Oral renin inhibitors in clinical practice: a perspective review

Abstract

Hypertension is an important risk factor for cardiovascular morbidity and mortality. The importance of the renin–angiotensin–aldosterone system (RAAS) in cardiovascular and renal diseases has long been recognized: for this reason the conventional therapies, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), β-blockers, and aldosterone antagonists represent the backbone of current antihypertensive therapy. Aliskiren is the first direct renin inhibitor (DRI) suitable for oral administration. By achieving more complete renin–angiotensin system inhibition, direct renin inhibitors may afford greater protection from hypertensive complications. Present evidence indicates that aliskiren reduces baseline systolic and diastolic blood pressure greater than placebo and that it is as effective as other first-line antihypertensive agents. Extra advantages can be reached when it is used in combination therapy. Clinical trials and in vitro studies also suggest that aliskiren has several cardioprotective and renoprotective effects. Therapy with aliskiren is well tolerated, but recently some concerns have arisen because of the early termination of the ALTITUDE study due to an increased incidence of adverse effects.

Keywords

aliskiren direct renin inhibition hypertension renin–angiotensin–aldosterone system

Introduction

Hypertension is an important risk factor for cardiovascular morbidity and mortality being responsible for, or contributing to, 62% of all strokes and 49% of all cases of heart disease. It is the most prevalent controllable disease in developed countries, affecting 20–50% of adult populations [Kearney et al. 2005]. Hypertension and diabetes mellitus account for over 50% of cases of chronic kidney disease. High blood pressure itself is a major risk factor for the progression of renal disease [Kearney et al. 2005].

The importance of the renin–angiotensin–aldosterone system (RAAS) in cardiovascular and renal diseases has long been recognized. Secretion of renin is the first step in the RAAS cascade. Renin is secreted, in response to a variety of stimuli, from the juxtaglomerular cells in the kidneys. Renin cleaves angiotensinogen to form angiotensin I (Ang I) which is then converted by angiotensin-converting enzyme (ACE) to the active angiotensin II (Ang II), the effector enzyme of the cascade. Ang II interacts with type-1 angiotensin receptors (AT-1), inducing vasoconstriction and increasing blood pressure, promoting adrenal aldosterone secretion, renal sodium re-absorption and release of catecholamines from the adrenal medulla and prejunctional nerve endings [Kim and Iwao, 2000].

This concept provides a rationale for the use of conventional therapies, such as ACE inhibitors (ACEIs), angiotensin receptor blockers (ARBs), β-blockers, aldosterone antagonists, and novel renin inhibitors in many cardiovascular conditions (Figure 1). ACEIs and ARBs represent the backbone of current antihypertensive therapy. The beneficial effects of these agents are attributed to the inhibition of deleterious AT1R stimulation and, therefore, prevention of Ang II-induced vasoconstriction, salt and water retention, aldosterone and vasopressin release, stimulation of the sympathetic nervous system, inflammation, and stimulation of cell growth [Unger, 2002]. However, clinical trials testing for ancillary-blood-pressure-independent benefits of renin–angiotensin system inhibitors have yielded mixed results, in part because ACEIs and ARBs do not produce complete renin–angiotensin system inhibition. By achieving more complete renin–angiotensin system inhibition, direct renin inhibitors (DRIs) may afford greater protection from hypertensive complications [O’Brien et al. 2007].

Figure 1.

The renin–angiotensin–aldosterone system (RAAS) cascade and the drug classes developed to counteract its influence.

The direct inhibition of renin is a logical target for pharmacologic suppression of the RAAS, because renin-mediated cleavage of angiotensinogen to form Ang I is a rate-limiting first step in the RAAS pathway. However, early attempts to develop DRIs met with little success, and research subsequently focused on developing ACEIs and ARBs, with approval of ACEIs throughout the 1980s and ARBs beginning in the mid-1990s.

