Article

Direct Renin Inhibitors in Hypertension - Outlook for End Organ Protection

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DOI:https://doi.org/10.15420/ecr.2007.0.2.57

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The copyright in this work belongs to Radcliffe Medical Media. Only articles clearly marked with the CC BY-NC logo are published with the Creative Commons by Attribution Licence. The CC BY-NC option was not available for Radcliffe journals before 1 January 2019. Articles marked ‘Open Access’ but not marked ‘CC BY-NC’ are made freely accessible at the time of publication but are subject to standard copyright law regarding reproduction and distribution. Permission is required for reuse of this content.

Globally, an estimated 26.4% of the adult population suffers from hypertension, and this figure is set to rise by 3% by 2025.1 The condition is asymptomatic and is often dubbed the ‘silent killer’ because it frequently goes undetected. The clinical significance of hypertension stems from the increased risk of end organ damage due to elevated blood pressure (BP) (see Figure 1). Chronic high BP is associated with the development of left ventricular hypertrophy (LVH), congestive heart failure (CHF), coronary artery disease, the acceleration of arteriosclerosis, myocardial infarction, peripheral arterial disease, the development of retinopathy and impaired renal function, which in turn can lead to renal failure.

The renin–angiotensin system (RAS) is vital in BP control, and chronic overactivation of the system is a major contributing factor in the development of essential hypertension.2 Furthermore, it is implicated in the pathophysiology and pathogenesis of many cardiovascular (CV) and renal diseases.3–9 The identification of the pivotal role of the RAS in hypertension led to the development of specific drugs to target the system, namely beta blockers, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs).10 Beta blockers reduce renin secretion by the kidney, ACE inhibitors block conversion of angiotensin I (Ang I) to angiotensin II (Ang II) and ARBs block Ang II receptors. Under normal physiological conditions, renin is released in response to a reduction in fluid volume and/or a decrease in blood pressure. Renin cleaves circulating angiotensinogen to form Ang I, which in turn is converted into Ang II by ACE. The coupling of this peptide with the Ang II receptor type 1 causes vasoconstriction and sodium and water retention in the kidney, while decreasing renin secretion through a negative feedback loop acting at the level of the juxtaglomerular apparatus.

Despite the promise of ACE inhibitors and ARBs, nearly 70% of patients still fail to achieve adequate BP control,11 and the desired improvements in CV morbidity and mortality have also failed to materialise.12,13 Since both ACE inhibitors and ARBs interrupt the negative feedback loop of the renin system, renin can still be released. Therefore, these compounds do not completely block the RAS, which impedes a full effect in reducing BP in hypertension.14 Direct inhibition of renin has been proposed as a therapeutic option in the treatment of arterial hypertension. Direct renin inhibitors target the rate-limiting step in the RAS, acting after beta blockers, which reduce renin release, and before ACE inhibitors and ARBs in the cascade.

In March 2007, the US Food and Drug Administration (FDA) approved aliskiren as the first orally effective direct renin inhibitor (DRI) for the treatment of hypertension as monotherapy or in combination with other antihypertensive medications. Aliskiren gained European approval for the treatment of high BP alone or in combination with other antihypertensive agents in August 2007. Since aliskiren acts on a different part of the RAS, it has the potential to widen therapeutic opportunities for hypertensive patients. Moreover, because elevated plasma renin activity (PRA) may represent a risk factor for target-organ damage, including LVH5 and renal dysfunction,6 direct renin inhibition may have considerable potential for the prevention of hypertension-associated end organ damage. This short review discusses the clinical features of aliskiren and considers its role within the context of the efficacy of both the ACE inhibitors and ARBs, and its potential for cardio-and reno-protection.

Aliskiren and Suppression of the Renin–Angiotensin System

Aliskiren is highly specific for human renin and binds to the active site of renin to inhibit the production of Ang I, which in turn blocks the synthesis of Ang II. Because renin has a high specificity for angiotensinogen, aliskiren essentially targets the rate-limiting step and thus may provide more complete control over the RAS.15 The high-affinity binding of aliskiren to renin leads to a rapid dose-dependent reduction in PRA.16–18 Furthermore, aliskiren in combination with ramipril or hydrochlorothiazide (HCTZ) significantly suppressed compensatory rises in PRA associated with ramipril or hydrochlorothiazide monotherapy. These reductions were comparable to those seen with aliskiren monotherapy.19–22 PRA levels were measured in a subset of patients in a randomised, double-blind, placebo-controlled dose-response study. Following a two-week withdrawal period, PRA levels in the aliskiren treatment group had not returned to baseline levels.18

Pharmacokinetics of Aliskiren

Aliskiren is approximately 50% protein-bound, does not undergo significant first-pass metabolism and is excreted primarily unchanged in the faeces.23 Importantly, in vitro studies showed that aliskiren has no clinically relevant interaction with the cytochrome P450 isoenzymes.24 In animal models, the drug’s concentration was found to be greater in the kidneys than in plasma.

