Clinical Utility of Renin Inhibitors

Jordan, Jens. Hannover Medical School Institute for Clinical Pharmacology, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.

Renin-angiotensin-system (RAS) inhibitors have been successfully applied in patients with cardiovascular and renal diseases. Over the years, large clinical trials with hard clinical endpoints showed that RAS inhibition with angiotensin receptor blockers or ACE inhibitors is beneficial in the treatment of heart failure, diabetic nephropathy, and various other common ailments. These findings together with marked progress in basic science created much enthusiasm among clinical scientists. Could more complete RAS inhibition provide an even greater benefit? Indeed, addition of mineralocorticoid receptor antagonists to another RAS inhibitor improved prognosis in patients with severe heart failure or left ventricular dysfunction after myocardial infarction. However, combination of ACE inhibitors with angiotensin receptor blockers was disappointing in terms of cardiovascular and renal risk reduction. Moreover, the combination was not more effective in lowering blood pressure than either drug alone. Recent clinical trials with the first orally active renin inhibitor aliskiren suggest that the site where the RAS is inhibited matters. Indeed, addition of the renin inhibitor aliskiren to an ACE inhibitor or to an angiotensin receptor blocker further lowers blood pressure. Furthermore, renin inhibition lowers circulating brain natriuretic peptide (BNP) concentrations in heart failure patients already on RAS inhibitors and beta-blockers. Finally, renin inhibition resulted in additional reduction in proteinuria in patients with diabetic nephropathy when added to an angiotensin receptor blocker. Together, these studies suggest that renin inhibitors are an interesting treatment strategy for hypertensive patients not sufficiently responding to or not tolerating first line antihypertensive drugs. Studies with surrogate endpoints suggest that renin inhibitors may provide additional benefit in terms of cardiovascular and renal risk reduction. Definitive clinical trials with hard endpoints are ongoing.