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Association of semaglutide treatment with coronary artery inflammation in type 2 diabetes mellitus patients: a retrospective study based on pericoronary adipose tissue attenuation

Cardiovascular Diabetology volume 23, Article number: 348 (2024) Cite this article

Abstract

Background

The pericoronary fat attenuation index (FAI) has emerged as a novel and sensitive biomarker reflecting the degree of coronary artery inflammation. Semaglutide has been demonstrated to exert a cardiovascular protective effect independent of hypoglycemia; however, its impact on coronary artery inflammation remains elusive. This study aimed to investigate the association between semaglutide treatment and coronary artery inflammation based on FAI in patients with type 2 diabetes mellitus (T2DM).

Methods

This study enrolled 497 T2DM patients who underwent coronary computed tomography angiography (CCTA) at Hebei General Hospital, of whom 93 treated with semaglutide (Sema+) and 404 did not (Sema-). Clinical data, laboratory indicators, and CCTA parameters were collected and compared between the two groups at baseline. Propensity score matching (PSM) was used to adjust for confounders, and pericoronary FAI was compared. Multivariate linear regression models were used to analyze the association between semaglutide treatment and pericoronary FAI.

Results

Before PSM, pericoronary FAI of the LAD and LCX was lower in patients treated with semaglutide than those without semaglutide treatment. The results of the PSM analysis revealed a lower FAI in all three major coronary arteries in the Sema + group compared to the Sema- group. Multivariate linear regression analyses revealed an independent association between semaglutide treatment and reduced FAI in all three major coronary arteries. This association varied across T2DM patients of differing profiles.

Conclusion

Semaglutide treatment may be associated with lower coronary artery inflammation in patients with T2DM, which might partially explain its cardiovascular protective mechanism.

Introduction

Diabetes is a burgeoning global health crisis, projected to affect 700 million people by 2045 [1, 2]. Type 2 diabetes mellitus (T2DM), its predominant subtype, is characterized by hyperglycemia resulting from insulin resistance and deficiency [3], alongside a plethora of complications [4, 5]. Cardiovascular disease (CVD) is the leading cause of mortality in T2DM patients [6]. CVD in T2DM arises from a complex interplay of vascular inflammation, endothelial dysfunction, and oxidative stress [7, 8]. Notably, coronary artery inflammation acts as a critical mediator in the initiation and progression of atherosclerosis, the primary instigator of acute cardiovascular events [9]. Hence, attenuating coronary artery inflammation is of paramount importance for improving cardiovascular outcomes in T2DM patients.

Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), has emerged as a pivotal therapy in the management of type 2 diabetes mellitus (T2DM), lauded for its robust glycemic control and cardiovascular protection [10]. Clinical evidence robustly supports semaglutide’s efficacy in reducing major adverse cardiovascular events (MACEs) and improving a broad spectrum of risk factors for CVD, including blood pressure, lipid profiles, and body weight [11,12,13]. Its cardioprotective mechanisms are multifaceted, affecting cardiac and vascular physiology directly and indirectly through metabolic optimization [14]. Preclinical and basic research also suggests the anti-inflammatory properties of semaglutide [15, 16]. Rakipovski et al.. illustrated its ability to suppress inflammation in hyperlipidemic mouse aortic walls, and Reppo et al.. reported decreased serum levels of the inflammatory markers hsCRP and ceruloplasmin in T2DM patients [17, 18]. However, the specific anti-inflammatory effects of semaglutide on the coronary artery remain unclear.

Pericoronary adipose tissue (PCAT), a specialized subset of epicardial adipose tissue (EAT) enveloping the coronary artery, plays dual roles in structural integrity and metabolic regulation [19, 20]. Its direct interaction with the coronary artery facilitates the bidirectional diffusion of proinflammatory cytokines [21]. Dysregulated PCAT function, exacerbated by hyperglycemia and dyslipidemia, triggers the secretion of proinflammatory cytokines into the arterial wall, accelerating atherosclerosis [22]. Moreover, inflamed artery walls can conversely alter adjacent PCAT, inducing morphological alterations in adipocytes, such as lipolysis, inhibition of lipogenesis, a reduction in the size of lipid molecules, and an increase in the water component, resulting in elevated computed tomography (CT) attenuation [23, 24]. This characteristic makes the fat attenuation index (FAI) of PCAT attenuation, measured via coronary CT angiography (CCTA), a noninvasive quantitative biomarker for coronary artery inflammation. Its reliability has been demonstrated, and it has emerged as a promising diagnostic tool for identifying high-risk populations and assessing the efficacy of anti-inflammatory therapies [19, 25].

