MinireviewAddressing the theoretical and clinical advantages of combination therapy with inhibitors of the renin–angiotensin–aldosterone system: Antihypertensive effects and benefits beyond BP control
Introduction
The renin–angiotensin–aldosterone system (RAAS) plays a key role in the pathophysiology and development of hypertension, atherosclerosis, congestive heart failure (CHF), type 2 diabetes mellitus (DM), and renal disease (Weir and Dzau 1999). Specifically, angiotensin II (Ang II) is a major effector of vasoconstriction, cell growth, sodium and water retention, and sympathetic activation; it appears to promote endothelial dysfunction, inflammation, oxidative stress, insulin resistance, and reduced β-cell responsiveness. The close relationship between the RAAS and hypertension has led to compelling indications to block the formation or activity of Ang II through use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) (Table 1) (Chobanian et al., 2003, Mancia et al., 2007).
Although ACEIs and ARBs are among the most effective and safe antihypertensives, when used as monotherapy they control blood pressure (BP) effectively (< 140/90 mm Hg in uncomplicated patients, < 130/80 mm Hg in diabetics/complicated patients) in only 40% to 60% of patients with mild-to-moderate hypertension (Ibrahim 2006). Furthermore, Weber and Giles (2006) noted that ACEIs and ARBs have not produced the major reductions in clinical outcomes that were predicted based on the centrality of the RAAS in the pathophysiology of cardiorenal disease. They speculate that additional novel methods of RAAS blockade may yield better control of hypertension and improved organ protection. One such approach explored combination therapy with ACEIs and ARBs. Although some studies have shown this combination to provide modest benefits beyond monotherapy with either class of agent, other studies, and particularly ONTARGET (Yusuf et al., 2008, Mann et al., 2008), have cast doubt on the long-term safety and effectiveness of this strategy.
Direct renin inhibitors (DRIs), when used in combination with ACEIs or ARBs, may provide more complete RAAS blockade, greater BP control, and better target-organ protection. This article reviews the importance of the RAAS in the cardiometabolic continuum, presents the pros and cons of dual RAAS blockade with ACEIs and ARBs, and examines the theoretical and practical benefits supporting the use of DRIs in combination with ACEIs or ARBs.
Section snippets
The biochemical physiology of the RAAS
Fig. 1 illustrates the current biochemical pathways involved in the production of biologically active angiotensins. In the RAAS, enzymatically inactive prorenin, primarily synthesized in the kidney and accounting for 70% to 90% of the renin in the circulation, is proteolytically converted to enzymatically active renin in response to renal baroreceptor signaling, sodium concentration changes, sympathetic nerve stimulation, and negative feedback by Ang II on juxtaglomerular cells (Atlas 2007).
RAAS blockade by ACEIs, ARBs, and DRIs
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. Table 2 summarizes the effects of DRIs, ACEIs, and ARBs on the RAAS.
As
ACEIs and ARBs: antihypertensive effects and clinical benefits beyond BP control
Monotherapy with ACEIs and ARBs effectively controls BP in approximately 40% to 60% of patients with mild-to-moderate hypertension (Ibrahim 2006). Both drug classes reduce the risk of adverse cardiovascular outcomes and are considered suitable for the initiation and maintenance of antihypertensive treatment, either as monotherapy or in combination with other antihypertensives (Chobanian et al., 2003, Mancia et al., 2007).
A number of compelling indications exist for using ACEIs and ARBs, which
Dual RAAS blockade with ACEIs and ARBs
As reviewed above, the existence of multiple pathways for the generation of the biologically active angiotensin peptides posits the question as to how effective current approaches are to suppress the activity of Ang II. At each of the points within the cascade of the RAAS, alternate enzymatic pathways can bypass the blockade of the primary enzyme while it is also possible that intracellularly the formation of angiotensin peptides does not follow what has been characterized in the circulation or
DRIs: suppression of PRA and potential role in dual RAAS blockade
As reviewed in the following sections, PRC increases in response to monotherapy with aliskiren, ACEIs, ARBs, amlodipine, aldosterone antagonists, or thiazide diuretics (or combination therapy with aliskiren plus any of these agents), whereas PRA decreases to below baseline when aliskiren is used alone or in combination with other antihypertensives (studies with thiazide diuretics are included because these agents increase PRA levels (Lijnen et al. 1981). Results are summarized below and in
Benefits beyond BP control
The potential benefits of dual RAAS therapy with aliskiren appear to extend beyond simple control of BP. Aliskiren is a potent, long-acting, renal vasodilator with a pronounced natriuretic effect in normotensive healthy volunteers on a low-sodium diet; its renal vasodilator effects are approximately twice as large as those of ACEIs and 40% greater than those of ARBs (Fisher et al. 2008). This suggests that aliskiren may provide greater and more effective blockade of the RAAS in the kidney.
Conclusions
From a theoretical standpoint, direct inhibition of renin has long been recognized as a promising target for inhibiting the RAAS, because renin is the first rate-limiting enzymatic step in the RAAS pathway. From a practical standpoint, ACEIs and ARBs have not provided the major improvements in clinical outcomes that might be predicted based on the central role of the RAAS in the cardiorenal disease continuum. Moreover, the value of combination ACEI/ARB therapy has been called into question,
Conflict of interest statement
Carlos M Ferrario receives compensation for speaking and consulting for Novartis, Inc., Daiichi Sankyo, Inc. Merck Inc., and Forest Pharmaceuticals.
Acknowledgements
Editorial support was provided by John Leinen, PhD, at Oxford PharmaGenesis Inc., Newtown, PA, and was funded by Novartis Pharmaceuticals Corporation, East Hanover, NJ. In addition to support provided by NHLBI grant PO1 HL051952, the author gratefully acknowledges grant support in part provided by Unifi, Inc., Greensboro, NC, and Farley-Hudson Foundation, Jacksonville, NC.
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