RNA Interference-Mediated ANGPTL3 Inhibition: The Emerging Therapeutic Potential of Zodasiran in Lipid Management

Recent advances in lipid-lowering therapies have highlighted angiopoietin-like protein 3 (ANGPTL3) as a promising target for addressing residual atherosclerotic cardiovascular disease (ASCVD) risk, particularly in patients with mixed dyslipidemia and familial hypercholesterolemia. Zodasiran, an investigational GalNAc-conjugated RNA interference (RNAi) therapeutic, selectively silences hepatic ANGPTL3 expression, leading to significant reductions in triglycerides, low-density lipoprotein cholesterol (LDL-C), nonhigh-density lipoprotein cholesterol, and apolipoprotein B. Phase 1 and 2 clinical trials have shown zodasiran to be well-tolerated, with dose-dependent and durable lipid-lowering effects and minimal adverse events. Compared to other ANGPTL3-targeting agents, zodasiran offers potential advantages in hepatic specificity, dosing frequency, and duration of action. Its efficacy in populations with limited LDL receptor function-such as those with homozygous familial hypercholesterolemia-suggests a potential role in LDL receptor-independent lipid lowering. However, long-term safety and cardiovascular outcome data remain lacking. Future research should focus on large-scale trials to evaluate clinical endpoints, optimize patient selection, and explore cost-effective strategies for broader access. Zodasiran exemplifies a promising new class of RNAi-based lipid-lowering agents with the potential to transform the treatment landscape for dyslipidemia and ASCVD prevention.