Against this backdrop, our study aimed to investigate the association between semaglutide and the FAI of PCAT, a surrogate marker of pericoronary inflammation, in T2DM patients, with the goal of providing a potential new theoretical basis for the cardiovascular protective effect of semaglutide.

Materials and methods

Study population

This retrospective study was approved by the Ethics Committee of Hebei General Hospital (No. 2024-LW-121), and the requirement for informed consent was waived. A total of 846 consecutive patients with T2DM who underwent CCTA at Hebei General Hospital from January 2023 to June 2024 were retrospectively recruited. Inclusion was contingent upon patients being aged 18 years or older and having a prior diagnosis of T2DM, adhering to established guidelines [26].

The exclusion criteria were as follows: (1) a history of cardiovascular disease, encompassing myocardial infarction, angina, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, stroke, and heart failure; (2) for patients on semaglutide therapy, a treatment duration of less than six months; (3) concurrent use of other GLP-1RAs or dipeptidyl peptidase-4 (DPP-4) inhibitors; (4) suboptimal image quality, atypical coronary origins, or myocardial bridges that impinge upon FAI measurements; and (5) absence of requisite laboratory or clinical data. A total of 497 patients met the inclusion and exclusion criteria (Fig. 1), among whom 93 were treated with semaglutide (Sema+) and 404 were not (Sema-).

Fig. 1
figure 1

Flow chart of patient screening for this study

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Data collection

Clinical data and laboratory indicators of patients, including age, gender, body mass index (BMI), smoking status (continuous or cumulative smoking for more than 6 months), duration of type 2 diabetes, presence of hypertension, dyslipidemia status, details of medication use, and hematological indices, were collected. Among the latter, key parameters included lymphocyte and neutrophil counts, fasting plasma glucose (FPG) levels, glycosylated hemoglobin (HbA1c), total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and lipoprotein(a) [Lp(a)] concentrations.

CCTA acquisition

CCTA was conducted via a dual-source CT scanner (Somatom ForceCT, Siemens Healthcare GmbH, Germany). The scanning ranged from the trachea carina to 2 cm below the cardiac apex, with a tube voltage of 100 kVp and a tube current-time product of 380–410 mAs. The enhanced scanning delay time was determined via BolusTracking technology. In cases where the patient’s resting heart rate exceeded 70 bpm, oral beta-blockers were administered. To ensure optimal image quality, all scans were completed in a single breath-hold. Imaging was either prospectively ECG-triggered or retrospectively ECG-gated, with image reconstruction focused at 75% of the R-R interval to align with left ventricular dispersion.

PCAT inflammation analysis

The optimal sequences of coronary artery images for each patient were selected and imported into validated FAI analysis software (Shukun Technology, version 1.0.4, China). The software autonomously traces the PCAT of the three main coronary arteries and calculates the FAI by averaging the EAT CT values, specified as -190 to -30 Hounsfield units (HU), within a radial distance equal to the average diameter of the vessel’s outer wall. To minimize interference from the aorta, the region of interest (ROI) in the right coronary artery (RCA) extends 40 mm downward from 10 mm below its origin, whereas in the left anterior descending (LAD) and left circumflex (LCX) arteries(Fig. 2), the ROI extends 40 mm downward from the coronary artery origin.

Fig. 2
figure 2

Representative case of PCAT attenuation in the LCX measured by CCTA. The color maps PCAT. (A) Cross-sectional view showing PCAT (CT values between − 190 and − 30 HU). (B) Image after surface recombination displaying PCAT (40 mm). (C) Straightened view of the segments of the proximal coronary artery. (D) Straightened view around the proximal 40 mm of the LCX. PCAT: pericoronary adipose tissue; LCX: left circumflex artery; CCTA: coronary computed tomography angiography

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Statistical analysis

Statistical analysis was performed via SPSS 27.0. The metrological data were first assessed for normality and homogeneity of variance. Normally distributed variables are presented as the mean ± standard deviation (SD) and were compared via Student’s t test; nonnormally distributed variables are described as the median (interquartile range) and were compared via the Mann‒Whitney U test. Categorical data are represented as counts (%), with group comparisons analyzed via the chi-square test.

