Aliskiren for Direct Renin Inhibition in Hypertension

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Direct renin inhibitors (DRIs) are the first new class of drugs in 14 years that are available for the treatment of hypertension. Cleavage of angiotensinogen to angiotensin I by renin is the initial rate-limiting step of the renin–angiotensin system (RAS) and has long been recognised as a preferred site for blockade of RAS.1 Angiotensin-converting enzyme inhibitors (ACEIs) work a step later, preventing the conversion of angiotensin I to angiotensin II. Angiotensin receptor blockers (ARBs) block the final step, which is the binding of angiotensin II to the angiotensin II type 1 (AT1) receptor (see Figure 1). There exist several limitations in the efficacy of RAS blockage with the current RAS inhibitors ACEIs and ARBs. Non-ACE pathways can be activated under an ACE-inhibited situation in some organs, such as the kidneys, heart and blood vessels, and angiotensin II generation may continue (angiotensin II escape).2,3 Under an AT1 receptor-inhibited condition, higher levels of circulating angiotensin II, which is not only a potent vasoconstrictor but also a generator of various growth-promoting pro-inflammatory cytokines, fibrosis and oxygen radical mediators, may bring about a harmful effect on the cardiovascular system.4 Only beta-blockers have been known to lower the secretion rate of renin from the kidneys to reduce its plasma concentration, as well as plasma renin activity (PRA). However, there is little evidence suggesting end-organ protection effects by RAS blockade with beta-blockers. In contrast, DRIs bind to the active site of the renin molecule blocking angiotensinogen cleavage, thus preventing the formation of angiotensin I.1 Blockade of the RAS at any point leads to a compensatory increase in renin release, as angiotensin II levels drop or its effects at AT1 receptors on juxtaglomerular cells in the kidney are blocked. However, DRIs are unique in counteracting the resultant increase in circulating renin concentration by inhibiting its action as an enzyme, i.e. reducing PRA.5 Of course, long-term outcome evaluation study is warranted to exclude concerns related to the elevation of plasma renin.6 However, initial results with DRIs have shown superior RAS blocking efficacy to beta-blockers and at least the same range as ACEIs or ARBs.7

Although a number of DRIs, such as ditekiren, enalkiren, zankiren and remikiren, have been synthesised in the past, they were not developed for clinical use due to poor oral bioavailability, low efficacy, short half-life and high cost of synthesis.5 However, by means of crystallography and computational molecular modelling, the orally active compound aliskiren was discovered.1,8,9

Pharmacological Profile of Aliskiren

Aliskiren is a highly specific inhibitor of human renin, with a concentration that produces a 50% inhibition (IC50) of 0.6nM, but showed more than 10,000-fold lower affinity for related aspartic peptidases.1 Aliskiren has long half-life, estimated as 40.7±10.7 hours, which is suitable for once-daily medication.4 However, although aliskiren is the first of the DRIs to achieve clinically feasible bioavailability, the mean absolute bioavailability of the hard gelatin 75mg capsule is still low, estimated at about 2.6%. In addition, the absorption of aliskiren is significantly reduced by concomitant food intake, with mean maximum concentration (Cmax) and area under the concentration–time curve (AUC) (0–1h) values reported as 81 and 62% of fasting state values, respectively. Thus, it is recommended that aliskiren be taken in the fasting state without food. Aliskiren is mainly eliminated unchanged in the faeces (91%), with 1.4% eliminated as oxidised metabolites and 0.6% excreted in the urine.10,11In vitro data indicate that aliskiren metabolism is not significantly affected by the cytochrome P450 system, which is consistent with the absence of significant interactions with many commonly used drugs such as lovastatin, atenolol, warfarin, digoxin, celecoxib, hydrochlorothiazide, ramipril, valsartan, metformin and amlodipine.12–15

Antihypertensive Efficacy of Aliskiren

In a dose-ranging study of 672 patients with mild to moderate hypertension, aliskiren 150, 300 and 600mg significantly reduced mean sitting blood pressure (BP) (systolic/diastolic) by 13.0/10.3, 14.7/11.1 and 15.8/12.5mmHg, respectively (p<0.0001 for systolic and diastolic BP compared with placebo, 3.8/4.9mmHg).16 In terms of antihypertensive efficacy, aliskiren 150mg is the recommended starting dose, and titration up to 300mg may provide additional benefit. Between 300 and 600mg, aliskiren does not provide additional benefit. Seventy to 80% of the maximal BP lowering was apparent by week two, and maximal reductions were achieved by week four. In addition, the antihypertensive effect of aliskiren persisted for up to two to four weeks after treatment withdrawal, showing significantly lower BP than placebo.17 In ambulatory BP analysis, aliskiren showed smooth, sustained effects with high troughto- peak ratios of 98% for the 300mg dose (see Figure 2).

