Diabetes has become one of the most prevalent and severe chronic diseases in modern society. The estimated prevalence of diabetes worldwide in the 20–79-year-old population reached 10.5% (536.6 million people) in 2021, and forecasts suggest a surge to 12.2% by 2045 [1]. Worldwide, 32.2% of type 2 diabetes mellitus (T2DM) patients have comorbid cardiovascular disease (CVD), which has become the top cause of death in this population, with coronary artery disease and stroke being the primary contributors [2, 3]. Long-term hyperglycemia-induced endothelial dysfunction, vascular inflammation, and oxidative stress are strongly linked to the initiation and progression of CVD in T2DM patients [4]. Inflammation plays a central role in coronary atherosclerosis by promoting arterial plaque formation and progression, significantly augmenting the risk of cardiovascular disease [5, 6]. This establishes inflammation as a modifiable cardiovascular risk factor and therapeutic target, underscoring the need to explore treatment strategies to reduce coronary inflammation and improve cardiovascular outcomes in patients with T2DM.

The attenuation value of peri-coronary adipose tissue (PCAT) visualized by coronary computed tomography angiography (CCTA) serves as a noninvasive biomarker for evaluating coronary artery inflammation. As specialized epicardial adipose tissue (EAT) surrounding coronary arteries, PCAT has dual functions in maintaining vascular structural integrity and metabolic regulation [7, 8]. PCAT secretes proinflammatory cytokines such as Interleukin-6 (IL-6) and Tumor necrosis factor-$\alpha$ (TNF-$\alpha$), establishing bidirectional signaling interactions with the wall of the coronary artery. Its dysfunction accelerates endothelial injury and atherosclerosis, whereas inflamed vascular walls reciprocally induce morphological changes in adjacent PCAT, such as enhanced lipolysis, inhibited lipogenesis, reduced lipid droplet volume, and increased water content, manifested as elevated computed tomography (CT) attenuation values. The peri-coronary fat attenuation index (FAI), assessed by CCTA, is defined as the mean CT value (between –190 and –30 HU) of adipose tissue within a 1$\times$ radius of the adventitial diameter of blood vessels and is used to quantify the degree of coronary inflammation [9, 10, 11]. The FAI exhibits high specificity for detecting local inflammation during the subclinical phase of coronary artery disease, prior to the development of significant stenosis. It enables anatomical localization of inflammation and facilitates the identification of unstable plaques and high-risk vascular territories. Moreover, FAI has emerged as a valuable tool for assessing treatment effects on coronary inflammation [12, 13].

Sodium-glucose transporter 2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have attracted considerable attention of their cardiovascular benefits [14, 15, 16]. Mechanistically, SGLT2 inhibitors improve cardiovascular outcomes through both glucose-dependent pathways (e.g., promoting urinary glucose excretion) and independent mechanisms (e.g., reducing cardiac preload, reducing inflammation, and inhibiting vascular/myocardial fibrosis) [17, 18]. GLP-1 receptor agonists activate GLP-1 receptors to delay gastric emptying and suppress appetite, promoting weight loss. They also directly improve vascular endothelial function, reduce oxidative stress and inflammation, inhibit atherosclerotic plaque progression, and lower cardiovascular risk by reducing blood pressure and heart rate while enhancing left ventricular systolic function [19, 20]. Clinical evidence shows that SGLT-2i significantly reduce the risk of cardiovascular death, heart failure hospitalization, and composite renal endpoints in patients with heart failure with reduced ejection fraction and chronic kidney disease (CKD) [21, 22]. GLP-1 receptor agonists decrease the risk of major adverse cardiovascular events (MACEs) in T2DM patients with atherosclerotic cardiovascular disease (ASCVD) [23, 24]. However, the specific anti-inflammatory effects of these two drug classes on coronary arteries remain undefined.

Therefore, this study sought to investigate whether combination therapy with SGLT-2i and GLP-1RA can more effectively alleviate subclinical coronary inflammation as characterized by FAI in patients with T2DM without major cardiovascular events, thereby providing imaging-based evidence for early-stage anti-atherosclerotic intervention in this high-risk population.

