliskiren (dose range40–1800 mg) indicate that plasma concentrations of thedrug peak (tmax) between 2 and 4 hours after admini-stration and mean plasma T1/2 of 23–36 hours after theadministration of multiple doses. Aliskiren pharmaco-kinetics deviates from dose linearity, as indicated by theresults obtained for single and multiple once-dailyadministrations over 1 week.49 In the dose range ofaliskiren investigated in healthy male subjects (40–1800mg), Cmax, Cmax, ss, AUC0–[infinity], and AUCtau increaseoverproportionally with doses above 80 mg; between-subject variability in Cmax and AUC is on average, 32%–70% for the dose range of 40–1800 mg.49 Consistent witha T1/2 of approximately 30 hours, exposure to aliskirenincreases after multiple once-daily administration (24-hour intervals), with steady state reached after approx-imately 7 days, and aliskiren accumulates (accumulationratio of 1.4–3.9), especially at higher doses.

After intravenous infusion of 20 mg of aliskirenover 20 minutes in healthy male subjects, plasmaclearance was found to be approximately 9 L/h, thehepatic extraction ratio was approximately 10%, andsteady-state volume of distribution (Vd) was approx-imately 135 L.17

Ethnic Differences: Aliskiren in Japanese and CaucasianSubjects

In Japanese (n = 19) and white (n = 19) healthy youngmale subjects, given a single oral dose of 300 mg ofaliskiren (day 1) and then daily on days 4–10, thepharmacokinetic parameters were comparable: for thesingle dose, the ratio of geometric means Cmax 1.12,AUC0–72 h 1.19 and at steady-state mean ratio Cmax

1.30, AUC0–tau 1.16. There was no difference in theplasma T1/2 of aliskiren between the 2 ethnic groups(29.7 6 10.2 h and 32.0 6 6.6 h, respectively).50 A singleoral dose of aliskiren significantly reduced PRA toa similar extent in Japanese and white subjects (by87.5% and 85.7%, respectively, compared with baseline;P , 0.01). At steady state, peak PRC level and AUC forthe concentration-time plot were not significantlydifferent between Japanese and white subjects.50

Effect of Age: Aliskiren in the Elderly

After a single oral dose of 300 mg of aliskiren in 29 elderlycompared with 28 young subjects, the AUC0–infinity was57% higher and Cmax was 28% higher in the elderly.Other parameters, including tmax and Vd/F, were similarbetween the 2 age groups. No differences in aliskirenexposure were observed between subjects aged 65–74years (n = 16) and .75 years (n = 13).51 However,aliskiren exposure is modestly increased in elderlysubjects as compared with the young subjects. Basedon its wide therapeutic index and shallow dose responsefor BP, no initial dose adjustment should be needed forelderly patients.52

Effect of Disease on the Pharmacokinetics of Aliskiren

Diabetes. Aliskiren showed a similar pharmacokineticprofile when given in a single 300-mg oral dose todiabetics (n = 30) and healthy individuals (n = 30): Cmax

394 versus 348 ng/mL, tmax 1.25 versus 1.0 hour, andT1/2 39 versus 41 hours.53

Renal dysfunction. In a study in patients (n = 17 men)with mild, moderate, or severe renal impairment andhealthy subjects (n = 17 men), after oral administrationof 300 mg of aliskiren daily for 7 days, the renalclearance decreased with the degree of renal impair-ment [1280 6 500 mL/h (mean 6 SD) in healthysubjects versus 243 6 186 mL/h to 559 6 220 mL/h inpatients with renal dysfunction], but the changes inexposure (measured by AUC) and drug accumulation,which increased with renal dysfunction, did notcorrelate with renal clearance, consistent with an effectof renal impairment on nonrenal drug disposition.54

However, no initial dose adjustment should be neededin patients with mild-to-moderate renal dysfunction.


242 Israili et al

Hepatic dysfunction. A pharmacokinetic study inpatients with mild, moderate, and severe hepaticfunction after a single 300 mg, showed that therewas no significant difference in AUC or Cmax inpatients as compared with healthy subjects, suggestingthat dosage adjustment is unlikely to be needed inpatients with liver disease.55

Pharmacokinetic Drug Interactions with Aliskiren

Aliskiren is metabolized by cytochrome P450 only toa minimal extent and it does not inhibit CYPisoenzymes. In vitro inhibition data for specificcytochrome P450 enzyme activities in human livermicrosomes indicate that interactions between aliskirenand its metabolites and drugs metabolically cleared byhuman cytochromes are unlikely. In a multiple-dosestudy, aliskiren showed no clinically relevant pharma-cokinetic interactions when coadministered with allo-purinol, celecoxib, or cimetidine in healthy subjects.56

In healthy individuals, single doses of aliskiren did notexhibit clinically important pharmacokinetic interac-tions with lovastatin, atenolol, celecoxib or cimeti-dine,57 or warfarin.58 No significant pharmacokineticinteractions were observed between aliskiren andamlodipine, hydrochlorothiazide, valsartan and ram-ipril,59 or metformin, pioglitazone and fenofibrate.60 Inhypertensive patients, coadministration of hydrochlo-rothiazide (HCTZ) (25 mg), irbesartan (150–300 mg), orramipril (5 mg) daily for 6 weeks had no significanteffect on plasma levels of aliskiren (300 mg).28,54

