Key result
Zilebesiran lowers office SBP by ~8 mmHg, with efficacy plateauing at 300 to 600 mg.
Why the study?
Zilebesiran is an investigational small-interfering RNA therapeutic for hypertension evaluated across Phase 1 and KARDIA Phase 2 monotherapy, add-on, and high-risk cohorts, but its global dose-response relationship and optimal dosing plateau had not been quantitatively synthesized.
Does zilebesiran (10–800 mg subcutaneous) exhibit a dose-dependent reduction in office and 24-hour ambulatory systolic blood pressure in patients with hypertension?
Meta-Analysis (n=1,491)
Does zilebesiran (10–800 mg subcutaneous) exhibit a dose-dependent reduction in office and 24-hour ambulatory systolic blood pressure in patients with hypertension?
This dose-response meta-analysis demonstrates that subcutaneous zilebesiran provides significant, nonlinear reductions in office and ambulatory systolic blood pressure that plateau between 300 mg and 600 mg, supporting 300 mg as the optimal dose for future cardiovascular outcome trials.
Supports 300-600 mg quarterly zilebesiran dosing for hypertension; extends randomized dose-response data to define optimal plateau.
Background Hypertension remains the leading modifiable driver of global cardiovascular mortality. Zilebesiran, an investigational small-interfering RNA (siRNA) therapeutic, silences hepatic angiotensinogen (AGT) synthesis—the most upstream precursor in the renin–angiotensin–aldosterone system—offering sustained blood-pressure (BP) lowering via semiannual subcutaneous dosing. Following the foundational NEJM Phase 1 study, the KARDIA Phase 2 program [1] evaluated monotherapy, add-on, and high-risk cohorts. However, the global dose–response relationship across these diverse clinical contexts has not been quantitatively synthesized. Purpose To characterize the dose-dependent antihypertensive effect of zilebesiran and identify the optimal dosing plateau using all available randomized evidence. Methods A dose–response meta-analysis was performed using a one-stage random-effects framework with restricted cubic splines (RCS). We incorporated data from 5 randomized trials (N = 1,491) across Phase 1, KARDIA-1, KARDIA-2, and KARDIA-3 trials [1,2]. Change from baseline in systolic BP (SBP) was modeled as a function of dose (10–800 mg). Office and 24-hour ambulatory BP were analyzed separately. Nonlinearity was evaluated via Wald χ2 tests; Bayesian hierarchical spline models assessed the posterior probability of efficacy across the dose range. Results Zilebesiran demonstrated a significant nonlinear dose–response for both office (χ2 = 9.23, p = 0.009) and ambulatory (χ2 = 26.16, p < 0.001) SBP. Bayesian posterior mean reductions were −7.6 mmHg (95% CrI: −8.7 to −6.6) for office and −6.9 mmHg (95% CrI: −10.6 to −3.6) for ambulatory SBP, with posterior simulations identifying a potential for SBP reductions exceeding 20 mmHg in optimized clinical subgroups. The dose-response curve exhibited a steep initial slope, with efficacy saturation observed between 300 mg and 600 mg. Doses above 600 mg (up to 800 mg) provided negligible incremental BP lowering, indicating a clear ceiling effect for AGT suppression. Conclusion Integrating Phase 1 and KARDIA Phase 2 data, zilebesiran demonstrates durable, dose-proportional BP reduction that plateaus at 300–600 mg. These findings consolidate zilebesiran as a first-in-class long-acting RNAi antihypertensive and support the selection of 300 mg as the optimal therapeutic dose for future cardiovascular outcome trials.dose-response for ambulatory BPdose-response for office BP
No takes yet. Share an insight, caveat, or question.
Keswani et al. (2026) conducted a meta-analysis in Hypertension (n=1,491). Zilebesiran was evaluated on Change from baseline in office and 24-hour ambulatory systolic blood pressure (SBP) (MD -7.6 mmHg (office SBP); MD -6.9 mmHg (ambulatory SBP), 95% CI -8.7 to -6.6, p=0.009 (office nonlinearity); <0.001 (ambulatory nonlinearity)). Zilebesiran lowered office SBP by -7.6 mmHg (95% CrI -8.7 to -6.6) and ambulatory SBP by -6.9 mmHg (95% CrI -10.6 to -3.6), plateauing at 300-600 mg.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: