First Direct Renin Inhibitor Approved for Hypertension

March 29, 2007

TekturnaCommentary By: Josh Olstein, PGY-3

Earlier this month the FDA approved Tekturna (aliskiren) the first drug in a novel class of antihypertensives that work by directly inhibiting renin. While Novartis has yet to release pricing information, don’t expect to see this new addition on the Bellevue or VA formulary any time soon.

The idea of treating hypertension by blocking the actions of renin has been toyed with by pharmaceutical companies for over twenty years with little success. Aliskiren is the first agent with satisfactory pharmacologic properties to be tested for efficacy in phase III clinical trials. Renin is secreted by the kidney in response to low blood pressure and catalyzes the first and rate-limiting step along the renin-angiotensin system (RAS), the conversion of angiotensinogen to angiotensin I. Over activity of the RAS is known to play a role in the pathology of hypertension, cardiovascular disease, and chronic kidney disease via the actions of angiotensin II. Our current therapeutic options for blocking the actions of the RAS include angiotensin converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARBs). Aliskiren now offers the ability to block the actions of the RAS at its point of origin.

Several industry sponsored randomized, double-blinded, placebo-controlled trials have studied the safety and efficacy of aliskiren for treatment of mild-to-moderate hypertension. One trial published in Circulation compared the blood pressure lowering effects of aliskiren (150mg or 300mg) compared to placebo and irbesartan (150mg). After 8 weeks of treatment, patients receiving aliskiren 150mg or 300mg had significantly larger reductions in both systolic and diastolic blood pressure versus placebo. The average decrease in blood pressure (SBP/DBP) for those taking aliskiren was 11.4/9.3 and 15.8/11.8 for 150mg and 300mg respectively. Reductions in blood pressure were similar between aliskiren and irbesartan however those taking 300mg of aliskiren had significantly lower diastolic blood pressure recordings. Of note, all the trials have shown smaller blood pressure reductions among African Americans than among Caucasian of Asian subjects.

All told, safety data is available for over 6,500 subjects who have participated in various studies of aliskiren. It appears to be generally well tolerated and safe. The most commonly reported adverse effect is diarrhea. Cough and rash have also been noted but have occurred about half as frequently as with ACE-I. Hypotension has been rare but reported and two cases of angioedema have also occurred.

Aliskiren will be available as a single daily dose pill in either 150mg or 300mg doses. It is approved for use both as mono-therapy and in combination with a thiazide diuretic or ARB. It’s clearance is largely hepatic (CYP3A4) and no renal dosing is recommended however patients with GFR <30 were excluded from study. No major drug/drug interactions are known however use of other drugs with similar metabolism may prolong the effects of aliskiren. Like ACE-I and ARBs, administration during pregnancy or nursing is contraindicated, and the manufacturers have recommended avoiding high fat meals at the time of administration as this lowers the absorption of aliskiren.

In a field were every millimeter does matter, this drug seems like a promising new addition to the arsenal in the fight against hypertension. However, unlike our abundant knowledge of the additional cardiac and renoprotective effects of ACE-I and ARBs, no long-term outcome data is available yet for aliskiren. While I look forward to possibly adding this drug to the regimen of a patient not yet at their blood pressure goal, it is still too early to abandon the less-expensive and life-prolonging agents we currently use.


Azizi M. Renin Inhibition. Current Opinion in Nephrology and Hypertension. 2006; 15 (5):501-510.

Gradman A et al. Aliskiren, a Novel Orally Effective Renin Inhibitor, Provides Dose-Dependent Antihypertensive Efficacy and Placebo-Like Tolerability in Hypertensive Patients. Circulation. 2005; 111 (8): 1012-1018.

Staessen J, Li Y, Richart T. Oral Renin Inhibitors. Lancet. 2006; 368 (9545): 1449-1456.