Are Injectable Antihypertensives the Answer to Improving Blood Pressure Control: SiRNAs and Antisense Oligonucleotide Agents

Hypertension remains the leading modifiable risk factor for cardiovascular morbidity and mortality worldwide, yet blood pressure control rates remain suboptimal despite the widespread availability of effective antihypertensive therapies. Poor long-term adherence, therapeutic inertia, and the need for lifelong daily treatment continue to limit the effectiveness of current pharmacological strategies. This review examines the biological rationale, available clinical evidence, and potential role of long-acting RNA-based therapies targeting hepatic angiotensinogen synthesis in hypertension. Small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs) targeting angiotensinogen represent a novel therapeutic approach that suppresses production of the unique precursor of the renin-angiotensin system. Zilebesiran has demonstrated sustained reductions in circulating angiotensinogen and ambulatory blood pressure following infrequent subcutaneous administration in phase 1 and phase 2 clinical trials. Antisense strategies have provided additional clinical validation of sustained angiotensinogen inhibition, although their antihypertensive efficacy has been less consistent. Ongoing clinical development is addressing long-term cardiovascular outcomes, safety, and optimal patient selection. RNA-based antihypertensive therapies may represent an important evolution in hypertension management by combining upstream renin-angiotensin system inhibition with prolonged pharmacological activity and reduced dependence on daily medication adherence. However, their future clinical role will depend on evidence regarding long-term safety, cardiovascular outcomes, reversibility, cost-effectiveness, patient selection, and integration with conventional antihypertensive therapy.