Direct Inhibition of Renin as a Cardiovascular Pharmacotherapy

Abstract

The important role of renin-angiotensin-aldosterone system blockade in the treatment of systemic hypertension, heart failure, diabetic kidney disease, and atherogenesis has been clearly established. The theoretical therapeutic advantages for inhibiting the detrimental effects of the renin-angiotensin system at its most upstream point have served as the impetus for the development of renin inhibitors. The advent of aliskiren, the first in a novel class of orally active, nonpeptide, highly specific, human renin inhibitors, provides a new modality in the armamentarium of renin-angiotensin system antagonists. Studies in marmosets and rats demonstrated that aliskiren reduced blood pressure in a dose-dependent manner and is highly efficacious in blocking plasma renin activity with parallel reductions in the levels of the other downstream constituents of the renin-angiotensin system. Clinical trials in hypertensive patients have confirmed these benefits with aliskiren whose blood pressure-lowering efficacy is similar to or better than those of standard therapeutic doses of enalapril, losartan, irbesartan, and hydrochlorothiazide. Aliskiren is well tolerated, with few reported adverse effects even at the highest doses tested. Given the established beneficial effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in the treatment of cardiovascular and renovascular diseases, future studies may further elucidate a similar protective role for aliskiren both as a monotherapy and as part of a combination therapy.

ACCF/AHA 2011 Expert Consensus Document on Hypertension in the Elderly

“…603 Combining aliskiren with HCTZ, ramipril, or amlodipine causes greater BP lowering than with either agent alone. 601,604 Evidence is lacking with combination aliskiren and beta blockers, or with maximal dose ACEIs, and only limited data are available in black patients with hypertension. 605 In patients Ͼ75 years of age, including those with renal disease with a GFR Ն30 mL/min/1.73 m 2 , aliskiren appears well tolerated with no dose adjustment necessary.…”

ACCF/AHA 2011 Expert Consensus Document on Hypertension in the Elderly

“…In another group of elderly patients with systolic hypertension, aliskiren, with optional add-on HCTZ (12.5 mg/d to 25 mg/d) and amlodipine (5 mg/d to 10 mg/d), appeared more effective and better tolerated overall versus ramipril (603). Combining aliskiren with HCTZ, ramipril, or amlodipine causes greater BP lowering than with either agent alone (601,604). Evidence is lacking with combination aliskiren and beta blockers, or with maximal dose ACEIs, and only limited data are available in black patients with hypertension (605).…”

First renin inhibitor, aliskiren, for the treatment of hypertension

“…There have been several reviews published with a general scope of pharmacology, pharmacokinetics, pharmacodynamics, drug interaction, and clinical studies of aliskiren [12][13][14][15][16][17]. In this paper, we performed a systematic analysis of the literature with particular attention to pivotal clinical studies submitted to the FDA in order to provide unbiased drug information for healthcare professionals, researchers, and policy makers.…”