Hypertension is a significant global health concern, contributing to cardiovascular mortality and the progression of kidney disease. Apart from the increased prevalence, nearly 80% of the patients fail to attain the recommended blood pressure (BP) targets due to variability in BP and challenges in adhering to daily, multi-drug treatment regimens. In a recent study published in JAMA, researchers reported that zilebesiran, a novel ribonucleic acid (RNA) interference therapeutic, is effective in reducing mild to moderate hypertension.
Zilebesiran specifically targets angiotensinogen production in the liver. Early-phase studies demonstrated promising results, indicating sustained reductions in blood pressure. The randomized, double-blind, dose-ranging study of zilebesiran vs placebo was performed at 78 sites across 4 countries from July 2021 to June 2023, adhering to the ethical standards, and obtained informed consent from participants. Adult participants with hypertension, excluding those with severe renal impairment or poorly controlled diabetes, underwent a washout period for previous antihypertensives. The study employed randomization to 1 of 4 subcutaneous zilebesiran regimens (150, 300, or 600 mg once every 6 months or 300 mg once every 3 months) or placebo (once every 3 months) for 6 months.
The primary focus of the study was on the change from baseline to month 3 in 24-hour mean ambulatory systolic BP among different zilebesiran doses compared to the placebo. Secondary outcomes included office systolic BP changes, the percentage of patients achieving specific systolic BP criteria without additional medication, and various blood pressure metrics. In the study, 1,517 individuals were initially considered, with 394 ultimately randomized to receive either placebo or varying doses of zilebesiran. Ultimately, 377 individuals (302 on zilebesiran and 75 on placebo) were evaluated, with 347 completing the 6 months. The participants’ demographics were diverse, with 44.3% female and 24.7% Black individuals, with an average age of 56.8 years. Baseline BP averaged 142/82 mm Hg. The primary outcome showed significant reductions in 24-hour mean ambulatory SBP at 3 months across zilebesiran doses compared to placebo.
Evaluation of secondary outcomes at 3 months reported similar findings, with reductions in office systolic BP and consistent benefits observed at 6 months. Zilebesiran significantly outperformed placebo in terms of participants meeting pre-defined BP response criteria. Additional benefits included substantial reductions in diastolic BP (DBP) and serum angiotensinogen levels.
The primary focus of the study was on the change from baseline to month 3 in 24-hour mean ambulatory systolic BP among different zilebesiran doses compared to the placebo. Secondary outcomes included office systolic BP changes, the percentage of patients achieving specific systolic BP criteria without additional medication, and various blood pressure metrics. In the study, 1,517 individuals were initially considered, with 394 ultimately randomized to receive either placebo or varying doses of zilebesiran. Ultimately, 377 individuals (302 on zilebesiran and 75 on placebo) were evaluated, with 347 completing the 6 months. The participants’ demographics were diverse, with 44.3% female and 24.7% Black individuals, with an average age of 56.8 years. Baseline BP averaged 142/82 mm Hg. The primary outcome showed significant reductions in 24-hour mean ambulatory SBP at 3 months across zilebesiran doses compared to placebo.
Evaluation of secondary outcomes at 3 months reported similar findings, with reductions in office SBP and consistent benefits observed at 6 months. Zilebesiran significantly outperformed placebo in terms of participants meeting pre-defined BP response criteria. Additional benefits included substantial DBP reductions and serum angiotensinogen levels.
Exploratory analyses revealed a reduced need for rescue antihypertensive medications in those treated with zilebesiran compared to placebo. Safety profiles were favorable, with serious adverse events (AEs) reported in a smaller percentage of zilebesiran-treated patients compared to placebo. Most AEs were mild to moderate, including injection site reactions and hyperkalemia.
Zilebesiran could be a potential treatment option for hypertension patients. However, further research is needed to determine its long-term safety and effectiveness, particularly when used in combination with other therapies. This could provide valuable insights into its broader applicability and role in comprehensive hypertension management strategies.
Reference
Bakris GL, Saxena M, Gupta A, Chalhoub F, Lee J, Stiglitz D, et al. RNA Interference With Zilebesiran for Mild to Moderate Hypertension: The KARDIA-1 Randomized Clinical Trial. JAMA [Internet]. 2024 Feb 16 [cited 2024 Feb 20]