Aliskiren may negligibly reduce the bioavailability ofdigoxin.61 Atorvastatin may increase the level/effect ofaliskiren, hence BP should be checked.61 Coadminstra-tion of ketoconazole results in increases in Cmax ofaliskiren by a factor of 1.8.61 When administeredconcomitantly with furosemide, the AUC of furose-mide was decreased; consequently, it is recommendedto monitor furosemide effects.62

Remikiren

After oral administration of remikiren in dosesranging from 30 to 1600 mg, bioavailability is only0.2%–0.3%, and plasma Cmax and AUC are highlyvariable, and not proportional to the dose.43,44 Thedrug is rapidly absorbed with a tmax of 0.9–1.6 hours;plasma T1/2 after an oral dose is about 7 hours, andafter intravenous dose it is 5.2–8.2 hours, withbiphasic elimination. The drug does not accumulateafter multiple dosing.

After oral administration of remikiren (40 mg),the bioavailability is very low (0.5%) and plasma Cmax

is 37 + 14 ng/mL.44 After intravenous administration,plasma T1/2 was 1.60 6 0.43 hours.44

Other renin inhibitors

The bioavailability of an oral dose of 200 mg of CGP38,560 is ,1% with Cmax of 9 ng/mL, and a T1/2 ofabout 1 hour.39 The oral bioavailability of ES-8891(240 mg) and FK 906 (400 mg) are very low, and plasmaCmax of 42.4 + 7.6 ng/mL and 167 ng/mL, respectively,are achieved.42

CLINICAL STUDIES OF RENININHIBITORS

The effect of orally administered renin inhibitors on BPis presented in Table 4. Aliskiren seems to be the mostpotent of the group. For some, such as remikiren(600 mg/d), there was no significant effect on BP evenafter 4 days of continuous administration in normo-tensive subjects,44 or a single dose of up to 1600 mg inhypertensive patients.70 It is not because of poorabsorption, because remikren decreased PRA, andaddition of hydrochlothiazide (12.5 or 25 mg/d)produced significant reduction of BP.48

Aliskiren

Aliskiren was the first of the orally effective renininhibitors approved in the United States (Tekturna�,2007), and in Europe (Rasilez�, 2007) for the treatmentof hypertension. It has sufficient bioavailability toproduce sustained suppression of PRA after oraladministration. However, at higher doses, it causesa reactive rise in renin levels.33,35 Pooled data from 8randomized multicenter trials in 8570 hypertensivepatients (duration of therapy of 6–52 weeks) show thataliskiren effectively reduces BP independently ofpatient age or sex. The BP reduction is dose dependentand BP is controlled for 24-hour up to a dose ofapproximately 300 mg daily (maximum dose); at thesedoses, aliskiren is very well tolerated.48,72,73 In 672patients randomized to treatment for 8 weeks withaliskiren 150, 300, and 600 mg compared with placebo,the reduction in mean sitting BP was significantlyhigher with aliskiren (systolic BP/diastolic BP:213.0/210.3, 214.7/211.1, and 215.8/212.5 mmHg, respectively) than with placebo (23.8/24.9 mmHg; all P , 0.0001 for systolic and diastolic BP). Themean 24-h ambulatory BP was also reduced signifi-cantly (P , 0.0001) with aliskiren compared to placebo;aliskiren had a smooth, sustained effect and hightrough-to-peak ratios. The BP-lowering effect ofaliskiren persisted for up to 2 weeks after treatmentwithdrawal. Aliskiren was well-tolerated; overalladverse event rates were 40.1%, 46.7%, and 52.4%with aliskiren 150, 300, and 600 mg, respectively, and43.0% with placebo. Few patients discontinued



treatment due to adverse events.48 The antihyperten-sive potency of aliskiren is approximately equivalent tothat of ACE inhibitors or ARBs, and diuretics. Afterabrupt withdrawal, persistent BP reduction andprolonged suppression of PRA is observed.73 Aliskirencan be effectively combined with the majority of otherantihypertensive agents (HCTZ, amlodipine, ramipril,valsartan). The dose may be taken with or withoutmeals (except high-fat meals). It is recommended thathypovolemia be corrected before initiation of therapy,and volume status should be monitored, especially inpatients on concurrent diuretics. The dose in childrenunder 18 years of age has not been established. There islimited experience with overdosage; treatment issymptom directed and supportive. Excretion of alsi-kiren in breast milk is unknown; the drug is notrecommended in lactating women. There are noadequate and well-controlled studies in pregnantwomen; aliskiren should be discontinued as soon aspossible after pregnancy is detected.

