Direct Renin Inhibitors in Hypertension – Outlook for End Organ Protection

Luis M Ruilope
2007 European Cardiology  
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
more » ... ve 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] [4] [5] [6] [7] [8] [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 LVH 5 and renal dysfunction, 6 direct renin inhibition may have considerable potential for the prevention of hypertensionassociated 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 cardioand 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 highaffinity binding of aliskiren to renin leads to a rapid dose-dependent reduction in PRA. [16] [17] [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 doseresponse 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
doi:10.15420/ecr.2007.0.2.57 fatcat:fimpp2yjszbvncajyrt3agm57m