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依洛尤单抗通过降低 2 型糖尿病脂蛋白(a)减轻冠状动脉脂肪组织密度:一项连续随访的 CCTA 研究。

Evolocumab attenuate pericoronary adipose tissue density via reduction of lipoprotein(a) in type 2 diabetes mellitus: a serial follow-up CCTA study.

机构信息

Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Medical Imaging, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China.

Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional Medicine, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China.

出版信息

Cardiovasc Diabetol. 2023 May 22;22(1):121. doi: 10.1186/s12933-023-01857-w.


DOI:10.1186/s12933-023-01857-w
PMID:37217967
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10204214/
Abstract

BACKGROUND: Pericoronary adipose tissue (PCAT) density is a biomarker of vessel inflammation, which is supposed to be increased in patients with type 2 diabetes mellitus (T2DM). However, whether the coronary inflammation revealed by this novel index could be alleviated after evolocumab treatment in T2DM remains unknown. METHODS: From January 2020 to December 2022, consecutive T2DM patients with low-density lipoprotein cholesterol ≥ 70 mg/dL on maximally tolerated statin and taking evolocumab were prospectively included. In addition, patients with T2DM who were taking statin alone were recruited as control group. The eligible patients underwent baseline and follow-up coronary CT angiography with an interval of 48-week. To render patients with evolocumab as comparable to those controls, a propensity-score matching design was used to select the matched pairs with a 1:1 ratio. Obstructive lesion was defined as the extent of coronary artery stenosis ≥ 50%; the numbers inside the brackets were interquartile ranges. RESULTS: A total of 170 T2DM patients with stable chest pain were included [(mean age 64 ± 10.6 [range 40-85] years; 131 men). Among those patients, 85 were in evolocumab group and 85 were in control group. During follow-up, low-density lipoprotein cholesterol (LDL-C) level (2.02 [1.26, 2.78] vs. 3.34 [2.53, 4.14], p < 0.001), and lipoprotein(a) (12.1 [5.6, 21.8] vs. 18.9 [13.2, 27.2], p = 0.002) were reduced after evolocumab treatment. The prevalence of obstructive lesions and high-risk plaque features were significantly decreased (p < 0.05 for all). Furthermore, the calcified plaque volume were significantly increased (188.3 [115.7, 361.0] vs. 129.3 [59.5, 238.3], p = 0.015), while the noncalcified plaque volume and necrotic volume were diminished (107.5 [40.6, 180.6] vs. 125.0 [65.3, 269.7], p = 0.038; 0 [0, 4.7] vs. 0 [0, 13.4], p < 0.001, respectively). In addition, PCAT density of right coronary artery was significantly attenuated in evolocumab group (- 85.0 [- 89.0, - 82.0] vs. - 79.0 [- 83.5, - 74.0], p < 0.001). The change in the calcified plaque volume inversely correlated with achieved LDL-C level (r =  - 0.31, p < 0.001) and lipoprotein(a) level (r =  - 0.33, p < 0.001). Both the changes of noncalcified plaque volume and necrotic volume were positively correlated with achieved LDL-C level and Lp(a) (p < 0.001 for all). However, the change of PCAT density only positively correlated with achieved lipoprotein(a) level (r = 0.51, p < 0.001). Causal mediation analysis revealed Lp(a) level mediated 69.8% (p < 0.001) for the relationship between evolocumab and changes of PCAT. CONCLUSIONS: In patients with T2DM, evolocumab is an effective therapy to decrease noncalcified plaque volume necrotic volume, and increase calcified plaque volume. Furthermore, evolocumab could attenuate PCAT density, at least in part, via the reduction of lipoprotein(a).

摘要

背景:冠状动脉周围脂肪组织(PCAT)密度是血管炎症的生物标志物,推测 2 型糖尿病(T2DM)患者的该标志物会增加。然而,用这种新指标揭示的冠状动脉炎症在 T2DM 患者接受依洛尤单抗治疗后是否会得到缓解尚不清楚。

方法:从 2020 年 1 月至 2022 年 12 月,连续纳入最大耐受剂量他汀类药物治疗且 LDL-C≥70mg/dL 的 T2DM 患者,并前瞻性纳入依洛尤单抗治疗的患者。此外,还招募了正在服用他汀类药物的 T2DM 患者作为对照组。所有符合条件的患者均在 48 周的间隔内行基线和随访冠状动脉 CT 血管造影检查。为了使接受依洛尤单抗治疗的患者与对照组具有可比性,采用倾向评分匹配设计,以 1:1 的比例选择匹配对。狭窄程度定义为冠状动脉狭窄程度≥50%;括号内的数字为四分位间距。

结果:共纳入 170 例稳定性胸痛的 T2DM 患者[(平均年龄 64±10.6[范围 40-85]岁;男性 131 例)。其中 85 例患者接受依洛尤单抗治疗,85 例患者接受对照组治疗。随访期间,低密度脂蛋白胆固醇(LDL-C)水平(2.02[1.26,2.78] vs. 3.34[2.53,4.14],p<0.001)和脂蛋白(a)(12.1[5.6,21.8] vs. 18.9[13.2,27.2],p=0.002)水平降低。阻塞性病变和高危斑块特征的发生率显著降低(所有 p<0.05)。此外,钙化斑块体积显著增加(188.3[115.7,361.0] vs. 129.3[59.5,238.3],p=0.015),而非钙化斑块体积和坏死体积减少(107.5[40.6,180.6] vs. 125.0[65.3,269.7],p=0.038;0[0,4.7] vs. 0[0,13.4],p<0.001)。此外,依洛尤单抗组右侧冠状动脉 PCAT 密度显著降低(-85.0[-89.0,-82.0] vs. -79.0[-83.5,-74.0],p<0.001)。钙化斑块体积的变化与实现的 LDL-C 水平(r=-0.31,p<0.001)和脂蛋白(a)水平(r=-0.33,p<0.001)呈负相关。非钙化斑块体积和坏死体积的变化与实现的 LDL-C 水平和 Lp(a)呈正相关(所有 p<0.001)。然而,PCAT 密度的变化仅与实现的脂蛋白(a)水平呈正相关(r=0.51,p<0.001)。因果中介分析显示,脂蛋白(a)水平介导了依洛尤单抗与 PCAT 变化之间 69.8%(p<0.001)的关系。

结论:在 T2DM 患者中,依洛尤单抗是一种有效的治疗方法,可减少非钙化斑块体积和坏死体积,增加钙化斑块体积。此外,依洛尤单抗至少部分通过降低脂蛋白(a)来减轻 PCAT 密度。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e276/10204214/ee86172a4bc2/12933_2023_1857_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e276/10204214/dd4a4e669288/12933_2023_1857_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e276/10204214/b9517419358d/12933_2023_1857_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e276/10204214/3704c3dff4ed/12933_2023_1857_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e276/10204214/ee86172a4bc2/12933_2023_1857_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e276/10204214/dd4a4e669288/12933_2023_1857_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e276/10204214/b9517419358d/12933_2023_1857_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e276/10204214/3704c3dff4ed/12933_2023_1857_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e276/10204214/ee86172a4bc2/12933_2023_1857_Fig4_HTML.jpg

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