This high concentration at the site of renin release could account for the profound effect of the drug on PRA. Aliskiren is still detectable in the kidneys up to three weeks after discontinuation, when plasma levels of aliskiren are undetectable.25 Aliskiren was well tolerated when administered alone and with an ARB in patients with renal and hepatic impairment.26,27 A multicentre trial examined the effects of a 300mg dose of the DRI in elderly (65 years of age) and in young (18–45 years of age) healthy volunteers. No significant difference in exposure to aliskiren or tolerance was noted between the two groups.28 Furthermore, the half-life of aliskiren has been shown to be the same in both healthy volunteers and those with type 2 diabetes, demonstrating that the pharmacokinetics of the drug are unaltered in the presence of diabetes.29

Aliskiren in Hypertension

Aliskiren has been extensively studied in clinical trials in both monotherapy and combination therapy settings. Data from these studies have shown aliskiren to be effective in lowering BP in patients with mild to moderate hypertension.22,30–34 Data from clinical trials also support the effectiveness of aliskiren combination therapy in lowering BP in hypertensive patients with obesity35 and diabetes.36 A more comprehensive review of the action of aliskiren on BP is provided by Roland Schmieder in the following article.

Renin Suppression and End Organ Protection

Chronic activation of the RAS perpetuates elevated BP and will eventually lead to organ damage.3 The recent Spanish CONTROLRISK study was designed to determine the CV risk profile of the hypertensive population in the primary care and specialist setting. The study found that target-organ damage and associated clinical conditions were more frequent in the specialist setting. The most frequently reported target-organ damage was LVH, and the most common associated clinical condition was ischaemic heart disease. Worryingly, the study found that both specialists and general practitioners strongly underestimated the CV risk, mainly in very-high-risk patients.37

In chronic hypertension, there is increasing evidence that locally produced Ang II is involved in the development of end organ damage via oxidative, proliferative, inflammatory and fibrotic pathways.9,38 Thus, antihypertensive treatments that target the RAS may provide superior cardio- and reno-protection in comparison with other agents.

Furthermore, the end organ protection conferred by agents that target the RAS may be partially independent of BP control. ACE inhibitors and ARBs have both been shown to reduce BP, and data suggest that they have some beneficial effects on CV and renal outcomes.39–46 However, despite their promise, ACE inhibitors and ARBs have not established clear clinical advantages in terms of end organ protection. This may be because ACE inhibitors and ARBs are limited by compensatory increases in plasma renin levels that can lead to adjustments in Ang II production and conversion.

Ang II is responsible for most of the detrimental effects of an overactive renal system; thus, a more complete inhibition of the effects of the last effector of the system is predicted to provide superior outcomes for CV and renal protection.12 An important predictor of the need for multiple antihypertensive therapies is the degree of CV and renal involvement. The presence of associated clinical conditions or advanced target-organ damage predicts more difficult control of BP and the need for more antihypertensive medication.47 As mentioned previously, ACE inhibitors and ARBs provide incomplete suppression of the RAS14 due to the fact that both classes of drugs disrupt the feedback loop by which Ang II inhibits the release of renin from the kidney, thus stimulating a reactive increase in renin activity.48 In comparison, while aliskiren is also associated with a reactive increase in renin, the high-affinity binding of aliskiren to renin leads to a rapid dose-dependent reduction in PRA.16–18,49

Studies have shown an increase in reno-protection using higher doses of ARBs.50,51 A dose three times that of the normal recommended dose of the ARB irbesartan showed enhanced renal protection and had fewer adverse side effects.50 Additionally, a combination of the ACE inhibitor trandolapril and the ARB losartan slowed progression of renal side effects in hypertension patients with renal disease.41 The Irbesartan in the Management of Proteinuric Patients at High Risk for Vascular Events (IMPROVE) trial enrolled hypertensive patients with elevated CV risk with early-stage renal disease and relatively low albumin excretion rates and compared the benefits of ramipril plus irbesartan and ramipril plus placebo. The study’s outcome measure was urinary protein excretion. The study’s adjusted week-20 baseline geometric ratios for ramipril plus irbesartan and ramipril plus placebo did not differ significantly, which suggests that monotherapy with agents that inhibit the RAS is sufficient treatment for patients with early-stage renal disease and relatively low albumin excretion.52