This study reports the results of the investigation of the relationship between the cardiovascular benefits of SGLT-2i combined with GLP-1RA and coronary inflammation in T2DM patients without known cardiovascular disease through the peri-coronary FAI, an imaging biomarker of coronary inflammation. This population is in a critical window period for atherosclerotic progression and urgently requires effective risk stratification and intervention strategies. As a tool capable of non-invasively detecting local coronary inflammation, FAI serves as an ideal surrogate endpoint for assessing early treatment responses. This study showed that SGLT-2i combined with GLP-1RA therapy was independently associated with a significant reduction in the FAI of the LAD, LCX, and RCA. After adjusting for confounders, the reduction in the LCX FAI with combination therapy was significantly greater than that with monotherapy, suggesting that combination therapy may confer cardiovascular benefits to T2DM patients by reducing coronary inflammation.

Multiple large-scale randomized controlled trials have confirmed that SGLT-2i and GLP-1RA can significantly reduce the risk of MACEs in T2DM patients [25, 26]. According to the 2025 American Diabetes Association (ADA) guidelines, in patients with T2DM complicated with ASCVD, heart failure, or CKD, SGLT-2i or GLP-1RA with proven cardiorenal protective evidence are preferentially recommended as first-line therapy (evidence level A) [27]. Observational studies have demonstrated the cardiovascular benefits of combined SGLT-2i and GLP-1RA therapy in patients with T2DM. For example, a UK CPRD cohort study showed that SGLT-2i/GLP-1RA combination therapy reduced the risk of MACEs by approximately 30% compared with monotherapy [28]. In a prospective observational study on T2DM patients with acute myocardial infarction (AMI), Marfella et al. [29] reported that, compared with either SGLT-2i or GLP-1RA monotherapy, combination therapy significantly reduced the risk of MACEs by 83%–84.6% and improved the myocardial salvage index (MSI). Further supporting these findings, a large retrospective cohort study by Chaiyakunapruk et al. [30] in the United States demonstrated that adding GLP-1RA to SGLT-2i reduced the risk of MACEs by 45%–46% in T2DM patients with ASCVD.

SGLT-2i reduce renal glucose reabsorption and promote glycosuria by inhibiting the activity of SGLT-2 protein in the proximal renal tubules. Their cardiorenal protective effects are achieved by alleviating volume overload to reduce cardiac workload, as well as by improving cellular energy metabolism. This process is often accompanied by activation of the AMP-activated protein kinase (AMPK) pathway, enhanced mitochondrial function, and mitigated oxidative stress. In addition, SGLT-2i exert prominent pleiotropic anti-inflammatory effects. Hyperglycemia and excessive volume overload under diabetic conditions lead to hyperactivation of the sympathetic nervous system, whereas SGLT-2i can lower sympathetic nerve tone through effective alleviation of volume overload, thereby suppressing neuroimmune-mediated inflammatory responses. SGLT-2i improve systemic metabolic disorders and insulin resistance via multiple mechanisms, including sustained glucose lowering, body weight reduction, and lipid profile regulation, thus exerting anti-inflammatory effects. GLP-1RA binds to GLP-1 receptors in the vascular wall, modulating endothelial cells, monocytes, macrophages, and vascular smooth muscle cells. This interaction not only enhances vascular endothelial function but also suppresses NLRP3 inflammasome activation, thereby reducing the release of proinflammatory cytokines (e.g., IL-1$\beta$), decreasing monocyte adhesion molecule expression, and mitigating oxidative stress injury [31, 32]. The two drugs synergistically reduce oxidative stress and monocyte adhesion, which may jointly enhance the protective effect on the cardiovascular system.

The peri-coronary FAI, an emerging imaging biomarker based on CCTA, reflects coronary inflammation and plaque stability by quantifying attenuation value changes in PCAT. Studies have shown that the peri-coronary FAI can independently predict MACEs. Patients with high peri-coronary FAI values face a 3.29-fold greater risk of MACEs than those with low values [33, 34]. The CRISP-CT study demonstrated that increased FAI values in the RCA and LAD are significantly positively correlated with all-cause and cardiac mortality [35]. These findings suggest that inflammation-targeted therapies may improve patient prognosis. Notably, this study primarily included individuals with a BMI $\ge$24 kg/m². Research has shown that overweight/obesity is strongly linked to the development and progression of T2DM, and that the mechanism involves inflammatory responses mediated by abnormal adipose tissue function. In the obese state, adipose tissue (including PCAT) secretes fewer protective factors with anti-inflammatory and antioxidant properties, such as adiponectin and omentin-1, and instead secretes large amounts of proinflammatory cytokines (IL-6 and TNF-$\alpha$). These cytokines induce insulin resistance by interfering with insulin signaling pathways and can directly drive coronary inflammatory responses, leading to a functional shift in PCAT from “protective” to “harmful” [10, 36]. Therefore, excluding patients with a BMI 24 kg/m² allowed for a more precise evaluation of the direct regulatory effect of these drugs on the “proinflammatory effect of adipose tissue in the obese state”, ensuring that the study results are more relevant to the target population requiring higher priority intervention in clinical practice.

