Class effects of subcutaneous lipoprotein(a)-lowering therapies: a systematic review and meta-analysis
A V Hernandez, L H Tanriverdi, M Dogan, A Y Su, R M Shan, M BanachAbstract
Background
Subcutaneous lipoprotein(a) [Lp(a)]-lowering agents have demonstrated potent lipid-lowering effects; however, the magnitude, consistency, and certainty of their class-level efficacy and safety remain incompletely defined.
Purpose
To quantify class-level effects of subcutaneous Lp(a)-lowering agents and to evaluate robustness through prespecified secondary and sensitivity analyses.
Methods
Random-effects pairwise meta-analyses of randomized controlled trials (RCTs) comparing subcutaneous Lp(a)-lowering agents with placebo were conducted. We searched CENTRAL, PubMed, Scopus, and Web of Science through April 10, 2025. Effect sizes were expressed as mean differences (MDs) for lipid outcomes and risk ratios (RRs) for clinical and safety outcomes. We performed subgroup analyses by atherosclerotic cardiovascular disease (ASCVD) setting and sensitivity analyses by excluding high risk of bias or short follow-up trials and by adding oral muvalaplin. Quality of evidence (QoE) was assessed using GRADE methods.
Results
Across seven RCTs (n=1181), evidence was very uncertain about the effects of Lp(a)-lowering agents on Lp(a) (MD −66.37%; 95% CI −81.63 to −51.10, I²=88.9%, very low QoE), low density lipoprotein cholesterol (LDL) (MD −14.30%; 95% CI −28.21 to −0.38; I²=71.9%, very low QoE) and apolipoprotein B (ApoB) (MD −12.56%; 95% CI −18.82 to −6.30; I²=48.2%, very low QoE) percent change vs. placebo. The effect of Lp(a)-lowering agents also was very uncertain on all-cause mortality (RR 0.74; 95% CI 0.26–2.17; I²=0.0%, very low QoE), adverse events (AEs; RR 1.06; 95% CI 0.86–1.31; I²=75.1%, very low QoE) and serious AEs (SAEs; RR 1.01; 95% CI 0.59–1.72; I²=0.0%, very low QoE), while their effect on AEs leading to discontinuation showed little to no difference (RR 0.97; 95% CI 0.29–3.19; I²=0.0%; low QoE). Effects were similar across ASCVD subgroups. LDL reduction was lower when excluding trials at high risk of bias (MD −12.25%; 95% CI −28.92 to 4.40) or when excluding trials with <12-month follow-up (MD −10.65%; 95% CI −32.75 to 11.45). The addition of muvalaplin to analyses did not modify effects on outcomes.
Conclusion
Subcutaneous Lp(a)-lowering agents had uncertain effects on Lp(a), LDL, and ApoB percent changes, as well as on mortality and adverse events, with little to no difference on AEs leading to discontinuation. These findings require cautious interpretation and further high-quality trials.Effect on Lp(a) percent change