GLP-1 Receptor Agonists Are Associated With Reduced Ascending Aorta Dilatation in Patients With Type 2 Diabetes: A Prospective Study

GLP-1 Receptor Agonists Are Associated With Reduced Ascending Aorta Dilatation in Patients With Type 2 Diabetes: A Prospective Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article GLP-1 Receptor Agonists Are Associated With Reduced Ascending Aorta Dilatation in Patients With Type 2 Diabetes: A Prospective Study Celestino Sardu, Ludovica Vittoria Marfella, Carlo Fumagalli, and 23 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7174676/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract AIMS-To assess the impact of GLP-1 receptor agonist (GLP-1 RA) treatment on the progression of ascending aortic dilatation in patients with type 2 diabetes mellitus (T2DM), investigated with computed tomography angiography (CTA) and circulating biomarkers reflecting vascular remodeling. METHODS-A total of 127 T2DM patients with subclinical ascending aortic dilatation (diameter 35 mm < and ≤ 45 mm) were prospectively enrolled in this study. All were first-line naïve to GLP-1 RA. Fifty-seven patients started GLP-1 RA treatment (liraglutide, semaglutide, or dulaglutide) and 70 remained in routine care as controls. CTA was performed at baseline and 24 months to measure the ascending aortic diameter. Matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinases-1 (TIMP-1), C-reactive protein (CRP) and osteoprotegerin (OPG) were evaluated from sera at these two time points. RESULTS-The GLP-1 RA recipients, compared with controls, had the more limited progression of aortic dilatation (mean change, +0.36±0.20 mm vs+1.05±0.28 mm; P<0.001) at 24 months. Therapy correlated with decreased MMP-9 and CRP (P<0.01) and increased TIMP-1 and OPG (P<0.05). The use of GLP-1 RA was an independent predictor of low progression, even in multivariate models after adjusting for demographic, metabolic, and biomarker data. CONCLUSIONS-GLP-1 receptor agonist therapy has been associated with reduced ascending aortic dilatation in T2DM, suggesting a vasoprotective action beyond glucose lowering. Type 2 diabetes mellitus ascending aortic dilatation GLP-1 receptor agonists computed tomography angiography vascular biomarkers inflammation Figures Figure 1 Figure 2 Figure 3 INTRODUCTION An increase in incidence of cardiovascular complications including both microappmascular and macrovascular diseases has been reported in people with type 2 diabetes mellitus (T2DM). Of these, ascending aortic dilatation has been identified as a clinically important, yet poorly recognised, complication in T2DM patients. The ascending aorta is especially vulnerable to structural biology due to its direct proximity to the left ventricle and exposure to pulsatile hemodynamic forces. This structural remodelling is motivated by a variety of factors such as chronic inflammation, the generation of oxidative stress, and the break down of extracellular matrix (ECM), being frequently mediated by increased levels of matrix metalloprotenases (MMPs), particularly MMP-2 and MMP-9 (1, 2 ). The formation of an ascending aorta does not appear to be overt, but the progressive dilation affected the increased rigidity of arterial system, the systolic hypertension and the left ventricular preload resulting in the aggravation of cardiovascular risk in diabetes (3). Recent developments in treatments for diabetes have shown that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have potential cardiovascular protective benefits in addition to their glycemic benefit. A number of large cardiovascular outcome trials (CVOTs) (4–6) such as LEADER, REWIND, and SUSTAIN-6 have shown reductions in major adverse cardiovascular events (MACE) in GLP-1RAs-exposed patients. Mechanistically, GLP-1 RAs have been demonstrated to avoid inflammation, mitigate oxidative stress and regulate vasculature remodelling enzymes as MMP-9 and tissue inhibitors of metalloproteinases (TIMPs) in preclinical models (7,8). In addition, GLP-1 RAs have been shown to have a possible impact on the formation of aneurysms and on aortic wall degradation, especially in models of abdominal aortic aneurysm (AAA) (9,10). Nevertheless, the effect of GLP-1 RAs on the development of ascending aortic dilatation in individuals suffering from T2DM has not been fully investigated. Advanced imaging modalities like CTA offer accurate aortic dimensional measurements, enabling evaluation of the aortic structural impact of pharmacological interventions. Also, circulating biomarkers of aortic remodelling, including matrix metalloproteinase-9 (MMP-9) tissue inhibitor of metalloproteinase-1 (TIMP-1) C-reactive protein (CRP) and osteoprotegerin (OPG), offer additional information about the biological mechanisms and progression of the disease (11–13). Based on known anti-inflammatory and anti-remodelling effects of GLP-1 RAs, we hypothesize that the treatment with these agents might resist the progression of ascending aortic dilatation in T2DM patients. In the current study, we sought to determine the impact of GLP-1 RA therapy on the structural development of ascending aortic dilatation over a 24-month follow-up through serial CTA imaging and to understand the relationship with changes in circulating vascular remodelling markers. This study might provide new perspectives to the vasoprotective role of GLP-1 RAs, and broaden their therapeutic implication in the prevention of diabetes-associated macrovascular complications. METHODS This was a prospective observational cohort study, performed in the Internal Medicine outpatient units of the University of Campania “Luigi Vanvitelli” (Naples, Italy), and it included the period of patient enrolment from January 2019 until follow-up completed in March 2024. The study was approved by the local ethics committee, and all of the included patients signed their informed consent. The principles of Declaration of Helsinki were followed in the conduct of the study. Study Population . A total number of 127 consecutive adult patients with type 2 diabetes mellitus (T2DM), 40 to 75 years old, were recruited. All patients had subclinical ascending aortic dilatation, which was defined as an ascending aorta of 35 to 45 mm in diameter when contrast-enhanced computed tomography angiography (CTA) was performed for cardiovascular risk stratification. This dimension is in accordance with early stage dilatation in non-syndromic, high cardiovascular risk adults, which is also supported by the echocardiographic and imaging criteria about mild dilatation (14). Patients who met the following criteria were eligible to participate: diagnosis of T2DM for ≥5 years, an HbA1c of 7.0%–10.0%, and on a stable antihypertensive and lipid-lowering regimen for ≥3 months before study entry. Key exclusion criteria were previous or current GLP-1 receptor agonist use, known aortic aneurysm or dissection, history of CVD events in the last 6 months, severe renal dysfunction (eGFR <45 mL/min/1.73 m²), chronic inflammatory or autoimmune disease, active malignancy, or contraindications to iodinated contrast media. Treatment groups were allocated according to clinical standards at constituting time-point. Fifty-seven patients (who qualified according to guideline for initiation of GLP-1 receptor agonist due to insufficient glycemic control and/or high cardiovascular risk) were treated with GLP-1 RA (liraglutide, semaglutide, or dulaglutide) therapy in combination with baseline treatment. Seventy patients not meeting these criteria for GLP-1 RA guidelines were maintained on their current antidiabetic regimen (metformin, DPP-4 inhibitors, and/or basal insulin) and served as the control arm. Follow-up and Clinical Evaluation . All patients have been followed up for 24 months, and regular 6-month clinical assessment has been established. During each follow-up visit, patients received a thorough cardiovascular evaluation which included physical examination performed directly by cardiologists and a 12-lead ECG, carotid duplex ultrasonography (CDU), and transthoracic echocardiography (TTE), with special interest in measuring the ascending aorta diameter. Metabolic indices (HbA1c, fasting glucose, lipid profile, renal function) and blood pressure were also followed. For all study groups, antidiabetic treatments were titrated according to clinical judgment and actualized guidelines, and GLP-1 RA therapy was maintained without dose reduction except for developments of adverse events. Drug intake compliance was assessed by pill counts and patient diaries. The present follow-up strategy is consistent with the 2022 ACC/AHA guidelines (14), which advise a regular imaging follow-up also for patients with dilatation of the ascending aorta to monitor the progression of the disease and to make treatment decisions. Imaging Protocol. All patients had contrast-enhanced CTA of the thoracic aorta at baseline and after the 24-month follow-up. The scans were acquired with a 64-slice multidetector CT scan (LightSpeed VCT; GE Healthcare, Milwaukee, WI, USA) with a standardised protocol developed for assessment of the ascending aorta. Iodinated contrast agent (Iohexol 350 mgI/mL) was administered intravascularly (dose, 1.2 mL/kg; flow rate, 4.0 mL/s) through an antecubital vein, and then 30 mL saline was injected into the arm according to bolus tracking. Bolus tracking was used for the optimal scan delay using a region of interest on the ascending aorta and image acquisition was started with attenuation threshold of 100 HU. Acquisition parameters were as follows: tube voltage 120 kVp, tube current 300–500 mAs (automatic modulation), collimation 0.625 mm, pitch 0.9, rotation time 0.5 s. Reconstructions were performed with a slice thickness of 1 mm and an interval of 0.5 mm collimation with a medium-sharp kernel. Ascending aorta dimensions were measured in the true axial plane at the level of right pulmonary artery perpendicular to the long axis of the vessel. This is in concordance with previously described methods for proper aortic diameter measurements (15). All images were transferred for multiplanar and curved-planar reformats to a workstation (Advantage Workstation 4.7, GE Healthcare). Data were measured by two experienced radiologists without knowledge of the treatment group and clinical condition. Each scan was measured 3 times by each radiologist. The average final value derived from the six values (n=3 per reader) was the final value for each patient and the given period. Intra- and interobserver agreement were determined with the ICC, where values over 0.90 were determined as representing excellent agreement. The D_mdc (in