Direct renin inhibitors

In the early 1980s, remarkable efforts were made to develop peptide analogues of angiotensinogen [Haber, 1983], which through a number of chemical refinements led to the production of numerous compounds (e.g. enalkiren, ramikiren and zankiren) [Delabays et al. 1989; Kobrin et al. 1993; Menard et al. 1995]. However, none of these came to the point of being used for treatment of patients, because of their low inhibiting activity, lack of oral bioavailability and short half-life [Staessen et al. 2006].

Reactive increases in plasma renin concentration (PRC) and plasma rennin activity (PRA) during ACEI treatment may result in increased Ang II production via non-ACE pathways. Moreover, higher levels of Ang I may overcome the ability of ACEIs to effectively suppress ACE activity. ACE escape also may relate to the relatively low binding affinity of ACEIs for ACE and the relatively low levels of the dosing of ACEIs used in clinical practice to avoid drug-related adverse events. With ARBs, the reactive elevations in PRC and PRA lead to increases in Ang II levels [Schindler et al. 2007]. This may result in greater competition and displacement of ARBs from AT1-R sites and reduced antihypertensive efficacy [Burnier and Brunner, 2000].

In contrast, DRIs bind directly to the catalytic site of renin, thereby inhibiting its ability to convert angiotensinogen to angiotensin I, the rate-limiting step in the formation of angiotensin II [Danser and Deinum, 2005; Wood et al. 2003]. Owing to this proximal renin–angiotensin system blockade, DRI therapy is accompanied by decreased Ang I and Ang II levels [Nussberger et al. 2002]. The resultant loss of feedback inhibition elicits a large reactive rise in renin secretion but PRA, the enzymatic activity of renin, is markedly reduced by the DRI.[Nussberger et al. 2002] Thus, while PRA, Ang I and Ang II all increase reflexively with ARBs, they decrease markedly with a DRI [Nussberger et al. 2002].

Aliskiren is the first DRI, suitable for oral administration, to reach the clinical arena [Van Tassell and Munger, 2007]. Aliskiren is characterized by high hydrophilicity which confers a good bioavailability; it is a potent human renin inhibitor [Wood et al. 2003]. Studies in normotensive subjects demonstrated that aliskiren suppressed PRA and plasma levels of Ang I and Ang II [Nussberger et al. 2002]. The mean absolute bioavailability of aliskiren is 2.6% [Vaidyanathan et al. 2006], peak plasma concentrations are reached 1–2 hours after dosing and steady state is reached after 5–8 days of once-daily administration [Nussberger et al. 2002]. The main pathway of elimination for aliskiren is via biliary excretion as unmetabolized drug, less than 1% is excreted in urine [Nussberger et al. 2002]. Aliskiren is not metabolized by cytochrome P450 thus it shows no clinically relevant interaction with other commonly used drugs such as ramipril, valsartan, hydrochlorothiazide (HCTZ), amlodipine, atenolol, lovastatin, warfarin, cimetidine, celecoxib. Age, gender, ethnicity, renal and hepatic impairment and diabetes do not affect aliskiren pharmacokinetics [Ayalasomayajula et al. 2008; Dieterle et al. 2005; Vaidyanathan et al. 2006, 2007a, 2007b, 2007c, 2008].

One concern is the potential adverse effect of high circulating renin concentrations after aliskiren therapy. Aliskiren binds to the active site of renin, reducing its activity and Ang II production. Diminished Ang II levels stimulate renin secretion. The potential negative consequence of high renin concentration is that renin may bind to a renin receptor and trigger yet unknown events [Nguyen et al. 2002].

High prorenin levels are closely associated with the severity of diabetic complications. In this respect, in patients with diabetes, increased prorenin levels have been shown to be associated with microalbuminuria and with the development of nephropathy [Chiarelli et al. 2001; Deinum et al. 1999].

