Effect of lipid-lowering therapies on lipoprotein(a) levels: a meta-analysis of randomized controlled trials

Aim: Epidemiological studies, Mendelian randomized studies, and genome-wide association studies confirmed that elevated lipoprotein(a) [Lp(a)] concentration is an independent risk factor for cardiovascular diseases. However, no approved therapy for patients with elevated Lp(a) levels is available. Our aim is to investigate to what extent PCSK9 inhibitors (PCSK9i), statins, and ezetimibe affect Lp(a) level. Methods: This meta-analysis was conducted according to the PRISMA guidelines. Databases were searched from inception to February 2023. Inclusion criteria were: (1) randomized controlled trials (RCTs) in adults (≥18 years), phase II, III or IV; (2) English language; (3) reporting the effects on Lp(a) levels; (4) with intervention duration more than 3 weeks. Pooled estimates were assessed by a random-effects model. Between-study heterogeneity was tested and measured by Cochrane’s Q test and I2 statistics. Results: Overall, 51 RCTs were included for PCSK9i (39,271 participants), 35 RCTs for statins (15,425 participants), and 14 RCTs for ezetimibe (5,607 participants). Starting from a baseline Lp(a) level of 33.12 mg/dL, participants treated with PCSK9i compared to placebo experienced an additional reduction in Lp(a) levels of -26.34% (95%CI -28.83 to -23.85). Lp(a) levels were marginally reduced by statins by -3.43% (95%CI -9.09 to 2.23) from a baseline Lp(a) level of 15.87 mg/dL, although this reduction was not statistically significant. Finally, ezetimibe had a negligible and still not statistically significant effect on Lp(a) levels (0.51% [95%CI -1.67 to 2.70]), from a baseline Lp(a) level of 20.80 mg/dL. Conclusions: Among the lipid-lowering approaches evaluated, only PCSK9i seemed to lower Lp(a) levels. Further research is requested to understand whether it translates into a clinically relevant cardiovascular benefit.