- Question
- Does adding a single subcutaneous dose of zilebesiran, an RNA interference therapeutic targeting angiotensinogen, lower blood pressure in patients with hypertension inadequately controlled on a standard antihypertensive drug?
- Design
- Phase 2, randomized, prospective, double-blind, placebo-controlled trial at 150 sites in 8 countries. After an open-label run-in of at least 4 weeks on a background drug, adherent patients were randomized 1:1 within each cohort.
- Population
- Adults with uncontrolled hypertension despite background treatment (indapamide, amlodipine, or olmesartan) and a 24-hour mean ambulatory systolic blood pressure of 130 to 160 mm Hg. Of 1491 patients entering the run-in, 663 were randomized (130 on indapamide, 240 on amlodipine, and 293 on olmesartan).
- Intervention
- A single subcutaneous dose of zilebesiran 600 mg added to the background drug (n = 332).
- Control
- Matching subcutaneous placebo added to the same background drug (n = 331).
- Primary outcome
- Between-group difference (zilebesiran vs placebo) in change from baseline in 24-hour mean ambulatory systolic blood pressure at 3 months, assessed within each cohort.
- Results
- The least-squares mean difference between zilebesiran and placebo was -12.1 mm Hg (95% CI, -16.5 to -7.6; P < .001) with indapamide, -9.7 mm Hg (95% CI, -12.9 to -6.6; P < .001) with amlodipine, and -4.5 mm Hg (95% CI, -8.2 to -0.8; P = .02) with olmesartan.
- Safety
- Zilebesiran was associated with more hyperkalemia (18 [5.5%] vs 6 [1.8%]), hypotension (14 [4.3%] vs 7 [2.1%]), and acute kidney failure (16 [4.9%] vs 5 [1.5%]) events than placebo, although most episodes were mild and resolved without medical intervention.
- Conclusion
- Adding single-dose zilebesiran significantly reduced systolic blood pressure at 3 months compared with placebo in patients with uncontrolled hypertension, with low rates of serious adverse events.
- Why it matters
- The trial showed that silencing hepatic angiotensinogen production with a single injection can be layered on top of usual antihypertensive therapy, opening a long-acting treatment pathway that could help with adherence. As a phase 2 study with a blood pressure endpoint, it does not yet establish effects on clinical outcomes.
Card generated automatically with AI from the abstract of the original publication and the trial registry; every figure was checked against those sources. It may contain errors: verify the data at the source before using it for clinical decisions.
Generated on October 18, 2026