A PAIRWISE AND NETWORK META-ANALYSIS COMPARING THE EFFICACY AND SAFETY OF RIBONUCLEIC ACID INTERFERENCE THERAPEUTICS IN THE MANAGEMENT OF HYPERTENSION

Objective: Hypertension is the primary leading cause of cardiovascular mortality. Despite numerous available interventions, hypertension is managed suboptimally in about 50 percent of patients. Small interfering ribonucleic acid (siRNA) represents a promising therapeutic for hypertension. This study investigates the efficacy and safety of siRNAs in hypertensive adults. Design and method: We performed a comprehensive electronic literature search of five databases till November 2024. Results: The analysis included four trials involving 486 patients. siRNAs significantly reduced ambulatory systolic blood pressure (SBP) and diastolic blood pressure (DBP) measurements compared to placebo: (millimeters of mercury [mmHg]; mean difference [MD]: -15.46; 95% confidence interval [CI]: -18.79 to -12.12; P < 0.00001) and (MD: -8.45; 95% [CI]: -10.6 to -6.23; P < 0.00001), respectively. Besides, both office SBP and DBP readings were significantly reduced (mmHg; [MD]: -8.07; 95% [CI]: -11.58 to -4.56); P < 0.00001) and (mmHg; [MD]: -5.18; 95% [CI]: -7.73 to -2.63; P < 0.0001), respectively. In the short term, siRNAs were well tolerated without significant adverse effects. On comparing different siRNA interventions, Zilbesiran 300 mg was ranked most effective in reducing ambulatory SBP and DBP after three months: surface under the cumulative ranking curves (SUCRAs): 71% and 77%, respectively. Regarding office BP readings, IONIS-AGT-LRx 80 mg with add-on therapy best-reduced SBP, SUCRAs: 88%, while Zilbesiran 300 mg best-reduced DBP, SUCRAs: 76%. The aforementioned BP reductions were statistically significant compared to placebo, but not between different doses of Zilbesiran (ranging from 150 mg to 800 mg) and IONIS-AGT-LRx 80 mg with or without add-on therapy. Interestingly, Zilbesiran 800 mg best reduced angiotensinogen levels after three and six months compared to other siRNAs and placebo. There were no significant differences between all the types of siRNAs and placebo regarding side effects, incidence of hyperkalemia, and reduction of estimated glomerular filtration rate. Conclusions: siRNAs effectively reduced blood pressure in hypertensive adults with an acceptable safety profile. Zilbesiran 800 mg best reduced angiotensinogen levels. Despite the absence of significant differences in either efficacy or safety between the doses or types of siRNAs, Zilbesiran 300 mg best reduced BP compared to placebo.