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. 2025 Apr 8:zwaf211.
doi: 10.1093/eurjpc/zwaf211. Online ahead of print.

Impact of evolocumab on plaque phenotypic changes in patients with acute coronary syndrome and elevated lipoprotein(a) levels: a HUYGENS secondary analysis

Giuseppe Di Giovanni  1 , Masashi Fujino  1 , Yu Kataoka  2 , Julie Butters  1 , Thomas Hucko  3 , Rishi Puri  4 , Steven E Nissen  4 , Adam J Nelson  1 , Peter J Psaltis  5 , Stephen J Nicholls  1
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Impact of evolocumab on plaque phenotypic changes in patients with acute coronary syndrome and elevated lipoprotein(a) levels: a HUYGENS secondary analysis

Giuseppe Di Giovanni et al. Eur J Prev Cardiol. .

Abstract

Aims: The proprotein convertase subtilisin/kexin Type 9 inhibitor, evolocumab, promoted plaque stabilization on serial imaging in patients following an acute coronary syndrome. The impact of evolocumab in patients with varying lipoprotein(a) [Lp(a)] levels is unknown.

Methods and results: Serial optical coherence tomography imaging was performed to evaluate changes in plaque composition in response to treatment with evolocumab 420 mg or placebo for 50 weeks. The current post hoc analysis compared demographics, biochemistry, and plaque imaging changes in those with baseline Lp(a) levels <125 (n = 71) and ≥125 nmol/L (n = 46). Among those with high Lp(a) levels, evolocumab treatment produced lower levels of LDL cholesterol (LDL-C) (21.7 ± 10.3 vs. 94.5 ± 22.9 mg/dL; P < 0.001) and Lp(a) [156.0 (136.0, 187.0) vs. 204.0 (170.5, 290.5) nmol/L; P = 0.007], compared with placebo. Changes in minimum fibrous cap thickness (FCT) (+51.6 ± 40.9 vs. +12.4 ± 23.9 μm; P < 0.001) and lipid arc (-60.9 ± 56.5° vs. -9.1 ± 70.8°; P = 0.008) were greater in the high Lp(a) group with evolocumab compared with placebo. Among patients with low Lp(a) levels, evolocumab produced lower levels of LDL-C (23.3 ± 34.9 vs. 82.9 ± 46.5 mg/dL; P < 0.001) and Lp(a) [11.5 (5.8, 23.8) vs. 25.0 (13.5, 41.0) nmol/L; P = 0.01] compared with placebo, but no differences were observed between groups in changes in minimum FCT (+45.9 ± 37.8 vs. +34.7 ± 36.0 μm; P = 0.21) and lipid arc (-59.9 ± 50.1° vs. -44.5 ± 46.1°; P = 0.18). Baseline Lp(a) levels significantly interacted with the impact of evolocumab on changes in minimum FCT (interaction P = 0.04).

Conclusion: The ability of evolocumab to more effectively promote plaque stabilization, compared with statin monotherapy, appears more pronounced in patients with higher Lp(a) levels, suggesting that Lp(a) may help identify those who benefit most from intensive lipid-lowering therapy.

Registration: ClinicalTrials.gov: NCT03570697.

Keywords: Acute coronary syndrome; Lipid-lowering therapy; Lp(a); Optical coherence tomography; Vulnerable plaque.

Plain language summary

Proprotein convertase subtilisin/kexin Type 9 inhibitors, such as evolocumab, have shown to promote plaque stabilization on serial imaging in patients following an acute coronary syndrome; however, their effects in patients with different levels of lipoprotein(a) [Lp(a)] are unknown.In patients with high Lp(a) levels, statins plus evolocumab significantly reduced LDL cholesterol (LDL-C) and Lp(a) levels, while also increasing the fibrous cap thickness and reducing lipid arc—features of plaque stabilization—compared with statins plus placebo.In patients with lower Lp(a) levels, although LDL-C and Lp(a) also significantly decreased, there was no significant difference in features of plaque stabilization between evolocumab and placebo. These findings suggest that adding evolocumab to statin therapy promotes greater plaque stabilization, particularly in patients with high Lp(a) levels, potentially modifying atherosclerosis more effectively.

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Conflict of interest statement

Conflict of interest: S.J.N. has received research support from AstraZeneca, Amgen, Anthera, CSL Behring, Cerenis, Eli Lilly, Esperion, Resverlogix, Novartis, InfraReDx, and Sanofi-Regeneron and is a consultant for Amgen, Akcea, AstraZeneca, Boehringer Ingelheim, CSL Behring, Daiichi Sankyo, Eli Lilly, Esperion, Kowa, Merck, Takeda, Pfizer, Sanofi-Regeneron, Novo Nordisk, CSL Seqirus, and Vaxxinity. A.J.N. has received research support from Amgen, Boehringer Ingelheim, Eli Lilly, Novartis, and Sanofi and is a consultant for Amgen, AstraZeneca, Boehringer Ingelheim, CSL Seqirus, Eli Lilly, GSK, Merck, Sanofi, Novartis, Novo Nordisk, and Vaxxinity. P.J.P. is the recipient of a Level 3 Future Leader Fellowship from the National Heart Foundation of Australia and has received research support from Abbott Vascular, Amgen, and Biotronik, consulting fees from Amgen, Esperion, Eli Lilly, Novartis, Novo Nordisk, and Sanofi, and speaker honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck Schering-Plough, Novartis, Novo Nordisk, Pfizer, and Sanofi and is a non-executive board director of Corcillum Systems. T.H. is a former employee of Amgen.

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