Effect of IL-6 Inhibition on Lipoprotein(a) Levels: A Systematic Review and Meta-Analysis

Inhibition of interleukin (IL)-6 signaling by monoclonal antibodies (mAb) inhibits apolipoprotein(a) synthesis and reduces circulating lipoprotein(a) [Lp(a)] concentration. The aims of this systematic literature review and meta-analysis were to summarize clinical evidence for and quantify the effect of anti-IL­6/IL-6 receptor (IL-6R) treatment on Lp(a) levels. Secondary inflammatory and lipid endpoints were also examined. Searches were conducted using PubMed, Cochrane Library, and Embase databases to identify studies reporting changes to Lp(a) levels following repeat doses of anti-IL-6/IL-6R mAbs. A random-effects meta-analysis compared the effect of IL-6 inhibition vs comparator on Lp(a) levels. A pre­post analysis assessed the effect of IL-6 inhibition on Lp(a) levels before and after treatment. Subgroup analyses by disease type, IL-6 inhibition agent, and comparators were conducted. Out of 96 records, 10 studies with 1201 participants were included. IL-6 inhibition was associated with significant reductions in Lp(a) levels vs baseline at 2-3 (standardized mean difference [SMD] -0.29; 95% CI -0.44 to -0.14; P = .0002; I 2 = 33%) and 6 months (SMD -0.33; 95% CI -0.51 to -0.15; P = .0003; I 2 = 0%). Compared with tumor necrosis factor inhibitors or placebo, IL-6 inhibition showed greater Lp(a) reductions at 2-3 (SMD -0.49; 95% CI -0.73 to -0.24; P = .0001; I 2 = 63%) and 6 months (SMD ­0.97; 95% CI -1.16 to -0.77; P < .00001; I 2 = 0%). This meta-analysis demonstrates significant reductions in Lp(a) levels with anti-IL­6/IL-6R therapy vs controls. The relevance of these findings warrants investigation in cardiovascular outcome trials.