Add-On Treatment With Zilebesiran for Inadequately Controlled Hypertension: The KARDIA-2 Randomized Clinical Trial

Area of Science:

• Cardiovascular Medicine
• Pharmacology
• RNA Therapeutics

Background:

• Hypertension remains a significant global health challenge, with many patients failing to achieve target blood pressure levels on existing monotherapies.
• Zilebesiran, an investigational RNA interference therapeutic, has previously shown potential in reducing serum angiotensinogen and systolic blood pressure (SBP) in monotherapy studies.

Purpose of the Study:

• To evaluate the efficacy and safety of adding zilebesiran to standard antihypertensive medications compared to placebo in adults with uncontrolled hypertension.

Main Methods:

• A phase 2, randomized, double-blind trial involving adults with uncontrolled hypertension receiving background indapamide, amlodipine, or olmesartan.
• Patients achieving target ambulatory SBP were randomized to receive a single subcutaneous dose of zilebesiran (600 mg) or placebo.
• The primary end point was the change in 24-hour mean ambulatory SBP from baseline at 3 months.

Main Results:

• Zilebesiran significantly reduced SBP compared to placebo across all background medication cohorts: -12.1 mm Hg with indapamide, -9.7 mm Hg with amlodipine, and -4.5 mm Hg with olmesartan.
• While adverse events like hyperkalemia, hypotension, and acute kidney failure were more frequent with zilebesiran, most were mild and resolved without intervention.

Conclusions:

• Single-dose zilebesiran added to standard antihypertensive therapy significantly lowered SBP in patients with uncontrolled hypertension.
• The findings support zilebesiran as a potential novel therapeutic option for managing resistant hypertension.