Cardiovascular Benefit of Lipoprotein(a) Reduction With PCSK9 Inhibitor

Investigators evaluated whether lower on-study and greater percentage reductions in lipoprotein(a) are associated with a lower risk for major adverse cardiovascular events.

Treatment with alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibody, significantly reduced lipoprotein(a) (Lp[a]), but this reduction may have only a modest additional cardiovascular (CV) benefit on top of low-density lipoprotein cholesterol (LDL-C) reduction, according to study results published in Atherosclerosis. However, the benefit was greater in patients with higher baseline Lp(a) levels.

Previous studies have suggested an association between levels of Lp(a) and risk for CV disease. In phase 3 ODYSSEY trials ( Identifier: NCT01663402), the PCSK9 inhibitor alirocumab reduced levels of both LDL-C and Lp(a) (by 23%-29%) and risk for major adverse CV events (MACE).

The goal of this post-hoc analysis using data from 10 phase 3 ODYSSEY trials was to assess the impact of Lp(a) reduction on the incidence of MACE and to examine whether there is any benefit independent of LDL-C reduction.

The ODYSSEY trials examined alirocumab with control (placebo or ezetimibe) in 4983 adults (age ≥18) with CV disease and/or risk factors and hypercholesterolemia despite treatment with lipid-lowering therapies.

During the study period, there was a -25.6% change in Lp(a) from baseline with alirocumab vs a -2.5% change with placebo in the placebo-controlled pool and a -21.4% change with alirocumab compared with 0% with ezetimibe in the ezetimibe-controlled pool.

During a median follow-up of 84.6 weeks (6699 total patient-years), 104 patients developed ≥1 MACE. These CV events included 20 coronary heart disease deaths, 64 nonfatal myocardial infarctions, 16 ischemic strokes, and 4 unstable angina episodes.

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Although the results showed a 12% relative risk reduction in MACE per 25% reduction in Lp(a) (P =.0254), after adjustment for baseline characteristics and percentage reduction in Lp(a)-corrected LDL-C or on-study Lp(a)-corrected LDL-C, there was no significant association between the risk for MACE with greater percentage Lp(a) reduction or lower on-study Lp(a).

When the analysis was stratified by baseline Lp(a) ≥50 vs <50 mg/dL, the association between Lp(a) reduction and MACE was statistically significant in patients with higher baseline Lp(a) with a 40% (95% CI, 0.39-0.92; P =.0201) relative risk reduction per 25% reduction in Lp(a); however, in patients with lower baseline Lp(a), the association was not significant (P =.3837).

The researchers acknowledged several study limitations, including relatively low median baseline level of Lp(a) and modest Lp(a) reduction, limited follow-up period, and small number of MACE. In addition, this analysis is post-hoc, according to pooled data from several studies.

“Reducing the risk of MACE by targeting Lp(a) may require more potent therapies which reduce Lp(a) to a greater degree and/or higher initial Lp(a) levels; both of these approaches are likely to offer greater absolute reductions in Lp(a) which is consistent with genetic studies,” concluded the researchers.

This analysis was funded by Regeneron Pharmaceuticals, Inc. and Sanofi.

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Ray KK, Vallejo-Vaz AJ, Ginsberg HN, et al. Lipoprotein(a) reductions from PCSK9 inhibition and major adverse cardiovascular events: pooled analysis of alirocumab phase 3 trials [published online June 6, 2019). Atherosclerosis. doi:10.1016/j.atherosclerosis.2019.06.896