Lepodisiran: Effects on Lipoprotein(a) and Cardiovascular Outcomes in Adults with Elevated Lp(a)

Introduction: Traditional risk reduction strategies like diet, exercise, and existing lipid- lowering medications have minimal impact on Lp(a) levels. Recent therapies targeting Lp(a) at the level of mRNA transcription of apo(a) or binding of apo(a) to apoB-100 have demonstrated substantial reductions of Lp(a). Lepodisiran is a GalNAc-conjugated small interfering RNA (siRNA) developed to inhibit LPA transcription, reducing apo(a) synthesis and circulating Lp(a) levels. This is an updated review of the mechanism of action, pharmacokinetics, clinical efficacy, and safety of Lepodisiran, as well as its effects on lipoprotein(a), with potential applications in treating patients with elevated cardiovascular risk. Methods: We conducted a literature search on PubMed, Google Scholar, and Scopus using keywords such as "Lepodisiran," "small interfering RNA therapies," and "lipoprotein(a)". Results: Lepodisiran demonstrated a dose-dependent and sustained reduction in Lp(a) levels, achieving a maximum reduction of up to 97% at the highest dose in a Phase 1 trial. A Phase 2 placebo-controlled trial similarly showed robust and durable decline in Lp(a) with a favorable safety profile. Discussion: Lepodisiran is a promising therapy, with sustained Lp(a) reduction and good safety. Ongoing phase 3 trials are poised to provide robust data on its long-term safety, clinical efficacy, and impact on Atherosclerotic Cardiovascular Disease (ASCVD) outcomes. Conclusion: Lepodisiran demonstrates potent and sustained reductions in Lp(a) levels with a favorable safety profile, making it a promising therapeutic candidate for Lp(a)-mediated cardiovascular risk. Ongoing long-term outcome studies are essential to confirm its clinical benefit.