Hypertension (HTN) remains the leading cause of disability-adjusted life-years worldwide, and is the leading risk factor for noncommunicable disease burden and premature mortality. Well known to cardiologists among these noncommunicable diseases are atherosclerosis and coronary artery disease (CAD), heart failure (HF), and stroke.

The KARDIA-1 study

Results from the KARDIA-1 RCT highlighted the potential of an RNA interfering agent, zilebesiran, to treat mild to moderate HTN.

Bakris GL, Saxena M, Gupta A, et al. RNA interference with zilebesiran for mild to moderate hypertension: the KARDIA-1 randomized clinical trial. JAMA. 2024;331(9):740–749.

In this phase 2 trial, subcutaneous doses of zilebesiran (150 mg, 300 mg, or 600 mg every 6 months; or 300 mg every 3 months) significantly decreased systolic BP (SBP) at both 3 and 6 months, compared with placebo.

The KARDIA-1 study was a placebo-controlled trial that specifically enrolled adults with a daytime mean SBP of 135 mm to 160 mm Hg. At month 3, participants receiving zilebesiran demonstrated a drop in 24-hour mean ambulatory SBP of 7.3 mm Hg with zilebesiran 150 mg (6-month dosing interval); a drop of 10 mm Hg with zilebesiran 300 mg (every 3 and 6 months, combined); and a drop of 8.9 mm Hg with zilebesiran 600 mg (6-month dosing interval). This compared with a reduction of 6.8 mm Hg on placebo.

The most common non-serious drug-related adverse effects, occurring in 16.9% of zilebesiran-treated participants, were injection-site reactions and mild hyperkalemia.

One limitation of the study was that follow-up was only 6 months, meaning that participants received only one or two doses of treatment with zilebesiran.

In his JAMA editorial on the trial, Dr. Ernesto Schiffrin commented, “The data from the trial represent a rigorous study that supports further investigation of zilebesiran as a therapeutic approach to treatment of patients with hypertension. If sustained BP reduction is confirmed with few adverse effects, zilebesiran administration every 6 months could represent a significant advance in hypertension therapeutics because it could potentially overcome lack of adherence to treatment, which remains to be demonstrated.”

Schiffrin EL. Adherence and lower blood pressure in patients with hypertension [editorial]. JAMA. 2024;331(9):733–735.

RNA-interfering agents in cardiology

The allure of therapeutic agents that can be delivered as infrequently as twice a year, with the attendant implications for improved adherence, enhances the promise of agents like zilebesiran. 

However, as with all long-acting agents, the flip side of the coin is that the duration of their effect can become problematic if significant adverse effects are encountered. This makes longer-term studies even more important.