Effect of angiopoietin-like protein 3 inhibitors on lipid profile and other biomarkers: a meta-analysis of randomized controlled trials

Abstract

Aims: Inhibition of angiopoietin-like protein 3 (ANGPTL3) has been proposed as a promising approach to reduce residual cardiovascular risk. We conducted a meta-analysis of randomized controlled trials (RCTs) to provide a comprehensive evaluation of the metabolic effects of ANGPTL3 inhibitors. Methods: Databases (PubMed, EMBASE, Web of Science, CENTRAL, ClinicalTrials.gov) were searched from inception to July 2025. Eligible studies were RCTs comparing ANGPTL3 inhibitors against placebo. Outcomes included triglycerides (TG), LDL-C, apolipoprotein B (ApoB), non-high-density lipoprotein cholesterol (non-HDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), very-low-density lipoprotein cholesterol (VLDL-C), apolipoprotein A1 (ApoA1), apolipoprotein C3 (ApoC3), lipoprotein(a) (Lp(a)), remnant cholesterol (RC), ANGPTL3 and C-reactive protein (CRP). Pooled estimates of percentage change from baseline were obtained using fixed- and random-effects models. Subgroup analysis was performed based on the mechanism of action: monoclonal antibodies (mAbs, evinacumab), antisense oligonucleotides (ASOs, vupanorsen), and small interfering RNAs (siRNA, zodasiran and solbinsiran). Results: Nine RCTs (1254 participants) were included. ANGPTL3 inhibition significantly reduced TG (−47.1%), LDL-C (−21.6%), ApoB (−19.9%), non-HDL-C (−31.5%), TC (−32.8%), VLDL-C (−40.6%), and RC (−72.7%). Modest but consistent reductions were also observed in Lp(a) (−11.5%), ApoA1 (−18.3%), and ApoE (−16.4%). ANGPTL3 inhibitors markedly reduced circulating ANGPTL3 protein (−70.7%), with no significant effect on high-sensitivity CRP. Subgroup analyses demonstrated greater reductions in LDL-C, ApoB, non-HDL-C, and TC with evinacumab compared to the other groups, whereas small interfering RNAs produced more pronounced VLDL-C lowering compared with vupanorsen. Conclusion: ANGPTL3 inhibition offers broad lipid-lowering benefits, with particularly marked reductions in TG-rich lipoproteins.