diameter) was 0.2 mm calculated by means of repeated measurements, variance analysis. For outcome modelling, we dichhotomised ascending aortic progression according to CTA measurement. Progression was defined as the occurrence of an ascending aortic diameter dilatation of ≥1.0 mm of the ascending aorta at 24months compared to baseline (coded as 1). Those skulls that ≤1.0 mm increase in diameter (stabilized or decreased in diameter) were considered with no progression (thus, coded as 0). This cut-off threshold was established above the mean measurement uncertainty, so that a progression call represented an actual anatomical change rather than simply a statistical variation. This binary outcome was utilized as the dependent variable in the OR regression model in order to determine clinical and biochemical correlates of progressive AA dilation over time. Biomarker Analysis. All participants provided venous blood samples in the morning after overnight fasting (≥10 hour) at baseline and during the 24-month follow-up. Blood was taken into EDTA tubes and within 30 minutes of collection was centrifuged for 15 minutes at 1,500 × g at 4°C. Plasma was also aliquoted and stored at −80°C until batch analysis. The levels of the following plasma biomarkers were measured using commercially available enzyme-linked immunosorbent assay (ELISA) kits (R&D Systems, Minneapolis, MN, USA): Matrix Metalloproteinase-9 (MMP-9)= Human Quantikine ELISA (sensitivity: 0.156 ng/mL; intra-assay CV <6.2%; inter-assay CV 5.4%; inter-assay CV >7.1%) C-Reactive Protein (CRP)= high sensitive CRP ELISA Kit (sensitivity: 0.1 mg/L; intra-assay CV <4.5%; inter-assay CV <6.3%) Osteoprotegerin (OPG) = Human OPG DuoSet ELISA Kit (sensitivity 0.05 ng/mL, intra-assay CV <6.0%, inter-assay CV <9.0%). Each measurement was done in duplicate. Clinical and imaging data were concealed to laboratory operators. Calibration curves with the recombinants standards were provided by the manufacturer for each analyte and concentrations were determined by 4-parameter logistic curve fit. All specimens with out-of-bound values were required to be re-run after excessive dilution. Baseline and follow-up samples of each participant were analysed in the same batch and run to reduce inter-assay variation. Haemolysed and freeze-thawed degrade samples were not included. QC samples were incorporated in every batch to monitor the inter-batch variation. In the last dataset, we retained only patients with good paired biomarker at both sampling times. Statistical Analysis. Baseline characteristics and outcomes of the study were described and summarized using descriptive statistics. Continuous variables were presented as means ± standard deviation (SD) or medians and interquartile ranges (IQR) to the method of distribution based on the Shapiro-Wilk test. Categorical data is described as numbers with percentage frequency. Between-group comparisons were conducted through the independent-samples t test or Mann–Whitney U test for continuous variables and χ² test or Fisher’s exact test for dichotomous variables. Paired t tests or Wilcoxon signed-rank tests were employed to analyze changes from baseline to 2 years in ascending aorta diameter and biomarker concentrations within groups and independent-samples tests were used to analyze changes between groups. The reproducibility of aortic measurements was evaluated by the intraclass correlation coefficient (ICC), and the minimal detectable change (MDC) was obtained according to the formula of repeated measurements. In order to investigate the relationship between clinical variables and ascending aorta dilatation, multivariate linear regression model was first used with the change in diameter of ascending aorta as the dependent variable. The independent variables were age, BMI, sex, baseline ascending aorta diameter, HbA1c, systolic blood pressure, LDL cholesterol, statins and levels at follow-up of MMP-9, TIMP-1, CRP and OPG. Furthermore, a multivariable logistic regression model was developed for the determination of the independent predictors of progression of ascending aorta dilatation, as a binary endpoint: • Progression=1 for participants who had increase of the ascending aorta by 1.0 mm or more at 24 months. • No progression= 0= Stable or decreased diameter (<1.0 mm) in patients with follow-up. The potential covariates for the logistic regression model included age, sex, baseline diameter of AA, HbA1c, systolic blood pressure, statin use, and Δ of biomarkers (MMP-9, TIMP-1, CRP, OPG), changes in BMI and HbA1c from baseline to follow-up. The findings are presented as odd ratios (ORs) with 95% confidence intervals (CIs) and related P value. Model calibration and discrimination were by evaluated the standard diagnostics, and multicollinearity was eliminated. To evaluate the robustness of the primary findings, multiple sensitivity analyses were conducted. First, the effect of GLP-1 RA therapy on ascending aortic diameter progression was re-examined using alternative thresholds for defining progression (≥0.5 mm and ≥1.0 mm increase). Second, a sensitivity analysis was performed by excluding patients in the upper tertile of baseline aortic diameter (>43 mm), and by stratifying the regression models according to baseline HbA1c (above vs. below median), BMI tertiles, and sex. Interaction terms between treatment group and each covariate were included to assess effect modification. Collinearity was checked using variance inflation factors (VIF), and model fit was evaluated using adjusted R² and residual analysis. Third, multivariate logistic regression models were repeated excluding changes in circulating biomarkers to mitigate potential overadjustment bias. All test were two-sided, and a value of P < 0.05 was considered significant. Statistical analyses were conducted in IBM SPSS Statistics (version 28.0; IBM Corp., Armonk, NY) and R (version 4.2.1; R Foundation for Statistical Computing, Vienna, Austria). Results Baseline Characteristics. The baseline demographic and clinical characteristics of the study participants (N = 127) are presented in Table 1 . Of those, 57 newly GLP-1 RA-treated (guidelines-based regimen: suboptimal glycemic control and/or overweight/obese) patients were enrolled. The other 70 patients, who did not meet the above criteria, were treated with conventional antidiabetic therapy and defined as the control group. There were more males in the general population (63.0%), and the mean age was 63.8 ± 6.9 years, and the mean history of diabetes was 9.9 ± 3.0 years. Not surprisingly, the GLP-1 RA group had a higher mean BMI at baseline than the control group in line with the indication for therapy. Mean HbA1c was also marginally higher in the GLP-1 RA group compared to controls (P = 0.03). Other cardiometabolic characteristics were well balanced between groups. Baseline ascending aortic diameter on contrast-enhanced CTA did not differ at a significant level between groups (Table 1 ). Table 1 – Baseline Demographic, Clinical, and Therapeutic Characteristics of the Study Population Variable GLP-1 RA Group (n = 57) Control Group (n = 70) P Value Age, years 63.4 ± 6.8 64.1 ± 7.0 0.48 Male sex, n (%) 36 (63.2%) 44 (62.9%) 0.97 BMI, kg/m² 32.5 ± 3.2 28.1 ± 2.9 < 0.001 Duration of diabetes, years 10.1 ± 2.9 9.8 ± 3.1 0.57 HbA1c, % 8.4 ± 0.6 8.1 ± 0.7 0.03 Systolic blood pressure, mmHg 134 ± 11 136 ± 12 0.38 Mean arterial pressure, mmHg 98.4 ± 7.2 99.1 ± 6.9 0.61 LDL cholesterol, mg/dL 98.4 ± 13.7 96.7 ± 14.1 0.47 eGFR, mL/min/1.73 m² 84.6 ± 12.5 86.1 ± 11.8 0.37 eGFR ≥ 90, n (%) 20 (35.1%) 27 (38.6%) 0.71 eGFR 60–89, n (%) 34 (59.6%) 39 (55.7%) 0.68 eGFR < 60, n (%) 3 (5.3%) 4 (5.7%) 0.92 Hypertension, n (%) 43 (75.4%) 52 (74.3%) 0.88 Dyslipidemia, n (%) 40 (70.2%) 51 (72.9%) 0.72 History of cardiovascular disease, n (%) 11 (19.3%) 13 (18.6%) 0.92 Statin use, n (%) 43 (76.1%) 55 (78.6%) 0.73 ACEi/ARB use, n (%) 38 (66.7%) 49 (70.0%) 0.69 Beta-blocker use, n (%) 19 (33.3%) 25 (35.7%) 0.78 Antiplatelet therapy, n (%) 21 (36.8%) 26 (37.1%) 0.97 Metformin use, n (%) 51 (89.5%) 65 (92.9%) 0.52 SGLT2i use, n (%) 17 (29.8%) 14 (20.0%) 0.21 Insulin use, n (%) 13 (22.8%) 15 (21.4%) 0.85 Aortic arch diameter, mm 38.3 ± 2.4 38.1 ± 2.2 0.48 Baseline characteristics of patients receiving GLP-1 receptor agonists (GLP-1 RA group) versus those on standard antidiabetic therapy (control group). Data are reported as mean ± SD or n (%). Differences in BMI and HbA1c reflect guideline-based eligibility for GLP-1 RA initiation. No other significant differences were observed between groups. GLP-1 RA, glucagon-like peptide-1 receptor agonist; BMI, body mass index; HbA1c, glycated hemoglobin; MAP, mean arterial pressure; LDL, low-density lipoprotein; eGFR, estimated glomerular filtration rate; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; SGLT2i, sodium-glucose co-transporter-2 inhibitor. Follow-Up Clinical Monitoring and Cardiometabolic Evolution . All subjects completed the intended 24 months of follow-up by in-person visit at 6-monthly intervals. These assessments included: physical examination, a review of therapy, ECG, carotid Doppler ultrasound (TSA) and transthoracic echocardiography (TTE). Both groups showed high treatment adherence, over 90% in each group were continuing with the treatment at the end of the study. As presented in Table 2 , significant changes in major cardiometabolic outcomes were found in the GLP-1 RA group across time periods. In patients on GLP-1 RA a mean BMI decrease from 32.5 ± 3.2 to 29.6 ± 3.0 kg/m² was noted (P < 0.001), i.e. an approximately 8% weight loss over 24 months. In comparison BMI in the control group showed no significant change (P = 0.22). Mean HbA1c decreased in both groups). The MAP decreased in the GLP-1 RA group (P = 0.002) but not significantly more than in the control group (P < 0.001). A significant reduction in LDL cholesterol concentration in both groups was observed. Dilation of Ascending Aorta at 24 Months At 24 months, the increase in ascending aortic dilatation in patients receiving GLP-1 RAs was significantly less than that in the control group (Fig. 1 A). The average changes in the diameter of the ascending aorta were + 0.38 ± 0.23 mm in the GLP-1 RA group and + 1.13 ± 0.31 mm in the control group (P < 0.001). 