Evolocumab enables rapid LDL-C reduction and inflammatory modulation during in-hospital stage of acute coronary syndrome: A pilot study on Chinese patients

Abstract

Background and aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) has long been considered a key regulator in lipid metabolism. Its role as a potential player in immune response has recently earned much attention. However, the effects of evolocumab, an approved PCSK9 monoclonal antibody, on lipid reduction and inflammation regulation in Chinese patients with acute coronary syndrome (ACS) during their in-hospital stage after an index event are not well known.

Methods: We conducted a case-crossover pilot study (http://www.clinicaltrials.gov/, NCT04730648) involving 31 patients hospitalized for ACS with elevated low-density lipoprotein cholesterol (LDL-C) level (≥70 mg/dL despite high-intensity statin) and 8 age- and gender-matched patients without coronary heart disease (CHD) as the baseline control. The patients with ACS received one dose of subcutaneous evolocumab (140 mg) on top of 10 mg/day rosuvastatin during hospitalization. Blood samples at baseline and 72 h post-evolocumab administration were collected for lipid and cytokine assessments.

Results: The patients without CHD shared similar risk factors and LDL-C levels with the patients with ACS but exhibited a more activated inflammatory status. After single-dose in-hospital evolocumab, the median LDL-C level of patients with ACS decreased from 109.0 to 41.4 mg/dL as early as 72 h, accompanied with reductions in other atherogenic lipids. Systemic inflammatory pattern was also altered, rendering a decrease in pro-inflammatory and anti-inflammatory cytokines.

Conclusion: In this case-crossover study of the effect of PCSK9 antibody among Chinese patients, evolocumab on top of high-intensity statin during hospitalization led to a remarkable and rapid reduction in atherogenic lipids and an alteration in inflammatory status at early-stage post-ACS.

Keywords: Chinese patients; acute coronary syndrome; atherogenic lipids; evolocumab; inflammatory cytokines.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Ou, Yu, Liang, Zhao, Li, Pang, Liu, Xu, Dong, Sun and Li.

Figures

Figure 1

Study flowchart. Definition of acute coronary syndrome (ACS) is clarified in Methods. Baseline blood samples were collected after percutaneous coronary intervention or coronary angiogram. Non-CHD indicates patients without coronary heart disease.

Figure 2

Baseline plasma cytokine and chemokine levels in patients with non-CHD and ACS. Cytokine and chemokine levels were measured using Luminex assay in 8 patients without CHD and 31 patients with ACS. (A) Heat map of log2 fold changes in 27 analytes at baseline (corrected by the average levels in patients without CHD). (B–K) Differentially expressed analytes at baseline in patients with ACS compared with patients without CHD. Data are presented as medians with interquartile ranges. Differences were tested using Mann–Whitney U-test.

Figure 3

Changes in lipid particles at 72 h post-evolocumab administration. Scattered plot of lipid profile data in Table 2. The dots of TG, TC, HDL-C, LDL-C, and sdLDL-C are aligned to the left Y axis, and the dots of Apo-A1, Apo-B, and Apo-E are aligned to the right Y axis. *P < 0.05, **P < 0.01, ****P < 0.0001. Differences were tested using Wilcoxon matched-pairs signed rank test. TG, triglyceride; TC, total cholesterol; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; sdLDL-C, small dense low-density lipoprotein cholesterol; Apo, apolipoprotein.

Figure 4

Comparison of plasma cytokine and chemokine levels between baseline and 72 h post-evolocumab administration in patients with ACS. Cytokine and chemokine levels were measured in 31 ACS patients using Luminex assay. (A) Heat map of log2 fold changes over the average baseline levels of 27 analytes. (B–H) Differentially expressed cytokines and chemokines. Differences were tested using Wilcoxon matched-pairs signed rank test. Data are shown as actual concentrations (left) or medians with interquartile ranges of values normalized by baseline mean (right). UA, unstable angina; NSTEMI, non-ST-elevation myocardial infarction; STEMI, ST-elevation myocardial infarction.

Figure 5

Short-term LDL-C-lowering efficacy of evolocumab in AMONG-US study and schematic diagram. Schematic diagram of the lipid-lowering and inflammation-regulating effects of evolocumab. The levels of TG, TC, LDL-C, sdLDL-C, ApoA1, ApoB, and ApoE, as well as the circulating levels of IL-1β, IL-6, IL-4, IL-13, MCP-1, VEGF, and GM-CSF, decreased at 72 h post-evolocumab administration compared with baseline in patients with ACS.