No dosage adjustment is necessary in the el-derly51,52 or in patients with hepatic dysfunction55

or mild-to-moderate renal impairment [glomerularfiltration rate (GFR) . 30 mL/min and/or Scr , 1.7mg/dL (women); Scr , 2 mg/dL (men)].38,54

However, the dose in patients with severe renalimpairment [GFR , 30 mL/minute and/or Scr . 1.7mg/dL (women); Scr . 2 mg/dL (men)] has not beenestablished.

Dose-Response Effect for Aliskiren

The dose–response effect for aliskiren (oral doses) hasbeen shown to be shallow. For example, the decrease inthe trough diastolic BP (corrected for placebo = 7 mm Hg)was 9.5 mm Hg at 150 mg, 12.5 mm Hg at 300 mg, and12.0 mm Hg at 600-mg oral dose (Table 5); in comparison,the decrease was 9.5 mm Hg for 150 mg of irbesartan.29

Comparison of Aliskiren With Other AntihypertensiveDrugs: Efficacy of Monotherapy

Once-daily administration of aliskiren to hypertensivepatients lowers BP as effectively as standard doses ofestablished ARBs (such as losartan, valsartan, andirbesartan), HCTZ, ACE inhibitors (such as ramipriland lisinopril), or long-acting calcium channel blocks(CCBs) (such as amlodipine).

A 12-week comparison of aliskiren (300 mg/d) withHCTZ (25 mg/d) in hypertensive patients (n = 1123)showed that aliskiren was more effective in decreasingBP than HCTZ.74 The long-term (52 week) efficacy,safety and tolerability of aliskiren (150–300 mg/d) wascompared with that of HCTZ (12.5–25 mg/d) in obesepatients (n = 396) with hypertension. Amlodipine (5–10mg) was permitted as add-on therapy to achieve BPcontrol (systolic/diastolic ,140/,90 mm Hg). Aliski-ren monotherapy provided significantly greater BPreduction than HCTZ at week 12 endpoint(216.7/212.3 vs. 212.2/29.1 mm Hg, P , 0.001),

Table 4. Effect of some renin inhibitors on BP.

Drug Subjects Oral dose* Change in BP† References

Aliskiren 18 NT 40–640 3 8 0/0 Nussberger et al63

197 HT 37.5–300 3 28 24/0 Stanton et al64

437 HT 150–300 3 56 213/29 Oparil et al22

652 HT 150–600 3 56 210/25‡§{ Gradman et al29

Remikiren 14 HT 600 3 8 211k van Paassen et al66

16 HT 600 3 1 210/27# van Paassen et al66

24 HT 600 3 8 2NA/210 Kobrin et al67

25 HT 100 3 8 29/26 Viskoper et al68

55 NT 600 3 4 0/0 Kleinbloesem et al44

49 HT 300–600 3 8 211/23 Rongen et al69

29 HT 100–1600 3 1 0/0 Himmelmann et al70

Zankiren 24 NT 10–250 3 1 26/28 Menard et al46

ES-8891 6 NT 240 3 1 0/0 Kokubo et al42

FK-906 14 HT 25–100 b.i.d. 232/220‡ Ogihara et al71

*Oral dose in mg, given for the indicated number of days.†Change in systolic BP/diastolic BP (mm Hg) at peak drug levels.‡Change in systolic BP/diastolic BP (mm Hg) at the maximum dose.§Change in systolic BP/diastolic BP (mm Hg) with or without HCTZ 12.5 mg q.d.{Change in systolic BP/diastolic BP (mm Hg) at trough drug levels.kMean arterial pressure in mm Hg.#Change in systolic BP/diastolic BP (mm Hg) at low salt diet.NT, normotensives; HT, hypertensives.


244 Israili et al

and at week 52 endpoint, there was a trend for lowerBP (219.9/215.5 vs. 217.5/213.3 mm Hg; P = 0.138for systolic BP and P = 0.007 for diastolic BP). Mean BPreductions from baseline with aliskiren-based therapywere similar in obese and nonobese patients, butHCTZ-based therapy provided significantlysmaller mean reductions in BP from baseline in obesepatients vs. nonobese patients (P , 0.05). Aliskiren-based therapy was generally well tolerated in obesepatients, and was associated with a significantly lowerincidence of hypokalemia (1.0% vs. 14.0%, P , 0.0001)than HCTZ-based therapy.75

A randomized, double-blind, parallel comparatorstudy was carried out to assess the BP-lowering effi-cacy of aliskiren (37.5–300 mg) and losartan (100 mg) inhypertensive patients.64 There was a dose-dependentreduction in daytime ambulatory systolic BP (Table 6)with aliskiren. The change in BP with 300 mg ofaliskiren was not different from that of 100 mg oflosartan. The drugs were well tolerated.

In a randomized, multicenter, double-blind, pla-cebo-controlled, active comparator, 8-week, parallelgroup trial in 652 patients with mild-to-moderatehypertension, the office, sitting diastolic BP-loweringeffects at trough of aliskiren (150, 300, or 600 mg daily)and irbesartan 150 mg daily were compared.29

Aliskiren significantly decreased trough diastolic BPat 8 weeks, in a dose-dependent manner, but the dose–response curve was flat (Table 5). Aliskiren, 150 mghad a similar antihypertensive effect as 150 mg of

irbesartan; higher dose (300 mg) of aliskiren hada greater BP-lowering effect than 150 mg of irbesartan.The safety profile of aliskiren was similar to that ofplacebo or irbesartan.