Propensity score matching (PSM) was performed to minimize confounding bias. The propensity score was calculated by a logistic regression model including variables of patient age, sex, BMI, cardiovascular risk factors (including dyslipidemia, hypertension, and smoking), the duration of diabetes and medications. Patients in the SEMA + and SEMA- groups were matched in a 1:1 ratio using the nearest neighbor method without replacement, and the caliper width was 0.02.

Univariate (Model 1) and multivariate (Model 2) linear regression analysis was used to investigate the association between semaglutide treatment and PCAT attenuation in T2DM patients. Covariate selection employed stepwise regression analysis to identify independent predictors (results not displayed herein), which were then incorporated and fine-tuned based on known factors and univariate analysis for a model with optimal fit. Variables ultimately adjusted for in Model 2 encompass age, sex, BMI, diabetes duration, dyslipidemia, smoking, statin use, CACS, LVEF, and fasting glucose. Subgroup analyses were conducted by stratifying for age, sex, BMI, dyslipidemia, diabetes duration and smoking status. A two-tailed p value of less than 0.05 was used to determine statistical significance.

Results

Patient characteristics

The baseline characteristics of the patients are shown in Table 1. The overall mean age was 63.49 ± 11.20 years, and 298 participants (60.0%) were male. Compared with those in the SEMA- group, patients in the SEMA + group were younger, more likely to be male and have a higher BMI, a greater proportion of patients with a history of hyperlipidemia and SGLT2i utilization, and higher levels of triglycerides and total cholesterol (P < 0.05). There were no significant differences in the duration of diabetes; the levels of inflammatory markers (CRP, WBC, leukocytes, and neutrophils); or the coronary artery calcification score (CACS) (P > 0.05). Patients treated with SEMA presented a lower pericoronary FAI of the LAD and LCX than did those in the SEMA- group; however, there was no statistically significant difference in RCA-PCAT attenuation between the two groups.

Table 1 Baseline characteristics of the participants
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Comparison of clinical features and PCAT attenuation between the two groups after propensity score matching

A total of 168 T2DM patients (Sema-84 versus Sema + 84) were matched in the propensity score-matched analysis. After controlling for age, sex, body mass index, cardiovascular risk factors (including dyslipidemia, hypertension, and smoking), the duration of diabetes and medications, there were no significant differences in blood glucose, blood lipids, inflammatory markers or the CACS between the two groups. These differences in the pericoronary FAI in the LAD and LCX between the two groups remained significant. Additionally, the RCA pericoronary FAI was lower in patients in the SEMA + group. The details are shown in Table 2; Fig. 3.

Table 2 Comparison of clinical features and pericoronary FAI values between the SEMA + and SEMA- groups after propensity score matching
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Fig. 3
figure 3

FAI of pericoronary in three main coronary arteries stratified by semaglutide after matching. n = 168 (84 in the Sema- group and 84 in the Sema + group). FAI: fat attenuation index; LAD: left anterior descending artery; LCX: left circumflex artery; RCA, right coronary artery

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Table 3 Univariate and multivariate linear regression analyses of semaglutide treatment and the pericoronary FAI
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Associations between semaglutide treatment and PCAT attenuation in T2DM patients

Univariate linear regression analysis revealed that semaglutide treatment was correlated with a decreased pericoronary FAI of the LAD (β = − 1.660, P < 0.05)and LCX(β =- 2.227, P < 0.05) in patients with T2DM, but not in RCA. After adjustment for covariates, the significant and independent correlations remained, and association between semaglutide treatment and FAI of RCA also became significant (LAD β = − 2.199, LCX β = − 2.745, RCA β = − 1.996, all P < 0.05).

Associations between semaglutide treatment and PCAT attenuation in subgroups of T2DM patients

Subgroup analyses, stratified by age(≥ 60 years), sex, BMI (≥ 24 kg/m2), dyslipidemia, diabetes duration (≥ 10 years) and smoking status, showed differential associations between semaglutide treatment and pericoronary FAI (Table 4). Notably, semaglutide treatment was correlated with lower FAI in those with diabetes duration < 10 years (LAD β = -2.606, P = 0.020; LCX β = -3.643, P = 0.009; RCA β = -3.204, P = 0.008) and non-smokers (LAD: β = -2.398, P = 0.010; LCX: β = -3.713, P < 0.001), with no significant correlation in patients with diabetes duration ≥ 10 years or in smokers.

