[The future of renin inhibition].Turk Kardiyol Dern Ars. 2009 Oct; 37 Suppl 7:32-8.TK
Although antihypertensive drugs currently used provide significant decreases in blood pressure and improve clinical results, cardiovascular morbidity and mortality are not sufficiently decreased; therefore, there is still a need for new approaches to the treatment of hypertension and related cardiovascular diseases. However, when a new blood-pressure lowering therapy is introduced, the question of whether this will be superior over other drug classes in terms of its advantages in hypertensive patients is frequently asked. In 1898, Tigerstedt and Bergman discovered "renin" as a consequence of an observation of blood-pressure elevation following the injection of rabbit renal extracts to rabbits; however, the first member of the renin system pharmacology, ACE inhibitors, could be developed in 1970's. This was followed by the development of angiotensin-receptor blockers (ARB) and, during the last 30 years, it has been shown that the pharmacologic blockage of renin-angiotensin system (RAS) improves the prognosis in hypertensive patients. It has been shown that renin system is the key system in the treatment of hypertension and related comorbidities and that the drugs which target renin system, such as ACE inhibitors and ARB, reduce the cardiovascular events to a large extent. In contrast, as the inhibition of angiotensin II (Ang II) production and effect prevents the negative feedback which helps Ang II to inhibit the renin release from the kidney, elevated Ang II levels suggest that renin enzyme, which can be considered to be the center of renin system, can be the optimal tool in the treatment. Aliskiren, which is the first oral direct renin inhibitor developed based on these ideas, was approved by the FDA in March 2007. During all this period, clinical studies have shown that aliskiren is as efficient as other antihypertensive drugs, and preclinical studies have shown that, in genetically modified rats, aliskiren is efficient in healing the cardiovascular damage associated with Ang II. The fact that the plasma renin activity (PRA), which increases with other antihypertensive therapies and is associated with increased cardiovascular complications, decreases with the use of direct renin inhibitors raises the question as to whether aliskiren may provide additional benefit in reducing cardiovascular morbidity and mortality. The ASPIRE HIGHER program designed to find an answer to this question includes several studies which investigate how aliskiren impacts the clinical results. The studies AVOID, ALOFT and ALLAY, which were completed within the ASPIRE HIGHER program, showed that aliskiren had beneficial effects for surrogate markers of cardiovascular and renal diseases, while AGELESS study showed that, in elderly with systolic hypertension, aliskiren (150 or 300 mg) provided a higher blood pressure lowering compared to ramipril (5 or 10 mg). In addition, many studies included in this program are ongoing and the results of these studies will provide more information about direct renin inhibition. Potential effects of RAS in cognitive functions and the functions of its different components such as angiotensin and AT4 receptor are the topics which are still awaiting answers.