Hopes and doubts about zilebesiran, a new antihypertensive drug

The aim of this work is to critically evaluate the benefits and risks of zilebesiran. A comprehensive literature search was conducted in PubMed and Google Scholar databases to identify relevant studies on zilebesiran and other small-interfering RNA (siRNA)-based therapies for hypertension. The search covered publications from January 2010 to December 2025. The following keywords and combinations were used: "zilebesiran", "siRNA therapy", "angiotensinogen inhibition" "hypertension". Hypertension is one of the most prevalent cardiovascular diseases worldwide. The effectiveness of the therapy is still unsatisfactory, which is caused, among other things, non-adherence to pharmaceutical treatment. A long-acting drug could reduce this non-adherence to some extent. The mechanism of action of zilebesiran is based on silencing the angiotensinogen gen by activation the RNA-induced silencing complex (RISC). In animal studies and then in patients with hypertension (KARDIA I and KADRIA 2), zilebesiran after a single subcutaneous administration reduced angiotensinogen concentrations in blood by 90% and a systolic blood pressure by 10-20 mm Hg compare to placebo for a period of 3-6 months. In the studies conducted so far, apart from a few cases of orthostatic hypotension and a slight increase in creatinine in the blood, no serious side effects were found. A large study, KARDIA 3, is currently underway to assess the antihypertensive efficacy and reduction of cardiovascular complications. Despite the promising results of previous studies further observation are still necessary regarding long-term hypotensive effectiveness, reduction of risk cardiovascular complication and side effects.