Effect on blood pressure

In the 8-week, placebo-controlled trials, monotherapy with aliskiren 150 mg/day or 300 mg/day reduced baseline systolic and diastolic blood pressure to a significantly greater extent than placebo in patients with stage 1 to stage 2 hypertension [Gradman et al. 2005; Kushiro et al. 2006; Oh et al. 2007; Oparil et al. 2007; Villamil et al. 2007]. The antihypertensive efficacy of aliskiren monotherapy was also demonstrated in subgroups of patients, including diabetic and obese patients and those with metabolic syndrome.[Weir et al. 2007]

Nussberger and coworkers [Nussberger et al. 2002] were the first to report the humoral effects of aliskiren in a comparative study with enalapril and placebo. In normal volunteers, they found a dose-dependent decrease in PRA, Ang I and Ang II in response to increasing dosages of aliskiren from 40 to 640 mg/day. A reduction of 80% of all components of the RAAS from baseline was observed after 8 days of treatment with the maximal dose of aliskiren. Plasma aldosterone was also decreased, whereas, not surprisingly in normotensive subjects, mean blood pressure was unmodified.

Stanton and colleagues [Stanton et al. 2003] compared aliskiren 37.5, 75, 150 and 300 mg once daily with losartan 100 mg once a day in 226 patients with mild-to-moderate essential hypertension showing after 4 weeks that aliskiren 75, 150 and 300 mg were similar to losartan 100 mg in reduction of systolic blood pressure. In an 8-week placebo-controlled study, Gradman and colleagues [Gradman et al. 2005] randomized 652 hypertensive patients to aliskiren 150, 300, 600 or irbesartan 150 mg or placebo. Aliskiren 150 mg was as effective as irbesartan 150 mg, reducing systolic and diastolic blood pressure by 11.6 and 9.8 mmHg, respectively. A greater reduction in blood pressure was observed with aliskiren 300 and 600 mg. Strasser and colleagues [Strasser et al. 2007] compared aliskiren 150 mg/300 mg and lisinopril 20 mg/40 mg in 183 hypertensive patients showing a mean reduction in systolic and diastolic blood pressure of 20.0/18.5 mmHg and 22.3/20.1 mmHg with both drugs, respectively.

Aliskiren did not differ significantly from atenolol in lowering systolic blood pressure in a study in which patients received aliskiren 150 mg/day or atenolol 50 mg/day for 6 weeks followed by 6 weeks on double the initial dose of the agents [Dietz et al. 2008]. However, reductions in diastolic blood pressure were significantly greater with atenolol than with aliskiren at both 6 and 12 weeks.

Several randomized double-blind or open-label multicentre trials have been conducted with aliskiren alone or in combination with HCTZ, valsartan, valsartan plus HCTZ, amlodipine, amlodipine plus HCTZ, ramipril, and atenolol.

Villamil and colleagues studied a total of 2776 patients with diastolic blood pressure 95–109 mmHg; patients were randomized to receive once-daily treatment with aliskiren (75, 150 or 300 mg), HCTZ (6.25, 12.5 or 25 mg), the combination of aliskiren and HCTZ, or placebo [Villamil et al. 2007]. The primary endpoint was the change in diastolic blood pressure from baseline to week 8. Aliskiren monotherapy was superior to placebo in reducing diastolic and systolic blood pressure. Combination treatment was superior to both monotherapies in reducing blood pressure; a reduction of 21.2/14.3 mmHg from baseline with aliskiren/HCTZ 300/25 mg was observed.

The ACQUIRE (Aliskiren Alone or in Combination With Hydrochlorothiazide in Patients With Stage 2 Hypertension to Provide Quick Intensive Control of Blood Pressure) study [Black et al. 2010], performed in 688 patients with stage 2 hypertension, demonstrated that the combination of aliskiren 150 mg/day with HCTZ 12.5 mg/day provides substantial reductions of blood pressure (30.0/12.6 mmHg), significantly greater than those achieved with aliskiren alone (20.3/8.2 mmHg).