The Heart Outcomes Prevention Evaluation (HOPE) study was pivotal in providing evidence that Ang II played a central role in atherosclerosis-related cardiac events,53 and demonstrated that the ACE inhibition therapy with ramipril decreased the CV event rate in high-risk cardiac patients. It is hoped that the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) will answer many of the questions surrounding the use of combination ACE inhibitor and ARB therapy in the prevention of CV and renal diseases in high-risk patients.54 The study is a double-blind, parallel-group study randomising 25,620 patients in 40 countries to one of three treatment arms: telmisartan, ramipril or telmisartan plus ramipril. The patient population in the ONTARGET study is over 55 years of age with a history of coronary artery disease, stroke, peripheral vascular disease or diabetes mellitus with end-organ damage. The primary end-point for ONTARGET is a composite of CV death, myocardial infarction, stroke and hospitalisation for heart failure. Completion of the ONTARGET programme is expected in 2008.

Because direct renin inhibition by aliskiren targets the first and rate-limiting step in the RAS, aliskiren has the potential to optimise RAS suppression. Thus, aliskiren may offer an important and useful adjunct to other antihypertensive treatments and could potentially improve end organ protection. Indeed, data from animal models suggest that aliskiren may have a significant effect on cardiac and renal damage associated with hypertension. However, aliskiren is species-specific for human renin, making pre-clinical testing in animals difficult. Two rat models have been created to assess organ-protective effects through renin-system suppression by aliskiren. The first is a double transgenic rat (dTGR) expressing the human renin gene and human angiotensinogen, which, if left untreated, develops severe hypertension and organ damage. The second is an mRen-2 rat expressing the mouse renin gene, which also develops severe hypertension and organ damage if left untreated.

To assess the progression of renal disease and the evolution of proteinuria or albuminuria, an estimation of the degree of intrarenal inflammation is usually made by measuring the degree of renal macrophage infiltration. Untreated dTGR rats were compared with aliskiren-treated and valsartan-treated rats.55 Both methods of suppressing the RAS were effective in diminishing intrarenal inflammation; however, interestingly, mortality was 100% in the untreated group, whereas in aliskiren-treated rats and the valsartan group there was a significant survival advantage. Antihypertensive doses of aliskiren and valsartan in dTGR rats had significantly lower renal damage, showing the potential for the use of a DRI in decreasing renal damage.

Patients with hypertension and concomitant diabetes are at an increased risk of developing diabetic nephropathy. To examine the effects of aliskiren on the progression of diabetic nephropathy, mRen-2 rats administered with streptozotocin at six weeks were used to model hypertension and diabetes.56 Urinary albuminuria was evaluated over a 68-day period. Aliskiren significantly reduced the level of transforming growth factor beta (TGFβ), which is overexpressed during the progression of diabetic nephropathy, and prevented the development of albuminuria. However, it is not yet evident whether aliskiren prevents or just slows the progression of diabetic nephropathy.

LVH is a common manifestation of CV disease.57 Both ACE inhibitors and ARBs have been demonstrated to induce regression of LVH.58 Two studies have evaluated aliskiren’s effect on LVH through echocardiography in dTGR rats. In the first study, 0.3mg and 3mg of aliskiren or 1mg and 10mg of valsartan were administered to rats daily.59 Aliskiren 3mg significantly improved the protective effect on LVH relative to no treatment. In the second study, the LVH effects of aliskiren 0.03mg and 0.3mg or losartan 2mg and 30mg were studied.55 Both doses of aliskiren provided a reduction in LVH, and the effects of aliskiren 3mg were comparable to those of losartan 30mg. These results suggest that aliskiren may provide protection against LVH and hence decrease morbidity and mortality from CV disease.

Ongoing and Future Clinical Trials in End Organ Protection

Several ongoing studies are currently evaluating the organ protection properties of aliskiren in hypertensive patients. These include a programme of clinical outcome studies and a series of surrogate marker studies.

The Action on Secondary Prevention through Intervention to Reduce Events Higher Programme

Several clinical end-point trials are planned as part of the Action on Secondary Prevention through Intervention to Reduce Events (ASPIRE) higher study programme. These studies of primary and secondary prevention of both CV and renal risk will have a particular focus on patients with diabetic nephropathy or CV disease.

