Is there a future for direct renin inhibitors?

Background: The renin-angiotensin-aldosterone system (RAAS) is a key regulator of blood pressure (BP), as well as volume and electrolytes, in both hypertensive and normotensive individuals. Inappropriate activation of the RAAS is important in hypertension-induced cardiovascular disease (CVD) and chronic kidney disease (CKD). Renin is the rate-limiting step in the RAAS cascade, which makes direct renin inhibitors (DRIs) an attractive target for RAAS suppression and treatment of hypertension. Current regimens using either angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) result in feedback upregulation of renin and aldosterone breakthrough, which contribute to incomplete suppression of the RAAS. Thereby, aliskiren - alone or in combination - might offer a novel therapeutic intervention to improve suppression of the RAAS, with potential to translate to improved CVD and CKD outcomes.

Methods: Herein, we present the current state of knowledge of DRIs in the preclinical and clinical realm and their antihypertensive efficacy in relation to cardiovascular and renal risk. Recent clinical trials (2007 - 2009) support the efficacy of aliskiren, and studies suggest the potential for improved CVD and CKD outcomes.

Results: An understanding of the mechanism of action of DRIs and a perspective of recent clinical trials.

Conclusions: The DRI aliskiren is an effective antihypertensive agent that preliminary data suggests has a beneficial effect in CVD and CKD. Combination of aliskiren with an ACEi or ARB may be better tolerated than the ACEi-ARB combination. Future work is needed to further quantify aliskiren's impact on hard CVD and CKD end points.