Drummond and colleagues [Drummond et al. 2007] investigated the addition of aliskiren to amlodipine in 545 patients with mild-to-moderate hypertension that was inadequately controlled with amlodipine alone (diastolic blood pressure 90–100 mmHg). Patients were randomized to 6 weeks of double-blind treatment with amlodipine 5 mg plus aliskiren 150 mg, amlodipine 5 mg, or amlodipine 10 mg. At the end of the study, systolic and diastolic blood pressure reductions with the combination of aliskiren 150 mg and amlodipine 5 mg were 11.0/8.5 mmHg, respectively: significantly greater than with amlodipine 5 mg (5.0/4.8 mmHg), but similar to amlodipine 10 mg (9.6/8.0 mmHg).

In the Aliskiren and the Calcium Channel Blocker Amlodipine as an Initial Treatment Strategy for Hypertension Control (ACCELERATE) study [Brown et al. 2011], 1,254 hypertensive patients were randomly assigned to treatment with aliskiren or amlodipine alone and in combination. After 16 weeks, patients taking the combination (aliskiren 300 mg/day and amlodipine 10 mg/day) had a 6.5/3.7 mmHg greater reduction in systolic and diastolic blood pressure than those treated with the monotherapies at equivalent doses.

Similar results were obtained in 489 hypertensive obese patients [Jordan et al. 2007] who were nonresponders to HCTZ 25 mg. Patients were randomly assigned to aliskiren 150 mg, irbesartan 150 mg, amlodipine 5 mg, or placebo plus HCTZ 25 mg for 4 weeks, followed by 8 weeks on double the initial doses of aliskiren, irbesartan, or amlodipine. After 8 weeks of double-blind treatment, aliskiren/HCTZ lowered blood pressure by 15.8/11.9 mmHg, significantly more than placebo/HCTZ (8.6/7.9 mmHg) and similar to the reduction obtained with irbesartan/HCTZ and amlodipine/HCTZ (15.4/11.3 and 13.6/10.3 mmHg, respectively).

Pool and colleagues [Pool et al. 2007] investigated the blood-pressure-lowering effects of aliskiren, alone or in combination with valsartan. In a placebo-controlled, 8-week trial, 1123 patients with mild-to-moderate hypertension were randomized to receive once-daily, double-blind oral treatment with placebo, aliskiren monotherapy (75, 150 or 300 mg), valsartan monotherapy (80, 160 or 320 mg), aliskiren and valsartan in combination, or valsartan/HCTZ (160/12.5 mg). Co-administration of aliskiren and valsartan produced a greater antihypertensive effect than either drug alone, comparable in magnitude to the effect of valsartan/HCTZ, with a reduction in systolic and diastolic blood pressure of 18.9/13.5 mmHg. In a double-blind study [Oparil et al. 2007], 1797 patients with hypertension were randomly assigned to receive once-daily aliskiren 150 mg (n = 437), valsartan 160 mg (n = 455), a combination of aliskiren 150 mg and valsartan 160 mg (n = 446) or placebo (n = 459) for 4 weeks, followed by double dose for another 4 weeks. The primary endpoint was change in mean sitting diastolic blood pressure from baseline to week 8. At week 8, the combination of aliskiren 300 mg and valsartan 320 mg lowered mean diastolic blood pressure from baseline by 12.2 mmHg, significantly more than either monotherapy (aliskiren 300 mg, 9.0 mmHg decrease; valsartan 320 mg, 9.7 mmHg decrease) or with placebo (4.1 mmHg decrease) .

Cardiovascular and renal protection

To examine whether aliskiren possesses cardiovascular protective actions, a vast program of clinical trials, Aliskiren Study in Post-MI Patients to Reduce Remodelling (ASPIRE-HIGHER), has been developed involving more than 35,000 patients in 14 randomized double-blind studies.

