Efficacy and safety of antisense oligonucleotide therapies targeting APoC-III in patients with severe hypertriglyceridemia: a meta-analysis of randomized controlled trials

Hypertriglyceridemia (HTG) increases cardiovascular and pancreatitis risk. Antisense oligonucleotide (ASO) therapies like volanesorsen and olezarsen target ApoC-III mRNA to reduce ApoC-III, enhancing lipoprotein lipase activity and lowering triglycerides (TGs). This meta-analysis evaluates the efficacy and safety of these ASOs in severe HTG. A systematic review (PROSPERO: CRD42024577110) was conducted following PRISMA, sourcing studies from PubMed, Scopus, Cochrane CENTRAL, and ClinicalTrials.gov until July 2024. Randomized controlled trials (RCTs) involving severe HTG (≥200 mg/dL) treated with volanesorsen or olezarsen vs. placebo were included. Data were synthesized using a random effects model in RevMan 5.4, and bias was assessed with the Cochrane tool. Of 31 identified articles, 9 RCTs (341 patients treated with ASOs, 209 controls) were included. ASOs significantly reduced TG levels [mean difference (MD): -53.72; 95% confidence interval (CI): -77.04 to -30.40; p<0.00001]. Reductions were also seen in very low-density lipoprotein cholesterol (MD: -55.76; p<0.00001), ApoC-III (MD: -74.78; p<0.00001), and APOB48 (MD: -69.45; p<0.00001). Olezarsen uniquely reduced APOB (MD: -15.60; p<0.00001). Non-high-density lipoprotein cholesterol (HDL-C) decreased (MD: -23.25; p<0.00001), while HDL-C increased (MD: +42.14; p<0.00001). Volanesorsen was linked to higher low-density lipoprotein-cholesterol (MD: +62.74; p=0.004). For safety, local injection reactions, thrombocytopenia, and nausea were more common with volanesorsen. Acute pancreatitis occurred only in the placebo group (relative risk: 0.15; p=0.0004), indicating ASO protection. This meta-analysis confirms that ASOs effectively lower TGs and improve lipid profiles in severe HTG.