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

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_RCA 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_RCA.

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).

Keywords: Coronary artery disease; Evolocumab; Lipoprotein(a); Multidetector computed tomography; Pericoronary adipose tissue.

Fig. 1

Flow chart of inclusion and exclusion. CCTA, coronary computed tomography angiography; LDL-C, low-density lipoprotein cholesterol; T2DM, type 2 diabetes mellitus

Fig. 2

A representative case of a type 2 diabetes patients treated with evolocumab for 48-week. A–C The baseline LDL-C and Lp(a) level was 3.6 mmol/L and 64 mg/dL. Baseline CCTA revealed noncalcified plaque with moderate stenosis of middle left anterior descending artery. The total plaque volume was 132.2 mm³ and the PCAT density of right coronary artery was − 79HU. D–F After 48-week treatment, both the LDL-C and Lp(a) level were reduced to 1.5 mmol/L and 19 mg/dL, respectively. The follow-up CCTA revealed the lesion regression with mild stenosis. The follow-up total plaque volume decreased to 11.8 mm³ and PCAT density of right coronary artery attenuated to − 85HU. CCTA, coronary computed tomography angiography; HU, hounsfield unit; Lp(a), lipoprotein(a); LDL-C, low-density lipoprotein cholesterol; PCAT, pericoronary adipose tissue

Fig. 3

The correlation analysis. A–D The change in the calcified plaque volume inversely correlated with achieved LDL-C level (r =  − 0.31, p < 0.001); There was a positive correlation between the change in noncalcified plaque volume and achieved LDL-C level (r = 0.65, p < 0.001); Similar finding were observed in the relationship between necrotic volume and achieved LDL-C level (r = 0.44, p < 0.001). However, the change of PCAT_RCA density did not correlated with achieved LDL-C level (r =  − 0.12, p = 0.11). E–H There was a negative association between the change of calcified plaque volume and achieved Lp(a) level (r =  − 0.33, p < 0.001); The change in the noncalcified plaque volume positively associated with achieved Lp(a) level (r = 0.68, p < 0.001); Similar finding were observed in the relationship between necrotic volume and achieved LDL-C level (r = 0.39, p < 0.001). In addition, the change in PCAT_RCA density positively correlated with achieved Lp(a) level (r = 0.51, p < 0.001). CCTA, coronary computed tomography angiography; Lp(a), lipoprotein(a); LDL-C, Low-density lipoprotein cholesterol; PCAT, pericoronary adipose tissue; RCA, right coronary artery

Fig. 4

Mediation analysis of the change of Lp(a) level for the relationship between evolocumab treatment and change of PCAT density. A The total effect of evolocumab on change of PCAT_RCA density is − 6.63 (95% CI − 8.53, − 4.99, p < 0.001). The changes of Lp(a) level had a significant indirect effect (β = − 4.61, 95% CI − 6.11, − 3.10, p < 0.001) and mediated 69.8% (p < 0.001) for the relationship evolocumab treatment and change of PCAT_RCA density. B The changes of Lp(a) level had a significant indirect effect (β = − 4.40, 95% CI − 5.83, − 2.95, p < 0.001) and mediated 74.7% (p < 0.001) for the relationship evolocumab treatment and change of PCAT_LAD density. C The changes of Lp(a) level had a significant indirect effect (β = - 4.36, 95% CI − 5.79, − 2.89, p < 0.001) and mediated 66.1% (p < 0.001) for the relationship between evolocumab treatment and change of PCAT_LMT density. *Adjusted for age, gender, body mass index, hypertension, low-density lipoprotein cholesterol, total plaque volume, noncalcified plaque volume, calcified plaque volume, necrotic volume, as well as high-risk plaque features. CI, confidence interval; LAD, left anterior descending; LMT, left main trunk; Lp(a), lipoprotein(a); LDL-C, low-density lipoprotein cholesterol; PCAT, pericoronary adipose tissue; RCA, right coronary artery