Year: 2007
Type: article
Abstract: The availability of an effective orally active direct renin inhibitor is a milestone in the long journey of scientists and clinicians interested in exploring how the renin-angiotensin-aldosterone system (RAAS) works and in exploiting this new knowledge for the possible benefit of patients. The developers of the new direct renin inhibitor should be commended on their perseverance. The search for such a compound had gone on for at least 3 decades, with little success. Everything involved in the development of this drug had to be studied in primates at great cost and with some questions regarding applicability to humans. The direct renin inhibitor that has just been approved by the US Food and Drug Administration has many positive attributes: placebo-like tolerability at clinically recommended doses (although the game is in the early innings, and problems could emerge later), additive efficacy with most other antihypertensive drug classes, and a long duration of action, which is important for patients who skip doses. This persistence of effect correlates with good 24-hour blood pressure (BP) control, which may result in target organ protection. Only randomized controlled trials will tell for sure. Having a direct renin inhibitor is also important because it gives the clinician and the patient an additional choice for therapy. Some patients cannot or will not tolerate presently available antihypertensive agents in doses and combinations sufficient to achieve adequate BP control. While the new direct renin inhibitor produces only modest BP reduction when administered as monotherapy, it lowers BP further when combined with antihypertensive agents from most other classes. It is intriguing that this additional BP lowering occurs even when the renin inhibitor is combined with the maximal recommended dose of a downstream RAAS blocker, specifically, an angiotensin II receptor blocker (ARB). Whether this means that neither the renin inhibitor nor the ARB alone fully shuts down the RAAS cascade or that the renin inhibitor acts by mechanisms in addition to shutting down angiotensin II production is unknown and is actively being studied. There is also an important bedside-to-bench aspect of having this agent available for clinical use: interest in studying the fundamental biology of the RAAS has burgeoned, and recent findings may help to elucidate the ultimate therapeutic role of direct renin inhibitors. Inhibition of renin activity reduces angiotensin generation, resulting in loss of the normal angiotensin-mediated feedback inhibition of renin synthesis and release. Thus, in hypertensive patients receiving aliskiren treatment, circulating levels of renin and its catalytically inactive precursor prorenin, which circulates in 10- to 100-fold excess of active renin, are actually elevated, while renin activity is suppressed. Conventional wisdom dictates that these elevated plasma renin and prorenin levels are without biologic significance, since renin has no function beyond its catalytic activity (ie, angiotensin generation). Recent findings have challenged that concept. Some observations suggest that human prorenin is potentially biologically active and can have vasculotoxic effects. Whether a distinct prorenin pathway occurs in humans and whether it is amplified in pathologic states and in the presence of direct renin inhibitor treatment is unknown and is the subject of much speculation. Future study is needed to assess the true pathophysiologic significance of the observation that elevated prorenin levels correlate with microvascular pathology in individuals with diabetes. We are awaiting the results of outcome studies to determine the effects of direct renin inhibitors on target organ damage and cardiovascular disease events in high-risk hypertensive patients, including persons with diabetes. This commentary was supported by Novartis, and Dr Oparil received an honorarium from Novartis for time and effort spent writing the manuscript. Dr. Oparil maintained full control of the content of the commentary; Novartis had no input in the choice of topic, author, or content.
Source: Journal of Clinical Hypertension
Author: Suzanne Oparil
Institutions: University of Alabama at Birmingham, UAB Medicine
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2042525634