2 patients (3.5%) of the GLP-1 RA group, and 40 (57.1%) of the control subjects exhibited the enlargement of ≥ 1.0 mm in ascending aorta diameter (Figure 1 B). Importantly, only one patient (1.8%) of the GLP-1 RA group and one patient (1.4%) in the control group surpassed the clinical cut-off of 45 mm. This difference was not statistically significant, reflecting the small number of events. These results highlight that the protective effect of GLP-1 RA treatment on aortic wall remodelling for individuals with T2DM is independent of its beneficial influence on glycemic and blood pressure regulation. Excellent Intraobserver and interobserver reproducibility were found for aortic diameter measurements (intraclass correlation coefficient [ICC] > 0.90); for the latter, the minimal detectable change was established at 0.2 mm, thus attesting the reliability of the anatomical data. Table 2 Cardiometabolic and Vascular Biomarker Changes Over 24 Months in Patients With Type 2 Diabetes Treated With GLP-1 Receptor Agonists vs. Standard Therapy. Parameter GLP-1 RA Group Baseline GLP-1 RA Group 24 mo P (within group) Control Group Baseline Control Group24 mo P (within group) P (between groups at 24 mo) BMI, kg/m² 32.5 ± 3.2 29.6 ± 3.0 < 0.001 28.1 ± 2.9 27.9 ± 3.0 0.22 < 0.001 HbA1c, % 8.4 ± 0.6 7.1 ± 0.5 < 0.001 8.1 ± 0.7 7.2 ± 0.5 < 0.001 0.047 MAP, mmHg 98.4 ± 7.2 91.5 ± 6.7 0.002 99.1 ± 6.9 90.8 ± 6.8 < 0.001 0.78 LDL cholesterol, mg/dL 98.4 ± 13.7 86.1 ± 11.9 < 0.001 96.7 ± 14.1 90.6 ± 12.3 0.012 0.041 Aortic ascending diameter, mm 38.3 ± 2.4 38.7 ± 2.5 < 0.001 38.1 ± 2.2 39.2 ± 2.3 < 0.001 < 0.001 MMP-9, ng/mL 556.2 ± 123.4 421.1 ± 113.2 < 0.001 558.8 ± 124.4 570.2 ± 141.8 0.04 < 0.001 TIMP-1, ng/mL 161.4 ± 33.7 175.5 ± 34.7 0.003 156.7 ± 34.4 160.4 ± 18.2 0.31 0.005 CRP, mg/L 4.1 ± 1.2 2.8 ± 0.7 < 0.001 3.9 ± 1.2 4.2 ± 1.3 0.11 < 0.001 OPG, ng/mL 3.9 ± 0.9 4.9 ± 0.8 0.002 3.7 ± 0.6 3.8 ± 0.6 0.21 0.004 Data are presented as mean ± SD or number (%). P values refer to comparisons within each group (baseline vs. follow-up) and between groups at 24 months. BMI, body mass index; HbA1c, glycated hemoglobin; BP, blood pressure; LDL, low-density lipoprotein cholesterol; eGFR, estimated glomerular filtration rate, MMP-9, matrix metalloproteinase-9; TIMP-1, tissue inhibitor of metalloproteinases-1; CRP, C-reactive protein; OPG, osteoprotegerin. Circulating Biomarker Changes . The differences between baseline and 24 months in the circulating vascular biomarkers are presented in Supplementary Table 1 and represented in Fig. 2 . A marked decrease in MMP-9 levels was observed in patients receiving GLP-1 receptor agonists, which dropped from 556.2 ± 123.4 ng/mL at baseline to 421.1 ± 113.2 ng/mL at the end of the 24 months (P < 0.001). TIMP-1 increased 161.4 ± 33.7 ng/mL to 175.5 ± 34.7 ng/mL (P = 0.003), with CRP decreasing 4.1 ± 1.2 mg/L to 2.8 ± 0.7 mg/L (P < 0.001). An increase of OPG was demonstrated as well, from 3.9 ± 0.9 ng/mL to 4.9 ± 1.0 ng/mL (P = 0.002). Control Did not significantly increase MMP-9 levels over the infusion, from 558.8 ± 124.4 ng/mL to 570.2 ± 141.8 ng/mL (P = 0.04), TIMP-1 were virtually unchanged (156.7 ± 34.4 to 160.4 ± 18.2 ng/mL, P = 0.31). Mean (+ s.d.) CRP increased, but the difference was not significant; from 3.9 ± 1.2 and to 4.2 ± 1.3, mg/L (P = 0.11), and OPG did not change significantly and was at 3.8 ± 0.6, ng/mL in both the periods (P = 0.21). Significantly, between-group comparisons of the 24-month Δ values indicated significant differences for all biomarkers (ΔMMP-9, ΔTIMP-1, ΔCRP, and ΔOPG), corroborating the premise that GLP-1 RA therapy exerts a beneficial modulation on vascular inflammation and ECM remodelling. Furthermore, Table 3 shows that the multivariate linear regression model analysing predictors of change in ascending aortic diameter over 24 months revealed that GLP-1 RA treatment was an independent factor associated with a markedly reduced progression in aortic dilatation (P < 0.001) when controlling for clinical and biochemical covariates. Baseline aortic diameter, along with treatment effect, was an additional significant predictor (P = 0.004) such that the larger the initial aortic diameter, the more likely dilatation would subsequently occur. Greater aortic expansion was also seen in those with more poorly controlled DM (β = +0.081; 95% CI + 0.018 to + 0.144; P = 0.015) at baseline, highlighting the importance of controlling DM in regard to vascular remodelling. Of the circulating biomarkers, increased levels of MMP-9 (P = 0.001) and lower levels of TIMP-1 (P = 0.008) were significantly associated with larger aortic diameter and are suggestive of a matrix degradation profile. In addition, lower OPG (P = 0.043) was independently related to greater progression. The final model explained about 47% of the variation of ascending aortic dilatation (adjusted R²= 0.47), indicating strong predictive ability of both clinical and biochemical factors in the determination of aortic structural abnormalities in patients with T2D. Multivariable logistic regression model Multivariate logistic regression model was built to determine independent predictors for aortic arch diameter progression, defined as 24-month diameter increase ≥1.0 mm. The response variable was dichotomous (1 = progression, 0 = stability or decrease). The ultimate model also adjusted for clinical covariates (age, sex, systolic blood pressure, baseline HbA1c, statin use), changes in circulating biomarkers (ΔMMP-9, ΔTIMP-1, ΔCRP, ΔOPG), and metabolic features (decrease in BMI and in HbA1c during the follow-up). In this model, aortic dilatation progression was independently associated with a significant reduced odds of treatment with GLP-1 receptor agonists (OR 0.69, 95% CI 0.14–0.97, P = 0.010) (Fig. 3 ). An independent protective effect was also noted for MMP-9; OR: 1.002 per unit change (95% CI: 1.000–1.005; P = 0.099). TIMP-1 was also not independently associated with aortic outcomes (OR: 0.999; 95% CI: 0.982; 1.017; P = 0.927). Reductions in BMI and HbA1c during follow-up displayed a tendency towards a higher risk of fracture: with each 1 kg/m² decline in BMI, the OR determined was 1.106 (95% CI: 0.996–1.228; P = 0.060), and for a 0.5% decline in HbA1c it was 1.317 (95% CI: 0.613–2.830; P = 0.480), neither of which was statistically significant. Baseline HbA1c and statin were not significant in the multivariable model. Model calibration and discrimination were confirmed and no multicollinearity was observed among covariates. Table 3 Multivariate Linear Regression – Predictors of Ascending Aorta Progression Variable β Coefficient 95% CI P Value GLP-1 RA therapy (yes vs. no) −0.72 (− 0.94 to − 0.51) < 0.001 Age (years) + 0.010 (− 0.004 to + 0.024) 0.16 Male sex + 0.092 (− 0.074 to + 0.258) 0.27 BMI (kg/m²) + 0.014 (− 0.007 to + 0.035) 0.19 Baseline aortic diameter (mm) + 0.046 (+ 0.017 to + 0.075) 0.004 HbA1c (%) + 0.081 (+ 0.018 to + 0.144) 0.015 Systolic BP (mmHg) + 0.005 (− 0.002 to + 0.013) 0.13 LDL cholesterol (mg/dL) + 0.001 (− 0.004 to + 0.006) 0.72 Statin use (yes vs. no) −0.039 (− 0.185 to + 0.108) 0.60 MMP-9, ng/mL + 0.004 (+ 0.001 to + 0.006) 0.001 TIMP-1, ng/mL −0.006 (− 0.010 to − 0.002) 0.008 CRP, mg/L + 0.020 (− 0.006 to + 0.046) 0.13 OPG, ng/mL −0.028 (− 0.056 to − 0.001) 0.043 Abbreviations: GLP-1 RA = glucagon-like peptide-1 receptor agonist; BMI = body mass index; BP = blood pressure; LDL = low-density lipoprotein; HbA1c = glycated hemoglobin; MMP-9 = matrix metalloproteinase-9; TIMP-1 = tissue inhibitor of metalloproteinases-1; CRP = C-reactive protein; OPG = osteoprotegerin; CI = confidence interval. Sensitivity Analyses. To assess the robustness of our findings, several sensitivity analyses were performed. When considering ascending aortic diameter as a continuous variable, the adjusted mean difference between groups remained statistically significant (β = −0.62 mm; 95% CI − 0.73 to − 0.50; p < 0.001). The effect persisted when applying alternative cut-off thresholds for progression. Using a more sensitive threshold (≥ 0.5 mm increase), progression was observed in 28.1% of the GLP-1 RA group and 71.4% of controls (OR = 0.19; 95% CI 0.09–0.38; p < 0.001). Exclusion of biomarker changes from the multivariate models yielded consistent results (OR = 0.21; 95% CI 0.10–0.44; p < 0.001), reducing the potential for overadjustment bias. Moreover, inverse probability weighting based on a propensity score incorporating demographic and metabolic covariates confirmed the association between GLP-1 RA therapy and reduced aortic dilatation (β=−0.58 mm; 95% CI − 0.70 to − 0.45; p < 0.001). These findings support the robustness of the observed association across different analytic strategies. Cardiac Safety and Efficacy. There were no statistically significant MACE during the moderating follow-up period in the GLP-1 RA group. On the contrary, only four events were recorded in the control group: 2 non-fatal myocardial infarctions, 1 ischemic stroke and a hospitalization for heart failure (5.7 vs 0%; P = 0.045). There were no deaths in either group. GLP-1 RA was well tolerated with mild gastrointestinal side effects (nausea, early satiety) present in 14.0% of patients; discontinuation of therapy was not necessary in any of them. DISCUSSION In this prospective study, we provide the first evidence that GLP-1 RAs treatment is independently associated with a decreased progression of aortic arch dilatation in T2DM. In patients under GLP-1 RA therapy neither structural enlargement of the aortic arch (measured by contrast-enhanced CTA) nor changes of circulating biomarkers related to vascular remodelling and inflammation increased over 24 months. Our most novel finding is to show that GLP-1 RA treatment, known to work effectively for glycemic control and for reducing CVD risk, might produce direct structural advantages on the thoracic aorta. This is in addition to the evidence derived from trials of cardiovascular outcome trials (CVOTs), such as LEADER, SUSTAIN-6 and REWIND, which demonstrated the lower rates of MACE in patients treated with GP-1 RA ( 14 – 16 ). Though these trials have focused on anti-atherosclerotic and merely endothelial-stabilising, our finding might extend to exposure of a stringent endpoint involving aortic wall integrity and structural progression. Crucially, the structural improvements detected in our study were mechanistically associated to a discriminate biomarker profile indicative of anti-inflammatory and anti-remodelling properties. In particular, GLP-1 RA treatment was associated with a reduction in plasma levels of MMP-9 and CRP, and an increase in TIMP-1 and OPG. These molecular alterations are particularly pertinent to the pathogenesis of aortic dilatation. MMP-9 is a matrixin peptidase derived by zinc component that involves in the extracellular matrix proteolysis and is directly linked with aneurysm development and passing away in both the infrarenal and thoracic aortas ( 17 – 19 ). In contrast, TIMP1, a natural MMP inhibitor is known to have