Hepatic Angiotensinogen-Lowering RNA Therapeutics for Blood Pressure Control in Hypertension

Background: Hepatic angiotensinogen (AGT)-lowering RNA therapeutics are emerging agents designed to provide durable upstream inhibition of the renin-angiotensin system in hypertension. Although individual randomized trials have shown blood pressure and AGT reductions, the overall efficacy-safety profile across RNA interference and antisense oligonucleotide strategies remains incompletely defined. Aim: We aimed to provide an updated class-level synthesis of randomized evidence evaluating RNA interference and antisense oligonucleotide therapeutics that lower hepatic AGT in adults with hypertension. Methods: PubMed, Embase, and Cochrane were systematically searched, identifying 1,559 records. The protocol was registered in PROSPERO (CRD420261411590). Randomized controlled trials evaluating hepatic AGT-lowering RNA therapeutics in adults with mild-to-moderate or uncontrolled hypertension were included. Controls included placebo or background antihypertensive therapy. Quantitative analyses were performed where comparable extractable data were available. Random-effects meta-analyses were performed. Continuous outcomes were pooled as mean differences (MDs), and binary outcomes as risk ratios (RRs), each with 95% confidence intervals (CIs). Results: A total of 9 randomized controlled trials were included, evaluating zilebesiran, IONIS-AGT-LRx, and tonlamarsen. Hepatic AGT-lowering RNA therapeutics significantly reduced 24-hour ambulatory systolic blood pressure measured by ambulatory blood pressure monitoring at approximately 3 months versus control (MD –13.16 mmHg; 95% CI –18.70 to –7.63). Circulating AGT was also significantly reduced (MD –66.82%; 95% CI –92.71 to –40.92). There was no significant difference in any adverse event (RR 1.11; 95% CI 0.91 to 1.35) or serious adverse event (RR 0.72; 95% CI 0.36 to 1.45). Hyperkalemia was more frequent with RNA therapeutics (RR 2.80; 95% CI 1.30 to 6.04), as were renal adverse events or acute kidney failure as reported by trials (RR 3.08; 95% CI 1.21 to 7.89). Hypotension or orthostatic hypotension was not statistically significant (RR 2.16; 95% CI 0.96 to 4.90). Conclusions: Hepatic AGT-lowering RNA therapeutics significantly reduced 24-hour ambulatory systolic blood pressure and circulating AGT levels in adults with hypertension. Overall and serious adverse events were not increased; however, hyperkalemia and renal adverse events were more frequent with RNA therapeutics.