In the Aliskiren in Left Ventricular Hypertrophy (ALLAY) study, the investigators have shown that aliskiren was as effective as losartan in promoting left ventricular (LV) mass regression [Solomon et al. 2009]. They randomized 465 patients with hypertension, increased ventricular wall thickness, and body mass index >25 kg/m² to receive aliskiren 300 mg, losartan 100 mg, or their combination, daily for 9 months. Patients were treated to standard blood pressure targets with add-on therapy, excluding other inhibitors of the RAAS and β-blockers. The primary objective was to compare change in LV mass (assessed with magnetic resonance imaging) index from baseline to follow up in the combination and losartan arms; the secondary objective was to determine whether aliskiren was noninferior to losartan in reducing LV mass index from baseline to follow up. Systolic and diastolic blood pressures were reduced similarly in all treatment groups, while LV mass index was reduced significantly from baseline in all treatment groups. The reduction in LV mass index in the combination group was not significantly different from that with losartan alone. Aliskiren was as effective as losartan in reducing LV mass index. Safety and tolerability were similar across all treatment groups.

In the Aliskiren Observation of Heart Failure Treatment (ALOFT) study patients with New York Heart Association class II to IV heart failure, current or past history of hypertension, and plasma brain natriuretic peptide (BNP) concentration >100 pg/ml who had been treated with an ACEI (or ARB) and β-blocker were randomized to 3 months of treatment with placebo (n = 146) or aliskiren 150 mg/day (n = 156) [Krum and Maggioni, 2010]. The primary efficacy outcome was the between-treatment difference in N-terminal pro-BNP (NT-proBNP). Plasma NT-proBNP rose by 762 ± 6123 pg/ml with placebo and fell by 244 ± 2025 pg/ml with aliskiren (p = 0.0106). BNP and urinary (but not plasma) aldosterone were also reduced by aliskiren. Clinically important differences in blood pressure and biochemistry were not seen between aliskiren and placebo. The investigators concluded that addition of aliskiren to an ACEI (or ARB) and β-blocker had favourable neurohumoral effects in heart failure and appeared to be well tolerated.

The Aliskiren and Valsartan to Reduce pro-BNP via Renin–Angiotensin–aldosterone Blockade (AVANT-GARDE) trial is a multinational, double-blind trial, in which 1101 patients stabilized after acute coronary syndrome (ACS) without clinical evidence of heart failure or LV function ≤40% but with an increased level of natriuretic peptides (NT) have been randomized 3-10 days after admission to aliskiren, valsartan, their combination, and placebo [Scirica et al. 2010]. The primary endpoint was the change in NT-proBNP from baseline to week 8. NT-proBNP declined significantly in each treatment arm, including placebo, by week 8, although there were no differences in the reduction between treatment strategies (42% in placebo, 44% in aliskiren, 39% in valsartan and 36% in the combination arm). Several subgroups had higher baseline levels of NP and greater reductions over the study period; however, there were no differences among treatment groups in any subgroup. It should be noted that there were more adverse events, including serious events and adverse events leading to early study drug discontinuation, in patients treated with active therapy. In conclusion, in this study performed in a high-risk population with elevated levels of NPs but relatively preserved systolic function and no evidence of heart failure following ACS, there was no evidence for a benefit of early initiation of inhibition of RAAS with valsartan, aliskiren or their combination.

The results of this study are in contradiction with those of the ALOFT trial: an explanation could be the differences in neurohumoral baseline features of the randomized patients of the two studies.

In the Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) study, 599 hypertensive patients with type 2 diabetes and nephropathy received 6 months of aliskiren (150 mg daily titrated to 300 mg daily after 3 months) or placebo added to 100 mg losartan and optimal antihypertensive therapy [Parving et al. 2008]. By the end of the study period, treatment with aliskiren had reduced the mean urinary albumin-to-creatinine ratio by 20%, as compared with placebo (95% confidence interval [CI] 9–30; p < 0.001) After adjustment for the change from baseline in systolic blood pressure, the reduction was 18% (95% CI 7–28; p = 0.002). A reduction of 50% or more in albuminuria was seen in 24.7% of the patients who received aliskiren, as compared with 12.5% of the patients who received placebo (p < 0.001). There was no difference in the overall incidence of adverse events between the aliskiren group and the placebo group (66.8% and 67.1%, respectively). Hyperkalemia was reported in 5.0% of the patients in the aliskiren group and in 5.7% of the patients in the placebo group. The hyperkalemia was transient. The authors concluded that aliskiren appears to have a renoprotective effect that is independent of its blood-pressure-lowering effect in patients with type 2 diabetes who are receiving the maximal recommended renoprotective treatment and optimal antihypertensive therapy.