As a monotherapy agent, aliskiren 300mg was more effective than irbesartan 150mg,18 ramipril 10mg19 and hydrochlorothiazide 25mg monotherapy,20 which implies that aliskiren is at least as effective as other RAS blocking agents. As a combination agent, aliskiren has shown addictive effects with a thiazide diuretic (hydrochlorothiazide),21 ACEI (ramipril),22 ARB (valsartan)23 and calcium channel blocker (amlodipine).24

Safety of Aliskiren

In a dose-ranging study evaluating antihypertensive efficacy and tolerability, aliskiren 150–600mg in 672 male and female patients was well tolerated at dosages up to 300mg once daily.16 There was a slightly higher incidence of generally mild/moderate and transient diarrhoea with aliskiren 600mg than with lower dosages or placebo. In a pooled analysis of data including 2,316 patients who received aliskiren monotherapy, the tolerability profile of aliskiren was also similar to that of placebo25 (see Table 1). However, DRIs are expected to share some adverse effects of ACEIs and ARBs, such as hyperkalaemia and deterioration of renal function, especially in high-risk patients.26 Therefore, the potential hazards of RAS inhibition, especially in situations where BP and renal function are renin-dependent, such as in the elderly, in salt-depleted patients, in patients with renal artery stenosis and in patients placed under anaesthesia, should be evaluated carefully. As with ACEIs and ARBs, aliskiren is contraindicated in pregnancy and should not be used in patients with bilateral renal artery stenosis. Because absorbed aliskiren is mainly excreted via the hepatobiliary tract, aliskiren should be given with caution to patients with hepatic cirrhosis.

Possible End-organ Protection Effects of Aliskiren

The ASPIRE HIGHER clinical trial programme is designed to evaluate the end-organ protecting effects of aliskiren, covering an extensive spectrum of disease condition, as well as a large number of patients (over 35,000). At the time of writing, the results of three short- to medium-term studies assessing the potential organ protection effects by surrogate end-point evaluation (Aliskiren Observation of Heart Failure Treatment [ALOFT], Aliskiren in the Evaluation of Proteinuria in Diabetes [AVOID] and Aliskiren Left Ventricular Assessment of Hypertrophy [ALLAY]) have been reported.

In the ALOFT study, aliskiren showed additional favourable neurohormonal effects on top of standard treatment of an ACEI (or ARB) and beta-blocker in patients with hypertension with stable heart failure.27 In the AVOID study, aliskiren showed an additional BP-independent renoprotective effect in patients with type 2 diabetes on top of a maximal dosage of ARB, losartan 100mg daily28 (see Figure 3). Finally, in the ALLAY study, aliskiren was as effective as losartan in reducing LVH in overweight hypertensive patients.

Regarding its end-organ protecting effect, the role of aliskiren as a component of dual RAS blockade over ACEIs has been particularly studied. Dual RAS blockage has long been expected to be more effective in end-organ protection over single RAS blocking agents such as ACEIs or ARBs.29 However, the effect of dual RAS blockage using ACEIs and ARBs has nearly been concluded to not have any benefit and sometimes to even be harmful due to increased adverse events.30,31 It has been hypothesised that ACEIs and ARBs in combination are unable to provide complete control of RAS, causing compensatory stimulation of renin activity and thus an angiotensin II surge.7 In this respect, dual RAS blockage with a combination of DRIs and ARBs has the theoretical benefit of blocking RAS at the initial and final steps without an angiotensin II surge. The initial clinical trial testing its role as a component of dual RAS blockade showed no increase of adverse events compared with either component as monotherapy, which is sharply contrasted with the increased incidence of adverse events with a combination of ACEIs and ARBs.23,32 The ongoing ASPIRE HIGHER clinical trial programme, of which full results are expected by 2012, will offer us more information regarding end-organ protecting effects of aliskiren.


Compared with ACEIs or ARBs, aliskiren has theoretical benefits of blocking RAS at its initial and rate-limiting step, thus reducing formation of both angiotensin I and angiotensin II. Aliskiren has a long half-life, exceeding 24 hours, which makes it suitable for once-daily medication. Results of initial clinical dose-ranging studies have shown sustained antihypertensive effects with high trough-to-peak ratios over 24 hours and the absence of rebound phenomenon after treatment withdrawal. Head-to-head clinical studies in mild to moderate hypertensive patients have demonstrated at least equivalent or possibly superior BP-lowering efficacy to current antihypertensive agents, with a favourable adverse effect profile. Aliskiren possesses BP-lowering effects with a thiazide diuretic, ACEIs, ARBs and calcium channel blocker. Aliskiren’s blocking ability at the initial point of RAS enables it to be used as a safe and effective component of dual RAS blocking agents over ACEIs, thus maximising end-organ protection by RAS blockage. The ongoing ASPIRE HIGHER clinical trial programme includes morbidity and mortality trials, as well as short- to medium-term studies, assessing the organ protection effects and antihypertensive efficacy in a special population of aliskiren, and will offer further insight regarding its end-organ protecting effects.


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