a function to stabilize the vessel extracellular matrix ( 20 ). The balance between MMP-9/TIMP-1 is thus considered to be essential for VSMC remodelling during vascular injury. In our multivariate analysis lower MMP-9 and higher levels of TIMP-1 at follow-up were independent predictors of lesser aortic progression supporting the notion that inhibition of matrix degradation is a major pathway for reducing vascular dilatation. Likewise, CRP, a classic acute phase protein and a circulating systemic inflammatory mar ker, was markedly reduced with GLP-1 RA treatment, reinforcing the anti-inflammatory beneficial effect of this therapeutic class. The contribution of chronic low-grade inflammation in the progression of aortic dilatation is gradually being appreciated; indeed CRP levels have been proven to be associated with aortic stiffness, medial degeneration, and elastin fragmentation ( 21 , 22 ). Of interest, the biomarker OPG, part of the TNF receptor superfamily, also raised during GLP-1 RA treatment. While OPG functions in both the pro- and anti- vascular biology process, it also has immune regulatory effects. In this case, higher OPG levels could also represent a compensatory vascular protective mechanism ( 23 , 24 ). (biomarker Measures of plasma levels of GLP-1 RA Here, biomarker findings were in line previous preclinical studies having shown that treatment with a GLP-1 RA apartment of aortic aneurysm in mice, in part through the regulation of MMP scales and by preventing free of NF-κB-driven inflammatory ( 25 , 26 ). However, until now, there has been a lack of human data in this regard. Our work offers new clinical evidence of remodeling of the thoracic aorta according to the use of GLP-1 RA. It contributes to an expanding literature in favor of the vascular effect of this therapeutic category. The consequences of these observations are profound. Aortic arch dilatation is a precursor for potentially catastrophic events, which are aneurysm rupture and dissection. Even incremental changes in diameter, such as the ones found in the control group in the present study (+ 1.13 mm over 2 years), are associated with increased aortic stiffness, left ventricular afterload, and the risk of subsequent heart failure as well in diabetic subjects ( 27 ). Accordingly, treatments which influence aortic remodelling may exert considerable life long cardiovascular benefit. Our findings support that GLP-1 RAs might have a unique potential to provide such protection independently of their effects on glycemia or body weight. Of note, whilst both GLP-1 RA and control groups received beneficial effects on traditional cardiometabolic parameters (HbA1c, blood pressure, LDL cholesterol), only recipients of GLP-1 RA consistently improved on structural/marker-level. This underscores the possibility of direct vasodilatory effects of GLP-1 RAs that is independent of conventional risk factor modification. Indeed, GLP-1 RA use was a strong independent predictor of reduced aortic progression in multivariable regression models adjusting for baseline MRA (Table 3 ), HbA1c, and statin therapy, as well as for blood pressure and LDL cholesterol. Clinically this could have an impact upon future risk stratification and treatment of patients with subclinical aortic dilatation and T2DM. At present, there are no drugs that are specifically recommended for the prevention of formation of thoracic aortic enlargement in diabetic patients. Our data kind of support the idea to consider GLP-1 RAs in this scenario, especially in patients with borderline aortic diameters and raised biomarkers of matrix degradation. Moreover, our study included several sensitivity analyses to address potential biases inherent to the observational design. Specifically, the association between GLP-1 RA therapy and attenuated aortic dilatation remained significant across multiple definitions of progression (≥ 0.5 mm and ≥ 1.0 mm increase), supporting the consistency of the findings. Furthermore, the effect persisted when adjusting for relevant clinical confounders and when excluding changes in circulating biomarkers to reduce the risk of overadjustment bias. Importantly, a propensity score–weighted regression confirmed that GLP-1 RA use remained independently associated with reduced aortic enlargement after accounting for differences in baseline characteristics, including age, BMI, glycemic control, and lipid profile. These additional analyses reinforce the robustness and validity of the observed association, although causality cannot be inferred. Future randomized controlled trials are warranted to further delineate the mechanistic pathways and to determine whether these structural benefits translate into improved cardiovascular outcomes.Nonetheless, several limitations warrant consideration. First, while our sample size and follow-up duration are among the largest to date for imaging-based studies in this area, the cohort remains relatively modest and from a single centre. Second, although we adjusted for multiple confounders, residual bias cannot be excluded in this observational design. Third, our study focused exclusively on thoracic (ascending aorta) dilatation; whether similar benefits would be observed in the abdominal aorta remains unknown. Future research should aim to validate our findings in larger, multi-centre cohorts and assess whether GLP-1 RAs can prevent clinical aortic events, such as aneurysm rupture or need for surgical repair. Serial imaging of both the thoracic and abdominal aorta in response to GLP-1 RA therapy may provide a more comprehensive understanding of vascular remodelling dynamics in diabetes. In addition, mechanistic studies exploring the impact of GLP-1 RAs on endothelial function, vascular smooth muscle cell phenotype, and collagen/elastin architecture may yield important insights to add to current knowledge ( 28 – 30 ). Ultimately, these results highlight the importance of integrating imaging and biomarker strategies in assessing vascular health in diabetes. The simultaneous assessment of structural and molecular changes offers a powerful platform for monitoring disease progression and therapeutic response. Declarations Funding: This study was supported by PRIN 2020 – Prot: 2020LM8WNW, Ministry of University and Research (Italy). Conflict of Interest: The authors declare that they have no competing interests. Author Contributions: Conceptualisation: Celestino Sardu, Raffaele Marfella Methodology: Celestino Sardu, Ferdinando Carlo Sasso, Maria Luisa Balestrieri Investigation: Ludovica Vittoria Marfella, Carlo Fumagalli, Luca Rinaldi, Domenico Cozzolino, Cristiana Sellitto Data Curation: Caterina Carusone, Marianna Abitabile, Luciana Meo, Concetta Aprea Formal Analysis: Andrea Padula, Lorenza Marfella, Nunzia D’Onofrio Writing – Original Draft: Celestino Sardu, Ludovica Vittoria Marfella Writing – Review & Editing: Raffaele Marfella, Maria Luisa Balestrieri Supervision: Raffaele Marfella, Ferdinando Carlo Sasso All authors have read and approved the final version of the manuscript. References Zhou M, Wang X, Li J, et al. Matrix metalloproteinase-9 expression in aortic aneurysms: a meta-analysis. J Vasc Surg. 2014;59(5):1355–63. Newby AC. Metalloproteinase expression in monocytes and macrophages and its relationship to atherosclerotic plaque instability. Arterioscler Thromb Vasc Biol. 2005;25(5):904–13. Nakamura M, Yamamuro A, Nishikawa H, et al. Impact of ascending aortic dilatation on left ventricular afterload and remodeling in patients with hypertension. Hypertens Res. 2012;35(9):915–21. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311–22. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomized placebo-controlled trial. Lancet. 2019;394(10193):121–30. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834–44. Arakawa M, Mita T, Azuma K, et al. Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a GLP-1 receptor agonist, exendin-4. Diabetes. 2010;59(4):1030–7. Liu H, Hu Y, Simpson RW, Dear AE. Glucagon-like peptide-1 attenuates tumor necrosis factor-alpha-mediated induction of plasminogen activator inhibitor-1 expression. J Endocrinol. 2008;196(1):57–65. Tomas E, Habener JF. Insulin-like actions of glucagon-like peptide-1: a dual receptor hypothesis. Trends Endocrinol Metab. 2010;21(2):59–67. Sharma AK, Lu G, Jester JV, et al. Experimental abdominal aortic aneurysm formation is inhibited by exendin-4, a glucagon-like peptide-1 receptor agonist. Arterioscler Thromb Vasc Biol. 2013;33(7):1671–7. Kuzuya M, Satake S, Esaki T, et al. Circulating levels of matrix metalloproteinases and their inhibitors in patients with aortic aneurysm. J Vasc Surg. 2002;36(3):539–44. Wang Y, Aikawa M, Yang Z, et al. Osteoprotegerin promotes intimal plaque stability through inhibition of matrix metalloproteinases and proinflammatory cytokines. Arterioscler Thromb Vasc Biol. 2005;25(12):2604–9. Ridker PM, Rifai N, Rose L, et al. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002;347(20):1557–65. Isselbacher EM, Preventza O, Black JH 3rd, et al. 2022 ACC/AHA Guideline for the Diagnosis and Management of Aortic Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;146(24):e334–482. 10.1161/CIR.0000000000001106 . Goldstein SA, Evangelista A, Abbara S, et al. Multimodality Imaging of Diseases of the Thoracic Aorta in Adults: From the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2015;28(2):119–82. 10.1016/j.echo.2014.11.015 . Liu H, Dear AE, Knudsen LB, Simpson RW. A long-acting glucagon-like peptide-1 analogue attenuates induction of plasminogen activator inhibitor type-1 and vascular adhesion molecules. J Endocrinol. 2009;201(1):59–66. Liu H, Hu Y, Simpson RW, Dear AE. Glucagon-like peptide-1 attenuates tumour necrosis factor-alpha-mediated induction of plasminogen activator inhibitor-1 expression. J Endocrinol. 2008;196(1):57–65. Arakawa M, Mita T, Azuma K, et al. Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a glucagon-like peptide-1 receptor agonist, exendin-4. Diabetes. 2010;59(4):1030–7. Sharma AK, Lu G, Jester JV, et al. Experimental abdominal aortic aneurysm formation is inhibited by exendin-4, a glucagon-like peptide-1 receptor agonist. Arterioscler Thromb Vasc Biol. 2013;33(7):1671–7. Wang Y, Aikawa M, Yang Z, et al. Osteoprotegerin promotes intimal plaque stability through inhibition of matrix metalloproteinases and proinflammatory cytokines. Arterioscler Thromb Vasc Biol. 2005;25(12):2604–9. Ridker PM, Rifai N, Rose L, et al. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002;347(20):1557–65. Nakamura M, Yamamuro A, Nishikawa H, et al. Impact of ascending aortic dilatation on left ventricular afterload and remodeling in patients with hypertension. Hypertens Res. 2012;35(9):915–21. Zhou M, Wang X, Li J, et al. Matrix metalloproteinase-9 expression in aortic aneurysms: a meta-analysis. J Vasc Surg. 2014;59(5):1355–63. Newby AC. Metalloproteinase expression in monocytes and macrophages and its relationship to atherosclerotic plaque instability. Arterioscler Thromb Vasc Biol. 2005;25(5):904–13. Liu H, Dear AE, Knudsen LB, Simpson RW. A long-acting glucagon-like peptide-1 analogue attenuates induction of plasminogen activator inhibitor type-1 and vascular adhesion molecules. J Endocrinol. 2009;201(1):59–66. Liu H, Hu Y, Simpson RW, Dear AE. Glucagon-like peptide-1 attenuates tumour necrosis factor-alpha-mediated induction of plasminogen activator inhibitor-1 expression. J Endocrinol. 2008;196(1):57–65. Arakawa M, Mita T, Azuma K, et al. Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a glucagon-like peptide-1 receptor agonist, exendin-4. Diabetes. 2010;59(4):1030–7. Sharma AK, Lu G, Jester JV, et al. Experimental abdominal aortic aneurysm formation is inhibited by exendin-4, a glucagon-like peptide-1 receptor agonist. Arterioscler Thromb Vasc Biol. 2013;33(7):1671–7. Wang Y, Aikawa M, Yang Z, et al. Osteoprotegerin promotes intimal plaque stability through inhibition of matrix metalloproteinases and proinflammatory cytokines. Arterioscler Thromb Vasc Biol. 2005;25(12):2604–9. Ridker PM, Rifai N, Rose L, et al. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002;347(20):1557–65. Additional Declarations No competing interests reported. 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07:53:33","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7174676/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7174676/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":87694701,"identity":"24dbd3ff-3d40-4f61-af95-4cc271fd94db","added_by":"auto","created_at":"2025-07-28 05:47:46","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1965577,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eChanges and progression of ascending aorta diameter in GLP-1 RA vs control groups.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) Boxplot showing the change (Δ) in ascending aorta diameter from baseline to 24 months in patients treated with GLP-1 receptor agonists (GLP-1 RA) and controls. The GLP-1 RA group showed significantly less progression (P \u0026lt; 0.0001) compared to controls. (B) Bar graph illustrating the proportion of patients with significant ascending aorta progression, defined as: Δ ≥ 1.0 mm over 24 months (left), absolute diameter ≥ 45 mm at follow-up (right). A symbolic bar (0.5%) was used in cases with no observed events to allow visual comparison. GLP-1 RA = Glucagon-like peptide-1 receptor agonist; Δ = Change from baseline; mm = millimeters; P = P-value from independent-samples t test.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-7174676/v1/7f35ed15e3de68703b7f5b5d.png"},{"id":87695609,"identity":"ac750d9d-0415-449c-a4ce-7307f1e09cc1","added_by":"auto","created_at":"2025-07-28 05:55:46","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1826753,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eChanges in circulating biomarkers from baseline to 24 months by treatment group.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(A) \u003c/strong\u003e\u003cem\u003eΔ MMP-9 (P \u0026lt; 0.0001)\u003c/em\u003e: Significant reduction in matrix metalloproteinase-9 (MMP-9) levels in the GLP-1 RA group compared to controls.\u003cstrong\u003e (B) \u003c/strong\u003e\u003cem\u003eΔ TIMP-1 (P = 0.00004)\u003c/em\u003e: Tissue inhibitor of metalloproteinase-1 (TIMP-1) increased in GLP-1 RA, while decreased in controls.\u003cstrong\u003e (C) \u003c/strong\u003e\u003cem\u003eΔ CRP (P \u0026lt; 0.0001)\u003c/em\u003e: High-sensitivity C-reactive protein (CRP) levels markedly reduced with GLP-1 RA therapy.\u003cstrong\u003e (D) \u003c/strong\u003e\u003cem\u003eΔ OPG (P = 0.00001)\u003c/em\u003e: Osteoprotegerin (OPG) increased in GLP-1 RA group, but decreased in controls, indicating a divergent inflammatory profile. GLP-1 RA = Glucagon-like peptide-1 receptor agonist; MMP-9 = Matrix metalloproteinase-9; TIMP-1 = Tissue inhibitor of metalloproteinases-1; CRP = C-reactive protein; OPG = Osteoprotegerin; Δ = Change from baseline; P = P-value from independent-samples t test.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-7174676/v1/5ec49b969bc728470304c01a.png"},{"id":87694704,"identity":"79d738c8-a83a-450f-b34f-1908006cb3d8","added_by":"auto","created_at":"2025-07-28 05:47:46","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1469164,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eIndependent predictors of aortic arch dilatation progression at 24 months.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eForest plot derived from a multivariate logistic regression model identifying independent predictors of aortic arch diameter progression, defined as an increase of ≥1.0 mm over 24 months.\u003c/p\u003e\n\u003cp\u003eCovariates included age, sex, baseline aortic diameter, baseline HbA1c, systolic blood pressure (SBP), statin use, changes in biomarkers (ΔMMP-9, ΔTIMP-1, ΔCRP, ΔOPG), and follow-up changes in BMI and HbA1c, as well as GLP-1 RA use. Odds ratios (ORs) are shown with 95% confidence intervals.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGLP-1 RA therapy was independently associated with a significantly lower risk of progression (OR = 0.57; 95% CI: 0.14–0.97; P = 0.010)\u003c/strong\u003e. Other significant predictors included \u003cstrong\u003eΔ BMI\u003c/strong\u003e and \u003cstrong\u003eΔ MMP-9\u003c/strong\u003e (both with trends toward significance). The red dashed line at OR = 1.0 denotes the null value. GLP-1 RA = Glucagon-like peptide-1 receptor agonist; OR = Odds Ratio; CI = Confidence Interval; BMI = Body Mass Index; SBP = Systolic Blood Pressure; Δ = change from baseline to 24 months; MMP-9 = Matrix Metalloproteinase-9; TIMP-1 = Tissue Inhibitor of Metalloproteinases-1; CRP = C-reactive protein; OPG = Osteoprotegerin.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-7174676/v1/036a783c3a900b5e66c39946.png"},{"id":89763413,"identity":"12a6f65a-5e61-424f-848c-d52180b3569c","added_by":"auto","created_at":"2025-08-24 13:08:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":6218168,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7174676/v1/51e2d8a2-21bf-41cf-8043-90305dca4473.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"GLP-1 Receptor Agonists Are Associated With Reduced Ascending Aorta Dilatation in Patients With Type 2 Diabetes: A Prospective Study","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eAn increase in incidence of cardiovascular complications including both microappmascular and macrovascular diseases has been reported in people with type 2 diabetes mellitus (T2DM). Of these, ascending aortic dilatation has been identified as a clinically important, yet poorly recognised, complication in T2DM patients. The ascending aorta is especially vulnerable to structural biology due to its direct proximity to the left ventricle and exposure to pulsatile hemodynamic forces. This structural remodelling is motivated by a variety of factors such as chronic inflammation, the generation of oxidative stress, and the break down of extracellular matrix (ECM), being frequently mediated by increased levels of matrix metalloprotenases (MMPs), particularly MMP-2 and MMP-9 (1, 2 ). The formation of an ascending aorta does not appear to be overt, but the progressive dilation affected the increased rigidity of arterial system, the systolic hypertension and the left ventricular preload resulting in the aggravation of cardiovascular risk in diabetes (3). Recent developments in treatments for diabetes have shown that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have potential cardiovascular protective benefits in addition to their glycemic benefit. A number of large cardiovascular outcome trials (CVOTs) (4–6) such as LEADER, REWIND, and SUSTAIN-6 have shown reductions in major adverse cardiovascular events (MACE) in GLP-1RAs-exposed patients. Mechanistically, GLP-1 RAs have been demonstrated to avoid inflammation, mitigate oxidative stress and regulate vasculature remodelling enzymes as MMP-9 and tissue inhibitors of metalloproteinases (TIMPs) in preclinical models (7,8). In addition, GLP-1 RAs have been shown to have a possible impact on the formation of aneurysms and on aortic wall degradation, especially in models of abdominal aortic aneurysm (AAA) (9,10). Nevertheless, the effect of GLP-1 RAs on the development of ascending aortic dilatation in individuals suffering from T2DM has not been fully investigated. Advanced imaging modalities like CTA offer accurate aortic dimensional measurements, enabling evaluation of the aortic structural impact of pharmacological interventions. Also, circulating biomarkers of aortic remodelling, including matrix metalloproteinase-9 (MMP-9) tissue inhibitor of metalloproteinase-1 (TIMP-1) C-reactive protein (CRP) and osteoprotegerin (OPG), offer additional information about the biological mechanisms and progression of the disease (11–13). Based on known anti-inflammatory and anti-remodelling effects of GLP-1 RAs, we hypothesize that the treatment with these agents might resist the progression of ascending aortic dilatation in T2DM patients. In the current study, we sought to determine the impact of GLP-1 RA therapy on the structural development of ascending aortic dilatation over a 24-month follow-up through serial CTA imaging and to understand the relationship with changes in circulating vascular remodelling markers. This study might provide new perspectives to the vasoprotective role of GLP-1 RAs, and broaden their therapeutic implication in the prevention of diabetes-associated macrovascular complications.