Abstract 4358409: RNA INTERFERENCE OF ANGPTL3 VIA ZODASIRAN: A NEXT-GENERATION APPROACH FOR TREATING ATHEROGENIC DYSLIPIDEMIA

Introduction: Atherogenic dyslipidemia contributes to residual cardiovascular risk despite current therapies. ANGPTL3 inhibition is a novel approach to reduce atherogenic lipids. Zodasiran, an RNA interference (RNAi) therapeutic conjugated to GalNAc, selectively silences ANGPTL3 in hepatocytes. Early studies show potent, sustained lipid reductions with a favorable safety profile, benefiting patients with mixed dyslipidemia or statin intolerance. Research Questions: This study evaluates zodasiran’s therapeutic potential, safety, and lipid-lowering efficacy in managing atherogenic lipids and cardiovascular risk. Goals: Primary goals are to assess reductions in triglycerides, LDL-C, non-HDL-C, apolipoprotein B, and remnant cholesterol after zodasiran treatment. Secondary goals include safety, glycemic effects, and advantages over existing therapies. Methods: Data from phase 1 and 2 trials in patients with dyslipidemia, including familial hypercholesterolemia and statin intolerance, were analyzed. Zodasiran was administered subcutaneously at varied doses with extended intervals. Lipid profiles and safety markers, including liver function and glycemic indices, were monitored over time. Results: Zodasiran induced dose-dependent, sustained reductions in triglycerides, LDL-C, non-HDL-C, apolipoprotein B, and remnant cholesterol. The RNAi approach showed more durable effects than monoclonal antibodies or antisense oligonucleotides targeting ANGPTL3. Safety was favorable, with no significant hepatotoxicity or liver fat accumulation. A transient glycated hemoglobin rise in diabetics at higher doses resolved without affecting insulin sensitivity. Conclusions: RNAi-mediated ANGPTL3 inhibition via zodasiran is a promising strategy for managing atherogenic dyslipidemia and cardiovascular risk. Its hepatocyte-specific action, prolonged dosing, and safety profile offer benefits over current treatments, especially for familial hypercholesterolemia and statin-intolerant patients. Long-term outcome trials are needed to confirm clinical benefit. Future research should explore biomarkers, combination therapies, and diverse populations to maximize impact.