In a double-blind study in 842 hypertensive patients(mean sitting diastolic BP 95–105 mm Hg), the long-term(26 weeks) efficacy, safety, and tolerability of aliskiren(150–300 mg/d) was compared with ramipril (5–10mg/d), with or without HCTZ (12.5–25 mg/d).76 Therewas a gradual increase in BP reduction with time, from 3weeks to 18 weeks, after that there was no furtherreduction. At week 26, aliskiren-based therapy pro-duced greater reduction of mean sitting systolic (17.9versus 15.2 mm Hg, P = 0.0036) and diastolic BP (13.2versus 12.0 mm Hg, P = 0.025), and higher rate of BPcontrol (72.5% versus 64.1%, P = 0.0075) than ramipril-based therapy (Table 7). BP reduction was maintainedduring active therapy. During withdrawal, BP increasedmore rapidly after stopping ramipril-based than alis-kiren-based therapy. Aliskiren therapy was well toler-ated. Overall adverse event rates were similar withaliskiren (61.3%) and ramipril (60.4%); cough was morefrequent with ramipril (9.5%) than aliskiren (4.1%).

Combination of Aliskiren with Other AntihypertensiveDrugs

In combination therapy, aliskiren further decreases BPwhen combined with HCTZ, amlodipine, irbesartan, orramipril, possibly by a synergistic action both in termsof efficacy and tolerability (Table 8).

Table 5. A comparison of the efficacy of aliskiren and irbesartan in hypertensive patients BP levels and % patients withcontrolled BP at end point.

Trough mean sittingdiastolic BP (mm Hg)

Trough mean sittingsystolic BP (mm Hg) No. of patients

with controlled BPTreatment/dose Baseline End point Baseline End point N (%)*

Placebo 98.9 6 3.3 92.3 6 9.6 152.3 6 12.1 147.3 6 17.6 27/130 (20.8)Aliskiren, 150 mg 98.8 6 3.4 89.4 6 8.7 151.3 6 11.1 140.4 6 14.2 48/127 (37.8)†Aliskiren, 300 mg 98.8 6 3.4 86.8 6 9.4 152.1 6 10.2 136.6 6 13.9 65/130 (50.0)†‡Aliskiren, 600 mg 99.1 6 3.7 87.5 6 9.6 152.6 6 11.5 137.0 6 16.2 59/129 (45.7)†‡Irbesartan, 150 mg 99.4 6 4.0 90.3 6 9.2 152.8 6 11.2 140.3 6 16.3 45/133 (33.8)†

*BP control was defined as trough mean sitting diastolic BP , 90 mm Hg and trough mean sitting systolic BP , 140 mm Hg at end point.Data are presented as the mean 6 SD; †P , 0.05 versus placebo; ‡P , 0.05 versus irbesartan 150 mg. Adapted from Gradman et al.29

Table 6. A comparison of the efficacy of aliskiren and losartan in hypertensive patients.

Week 4, end point ALIS ALIS ALIS ALIS LOS

N 39 41 41 40 36Dose (mg) 37.5 75 150 300 100Systolic BP*(mm Hg) 20.3 6 1.5 25.5 6 2.0 28.0 6 2.0 211.5 6 2.0 211.5 6 2.5Diastolic BP*(mm Hg) +0.3 6 2.0 24.0 6 1.0 25.0 6 1.2 27.5 6 1.5 26.0 6 1.5

*The values (mean 6 SEM) are changes in daytime ambulatory BP. ALIS, aliskiren; LOS, losartan.Adapted from Stanton et al.64



Renin Inhibitor + Diuretic. Aliskiren in combinationwith HCTZ seemed to lower BP more than the combi-nation with an ARB (aliskiren + ARB), but still failed tocontrol BP (,140/,90) in 50% of the patients.28,77

Administration of a fixed combination of aliskirenand hydrochlorothiazide (in one pill) was effective incontrolling BP for up to 1 year.78

Renin Inhibitor + ARB. When given with an ARB,aliskiren produces significant additional BP reductionindicative of complimentary pharmacology and morecomplete RAAS blockade. In 569 hypertensive patients,aliskiren (150–600 mg/d) significantly decreased sys-tolic BP in a dose-dependent way; the decrease in BPwith 300 mg of aliskiren was similar to that produced by150 mg of irbesartan.27,29 In a randomized, double-blind,placebo-controlled study, 1797 patients with stages 1–2diastolic hypertension (mean sitting diastolic BP = 95–109 mm Hg) were randomized to receive aliskiren +valsartan (150/160 mg), 150 mg of aliskiren, 160 mg ofvalsartan, or placebo for 4 weeks, followed by 4 weekson double dose regimen. At 8 weeks, the combinationwas superior (Table 9) to single doses of the drugs orplacebo in reducing both systolic and diastolic BP.22,24,79

The rates of adverse events were similar (34%–37%),with headache being most common.22,24 However,hyperkalemia was significantly more common in patientswho received both valsartan and aliskiren.

