Blood Pressure Lowering in Essential Hypertension With an Oral Renin Inhibitor, Aliskiren

Abstract

Abstract-Inhibition of the first and rate-limiting step of the renin-angiotensin system has long been an elusive therapeutic goal. Aliskiren, the first known representative of a new class of completely nonpeptide, orally active, renin inhibitors, has been shown to inhibit the production of angiotensin I and II in healthy volunteers and to reduce blood pressure (BP) in sodium-depleted marmosets. The aim of this randomized, double-blind, active comparator trial study was to assess the BP-lowering efficacy and safety of aliskiren. Key Words: renin Ⅲ blood pressure Ⅲ hypertension, essential Ⅲ blood pressure monitoring, ambulatory Ⅲ receptors, angiotensin Ⅲ losartan T he renin-angiotensin system (RAS) has well-established roles in both blood pressure (BP) regulation and atherogenesis. 1,2 Recent clinical trial evidence suggests that blockade of the RAS by angiotensin-converting enzyme inhibition or by angiotensin receptor blockade may influence largevessel atherosclerosis and cardiovascular morbidity and mortality independent of BP lowering. 3,4 As renin catalyzes the first and rate-limiting step of the system and has high specificity for angiotensinogen, blockade of the production of angiotensin (Ang) II by direct inhibition of renin has long been a therapeutic goal. Indeed, intravenous administration of the early renin inhibitors, such as enalkiren and remikiren, did reduce angiotensin levels and lower BP without any important adverse effects. 5-8 However, to date, due to relatively low potency, poor oral bioavailability (Ͻ1%), short durations of action, and high costs of synthesis, none of these peptide and peptidomimetic inhibitors has made it to the end of clinical trials. 9 Aliskiren, an octanamide, is the first known representative of a new class of completely nonpeptide, low-molecularweight, orally active transition-state renin inhibitors. 10 Designed through the use of molecular modeling techniques, it is a potent and specific in vitro inhibitor of human renin (IC50 in the low nanomolar range), with a plasma half-life of Ϸ24 hours. 10 Aliskiren has good water solubility and low lipophilicity and is resistant to biodegradation by peptidases in the intestine, blood circulation, and the liver. 10 When administered orally to sodium-depleted marmosets, it caused significant and sustained reductions in arterial blood pressure (unpublished data). In single-dose and multiple-dose tolerability studies in healthy normotensive male volunteers, oral doses up to 640 mg daily for 8 days were well tolerated and did not result in any significant toxicity. 11 Micromolar plasma concentrations were achieved, and aliskiren was shown to cause a dose-dependent decrease in plasma renin activity (PRA), to effectively block the formation of both Ang I and Ang II, and to decrease plasma and urine aldosterone levels. 11 In this study, we studied for the first time the efficacy, safety, and tolerability of 4 weeks of treatment with 37.5, 75, 150 and 300 mg aliskiren in healthy individuals with mild to moderate hypertension. We compared...

Pretreatment levels of plasma renin activity predict ambulatory blood pressure response to valsartan in essential hypertension

“…Reductions in ABP by valsartan were significantly smaller in hypertensive patients with lower PRA levels than in those with higher PRA levels. These findings are well in agreement with our earlier observation regarding telmisartan, 4 and earlier observations by other investigators regarding losartan 5 and irbesartan. 6 Therefore, measurements of pretreatment PRA levels are thought to be useful to predict the ABPlowering effects of ARBs, irrespective of drugs, and should be performed routinely before the initiation of antihypertensive medication, especially in untreated and newly diagnosed patients with essential hypertension.…”

“…[1][2][3] To date, several investigators have studied the association of pretreatment plasma renin activity (PRA) levels with ambulatory blood pressure (ABP) responses to ARBs in essential hypertension. [4][5][6] Recently, we showed that ABP reductions by telmisartan were significantly smaller in hypertensive patients with lower PRA levels than in those with higher PRA levels. 4 However, it is uncertain whether the same is true of all ARBs.…”

“…[1][2][3] Therefore, monotherapy with a RAS blocker, such as an ARB or a renin inhibitor, 5,6,10 may not be suitable for uncomplicated patients with low-renin hypertension who are free from congestive heart failure, diabetes mellitus or chronic kidney disease.…”

“…K It is assumed that patients with lower renin hypertension respond less to monotherapy with a RAS blocker, such as an ARB, than those with higher renin hypertension. K Although several investigators have suggested that some kinds of ARBs show ABP-lowering effects dependent on pretreatment PRA levels in patients with essential hypertension, [4][5][6] it is uncertain whether the same is true of valsartan.…”

Aliskiren Reduces Blood Pressure and Suppresses Plasma Renin Activity in Combination With a Thiazide Diuretic, an Angiotensin-Converting Enzyme Inhibitor, or an Angiotensin Receptor Blocker

“…[11][12][13] Once-daily oral doses of aliskiren of Յ640 mg caused dose-dependent and sustained RAAS inhibition with excellent tolerability in healthy volunteers, 14 whereas recent studies in patients with mild-tomoderate hypertension have shown that aliskiren provides antihypertensive efficacy and safety at least equivalent to the ARBs losartan and irbesartan. 15,16 The aim of the 3 open-label studies presented in this article was to investigate the antihypertensive efficacy of aliskiren, when combined with a diuretic (hydrochlorothiazide [HCTZ]), an ACE inhibitor (ramipril), or an ARB (irbesartan) in patients with mild-to-moderate hypertension. Ambulatory blood pressure measurement (ABPM) was used to assess the effects of aliskiren throughout the 24-hour dosing interval, and the effects of aliskiren on PRA were also investigated to examine whether RAAS suppression was optimized in combination with agents known to stimulate PRA.…”