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It has been hypothesized that proximal inhibition of renin may exert complete inhibition of the renin–angiotensin–aldosterone system (RAAS), leading to prevention of recurrent events.1,2 In the recently published Aliskiren trial in Type 2 diabetes mellitus using cardiorenal end points (ALTITUDE), aliskiren was associated with a trend toward higher composite cardiovascular events (primary end point) compared with placebo. In this review, we provide a summary of the preclinical and clinical data that leads to the development of renin inhibitors and offers perspectives on the findings from ALTITUDE, based on new information on RAAS components and their inhibition.Theoretically, complete suppression of RAAS by renin inhibition has broad applicability in disease states associated with excess activation of the RAAS and continued production of angiotensin II (Ang II) despite angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) therapy. Pharmacological agents to treat hypertension (HTN) are well known for stimulating plasma renin activity (PRA), and it has been postulated that direct renin inhibitors (DRIs) may have synergistic effects with these agents.1 Initial attempts to develop DRIs failed because of lack of affinity toward the active site of renin and poor pharmacokinetic properties after oral administration.3 Aliskiren was synthesized using both crystal structure analysis of renin inhibitor complexes and computational molecular modeling with the intent of addressing issues of solubility and affinity. Aliskiren demonstrated subnanomolar inhibition of human renin (IC50=0.6 nmol/L) with a high degree of distribution in renal glomeruli and small cortical blood vessels.4,5 It lowered blood pressure (BP) in marmosets and was subsequently studied in a variety of disease contexts in both animals and humans.4 Aliskiren was approved for the treatment of HTN by both the US Food and Drug Administration and the European Medicines Agency in 2002. In head-to-head clinical …

Complete Renin–Angiotensin–Aldosterone System (RAAS) Blockade in High-Risk Patients