Impact of PCSK-9 Inhibitors on Lipoprotein(a): A Meta-analysis and Meta-regression of Randomized Controlled Trials

Background Lipoprotein(a) [Lp(a)] has been independently associated with increased cardiovascular risk. We examined the effect of monoclonal antibody proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) on plasma Lp(a) levels across multiple clinical trials. Methods Studies were retrieved comparing the effect of PCSK9i vs. placebo on Lp(a) levels. The primary outcome was percent change in Lp(a) levels. Secondary outcomes included percent change in additional cholesterol markers. Factors associated with the treatment effect were determined by meta-regression analysis. Subgroup analyses were done to explore potential treatment effect differences based on comparator, PCSK9i type, treatment duration, and presence of familial hypercholesterolemia (FH). Results 47 studies with 67,057 patients were analyzed. PCSK9i reduced Lp(a) levels on average of -27% (95% CI: -29.8 to -24.1, p<0.001). Concurrent reduction in LDL-C, non-HDL-C, total cholesterol, triglycerides ApoB, ApoA-1, and increased HDL-C were also observed with PCSK9i use. Factors associated with the treatment effect included mean percent change in LDL-C (p=0.02, tau 2 =177.1, R 2 =0.00) and Apo-B (p<0.00, tau 2 =114.20, R 2 =1.42). Subgroup analyses revealed consistent treatment effect amongst comparators (vs. placebo: -27.69% (95% CI: - 30.85 to -24.54, p<0.00), vs. ezetimibe: -24.0% (95% CI: -29.95% to -18.01, p<0.00), type of PCSK9i, evolocumab: -29.35% (95% CI: -33.56 to -25.14, p<0.00) vs. alirocumab: -24.50% (95% CI: -27.96 to -21.04, p<0.00), and presence of FH: -25.63% (95% CI: -31.96% to -19.30, p<0.00 vs. no FH: -27.22% (95% CI: -30.34. to -24.09, p<0.00). Varying treatment effects were noted in the duration of treatment (12 weeks or shorter: -32.43% (95% CI: -36.63 to -28.23 vs. >12 weeks: -22.31% (95% CI: -25.13 to -19.49, p<0.00), p interaction <0.01. Conclusion PCSK9 inhibitors reduce Lp(a) levels by an average of 27%. Mean percent change in LDL-C and Apo-B were associated with treatment effect. PCSK9i also significantly reduced other atherogenic lipoproteins. Across multiple clinical trials, PCSK9i has a consistent effect of significantly lowering Lp(a) levels.