A fixed dose combination (Valturna�) of aliskirenand valsartan (150/160 mg, 300/320 mg) has recentlybeen approved by the US-FDA for the treatment ofhypertension (November 2009).

Intravenous administration

Although, the renin inhibitors have been developed fororal dosing, many renin inhibitors have been tested for

their BP-lowering effect in healthy volunteers whengiven by the intravenous route, for example, enalki-ren,80,81 CGP 38560A,82,83 H142,84,85 remikiren,68,86 andR-PEP-27.87 In sodium-replete normotensive individu-als, the effect of intravenous drug administration on BPis minimal.81 However, in sodium-depleted volunteers,the BP is decreased,81 and in some there may be a sharpdrop in BP and bradycardia.85 In hypertensive patients,intravenous administration of some renin inhibitorsreduces BP, for example, CGP 38560A,83 enalkiren,40,88–

92 remikiren,13 RO 42-5892,93 and SR 43845.94 Thehypotensive effect of intravenously administered renininhibitors is enhanced by sodium depletion,94 with lowsodium diet or pretreatment with a diuretic.91,94

Table 8. Combination therapy with a renin inhibitor anda diuretic, an ACE inhibitor, or an ARB in hypertensive-patients.

Aliskiren + HCTZ

Week 6 end point ALIS ALIS/HCTZDose (mg) 150 150/25N 23 23Change in daytime ABPM

Systolic/diastolic (mm Hg) 210/26 218*/211*Change in night-time ABPM

Systolic/diastolic (mm Hg) 29/25 216†/28

Aliskiren + Ramipril

Week 6 end point RAM RAM/ALISDose (mg) 5 5/150N 21 21Change in daytime ABPM

Systolic/diastolic (mm Hg) 26/26 214‡/29‡Change in night-time ABPM

Systolic/diastolic (mm Hg) 23/21 210§/27

Aliskiren + Irbesartan

Week 6 end point IRB RAM/ALISDose (mg) 150 150/150N 23 23Change in daytime ABPM

Systolic/diastolic (mm Hg) 212/27 214/27Change in night-time ABPM

Systolic/diastolic (mm Hg) 29/41 214{/27{

*P , 0.001 ALIS versus combination.†P , 0.05 ALIS versus combination.‡P , 0.001 RAM versus combination.§P , 0.05 RAM versus combination.{P , 0.05 IRB versus combination.ALIS, aliskiren; ABPM, ambulatory BP monitoring; IRB, irbesartan;RAM, ramipril in Japanese hypertensive patients.95 Adapted fromO’Brien et al.28

Table 7. A comparison of the efficacy of aliskiren andramipril in hypertensive patients.

Week 26 end point ALIS* RAM*

N 414 418Dose (mg) 150–300 5–10msSystolic BP† (mm Hg) 217.9 6 0.7 215.2‡6 0.6msDiastolic BP† (mm Hg) 213.2 6 0.4 212.0§6 0.4Patients (%) achieving

BP control72.5 64.1‡

*Hydrocholorothiazide (12.5–25 mg) was added if BP was notcontrolled after 8 weeks of treatment.†The values are mean 6 SEM.ALIS versus RAM §P , 0.05; ‡P , 0.005.ALIS, aliskiren; RAM, ramipril; msSystolic BP, mean sittingsystolic BP; msDiastolic BP, mean sitting diastolic BP. Adaptedfrom Anderson et al.76


246 Israili et al

Ethnic differences in efficacy andtolerability—aliskiren in Japanese hypertensives

Aliskiren given for 8 weeks at doses of 75, 150, or 300mg produced significant, dose-dependent reductions inmean sitting diastolic BP (P , 0.0005 versus placebo foreach dose) and mean sitting systolic BP (P , 0.001versus placebo for each dose). The placebo-correctedreductions in mean sitting systolic/diastolic BP were5.7/4.0, 5.9/4.5, and 11.2/7.5 mm Hg in the aliskiren75-, 150-, and 300-mg groups, respectively. After 8weeks of treatment, 47.8%, 48.2%, and 63.7% ofpatients in the aliskiren 75-, 150-, and 300-mg groups,respectively (placebo = 27.8%) achieved a successfultreatment response (diastolic BP ,90 mm Hg and/orreduced by . or =10 mm Hg from baseline; P , 0.005versus placebo for each dose). Aliskiren treatment waswell tolerated; the incidence of adverse events in theactive treatment groups (53%–55%) was similar to thatin the placebo group (50%).95 The efficacy andtolerability of aliskiren was similar in Japanese andhealthy white subjects.50,95

