Abstract Body (Do not enter title and authors here): Background
Hypertriglyceridemia is an independent risk factor for cardiovascular diseases. Apolipoprotein C-III (APOC3) inhibition through the antisense oligonucleotides volanesorsen, olezarsen, and plozasiran, reduced triglycerides in the previous trials. However, the safety and efficacy of the three medications have not been compared yet.

Methods
A network meta-analysis was performed to compare multiple doses of the three medications to each other through the placebo. Nine randomized controlled trials (RCTs) were retrieved by searching PubMed, EMBASE, Web of Science, SCOPUS, and Cochrane. The mean difference (MD) and 95% confidence interval (CI) were used for continuous outcomes. The risk ratio (RR) and 95% CI were used for dichotomous outcomes.

Results
A total of 782 patients were included. Volanesorsen 300 mg once weekly showed the most significant reduction in triglyceride levels (MD = -90.98%, 95% CI: [-109.2%; -72.8%]; p<0.01). Only plozasiran once monthly, regardless of the dose, showed a non-significant reduction in triglycerides, which should be taken with caution as the data were derived from a phase 1 trial with a small sample size. All the regimens significantly reduced APOC3 levels compared to placebo with plozasiran 100 mg and 50 mg once monthly and volanesorsen 300 mg once weekly, showing the most significant reduction (MD range: -92.8% to -88.4%; p<0.01). Plozasiran regimens, especially the 25 mg, 50 mg, and 10 mg once monthly dosages, respectively, reduced total cholesterol levels the most compared to placebo (MD range: -30.6% to -23.5%; p<0.01). Only volanesorsen, regardless of the dose, did not significantly reduce total cholesterol compared to placebo. None of the treatments showed a statistically significant difference in the adverse events rate compared to placebo.

Conclusion
APOC3 antisense oligonucleotide inhibitors effectively reduced triglyceride, APOC3, and total cholesterol levels in hypertriglyceridemia, with an acceptable safety profile. However, due to the relatively small sample size, the results should be interpreted with caution. Further research is needed to confirm the beneficial effects of APOC3 inhibitors and provide strong evidence on the effects of each medication regimen.