Key result
Single-dose zilebesiran cuts angiotensinogen ~90% to lower SBP for three to six months vs placebo.
Why the study?
Does zilebesiran safely and effectively reduce blood pressure in patients with hypertension?
Does zilebesiran safely and effectively reduce blood pressure in patients with hypertension?
Effect estimate: 10-20 mm Hg reduction
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“The main problem with zilebesiran is that it only has a modest effect on blood pressure, and it is likely to have to be used as add-on therapy, which will probably reduce any benefits on adherence it has. It was also difficult to reliably interpret the results of KARDIA-1 as blood pressure went up significantly in the placebo group. KARDIA-1 did not answer previous concerns about zilebesiran; (i) what happens during volume depletion, sepsis, and pregnancy when angiotensinogen is inhibited long term or (ii) will it be effective in a high sodium diet.”
“Some will say patients do not like shots and will be just as noncompliant or worse than they are with pills. They will point to the cholesterol-lowering injectable medications, which have not exactly taken off in my practice. However, up until recently, these shots needed to be injected every two to four weeks; for Zb, we are talking about every four to six months. This has to be an easier sell.”
Zilebesiran is a novel, long-acting siRNA therapy that effectively lowers blood pressure for 3-6 months after a single injection by silencing hepatic angiotensinogen synthesis, offering a potential solution to poor medication adherence in hypertension.
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.
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Głuszek et al. (2026) conducted a review in Hypertension. Zilebesiran vs. Placebo was evaluated on Systolic blood pressure (10-20 mm Hg reduction). Zilebesiran administered as a single subcutaneous injection reduced blood angiotensinogen concentrations by 90% and systolic blood pressure by 10-20 mm Hg compared to placebo for 3 to 6 months.
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