Aliskerin in Obese Hypertensives

The renin system is activated in obesity-associatedarterial hypertension. Obese hypertensive patients(n = 489) who had not responded to 4 weeks oftreatment with HCTZ (25 mg) were randomized toreceive daily aliskiren (150 mg), irbesartan (150 mg),amlodipine (5 mg), or placebo for 4 weeks (added to 25mg of HCTZ), followed by 8 weeks on double theinitial doses of aliskiren, irbesartan, or amlodipine. Thecombination aliskiren/HCTZ lowered BP by 15.8/11.9mm Hg, significantly more (P , 0.0001) thanplacebo/HCTZ (n = 500; 8.6/7.9 mm Hg), but similarto that with the combination of irbesartan/HCTZ(15.4/11.3 mm Hg) or amlodipine/HCTZ (13.6/10.3mm Hg). The tolerability was similar in all groups,except for peripheral edema, which was highest withamlodipine/HCTZ (11.1% versus 0.8%–1.6% in othergroups). The investigators concluded that the combi-nation of aliskiren/HCTZ is a good therapeutic optionin obese patients who fail to achieve BP control withHCTZ alone.96

Table 9. Efficacy of aliskiren and valsartan, individually and in combination in hypertensive patients.

Week 4 end point ALIS/VAL ALIS VAL PBO

Dose (mg) 150/160 150 160 —N 438 430 453 455Change in DBP (mm Hg) 210.5 6 0.4* 27.5 6 0.4*† 28.7 6 0.4*† 24.8 6 0.4Change in SBP (mm Hg) 215.3 6 0.6* 210.7 6 0.6*† 210.9 6 0.6*† 25.2 6 0.6

Week 8 end point ALIS/VAL ALIS VAL PBO

Dose (mg) 300/320 300 320 —N 438 430 453 455Change in DBP (mm Hg) 212.2 6 0.4* 29.0 6 0.4*† 29.7 6 0.4*† 24.1 6 0.4Change in SBP (mm Hg) 217.2 6 0.7* 213.06 0.7*† 212.8 6 0.7*† 24.6 6 0.7BP control rate (%)‡ 49.3* 37.4*† 33.8*† 16.5

*P , 0.0001 versus PBO.†P , 0.0001 versus ALIS/VAL.‡SBP/DBP ,140/,90 mm Hg. ALIS, aliskiren; DBP, diastolic BP; PBO, placebo; SBP, systolic BP; VAL, valsartan. Adapted from Oparil et al.20,24

Table 10. Adverse effects profile of aliskiren, valsartan and combination.

Adverse events Placebo Aliskiren Valsartan Valsartan + aliskiren

Headache 9% 3% 5% 4%Nasopharyngitis 2% 4% 4% 3%Dizziness 2% 2% 2% 2%Fatigue 1% 1% 2% 2%Nausea 2% 1% 2% 2%Any adverse event 37% 34% 37% 35%Any serious adverse event 1% 2% 1% 0.7%

Discontinuation rate due to adverse effects was between 2% and 3%. Adapted from Oparil et al.20,24



In the long-term (52 week) comparator study ofaliskiren (150–300 mg/d) and HCTZ (12.5–25 mg/d),mean BP reductions from baseline with aliskiren-basedtherapy were similar in obese and nonobese patients,while HCTZ-based therapy provided significantlysmaller mean reductions in BP from baseline in obesepatients vs. nonobese patients (P , 0.05). Aliskiren-based therapy was generally well tolerated in obesepatients, and was associated with a significantly lowerincidence of hypokalemia (1.0% vs. 14.0%, P , 0.0001)than HCTZ-based therapy.75

Aliskerin in diabetic hypertensives

Aliskiren seems to be a better agent than ramipril incontrolling high BP in diabetic patients with hyper-tension97; a combination of aliskiren with ramipril wasmore effective.97

Aliskiren in the elderly

Aliskiren is well tolerated by tolerated by patients of allage groups, including the very old ones.51,52 Based onpharmacokinetic data, no initial dose adjustment ofaliskiren should be needed for elderly patients.51

CARDIO-RENOPROTECTIVE EFFECTOF RENIN INHIBITORS

Besides their utility as antihypertensive agents, theability to decrease renin and PRA, the more completeinhibition of the RAAS, the expected limitation ofangiotensin II and aldosterone escape phenomena, andthe prevention of possible direct damaging effects ofrenin on the kidney make the renin inhibitors useful inpatients with cardiac and renal dysfunction.

In a study in spontaneously hypertensive rats, givenan ACE inhibitor, ARB, renin inhibitor, or thecombination of hydralazine and HCTZ for 7 days toobtain the same decrease in BP, the effects of blockadeof the RAAS at 3 different sites on regression of leftventricular hypertrophy were investigated. Treatmentwith the ACE inhibitor, ARB, or renin inhibitor signifi-cantly decreased left ventricular mass, but hydralazine(plus HCTZ) had no effect.98 These findings indicatedthat blockade of the RAAS regressed left ventricularhypertrophy irrespective of the site of the blockade andindependent of hemodynamic changes. Even thoughthe study is of a short duration, the trend is positive.98

In humans, aliskiren has also been shown to have afavorable influence on the regression of cardiac hyper-trophy as shown in the aliskiren in Left-VentricularHypertrophy trial.99