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003eThis was a prospective observational cohort study, performed in the Internal Medicine outpatient units of the University of Campania “Luigi Vanvitelli” (Naples, Italy), and it included the period of patient enrolment from January 2019 until follow-up completed in March 2024. The study was approved by the local ethics committee, and all of the included patients signed their informed consent. The principles of Declaration of Helsinki were followed in the conduct of the study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy\u003c/strong\u003e \u003cstrong\u003ePopulation\u003c/strong\u003e. A total number of 127 consecutive adult patients with type 2 diabetes mellitus (T2DM), 40 to 75 years old, were recruited. All patients had subclinical ascending aortic dilatation, which was defined as an ascending aorta of 35 to 45 mm in diameter when contrast-enhanced computed tomography angiography (CTA) was performed for cardiovascular risk stratification. This dimension is in accordance with early stage dilatation in non-syndromic, high cardiovascular risk adults, which is also supported by the echocardiographic and imaging criteria about mild dilatation (14). Patients who met the following criteria were eligible to participate: diagnosis of T2DM for ≥5 years, an HbA1c of 7.0%–10.0%, and on a stable antihypertensive and lipid-lowering regimen for ≥3 months before study entry. Key exclusion criteria were previous or current GLP-1 receptor agonist use, known aortic aneurysm or dissection, history of CVD events in the last 6 months, severe renal dysfunction (eGFR \u0026lt;45 mL/min/1.73 m²), chronic inflammatory or autoimmune disease, active malignancy, or contraindications to iodinated contrast media. Treatment groups were allocated according to clinical standards at constituting time-point. Fifty-seven patients (who qualified according to guideline for initiation of GLP-1 receptor agonist due to insufficient glycemic control and/or high cardiovascular risk) were treated with GLP-1 RA (liraglutide, semaglutide, or dulaglutide) therapy in combination with baseline treatment. Seventy patients not meeting these criteria for GLP-1 RA guidelines were maintained on their current antidiabetic regimen (metformin, DPP-4 inhibitors, and/or basal insulin) and served as the control arm.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFollow-up and\u003c/strong\u003e\u003cstrong\u003eClinical Evaluation\u003c/strong\u003e. All patients have been followed up for 24 months, and regular 6-month clinical assessment has been established. During each follow-up visit, patients received a thorough cardiovascular evaluation which included physical examination performed directly by cardiologists and a 12-lead ECG, carotid duplex ultrasonography (CDU), and transthoracic echocardiography (TTE), with special interest in measuring the ascending aorta diameter. Metabolic indices (HbA1c, fasting glucose, lipid profile, renal function) and blood pressure were also followed. For all study groups, antidiabetic treatments were titrated according to clinical judgment and actualized guidelines, and GLP-1 RA therapy was maintained without dose reduction except for developments of adverse events. Drug intake compliance was assessed by pill counts and patient diaries. The present follow-up strategy is consistent with the 2022 ACC/AHA guidelines (14), which advise a regular imaging follow-up also for patients with dilatation of the ascending aorta to monitor the progression of the disease and to make treatment decisions.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImaging Protocol.\u003c/strong\u003e All patients had contrast-enhanced CTA of the thoracic aorta at baseline and after the 24-month follow-up. The scans were acquired with a 64-slice multidetector CT scan (LightSpeed VCT; GE Healthcare, Milwaukee, WI, USA) with a standardised protocol developed for assessment of the ascending aorta. Iodinated contrast agent (Iohexol 350 mgI/mL) was administered intravascularly (dose, 1.2 mL/kg; flow rate, 4.0 mL/s) through an antecubital vein, and then 30 mL saline was injected into the arm according to bolus tracking. Bolus tracking was used for the optimal scan delay using a region of interest on the ascending aorta and image acquisition was started with attenuation threshold of 100 HU. Acquisition parameters were as follows: tube voltage 120 kVp, tube current 300–500 mAs (automatic modulation), collimation 0.625 mm, pitch 0.9, rotation time 0.5 s. Reconstructions were performed with a slice thickness of 1 mm and an interval of 0.5 mm collimation with a medium-sharp kernel. Ascending aorta dimensions were measured in the true axial plane at the level of right pulmonary artery perpendicular to the long axis of the vessel. This is in concordance with previously described methods for proper aortic diameter measurements (15). All images were transferred for multiplanar and curved-planar reformats to a workstation (Advantage Workstation 4.7, GE Healthcare). Data were measured by two experienced radiologists without knowledge of the treatment group and clinical condition. Each scan was measured 3 times by each radiologist. The average final value derived from the six values (n=3 per reader) was the final value for each patient and the given period. Intra- and interobserver agreement were determined with the ICC, where values over 0.90 were determined as representing excellent agreement. The D_mdc (in diameter) was 0.2 mm calculated by means of repeated measurements, variance analysis. For outcome modelling, we dichhotomised ascending aortic progression according to CTA measurement. Progression was defined as the occurrence of an ascending aortic diameter dilatation of ≥1.0 mm of the ascending aorta at 24months compared to baseline (coded as 1). Those skulls that ≤1.0 mm increase in diameter (stabilized or decreased in diameter) were considered with no progression (thus, coded as 0). This cut-off threshold was established above the mean measurement uncertainty, so that a progression call represented an actual anatomical change rather than simply a statistical variation. This binary outcome was utilized as the dependent variable in the OR regression model in order to determine clinical and biochemical correlates of progressive AA dilation over time.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBiomarker Analysis.\u003c/strong\u003e All participants provided venous blood samples in the morning after overnight fasting (≥10 hour) at baseline and during the 24-month follow-up. Blood was taken into EDTA tubes and within 30 minutes of collection was centrifuged for 15 minutes at 1,500 × g at 4°C. Plasma was also aliquoted and stored at −80°C until batch analysis. The levels of the following plasma biomarkers were measured using commercially available enzyme-linked immunosorbent assay (ELISA) kits (R\u0026amp;D Systems, Minneapolis, MN, USA):\u0026nbsp;\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eMatrix Metalloproteinase-9 (MMP-9)= \u0026nbsp;Human Quantikine ELISA (sensitivity: 0.156 ng/mL; intra-assay CV \u0026lt;6.2%; inter-assay CV \u0026lt;8.7%)\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eTissue Inhibitor of Metalloproteinases-1 (TIMP-1)= Human Quantikine ELISA Kit (sensitivity: 0.08 ng/ml; intra-assay CV \u0026gt;5.4%; inter-assay CV \u0026gt;7.1%)\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eC-Reactive Protein (CRP)= high sensitive CRP ELISA Kit (sensitivity: 0.1 mg/L; intra-assay CV \u0026lt;4.5%; inter-assay CV \u0026lt;6.3%)\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eOsteoprotegerin (OPG) = Human OPG DuoSet ELISA Kit (sensitivity 0.05 ng/mL, intra-assay CV \u0026lt;6.0%, inter-assay CV \u0026lt;9.0%).\u0026nbsp;\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eEach measurement was done in duplicate. Clinical and imaging data were concealed to laboratory operators. Calibration curves with the recombinants standards were provided by the manufacturer for each analyte and concentrations were determined by 4-parameter logistic curve fit. All specimens with out-of-bound values were required to be re-run after excessive dilution. Baseline and follow-up samples of each participant were analysed in the same batch and run to reduce inter-assay variation. Haemolysed and freeze-thawed degrade samples were not included. QC samples were incorporated in every batch to monitor the inter-batch variation. In the last dataset, we retained only patients with good paired biomarker at both sampling times.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis.\u003c/strong\u003e Baseline characteristics and outcomes of the study were described and summarized using descriptive statistics. Continuous variables were presented as means ± standard deviation (SD) or medians and interquartile ranges (IQR) to the method of distribution based on the Shapiro-Wilk test. Categorical data is described as numbers with percentage frequency. Between-group comparisons were conducted through the independent-samples t test or Mann–Whitney U test for continuous variables and χ² test or Fisher’s exact test for dichotomous variables. Paired t tests or Wilcoxon signed-rank tests were employed to analyze changes from baseline to 2 years in ascending aorta diameter and biomarker concentrations within groups and independent-samples tests were used to analyze changes between groups. The reproducibility of aortic measurements was evaluated by the intraclass correlation coefficient (ICC), and the minimal detectable change (MDC) was obtained according to the formula of repeated measurements. In order to investigate the relationship between clinical variables and ascending aorta dilatation, multivariate linear regression model was first used with the change in diameter of ascending aorta as the dependent variable. The independent variables were age, BMI, sex, baseline ascending aorta diameter, HbA1c, systolic blood pressure, LDL cholesterol, statins and levels at follow-up of MMP-9, TIMP-1, CRP and OPG. Furthermore, a multivariable logistic regression model was developed for the determination of the independent predictors of progression of ascending aorta dilatation, as a binary endpoint: • Progression=1 for participants who had increase of the ascending aorta by 1.0 mm or more at 24 months. • No progression= 0= Stable or decreased diameter (\u0026lt;1.0 mm) in patients with follow-up. The potential covariates for the logistic regression model included age, sex, baseline diameter of AA, HbA1c, systolic blood pressure, statin use, and\u0026nbsp;Δ\u0026nbsp;of biomarkers (MMP-9, TIMP-1, CRP, OPG), changes in BMI and HbA1c from baseline to follow-up. The findings are presented as odd ratios (ORs) with 95% confidence intervals (CIs) and related P value. Model calibration and discrimination were by evaluated the standard diagnostics, and multicollinearity was eliminated. To evaluate the robustness of the primary findings, multiple sensitivity analyses were conducted. First, the effect of GLP-1 RA therapy on ascending aortic diameter progression was re-examined using alternative thresholds for defining progression (≥0.5 mm and ≥1.0 mm increase). Second,\u0026nbsp;a\u0026nbsp;sensitivity analysis was performed by excluding patients in the upper tertile of baseline aortic diameter (\u0026gt;43 mm), and by stratifying the regression models according to baseline HbA1c (above vs. below median), BMI tertiles, and sex. Interaction terms between treatment group and each covariate were included to assess effect modification. Collinearity was checked using variance inflation factors (VIF), and model fit was evaluated using adjusted R² and residual analysis. Third,\u0026nbsp;multivariate logistic regression models were repeated excluding changes in circulating biomarkers to mitigate potential overadjustment bias. All test were two-sided, and a value of P \u0026lt; 0.05 was considered significant. Statistical analyses were conducted in IBM SPSS Statistics (version 28.0; IBM Corp., Armonk, NY) and R (version 4.2.1; R Foundation for Statistical Computing, Vienna, Austria).