(A-095) Efficacy and Safety of APOC3-Targeting Therapies, Olezarsen and Plozasiran in Severe Hypertriglyceridemia: A Meta-Analysis of Randomized Controlled Trials

Background: Severe hypertriglyceridemia (sHTG) remains a significant contributor to cardiovascular morbidity and mortality, yet traditional lipid-lowering therapies like statins have shown limited efficacy in lowering triglycerides (TG) in patients with sHTG and familial chylomicronemia syndrome (FCS), necessitating the development of novel apolipoprotein C3 (APOC3)-targeting therapies, such as olezarsen and plozasiran. This meta-analysis analyzes the safety and therapeutic efficacy of these drugs on TG levels, given the variability in outcomes across individual trials, aiming to enhance existing literature on these drugs.

Objectives: 1) To evaluate the efficacy of olezarsen and plozasiran in reducing TG levels in this subset of patients with sHTG and FCS. 2) To assess the incidence of adverse events and safety profiles of these drugs within this specific population.

Methods: Study design: A systematic review and meta-analysis of RCTs evaluated the efficacy of olezarsen and plozasiran in reducing TG and APOC3 levels and their safety concerns in patients with FCS and sHTG. Setting: RCTs published between 2022–2024 were identified via PubMed, Scopus, and other databases. Inclusion criteria focused on studies reporting TG and APOC3 outcomes. Interventions included APOC3 inhibitors olezarsen and plozasiran for TG reduction. Primary outcome assessed was percentage TG reduction in patients with TG level greater than 500 mg/dl. Secondary outcome assessed was adverse events. Statistical Analysis: We used a random-effects meta-analysis with Hartung-Knapp adjustment. Heterogeneity among trials was assessed using I² statistics.

Results: We included four RCTs with 494 patients with sHTG and 66 with FCS. 68% were males recruited from centers across the United States, Canada, and Europe. Our pooled meta-analysis revealed a mean TG reduction of -61.04% (95% CI: -69.54% to -52.54%, p = 0.0002), indicating substantial efficacy, assessed commonly at 6 months with an average trial length of 13 months. Our study showed moderate heterogeneity with an I² of 39%. Study-specific TG reductions ranged from-43.5% (95% CI: -69.10% to -17.90%) to -74.2% (95% CI: -89.10% to -59.30%), showing clinically significant improvements. Adverse events were generally mild, including injection-site reactions and nasopharyngitis. No major adverse events were reported.

Conclusions: Olezarsen and plozasiran significantly reduce TG levels with favorable safety profiles and, thus, are promising for managing FCS and sHTG. The lack of reporting of major adverse events could possibly be due to small sample sizes and relatively short periods of follow-up. Future studies should recruit more participants, and post-marketing monitoring should be continued to detect any major adverse event.