The Aliskiren Observation of Heart Failure Treat-ment trial (ALOFT) showed that the addition of

aliskiren to an ACE inhibitor or ARB and a b-blockerleads to favorable effects on neurohormonal actions(reduction in plasma brain natriuretic peptide) in heartfailure; aliskiren was well tolerated in these patientswith heart failure receiving ACE inhibitors or ARBs,although the study was not powered to show clinicalbenefit.31

In patients with chronic congestive heart failure (CHF)(n = 9), intravenous administration of enalkiren(1.0 mg/kg) produced increases in cardiac index (from2.0 6 0.3 to 2.3 6 0.1 liter/min/m2) and stroke volumeindex (from 26 6 3 to 34 6 4 mL/m2) and decreases inleft ventricular filling pressure (from 31 6 3 to 25 6

3 mm Hg), mean right atrial pressure (from 15 6 1to 13 6 2 mm Hg), heart rate (from 78 6 5 to 72 6 6beats/min), and systemic vascular resistance (from2199 6 594 to 1339 6 230 dynes�s�cm25) (all P , 0.01–0.05). These observations indicate that renin inhibitionproduces hemodynamic benefits in patients withchronic CHF and could potentially provide a novelapproach to interfering with the RAAS in patients withthis disorder.100

In a double-blind trial, 36 patients with CHF (NewYork Heart Association Class 2 or 3) were givenintravenous remikiren, enalaprilat, or their combination.Remikiren and enalaprilat were associated with similarrapid reductions in systemic vascular resistance and BP.These hemodynamic changes were proportional to thebaseline PRA. Both drugs also equally lowered BP in theright atrium and pulmonary artery and the pulmonary-capillary wedge pressure. During exercise, remikirenand enalaprilat similarly increased the stroke volumeindex and reduced pulmonary-capillary wedge pres-sure. The combination of both drugs did not induceadditive hemodynamic changes.101

Remikiren increased renal blood flow and decreasedrenal vascular resistance (RVR) in healthy and hyper-tensive sodium-depleted men who received angioten-sin II infusion.102 Similarly, in 14 hypertensive patientswith normal or impaired renal function, remikirengiven once daily at a dose of 600 mg reduced meanarterial pressure from baseline by 11.2% at peak plasmaconcentration and by 6.0% at trough levels.103 In thisstudy, GFR remained stable, whereas effective renalplasma flow increased, and free-fraction and RVRdecreased by 15% and 10%, respectively; remikiren alsoreduced proteinuria by 27%, indicating a reduction inglomerular protein leakage; remikiren also induceda cumulated sodium loss of 282 6 22 mmoL anda positive potassium balance of 49 6 9 mmoL (both P ,

0.01). These data are consistent with a renoprotectivepotential of renin inhibition.103

The apparent renoprotective effect of the 8-day courseof remikiren contrasted with its weak BP-lowering


248 Israili et al

activity and probably reflected specific uptake of thedrug by the kidney.104 Zankiren also induced a largerenal vasodilator response in normal volunteers on lowsodium diet.105

The renoprotective effect of a renin inhibitor issimilar to that of an ACE inhibitor, as shown bya study106 in which 6 hospitalized patients (proteinuria5.8 6 2.9 g/d) were treated with remikiren (600 mg/dfor 8 days), and 8 ambulant patients (proteinuria 7.5 6

2.7 g/d) were treated for 6 weeks with trandolapril(4 mg/d). Although, both drugs decreased BP signif-icantly during the day and during the night, thedecrease in proteinuria was significant only duringthe day: from 0.29 6 0.15 to 0.22 6 0.11 g/h (P , 0.05)with remikiren, and from 0.33 6 0.14 to 0.16 6 0.08 g/h(P , 0.05) with trandolapril. Night-time proteinuriadecreased but not significantly: from 0.23 6 0.11 to0.19 6 0.11 g/h (P = NS) with remikiren, and from0.29 6 0.17 to 0.20 6 0.12 g/h (P = NS) withtrandolapril. In patients with diabetic nephropathy,addition of aliskiren to losartan resulted in a 20%greater reduction in proteinuria.107

In animal experiments, aliskiren attenuated renaldamage.108 In transgenic rats, aliskiren at antihyper-tensive doses, attenuated end-organ (renal and cardiac)damage, similar to that produced by valsartan.109

Results from a number of clinical studies (Aliskiren inLeft Ventricular Hypertrophy [ALLAY] trial, ALOFT,and Aliskiren in the eValuation Of proteinuria InDiabetes [AVOID] trial) suggest that aliskiren (with orwithout ACE inhibitors/ARBs) has positive effects onthe markers of cardiovascular and renal damage inpatients with type 2 diabetes and nephropathy, heartfailure and left ventricular hypertrophy.31,99,110,111 Asuggestion has been made that aliskiren may haverenoprotective actions superior to those of ACEinhibitors and ARBs.112 There are some large ongoingstudies to assess the cardio-renal protective effect ofaliskiren (ALTITUDE, involving more than 8000 patientsstudying the effect of addition of aliskiren 300 mg/d toACE inhibitor/ARB treatment on cardiovascular andrenal morbidity and mortality,113 and ASPIRE HIGHER,the largest trial to study the beneficial effects of aliskirenon cardio-renal protection is ongoing111).