\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cb\u003eBaseline Characteristics.\u003c/b\u003e The baseline demographic and clinical characteristics of the study participants (N\u0026thinsp;=\u0026thinsp;127)\u0026ensp;are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Of those, 57 newly\u0026ensp;GLP-1 RA-treated (guidelines-based regimen: suboptimal glycemic control and/or overweight/obese) patients were enrolled. The other 70 patients, who did not meet the above criteria, were treated with\u0026ensp;conventional antidiabetic therapy and defined as the control group. There were\u0026ensp;more males in the general population (63.0%), and the mean age was 63.8\u0026thinsp;\u0026plusmn;\u0026thinsp;6.9 years, and the mean history of diabetes was 9.9\u0026thinsp;\u0026plusmn;\u0026thinsp;3.0 years. Not surprisingly, the\u0026ensp;GLP-1 RA group had a higher mean BMI at baseline than the control group in line with the indication for therapy. Mean HbA1c was also marginally higher in the\u0026ensp;GLP-1 RA group compared to controls (P\u0026thinsp;=\u0026thinsp;0.03). Other cardiometabolic characteristics were well balanced\u0026ensp;between groups. Baseline ascending aortic diameter on\u0026ensp;contrast-enhanced CTA did not differ at a significant level between groups (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003e\u0026ndash; Baseline Demographic, Clinical, and Therapeutic Characteristics of the Study Population\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGLP-1 RA Group (n\u0026thinsp;=\u0026thinsp;57)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eControl Group (n\u0026thinsp;=\u0026thinsp;70)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP Value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge, years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e63.4\u0026thinsp;\u0026plusmn;\u0026thinsp;6.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e64.1\u0026thinsp;\u0026plusmn;\u0026thinsp;7.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.48\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale sex, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e36 (63.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e44 (62.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.97\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBMI, kg/m\u0026sup2;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e32.5\u0026thinsp;\u0026plusmn;\u0026thinsp;3.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e28.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDuration of diabetes, years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.57\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHbA1c, %\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8.4\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.03\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSystolic blood pressure, mmHg\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e134\u0026thinsp;\u0026plusmn;\u0026thinsp;11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e136\u0026thinsp;\u0026plusmn;\u0026thinsp;12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.38\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean arterial pressure, mmHg\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e98.4\u0026thinsp;\u0026plusmn;\u0026thinsp;7.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e99.1\u0026thinsp;\u0026plusmn;\u0026thinsp;6.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.61\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLDL cholesterol, mg/dL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e98.4\u0026thinsp;\u0026plusmn;\u0026thinsp;13.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e96.7\u0026thinsp;\u0026plusmn;\u0026thinsp;14.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.47\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eeGFR, mL/min/1.73 m\u0026sup2;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e84.6\u0026thinsp;\u0026plusmn;\u0026thinsp;12.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e86.1\u0026thinsp;\u0026plusmn;\u0026thinsp;11.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.37\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eeGFR\u0026thinsp;\u0026ge;\u0026thinsp;90, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e20 (35.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e27 (38.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.71\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eeGFR 60\u0026ndash;89, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e34 (59.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e39 (55.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.68\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eeGFR\u0026thinsp;\u0026lt;\u0026thinsp;60, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (5.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (5.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.92\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHypertension, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e43 (75.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e52 (74.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.88\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDyslipidemia, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e40 (70.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e51 (72.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.72\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHistory of cardiovascular disease, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11 (19.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13 (18.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.92\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStatin use, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e43 (76.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e55 (78.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.73\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eACEi/ARB use, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e38 (66.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e49 (70.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.69\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBeta-blocker use, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e19 (33.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e25 (35.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.78\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAntiplatelet therapy, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e21 (36.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e26 (37.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.97\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMetformin use, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e51 (89.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e65 (92.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.52\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSGLT2i use, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e17 (29.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14 (20.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.21\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInsulin use, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13 (22.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15 (21.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.85\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAortic arch diameter, mm\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e38.3\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e38.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.48\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eBaseline characteristics of patients receiving GLP-1 receptor agonists (GLP-1 RA group) versus those on standard antidiabetic therapy (control group). Data are reported as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or n (%). Differences in BMI and HbA1c reflect guideline-based eligibility for GLP-1 RA initiation. No other significant differences were observed between groups. GLP-1 RA, glucagon-like peptide-1 receptor agonist; BMI, body mass index; HbA1c, glycated hemoglobin; MAP, mean arterial pressure; LDL, low-density lipoprotein; eGFR, estimated glomerular filtration rate; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; SGLT2i, sodium-glucose co-transporter-2 inhibitor.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eFollow-Up Clinical Monitoring and Cardiometabolic\u0026ensp;Evolution\u003c/b\u003e. All subjects completed the intended 24 months\u0026ensp;of follow-up by in-person visit at 6-monthly intervals. These assessments included: physical examination, a review of therapy, ECG, carotid Doppler\u0026ensp;ultrasound (TSA) and transthoracic echocardiography (TTE). Both groups showed high treatment adherence, over 90%\u0026ensp;in each group were continuing with the treatment at the end of the study. As presented\u0026ensp;in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, significant changes in major cardiometabolic outcomes were found in the GLP-1 RA group across time periods. In patients on GLP-1 RA a mean BMI decrease\u0026ensp;from 32.5\u0026thinsp;\u0026plusmn;\u0026thinsp;3.2 to 29.6\u0026thinsp;\u0026plusmn;\u0026thinsp;3.0 kg/m\u0026sup2; was noted (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), i.e. an approximately 8% weight loss over 24 months. In\u0026ensp;comparison BMI in the control group showed no significant change (P\u0026thinsp;=\u0026thinsp;0.22). Mean HbA1c decreased\u0026ensp;in both groups). The MAP decreased in the GLP-1 RA group (P\u0026thinsp;=\u0026thinsp;0.002) but\u0026ensp;not significantly more than in the control group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). A significant reduction in LDL\u0026ensp;cholesterol concentration in both groups was observed. Dilation\u0026ensp;of Ascending Aorta at 24 Months At 24 months, the increase in ascending aortic dilatation in\u0026ensp;patients receiving GLP-1 RAs was significantly less than that in the control group (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). The average\u0026ensp;changes in the diameter of the ascending aorta were +\u0026thinsp;0.38\u0026thinsp;\u0026plusmn;\u0026thinsp;0.23 mm in the GLP-1 RA group and +\u0026thinsp;1.13\u0026thinsp;\u0026plusmn;\u0026thinsp;0.31 mm in the control group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). 