The 36-week ASPIRE trial is assessing the safety and efficacy of aliskiren when added to optimised standard therapy – including an ACE inhibitor or an ARB – in high-risk post-myocardial infarction patients who have left ventricular systolic dysfunction with or without heart failure. The primary outcome measure for ASPIRE is change in left ventricular end systolic volume (LVESD) as measured by echocardiography. Secondary outcome measures include CV-related deaths, hospitalisation for heart failure, recurrent myocardial infarction, stroke and resuscitated sudden deaths.

The Aliskiren Trial in Type 2 Diabetic Nephropathy (ALTITUDE) trial began recruiting participants in October 2007. It aims to determine whether 300mg of once-daily aliskiren, on top of conventional treatment (including ACE inhibitor or ARB), in patients with diabetes type 2 and pre-existing disease of the heart and the circulatory system and/or kidney disease can reduce death and disease caused by diabetic complications (see Figure 2).60 The randomised, double-blind, placebo-controlled, parallel-group study will include three categories of high-risk patients with type 2 diabetes (aged ≥35 years): those with albuminuria – urinary albumin to creatinine ratio (UACR) 200mg/g; those with microalbuminuria – UACR 20–<200mg/g and estimated glomerular filtration rate (eGFR) ≥30–<60ml/min/1.73m2; and those with a history of CV disease and eGFR ≥30–<60ml/min/1.73m2. The primary outcome measure is time to first event for the composite end-point of CV death, resuscitated sudden death, myocardial infarction, stroke, unplanned hospitalisation for heart failure, onset of end-stage renal disease or doubling of baseline creatinine concentration.

Surrogate-marker Trials

Three studies are assessing the effects of aliskiren on surrogate markers of organ damage.

Preliminary results from the 12-week Aliskiren Observation of Heart Failure Treatment (ALOFT) study were recently presented at the European Society of Cardiology Congress in Vienna 2007.61 The early data suggest increased end organ benefits with aliskiren. Patients in the study had New York Heart Association (NYHA) heart failure class 2–4 with current or prior hypertension and plasma brain-type natriuretic peptide (BNP) concentrations >100pg/ml. In the study, the patients in NYHA heart failure class 2–4 were randomised to aliskiren or placebo plus combined treatment of a beta blocker and either an ACE inhibitor or an ARB, as tolerated. The publication of more detailed final analysis is eagerly awaited.

Two other studies, Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) and Aliskiren in Left Ventricular Hypertrophy (ALLAY), are also assessing the effects of aliskiren on end organ protection. The AVOID study is examining aliskiren versus placebo, plus losartan, on UACR in 599 patients with hypertension, diabetes type 2 and proteinuria. UACR is a sensitive test for albuminuria, which occurs as the result of kidney failure and can be used to assess its progression.62

The results were presented at the 2007 meeting of the American Society of Nephrology in San Francisco63 and showed a 20% further decrease in albuminuria in type 2 diabetic patients when aliskiren was added on top of losartan 100mg. The finding is interesting, not only for the potential effect on renal protection, but also because UACR has been demonstrated to be a predictor of CV events, with a reduction in UACR correlated with a decrease in CV events in hypertensive patients.64,65

The ALLAY study is also using a combination of losartan and aliskiren versus placebo and monotherapy with losartan. The trial will include 480 overweight patients with hypertension and LVH. LVH will be measured using magnetic resonance imaging (MRI). The study will provide useful insights into the potential benefit of aliskiren on CV morbidity and mortality.

Summary

Aliskiren is a novel direct renin inhibitor (DRI) that targets the rate-limiting step of the RAS. In clinical trials, direct renin inhibition has been demonstrated to be effective at reducing BP when used as monotherapy. In addition, direct renin inhibition with aliskiren has been shown to provide further BP control when used in combination with ACE inhibitors, ARBs, diuretics and calcium channel blockers.

In contrast to other agents that target the RAS, aliskiren’s mode of action results in a decrease in PRA. This has important potential implications, especially in terms of hypertension-related end organ damage. Because ACE inhibitors and ARBs cause a reactive increase in renin, the resultant production of Ang I is available for conversion to Ang II by ACE-independent pathways. Essentially, ACE inhibitors and ARBs do not provide complete suppression of the RAS, whereas aliskiren’s action at the rate-limiting step offers the potential for blocking the RAS at its initial point of activation. By optimising RAS suppression, aliskiren offers potentially improved end organ protection beyond that achieved with current antihypertensive therapies.

Aliskiren has been demonstrated to provide end organ protection in the heart and kidney in transgenic rats, and the early results from ongoing trials including aliskiren look promising in terms of end organ protection. It is hoped that the ASPIRE higher study programme will provide further useful data on the potential of direct renin inhibition on CV and renal outcomes.

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