ADVERSE EFFECTS OF RENININHIBITORS

The major adverse effects (in 1%–10% of patients),include malaise, palpitation, dizziness (2%), rash (1%),hyperkalemia (monotherapy #1%; concurrent with ACEinhibitors in patients with diabetes or renal dysfunction,and those on potassium supplements 6%), diarrhea (1%

to 2%), nocturia, increase in creatinine kinase (.300% in1%), increase in blood urea nitrogen and serum creatinine(#7%), and cough (1%).114–117 Other adverse effects(,5%) include angioneurotic edema, abdominal pain,anemia, angina, gastroesophageal reflux, gout, myositis,renal stone formation, rhabdomyolysis, seizure, andhyperuricemia.118 Hypotension may also occur inpatients with an activated RAAS, such as in volume orsalt-depleted patients, such as or patients on diuretics.Contraindications to the use of aliskiren include:hypersensitivity to aliskiren or any component of theformulation, history of idiopathic or hereditary angioe-dema, history of ACE inhibitor- or ARB-related angioe-dema, bilateral renal artery stenosis, and pregnancy.118

In one of the large studies, sponsored by the drugindustry, the reported adverse effect profile has beenclaimed to be similar to that of placebo or valsartan(Table 10).20,24

THE FUTURE OF RENIN INHIBITORSAS ANTIHYPERTENSIVE AGENTS

There are 2 opposing views about the future of renininhibitors based upon the following observations: (1)analysis of the clinical trials involving over 5000hypertensive patients show that aliskiren is not moreeffective as an antihypertensive agent than ACEinhibitors, ARBs, diuretics or calcium channel blockers;(2) aliskiren has a shallow antihypertensive dose–response curve; (3) the combination of aliskiren with anACE inhibitor or ARB lowered BP to a greater extentthan aliskiren alone, yet, BP control was achieved inless than 50% of patients; (4) aliskiren stimulateskidney renin secretion to a greater degree than do ACEinhibitors or ARBs, its antihypertensive capabilities canbe counteracted by large reactive increases in reninsecretion, especially at higher dosage; (5) the high costof medication, continuing problems with oral bio-availability,33,35 Laragh et al. have recommended thatin most patients, treatment of hypertension should becarried out with safe and less expensive, equallyeffective and widely available generic ACE inhibitorsor ARBs.33 The drug has not been tested in re-novascular hypertension or severe hypertension. Inaddition, the overall adverse effect profile of aliskirendoes not seem to be any better than that of otherantihypertensive drugs, as aliskiren contributes to theonset of angioedema, cough, diarrhea, and abdominalpain, hyperuricemia, gout attacks, kidney stones andskin rash. Hence, it has been suggested that:33,118 ‘‘Inpractice, it is better not to use aliskiren to treathypertensive patients because better-assessed antihy-pertensive drugs with longer follow-up are available.’’



Furthermore, long-term renin inhibition therapy mayinduce pharmacologic tolerance with renin hyperse-cretion, and the phenomenon of rebound hypertensionafter abrupt cessation of chronic therapy. This hyper-secretion also would result in an increased release ofprorenin, which might have unknown effects on localtissue RAAS. In addition, excessive levels of prorenin,with its localized vasodilatory potential, also maypredispose to hypoperfusion injury in various tissues,especially in patients with diabetes mellitus.119

On the other hand, in the opinion of Fisher andHollenberg105 the potential of renin inhibition inhuman therapy has been underestimated and indeedshows substantial promise, thus prompting the searchfor a better orally acting renin inhibitor. In addition, therole of prorenin in the pathogenesis of microvascularinjury is beginning to unravel, as a number of studieshave shown that the onset of microvascular disease(nephropathy and retinopathy) in diabetic and hyper-tensive patients coincides with elevated plasma levelsof prorenin.119–122 If renin inhibitors block the bindingof prorenin to the renin receptor, these agents may bevaluable in controlling the microvascular disease,especially in the kidney and eye.

In addition, renin inhibition has potential therapeuticefficacy in the treatment of renovascular and CV disease(see earlier). Renin inhibition may also have clinicalutility in stroke, myocardial infarction, scleroderma,renal trauma, and acute closure of renal artery grafts,because all of these pathologies are associated with highplasma renin levels.123–128 The demonstration of re-duction of intraocular pressure in unanesthesizedrabbits and anesthesized monkeys by topical applica-tion of enalkiren suggests a possible functional role ofRAAS in modulation of intraocular pressure and thepotential clinical utility of renin inhibitors as ocularpressure-lowering agents.129 Finally, renin inhibitors arepromising drugs for combating renal fibrosis as shownin severely hypertensive double transgenic rats harbor-ing the human renin and angiotensinogen genes.109

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