Evolocumab promotes plaque stabilization in NSTEMI patients with high Lp(a)

In a post-hoc analysis of HUYGENS among NSTEMI patients, evolocumab plus statin therapy increased the fibrous cap thickness and reduced the lipid arc compared with statin monotherapy in participants with baseline Lp(a) ≥125 nmol/L but not in those with lower Lp(a).

This summary is based on the publication of Di Giovanni G, Fujino M, Kataoka Y, et al. - Impact of evolocumab on plaque phenotypic changes in patients with acute coronary syndrome and elevated lipoprotein(a) levels: a HUYGENS secondary analysis. Eur J Prev Cardiol. 2025 Apr 8:zwaf211 [Online ahead of print]. doi: 10.1093/eurjpc/zwaf211.

Introduction and methods

Background

Elevated Lp(a) levels are associated with vulnerable plaque characteristics, including thin fibrous caps and large lipid pools, on optical coherence tomography (OCT) [1-3]. PCSK9 inhibitors lower Lp(a) levels, which is related to a reduction of CV events [4,5]. In the HUYGENS (High-Resolution Assessment of Coronary Plaques in a Global Evolocumab Randomized Study) trial, addition of evolocumab to statin therapy resulted in a greater increase in minimum fibrous cap thickness (FCT) and larger reduction in plaque lipid content as assessed by OCT compared with statin monotherapy in patients with NSTEMI [6]. However, the effects of evolocumab on vulnerable plaque features in ACS patients with varying Lp(a) levels are unknown.

Aim of the study

In a post-hoc analysis of the HUYGENS trial, the authors investigated whether baseline Lp(a) level influences the treatment effects of evolocumab in combination with statin therapy on vulnerable plaque characteristics in NSTEMI patients.

Methods

The HUYGENS trial was an international, multicenter, double-blind, placebo-controlled, phase 3 RCT in which 164 patients undergoing clinically indicated coronary angiography for NSTEMI, with interventional treatment of the culprit plaque, were randomized to subcutaneous evolocumab 420 mg monthly or placebo for 52 weeks, in addition to maximally tolerated statin therapy. Inclusion criteria included angiographic stenosis 20%–50% in a nonculprit vessel, elevated LDL-c levels (dependent on the use of statin therapy), and evidence of plaque vulnerability at baseline (i.e., ≥1 OCT image showing FCT ≤120 μm and ≥1 OCT image with lipid arc >90° in a segment). Participants underwent OCT of a nonculprit vessel at baseline and 50 weeks. Baseline Lp(a) measurements and serial OCT imaging were available for 117 patients.

Main results

• In the group of patients with high baseline Lp(a) levels (≥125 nmol/L; n=46), participants treated with evolocumab had lower mean ± SD LDL-c levels (21.7 ± 10.3 vs. 94.5 ± 22.9 mg/dL; P<0.001) and lower median Lp(a) levels (156.0 nmol/L; IQR: 136.0–187.0 vs. 204.0 nmol/L; IQR: 170.5–290.5; P=0.007) at follow-up than those receiving placebo.
• Among patients with baseline Lp(a) <125 nmol/L (n=71), evolocumab treatment also resulted in lower mean ± SD LDL-c levels (23.3 ± 34.9 vs. 82.9 ± 46.5 mg/dL; P<0.001) and lower median Lp(a) levels (11.5 nmol/L; IQR: 5.8–23.8 vs. 25.0 nmol/L; IQR: 13.5–41.0; P=0.01) compared with placebo.
• At baseline, there were no differences in OCT plaque parameters between patients with high and those with low Lp(a) levels (all P>0.05).
• Among participants with baseline Lp(a) ≥125 nmol/L, mean ± SD changes from baseline to 50 weeks in minimum FCT (51.6 ± 40.9 vs. 12.4 ± 23.9 μm; P<0.001) and maximum lipid arc (–60.9 ± 56.5° vs. –9.1 ± 70.8°; P=0.008) were greater with evolocumab than placebo.
• However, in the group with low baseline Lp(a) levels, there were no differences in mean ± SD changes in minimum FCT (45.9 ± 37.8 vs. 34.7 ± 36.0 μm; P=0.21) and maximum lipid arc (–59.9 ± 50.1° vs. –44.5 ± 46.1°; P=0.18) between evolocumab-treated and placebo-treated patients.
• An interaction was observed between the baseline Lp(a) level and the treatment effect of evolocumab on the change in minimum FCT (P for interaction=0.04).

Conclusion

This post-hoc analysis of the HUYGENS trial among NSTEMI patients showed that treatment with evolocumab, in addition to statin therapy, increased the minimum FCT and reduced the maximum lipid arc at 50 weeks compared with placebo in participants with baseline Lp(a) ≥125 nmol/L but not in those with lower Lp(a) levels. The authors point out that “in patients with elevated Lp(a) levels, the significant benefit of evolocumab over statin monotherapy was not due to a greater absolute effect of evolocumab in increasing minimum FCT and reducing maximum lipid arc, but rather to the limited response to statin monotherapy in this subgroup.” And they add, “While these results highlight the potential role of Lp(a) in determining the response to lipid-lowering therapy, they do not establish a causal relationship with plaque modifiability.”

Find this article online at Eur J Prev Cardiol.

References

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