Madrid, Spain - New phase 3 clinical data on the oral renin inhibitor aliskiren (Rasilez, Novartis) showed that the drug was effective at lowering blood pressure in diabetic patients with hypertension both as monotherapy and in coadministration with ramipril.

Aliskiren was filed for approval in the US in April 2006 as a new antihypertensive agent. A European submission is planned for the end of this year.

In the current study, presented by Dr Yagiz Uresin (Istanbul Medical Faculty, Turkey) at this week's European Society of Hypertension (ESH) meeting in Madrid, combination therapy with aliskiren and ramipril (Altace, King Pharmaceuticals/Wyeth) provided significant additional antihypertensive benefit over either agent alone, and aliskiren alone appeared to reduce systolic pressure more than ramipril alone. In addition there was a suggestion that the cough associated with ramipril may be reduced if aliskiren is added.

Uresin commented to heartwire that inhibitors of the renin angiotensin system (RAS) are attractive choices for antihypertensive therapy in diabetic patients because they offer improved renal protection. "It has been shown that enhanced blockade of the RAS with use of two different agents such as an ACE inhibitor and an angiotensin II blocker gives enhanced renal protection. Unlike current RAS inhibitors, aliskiren suppresses the RAS at its point of activation. Consequently, coadministration of aliskiren with an ACE inhibitor may provide improved RAS suppression."

The present study involved 837 patients with diabetes and hypertension. Such patients are at an increased cardiovascular risk, have a lower blood-pressure goal than patients without diabetes, and often require therapy with multiple antihypertensive therapies, Uresin noted.

Patients were randomized to one of three treatment strategies—ramipril alone, aliskiren alone, or a combination of the two agents. Ramipril was started at a dose of 5 mg once daily, and aliskiren was started a dose of 150 mg daily; after four weeks, both doses were doubled for another four weeks of treatment.

At the end of the eight-week treatment period, diastolic blood-pressure reductions were similar with aliskiren and ramipril monotherapy, but greater with the combination. And systolic blood-pressure reductions were significantly greater with both aliskiren monotherapy and aliskiren/ramipril combination therapy compared with ramipril monotherapy. By the end of the study, significantly more patients had responded to aliskiren monotherapy and aliskiren/ramipril combination therapy than ramipril monotherapy.

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All treatments were well tolerated. As expected, the incidence of cough was lower with aliskiren than ramipril. But unexpectedly, the incidence of cough was lower in the combination group than with ramipril alone, which Uresin said may suggest an attenuation of ACE-inhibitor-induced cough with aliskiren. To heartwire, he commented: "We must be cautious, as this is just one observation from one study, but it does look as if cough was reduced in the combination group compared with the ramipril-alone group, suggesting that the inhibition of renin is also having an effect on bradykinin. But this obviously needs more study."

Aliskiren is the first direct renin inhibitor to be developed and, if approved, will be the first new treatment approach to hypertension in more than a decade. Several outcome studies are now under way with the drug, including the following:

• Left-ventricular hypertrophy (LVH) study—Comparing aliskiren 300 mg vs losartan (Cozaar, Merck) 100 mg and the combination of both over a nine-month period in patients with hypertension and LVH. The major end point will be left ventricular mass (and structure) by magnetic resonance imaging.
• Diabetic proteinuria study—Comparing the effects of aliskiren 300 mg with placebo over a six-month treatment period in patients with type 2 diabetes and proteinuria who are on an angiotensin-receptor blocker. The primary end point is the percent reduction in urinary albumin/creatinine ratio.
• Heart-failure study—Comparing the effects of aliskiren 150 mg with placebo over a 12-week treatment period in patients with hypertension and stable heart failure already on other optimal CHF therapy. The primary end point is the reduction in brain natriuretic peptide, a biomarker for heart failure.

Results from all three of these studies are expected in the second half of 2007.