Table 4 Multivariate linear regression analyses between semaglutide treatment and the pericoronary FAI in different subgroups of T2DM patients
Full size table

Among patients under 60 years of age, semaglutide was associated with a more pronounced reduction in FAI of LCX (β = -3.007, P = 0.037) and RCA (β = -3.128, P = 0.016), compared to those ≥ 60 years (LCX: β = -2.750, P = 0.045; RCA: P > 0.05). Semaglutide use showed more significant declines for females in FAI of LAD (β = -3.318, P = 0.026) and LCX (β = -3.381, P = 0.045) compared to males (LAD: β = -2.155, P = 0.041; LCX: β = -2.500, P = 0.039).

In the subgroup with BMI < 24 kg/m² or without dyslipidemia, semaglutide use was associated with a more substantial reduction in FAI of LCX (BMI < 24 kg/m²: β = -6.720, P = 0.014; without dyslipidemia: β = -4.435, P = 0.002), with no significant association with FAI of LAD and RCA in either subgroup. Conversely, a significant association between semaglutide use and FAI of LAD and RCA was observed in subgroups with BMI ≥ 24 kg/m² (LAD: β= -2.301, P = 0.013; RCA: β = -1.838, P = 0.050) or dyslipidemia (LAD: β = -2.402, P = 0.046; RCA: β = -2.702, P = 0.021).

Discussion

Understanding how semaglutide reduces cardiovascular risk is crucial for optimizing treatment strategies in T2DM patients, especially those at high risk for coronary artery disease. Our study aimed to explore if these benefits might be partly due to its impact on coronary artery inflammation, as indicated by PCAT attenuation. We found that semaglutide treatment was associated with lower coronary artery inflammation, and this association varied across T2DM patients of differing profiles. This potential reduction in inflammation might provide a possible reference for clinical practice in the management of T2DM patients.

In recent years, the pericoronary FAI, as assessed by CCTA, has emerged as a novel and sensitive biomarker reflecting the degree of coronary artery inflammation [20]. It has been shown to be of positively association with age, sex, cardiovascular risk factors, and CACS [27]; notably, statins or anti-inflammatory therapies (e.g., tumor necrosis factor-an in psoriasis patients) are associated with a lower FAI [25, 28]. Our multivariate regression analysis among T2DM patients not only demonstrated a negative association between semaglutide and coronary artery inflammation, but also showed that smoking, dyslipidemia, and extended diabetes duration, higher BMI and fast glucose levels, increased CACS and reduced LVEF seemed to be risk factors for exacerbated coronary artery inflammation; while statin treatment might serve as protective factors. Among these, smoking status and CACS were among the most significant. Independent of the degree of coronary stenosis, myocardial ischemia, or the presence of high-risk plaques (e.g., spotty calcifications), pericoronary FAI offers a fresh perspective on the risk stratification of epicardial coronary diseases [29]. The CRISP-CT study revealed that a high pericoronary FAI around the proximal RCA and LAD was predictive of all-cause and cardiac mortality [30]. A meta-analysis encompassing 7797 subjects further corroborated the association between a high FAI and MACE [31].

T2DM is recognized as an independent risk factor for atherosclerosis, increasing the risk of CVD [32]. Studies have shown that T2DM patients exhibit a greater FAI of the pericoronary than non-T2DM patients do [33, 34], with particularly heightened FAI in those lacking glycemic control interventions or those with poorly controlled T2DM [34]. Ichikawa et al.. reported that a high LAD pericoronary FAI in T2DM patients could significantly predict cardiovascular events [35]. Liu et al.. incorporated lesion-specific pericoronary FAI with the CACS, providing incremental predictive power for MACEs in patients with T2DM [36]. These findings suggest that an elevated pericoronary FAI may underlie one of the intrinsic mechanisms related to increased cardiovascular risk in diabetic patients [20]. Therapeutic strategies targeting the reduction of FAI and the amelioration of coronary artery inflammation may be associated with lower cardiovascular risk and more significant benefits in T2DM patients.

