A New Avenue for the Long-Term Upstream Inhibition of the Renin-Angiotensin-Aldosterone System by Inhibiting Angiotensinogen RNA

The renin-angiotensin system (RAS) plays a pivotal role in the pathophysiology of several conditions such as hypertension, heart failure and chronic kidney disease. In the last fifty years different therapeutic strategies, including angiotensin converting enzyme inhibitors (ACEi), type 1 angiotensin II receptor blockers (ARBs) and angiotensin receptor neprilysin inhibitors (ARNi), have been developed to counteract this neurohormonal dysregulation. However, all these therapeutic strategies have a relatively short-term action and they need to be administered orally once or more times every day to achieve the therapeutic purposes with a risk of poor therapeutic adherence.More recently, the search for a new effective strategy to provide a long-term control of hypertension was recently boosted by the availability of novel technologies, such as the angiotensinogen suppression in the liver realized through the silencing of RNA with zilebesiran, a small interfering RNA (siRNA) agent.The purpose of this article is to review the available data on Zilebesiran and to discuss in detail potential advantages in the clinical use as well as the still unresolved potential risks.