A long-lasting approach could make it easier for patients with high blood pressure to keep their condition under control – and ditch daily pills – after those receiving the experimental drug zilebesiran alongside standard therapy saw greater BP reductions than patients on standard treatment alone, reports Science Daily.
The clinical trial, led by Queen Mary University of London, suggests that this single injection given six-monthly may significantly lower blood pressure over time. The findings, published in JAMA, point to a long-lasting treatment option that could improve how hypertension is managed.
The global study, called KARDIA-2, included 663 adults with high blood pressure that was not well controlled with their usual medications. Participants received an injection of zilebesiran in addition to their existing blood pressure treatments. The drug works by blocking a key liver protein, helping blood vessels relax.
These results could have wide-reaching implications, the researchers said. High blood pressure affects about one in three adults in the UK and is a major risk factor for serious health problems, including heart attacks, strokes, and death if not properly managed.
Dr Manish Saxena, clinical co-director of the William Harvey Clinical Research Centre at Queen Mary University of London and a hypertension specialist at Barts Health NHS Trust, led the UK portion of the eight-country study and is a senior author of the publication.
“Hypertension is a global health concern and a leading cause of heart attacks and strokes,” he said. “This study demonstrates the efficacy and safety of zilebesiran, when added to commonly used first line blood pressure lowering drugs. The novelty of this treatment is its long duration; giving just one injection every six months could help millions of patients to better manage their condition.”
How Zilebesiran works
Zilebesiran is an investigational drug that uses RNA interference technology to reduce blood pressure. It works by blocking the production of a protein in the liver (angiotensinogen), which plays a key role in regulating blood pressure. By lowering levels of this protein, blood vessels are able to relax, leading to reduced blood pressure.
The treatment is administered as an injection under the skin.
Researchers are continuing to study zilebesiran in a follow-up phase 2 trial known as KARDIA-3. This study will explore whether the drug can benefit people who have high BP along with established cardiovascular disease or those at high risk for such conditions.
In addition, a large global outcomes study is planned for later this year. This trial will examine whether the treatment can reduce the risk of major cardiovascular events, including strokes and cardiovascular death.
Study details
Add-on treatment with zilebesiran for inadequately controlled hypertension: The KARDIA-2 Randomised Clinical Trial
Akshay Desai, Adam Karns, Jolita Badariene et al.
Published in JAMA on 28 May 2025
Abstract
Importance
In prior monotherapy studies of patients with hypertension, single subcutaneous doses of zilebesiran, an investigational RNA interference therapeutic, reduced serum angiotensinogen levels and systolic blood pressure (SBP) at three and six months.
Objective
To evaluate the efficacy and safety of zilebesiran vs placebo when added to a standard antihypertensive medication.
Design, Setting, and Participants
This phase 2, randomised, prospective, double-blinded trial enrolled adults with uncontrolled hypertension from 150 sites across eight countries between January 2022 and June 2023. The final follow-up date was December 11, 2023, and analyses were conducted on March 1, 2024.
Interventions
Eligible patients were initially randomised in cohorts to receive open-label run-in treatment for at least 4 weeks with indapamide 2.5 mg, amlodipine 5 mg, or olmesartan 40 mg (4:7:10 randomisation), each administered once daily. Within cohorts, adherent patients with 24-hour mean ambulatory SBP of 130 mm Hg to 160 mm Hg were subsequently randomised (1:1) to additional blinded treatment to receive single subcutaneous doses of zilebesiran 600 mg or matching placebo.
Main Outcomes and Measures
The primary end point in each cohort was the difference between zilebesiran and placebo in change from baseline in 24-hour mean ambulatory SBP at three months.
Results
Of 1491 patients entering the run-in phase, 663 (130 receiving indapamide, 240 receiving amlodipine, and 293 receiving olmesartan) were randomised to receive zilebesiran (n = 332) or placebo (n = 331). The least-squares mean difference between zilebesiran and placebo in change from baseline to 3 months in 24-hour mean ambulatory SBP was −12.1 mm Hg (95% CI, −16.5 to −7.6; P < .001) for indapamide, −9.7 mm Hg (95% CI, −12.9 to −6.6; P < .001) for amlodipine, and −4.5 mm Hg (95% CI, −8.2 to −0.8; P = .02) for olmesartan. Across cohorts, more patients who received zilebesiran than placebo experienced 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, but most episodes were mild and resolved without medical intervention.
Conclusions and Relevance
In patients with uncontrolled hypertension despite treatment with indapamide, amlodipine, or olmesartan, the addition of single-dose zilebesiran resulted in significant SBP reductions compared with placebo at 3 months, with low rates of serious adverse events.
See more from MedicalBrief archives:
Revised US guidelines on hypertension
Majority of hypertension patients not adequately treated – WHO report
Strong results for two BP-lowering drugs in resistant hypertension