Several extensive randomized controlled trials have confirmed the efficacy of GLP-1RAs in reducing MACE in T2DM patients [13, 14], suggesting strong recommendations in diabetes and cardiology guidelines for their use in high-risk patients [5, 37, 38]. Currently, studies on the correlation between GLP-1RA treatment and FAI are limited. Biesenbach et al.. reported that liraglutide is associated with LAD-PCAT attenuation in asymptomatic patients with T2DM [39]. Iacobellis G et al. observed a reduction in EAT and RCA-PCAT attenuation as well as an improvement in psoriasis outcomes in response to semaglutide therapy in a psoriasis patient with abdominal obesity and T2DM [40]. In this study, we first found a significant association between semaglutide treatment and a lower pericoronary FAI in the population with T2DM, which might provide an additional possible theoretical basis for the cardiovascular protective effect of semaglutide. In terms of mechanism, preclinical studies have shown that GLP-1RAs exert anti-inflammatory effects partly by targeting endothelial cells, monocytes, macrophages, and vascular smooth muscle cells within the blood vessel wall via the GLP-1 receptor [41]. This leads to enhanced vascular endothelial function, suppression of monocyte‒macrophage adhesion and aggregation, and attenuation of oxidative stress [16, 17, 42].

Notably, this study also revealed that semaglutide treatment was associated with a more significant reduction in coronary artery inflammation in subgroups characterized by diabetes duration less than 10 years, non-smoking status, age under 60 years, and female sex, with no significant association in patients with diabetes duration above 10 years or in smokers. This may provide a potential indication for personalized selection of semaglutide treatment in T2DM patients.

As a single-center retrospective study, the major limitation of this study is the lack of randomization, blinding and a placebo-controlled group. The causal relationship between semaglutide treatment and PCAT attenuation could not be directly explained by our current work. Even though we used propensity score matching and regression modeling to control for confounders, unmeasured (e.g., duration and dosage of the drug) and residual confounders may have biased our results. The sample sizes for the present study are relatively limited. Future randomized controlled trials could help confirm our findings.

Conclusion

Semaglutide treatment may be associated with lower coronary artery inflammation in patients with T2DM, which might partially explain its cardiovascular protective mechanism.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

FAI:

Fat attenuation index

PCAT:

Pericoronary adipose tissue

EAT:

Epicardial adipose tissue

T2DM:

Type 2 diabetes mellitus

CCTA:

Coronary computed tomography angiography

PSM:

Propensity score matching

CVD:

Cardiovascular disease

GLP-1RA:

Glucagon-like peptide-1 receptor agonist

MACE:

Major adverse cardiovascular events

DPP-4i:

Dipeptidyl peptidase-4 inhibitor

SGLT2i:

Sodium-dependent glucose transporter 2 inhibitor

PCSK9i:

Proprotein convertase subtilisin/kexin type 9 inhibitor

BMI:

Body mass index

FPG:

Fasting plasma glucose

HDL-C:

High-density lipoprotein cholesterol

LDL-C:

Low-density lipoprotein cholesterol

Lp(a):

Lipoprotein a

LVEF:

Left ventricular ejection fraction

CACS:

Coronary artery calcification score

Hu:

Hounsfield units

ROI:

Region of interest

RCA:

Right coronary artery

LAD:

Left anterior descending artery

LCX:

Left circumflex artery

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Acknowledgements

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Funding

This work was supported by Hebei Province Medical Technology Tracking Project (No. GZ2023013) and the Key Research and Development Program of Hebei Province (No. 18277791D).

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Author notes

  1. Yanhong Li and Wenjing Yao contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiology Center, Hebei General Hospital, Shijiazhuang, China

    Yanhong Li, Wenjing Yao, Tianxing Wang, Qian Yang, Feifei Zhang, Fan Wang & Yi Dang

  2. Department of Internal Medicine, Graduate School of Hebei Medical University, Shijiazhuang, China

    Yanhong Li & Kexin Song

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Contributions

YH contributed to the study design, data collection, statistical analysis, and drafting of the manuscript. WJ participated in the study design and data collection and reviewed the manuscript. TX, KX and FW participated in data collection, and QY and FF contributed to the editing and review of the manuscript. YD participated in the study design, contributed to the quality control of the data, and edited and reviewed the manuscript. All the authors have read and approved the final manuscript.

Corresponding authors

Correspondence to Qian Yang or Yi Dang.

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Ethics approval and consent to participate

This research protocol received approval from the Ethics Review Committee of Hebei General Hospital (No. 2024–LW-121) and was conducted in accordance with the principles outlined in the Declaration of Helsinki. However, due to the retrospective nature of this study, patient informed consent was waived.

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Li, Y., Yao, W., Wang, T. et al. Association of semaglutide treatment with coronary artery inflammation in type 2 diabetes mellitus patients: a retrospective study based on pericoronary adipose tissue attenuation. Cardiovasc Diabetol 23, 348 (2024). https://doi.org/10.1186/s12933-024-02445-2

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Keywords

Cardiovascular Diabetology

ISSN: 1475-2840