Comparative efficacy of APOC3- and ANGPTL3-targeted therapies in severe hypertriglyceridemia: a systematic review and network meta-analysis

Background Severe hypertriglyceridemia and familial lipid disorders, including familial chylomicronemia syndrome (FCS) Multifactorial Chylomicronemia Syndrome (MCS), and partial lipodystrophy, lead to extreme triglyceride(TG) elevation and increased risk of pancreatitis, yet conventional therapies often fail to achieve adequate control. APOC3 and ANGPTL3 are key regulators of triglyceride metabolism, and gene-silencing therapies targeting these pathways markedly reduce triglyceride-rich lipoproteins. However, the comparative efficacy of these agents in lipid management remains unclear. Purpose To compare the efficacy and safety of APOC3- and ANGPTL3-targeted therapies for triglyceride reduction in patients with severe hypertriglyceridemia (sHTG) using a systematic review and network meta-analysis of randomized controlled trials. Methods We searched PubMed, Embase, and Cochrane Central for randomized controlled trials evaluating APOC3- and ANGPTL3-directed therapies versus placebo. A frequentist random-effects network meta-analysis was performed to estimate binary outcomes with odds ratios (OR), continuous outcomes with mean difference (MD) and 95% confidence intervals (CI). P-scores were used to rank intervention. Publication bias was evaluated through funnel plot analysis Results Olezarsen 80 mg, Olezarsen 50 mg, Plozasiran 10 mg, Plozasiran 25 mg, Plozasiran 50 mg, and Volanesorsen 300 mg were all significantly superior to placebo in reducing triglyceride levels (Figure 1). In P-score rankings, Volanesorsen 300 mg and higher doses of Olezarsen demonstrated the highest likelihood of achieving greater reductions in triglycerides. Olezarsen 50 mg (OR 0.10; 95% CI 0.03-0.31; p<0.001) and Olezarsen 80 mg (OR 0.18; 95% CI 0.07-0.48; p=0.0007) significantly reduced the incidence of acute pancreatitis compared with placebo; Plozasiran pooled also lowered pancreatitis risk (OR 0.17; 95% CI 0.03–0.93; p=0.04), other regimens showed no significant differences. Conclusions This systematic review and network meta-analysis indicate Volanersorsen and higher doses of Olezarsen are most effective in reducing TG. Meanwhile, Olezarsen and Plozasiraan have greater effect in decreasing Acute Pancreatitis incidence, suggesting Olazarsen may be a preferable treatment for hypertriglyceridemia.