A recent study confirmed that increased PCAT attenuation around the LAD in T2DM patients is significantly associated with cardiovascular events [37], suggesting that treatment strategies to reduce peri-coronary FAI may lower the risk of adverse cardiovascular events in T2DM patients. To date, investigations into the associations between SGLT-2i/GLP-1RA therapy and the peri-coronary FAI are relatively few. Studies by Liu et al. [38] and Li et al. [39] have shown that dapagliflozin and semaglutide may alleviate coronary inflammation in T2DM patients by lowering the peri-coronary FAI. Biesenbach et al. [40] demonstrated that liraglutide is linked to a lower LAD FAI in asymptomatic T2DM patients. However, the effect of the combined use of these two classes of drugs on the peri-coronary FAI remains unclear. Our study revealed that combined SGLT-2i and GLP-1RA treatment is negatively correlated with coronary inflammation in T2DM patients and has advantages over monotherapy in some cases. Subgroup analysis indicated that the association between combined SGLT-2i and GLP-1RA therapy and reduced FAI was consistent across patients stratified by age, T2DM duration, hyperlipidemia, or smoking history. A significant interaction was observed only for sex regarding its effect on LCX FAI, suggesting a potential sex-specific response. These findings offer insights for personalized treatment strategies in T2DM.

This study has several limitations. First, due to the limited sample size, we grouped SGLT-2i and GLP-1RA into a single monotherapy group for analysis, thus failing to evaluate the independent effects of these two drug classes on the peri-coronary FAI, and were unable to fully exclude intra-group heterogeneity. Second, the retrospective study design is subject to selection bias (e.g., a higher proportion of young males in the combination therapy group and imbalances in medication use across some groups), and it was not possible to control for unmeasured confounding factors such as dietary patterns and physical activity. Although adjustments were made via multivariate models, the lack of randomization, blinding, and placebo control means this study can only reveal associations rather than causal relationships. Third, the relatively small overall sample size (n = 292) and the combination therapy subgroup (n = 43) may have limited statistical power, potentially affecting the results of some subgroup analyses. Fourth, we excluded patients with a BMI 24 kg/m². While this focused the study on the high-risk overweight/obese population, it also restricted the generalization of the results to normal-weight patients with T2DM. Finally, the non-inclusion of indices such as epicardial fat volume and inflammatory cytokines limited the in-depth investigation of the potential anti-inflammatory mechanisms of combination therapy. Future multicenter, prospective randomized controlled trials (RCTs) are needed to validate the findings of this study, distinguish the independent effects of the two drugs, and expand the study population to enhance generalizability.

The combined use of SGLT-2 inhibitors and GLP-1 receptor agonists may be correlated with a decrease in the peri-coronary fat attenuation index in T2DM patients, suggesting their potential role in alleviating coronary inflammation. Compared with monotherapy, this combination therapy might offer potential advantages.

The datasets utilized or analyzed during the current study are available from the corresponding author upon reasonable request.

TXW contributed to the study design, data collection, statistical analysis, and drafting of the manuscript. YHL participated in the study design and data collection and critically reviewed the manuscript. WJY, SHC, SJZ, YTW and CW participated in data collection, assisted in data collation and verification, and reviewed the manuscript section related to data acquisition. FFZ contributed to the study design and the editing and critical review of the manuscript. YD participated in the study design, contributed to the quality control of the data, and edited and critically reviewed the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

The study was carried out in accordance with the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of Hebei General Hospital (Protocol No. 2025-LW-0144). As this is a retrospective analysis, the requirement for patient informed consent was waived in accordance with the relevant regulatory guidelines.

Not applicable.

This work was supported by the government-funded project for training outstanding clinical medicine talent of Hebei Province (Grant No. ZF2024010) and the Hebei Provincial Major Science and Technology Support Program (Grant No. 252W7703D).

The authors declare no conflicts of interest.

Supplementary material associated with this article can be found, in the online version, at https://doi.org/10.31083/RCM47415.