Renin inhibitors and cardiovascular and renal protection: an endless quest?

Renin-angiotensin system (RAS) blockade with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) has become a major therapeutic approach in medicine since the end of the 1970's. Although these molecules were the first RAS blockers to be developed, it would have been physiologically and pharmacologically more pertinent to selectively inhibit renin itself. Indeed, the reaction between renin and its unique substrate, angiotensinogen, is the highly regulated and rate-limiting step of the RAS. The development of direct renin inhibitors (DRI) has been a slow and complex process and the synthesis of the first orally active DRI, aliskiren, was only achieved in the 2000's. Its pharmacological profile in patients with hypertension, diabetic nephropathy or heart failure, in addition to experimental evidence, suggests that aliskiren may be of value for the management of cardiovascular and renal diseases. However, the long-term, randomized, placebo-controlled, morbidity/mortality trial, ALTITUDE, which included 8,600 patients with type 2 diabetes, proteinuria and a high cardiovascular risk already treated with ACE inhibitors or ARBs was terminated in December 2011 because of futility and an increased incidence of serious adverse events in the aliskiren 300 mg arm. Other long-term studies are still ongoing to demonstrate the safety and efficacy of aliskiren to reduce cardiovascular morbidity and mortality in patients with heart failure and in elderly individuals (≥65 years) with systolic blood pressure of 130 to 159 mmHg, no overt cardiovascular disease, and a high cardiovascular risk profile. In the meantime, according to the European Medicines Agency recommendations, aliskiren should not be prescribed to diabetic patients in combination with ACE inhibitors or ARBs.

RCT Entities:   Population Interventions Outcomes