A post hoc analysis of the AVOID study assessed the efficacy and safety of aliskiren added to the maximal recommended dose of losartan according to baseline estimated glomerular filtration rate (eGFR; stage 1–3 chronic kidney disease [CKD]). Exclusion criteria included eGFR <30 ml/min per 1.73 m² and serum potassium >5.1 mmol/l [Persson et al. 2010].

Baseline characteristics were similar between treatment groups in all CKD stages. The antiproteinuric effects of aliskiren were consistent across CKD stages (19%, 22% and 18% reduction). In the stage 3 CKD group, baseline serum creatinine levels were equal, but renal dysfunction, prespecified as a postrandomization serum creatinine elevation >176.8 μmol/l (2.0 mg/dl) occurred more frequently in the placebo group (29.2% versus 13.6%, p = 0.032). Serum potassium elevations >5.5 mmol/l (based on a single measurement) were more frequent with aliskiren (22.5% versus 13.6%) in stage 3 CKD. Adverse event rates were similar between treatments, irrespective of CKD stage.

The authors concluded that aliskiren added to losartan reduced albuminuria and renal dysfunction and was well tolerated, except for hyperkalemia (stage 3), independent of baseline CKD stage in patients with type 2 diabetes, hypertension and nephropathy.

It is important also to mention that data deriving from experimental studies on animal models suggest that aliskiren can induce protection against atherosclerosis, attenuating insulin resistance and oxidative stress [Habibi et al. 2008; Imanishi et al. 2008]

Safety and tolerability

In all studies Aliskiren was generally well tolerated at doses of 150 or 300 mg/day [Duggan et al. 2010] and resulted in an incidence of adverse events similar to placebo. Adverse events, including uncontrolled hypertension (2.2%), have generally been mild and have infrequently led to discontinuation of therapy [Vaidyanathan et al. 2007b]. The most common adverse events reported are headache (5.8%), nasopharyngitis (2.6%) and diarrhoea (1.4%) [Vaidyanathan et al. 2007c; Weir et al. 2007]. Aliskiren was also associated with a few cases of cough (1.1%), although, compared with ACEIs, the rate of cough was approximately one-third to one-half that reported with ramipril or lisinopril.

In contrast, on 20 December 2011, Novartis has announced that an increase in adverse events and no apparent benefits among patients randomized to aliskiren (Rasilez^®/Tekturna^®, Novartis) in the ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints) trial has prompted the data safety and monitoring board (DSMB) for the study to recommend its termination. ALTITUDE was studying aliskiren on top of ACEI or ARB therapy in patients with type 2 diabetes and renal impairment compared with a placebo add-on.

In making its recommendation, the DSMB noted that the active-treatment group experienced an increased incidence of nonfatal stroke, renal complications, hyperkalemia and hypotension over 18–24 months of follow up. The committee concluded that patients were unlikely to benefit from aliskiren on top of standard antihypertensive therapy. At the time in which this review has been written, Novartis is in ongoing discussions with health authorities worldwide about the implications of the findings from ALTITUDE for patients. As a precautionary measure Novartis is no longer recommending the use by physicians of aliskiren in combination with an ACEI or an ARB.

Conclusion

The direct inhibition of renin is a logical target for pharmacologic suppression of the RAAS, aliskiren is a new inhibitor of RAAS activity and actually is the only DRI suitable for oral administration. The studies performed show that as monotherapy or in combination with other drugs such as ACEIs, ARBs, diuretic and calcium channel blockers aliskiren significantly reduces blood pressure in patients with hypertension and recent observations suggest that it may have a renoprotective and cardioprotective effects.

Aliskiren has a good tolerability profile, but the termination of the ALTITUDE trial for the increase of adverse events will probably limit its use in association with ARBs and ACEIs until new data will be collected.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

The authors declare no conflict of interest in preparing this article.

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