Novel therapy in the management of hypertension: Preliminary experience with renin inhibitors

Abstract

Suppressing the renin-angiotensin system (RAS) has become a crucial strategy for combating cardiovascular and renal disease—one that has been validated by the clinical success of angiotensin-converting enzyme inhibitors and angiotensin II (Ang II) receptor blockers (ARBs). Yet these agents may be limited in their ability to completely inhibit the RAS long-term. Because renin acts early in the RAS cascade, inhibiting the RAS at this step has long been considered a logical therapeutic target. Efforts to develop renin inhibitors have been underway for decades, but poor bioavailability, short duration of action, and high production costs have impeded their clinical development. Designed using molecular modeling techniques, aliskiren is the first agent in a new class of nonpeptide, low-molecular weight, orally active renin inhibitors. Aliskiren has demonstrated potent in vitro affinity for human renin, and has exhibited dose-dependent reductions in plasma renin activity (PRA), Ang II levels, and blood pressure (BP) in preclinical models. In sodium-depleted marmosets, aliskiren showed dose-dependent reductions in BP, and greater BP reductions than the previous-generation renin inhibitors, remikiren and zankiren. In spontaneously hypertensive rats, aliskiren 30 mg/kg/d yielded modest BP reductions; when administered in combination with benazepril or valsartan, however, BP reductions appeared synergistic. In the double-transgenic rat model, which expresses human renin and angiotensinogen, and becomes severely hypertensive and dies of organ failure if left untreated, 9 weeks of therapy with either aliskiren or valsartan significantly reduced left ventricular wall thickness and cardiac hypertrophy. Furthermore, both agents similarly reduced albuminuria and renal and cardiac fibrosis, as well as kidney and heart macrophage and T-cell accumulation. All untreated rats died by Week 8. The pharmacokinetics and pharmacodynamics of aliskiren were examined in 18 volunteers in a double-blind, 3-way crossover trial. During 3 periods of 8 days, each followed by a 6-day washout, each volunteer was randomized to receive 2 dosages of aliskiren (40 mg and 80 mg/d, or 160 mg and 640 mg/d) and either placebo or 20 mg/d enalapril. Aliskiren reduced PRA and angiotensin I (Ang I) and Ang II levels, while PRA and Ang I were increased with enalapril. The half-life of aliskiren was 29 hours. Aliskiren efficacy and safety were evaluated in a randomized, double-blind trial in 226 patients, aged 21–70 years, with mild-to-moderate hypertension. Patients received aliskiren (37.5 mg, 75 mg, 150 mg, or 300 mg) or losartan (100 mg) once daily for 4 weeks. Aliskiren yielded dose-dependent reductions in systolic and diastolic BP; at the 300-mg/d dose, the mean BP reduction was comparable to that of high-dose losartan. Losartan and all aliskiren doses were equally well tolerated. Aliskiren was also studied in a double-blind, placebo-controlled, 8-week trial of 652 patients with mild-to-moderate hypertension. Patients were randomized to once-daily aliskiren (150 mg, 300 mg, or 600 mg), irbesartan 150 mg, or placebo. The antihypertensive efficacy of aliskiren 150 mg/d was comparable to that of irbesartan; the reduction in diastolic BP with aliskiren 300 mg/d was significantly greater than with irbesartan. Tolerability with aliskiren up to 600 mg/d was similar to that with irbesartan. A double-blind, randomized, placebo-controlled, 4-period crossover study examined the effects of single doses of aliskiren 300 mg, valsartan 160 mg, and their combination (aliskiren 150 mg plus valsartan 80 mg) in 12 mildly sodium-depleted, normotensive, male subjects. As expected, PRA, Ang I, and Ang II were significantly reduced with aliskiren and increased with valsartan. However, the ARB-associated increases in PRA and Ang I and Ang II levels were eliminated with the addition of aliskiren to valsartan. Aliskiren thus appears to be a useful addition for the management of hypertension. Further investigation of the effects of aliskiren on end-organ protection is needed.