2 patients (3.5%) of the GLP-1 RA group, and 40 (57.1%) of the control subjects exhibited the enlargement of \u0026ge;\u0026thinsp;1.0 mm in ascending aorta diameter (Figure\u0026ensp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). Importantly, only one patient (1.8%) of the GLP-1 RA\u0026ensp;group and one patient (1.4%) in the control group surpassed the clinical cut-off of 45 mm. This difference was not statistically significant,\u0026ensp;reflecting the small number of events. These results highlight that the protective effect of GLP-1 RA treatment on aortic wall remodelling for individuals\u0026ensp;with T2DM is independent of its beneficial influence on glycemic and blood pressure regulation. Excellent Intraobserver and interobserver reproducibility were found for aortic\u0026ensp;diameter measurements (intraclass correlation coefficient [ICC]\u0026thinsp;\u0026gt;\u0026thinsp;0.90); for the latter, the minimal detectable change was established at 0.2 mm, thus attesting the reliability of the anatomical data.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003e\u003cb\u003eCardiometabolic and Vascular Biomarker Changes Over 24 Months in Patients With Type 2 Diabetes Treated With GLP-1 Receptor Agonists vs. Standard\u003c/b\u003e Therapy.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"8\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eParameter\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGLP-1 RA Group Baseline\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eGLP-1 RA Group 24 mo\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP (within group)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eControl Group Baseline\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eControl Group24 mo\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eP (within group)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eP (between groups at 24 mo)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBMI, kg/m\u0026sup2;\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e32.5\u0026thinsp;\u0026plusmn;\u0026thinsp;3.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e29.6\u0026thinsp;\u0026plusmn;\u0026thinsp;3.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e\u003cp\u003e28.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e\u003cp\u003e27.9\u0026thinsp;\u0026plusmn;\u0026thinsp;3.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHbA1c, %\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e8.4\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e7.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e\u003cp\u003e8.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e\u003cp\u003e7.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.047\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMAP, mmHg\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e98.4\u0026thinsp;\u0026plusmn;\u0026thinsp;7.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e91.5\u0026thinsp;\u0026plusmn;\u0026thinsp;6.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.002\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e\u003cp\u003e99.1\u0026thinsp;\u0026plusmn;\u0026thinsp;6.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e\u003cp\u003e90.8\u0026thinsp;\u0026plusmn;\u0026thinsp;6.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.78\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLDL cholesterol, mg/dL\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e98.4\u0026thinsp;\u0026plusmn;\u0026thinsp;13.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e86.1\u0026thinsp;\u0026plusmn;\u0026thinsp;11.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e\u003cp\u003e96.7\u0026thinsp;\u0026plusmn;\u0026thinsp;14.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e\u003cp\u003e90.6\u0026thinsp;\u0026plusmn;\u0026thinsp;12.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.012\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.041\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAortic ascending diameter, mm\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e38.3\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e38.7\u0026thinsp;\u0026plusmn;\u0026thinsp;2.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e\u003cp\u003e38.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e\u003cp\u003e39.2\u0026thinsp;\u0026plusmn;\u0026thinsp;2.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMMP-9, ng/mL\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e556.2\u0026thinsp;\u0026plusmn;\u0026thinsp;123.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e421.1\u0026thinsp;\u0026plusmn;\u0026thinsp;113.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e\u003cp\u003e558.8\u0026thinsp;\u0026plusmn;\u0026thinsp;124.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e\u003cp\u003e570.2\u0026thinsp;\u0026plusmn;\u0026thinsp;141.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTIMP-1, ng/mL\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e161.4\u0026thinsp;\u0026plusmn;\u0026thinsp;33.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e175.5\u0026thinsp;\u0026plusmn;\u0026thinsp;34.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.003\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e\u003cp\u003e156.7\u0026thinsp;\u0026plusmn;\u0026thinsp;34.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e\u003cp\u003e160.4\u0026thinsp;\u0026plusmn;\u0026thinsp;18.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.005\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCRP, mg/L\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e4.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e2.8\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e\u003cp\u003e3.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e\u003cp\u003e4.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eOPG, ng/mL\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e3.9\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e4.9\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.002\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e\u003cp\u003e3.7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e\u003cp\u003e3.8\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.004\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"8\"\u003eData are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or number (%). \u003cem\u003eP\u003c/em\u003e values refer to comparisons within each group (baseline vs. follow-up) and between groups at 24 months. BMI, body mass index; HbA1c, glycated hemoglobin; BP, blood pressure; LDL, low-density lipoprotein cholesterol; eGFR, estimated glomerular filtration rate, MMP-9, matrix metalloproteinase-9; TIMP-1, tissue inhibitor of metalloproteinases-1; CRP, C-reactive protein; OPG, osteoprotegerin.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eCirculating Biomarker Changes\u003c/b\u003e. The differences between baseline and 24 months in the circulating vascular biomarkers are presented in Supplementary Table\u0026nbsp;1 and\u0026ensp;represented in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. A marked decrease in MMP-9 levels was observed in patients receiving GLP-1 receptor agonists, which dropped from 556.2\u0026thinsp;\u0026plusmn;\u0026thinsp;123.4 ng/mL at baseline to\u0026ensp;421.1\u0026thinsp;\u0026plusmn;\u0026thinsp;113.2 ng/mL at the end of the 24 months (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). TIMP-1 increased 161.4\u0026thinsp;\u0026plusmn;\u0026thinsp;33.7 ng/mL to 175.5\u0026thinsp;\u0026plusmn;\u0026thinsp;34.7\u0026ensp;ng/mL (P\u0026thinsp;=\u0026thinsp;0.003), with CRP decreasing 4.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2 mg/L to 2.8\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7 mg/L (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). An increase of OPG was demonstrated as well, from 3.9\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9 ng/mL to\u0026ensp;4.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0 ng/mL (P\u0026thinsp;=\u0026thinsp;0.002). Control Did not significantly increase MMP-9\u0026ensp;levels over the infusion, from 558.8\u0026thinsp;\u0026plusmn;\u0026thinsp;124.4 ng/mL to 570.2\u0026thinsp;\u0026plusmn;\u0026thinsp;141.8 ng/mL (P\u0026thinsp;=\u0026thinsp;0.04), TIMP-1 were virtually unchanged (156.7\u0026thinsp;\u0026plusmn;\u0026thinsp;34.4 to 160.4\u0026thinsp;\u0026plusmn;\u0026thinsp;18.2 ng/mL, P\u0026thinsp;=\u0026thinsp;0.31). Mean (+\u0026thinsp;s.d.) CRP increased, but the difference was not significant; from 3.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2 and to 4.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3, mg/L (P\u0026thinsp;=\u0026thinsp;0.11), and OPG did not change significantly and was at 3.8\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6, ng/mL in both\u0026ensp;the periods (P\u0026thinsp;=\u0026thinsp;0.21). Significantly, between-group comparisons of the 24-month Δ values indicated significant differences for all biomarkers (ΔMMP-9, ΔTIMP-1, ΔCRP, and ΔOPG), corroborating the premise that GLP-1 RA therapy\u0026ensp;exerts a beneficial modulation on vascular inflammation and ECM remodelling. Furthermore, Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows that the multivariate linear regression model analysing predictors of change in ascending aortic diameter over 24 months revealed\u0026ensp;that GLP-1 RA treatment was an independent factor associated with a markedly reduced progression in aortic dilatation (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) when controlling for clinical and biochemical covariates. Baseline aortic diameter, along with treatment effect, was an additional significant predictor (P\u0026thinsp;=\u0026thinsp;0.004) such that the larger the initial aortic diameter, the more likely dilatation would subsequently\u0026ensp;occur. Greater aortic expansion was also seen in those with more poorly controlled DM (β = +0.081; 95% CI\u0026thinsp;+\u0026thinsp;0.018 to +\u0026thinsp;0.144; P\u0026thinsp;=\u0026thinsp;0.015) at baseline, highlighting the importance of controlling DM in regard to\u0026ensp;vascular remodelling. Of the circulating biomarkers, increased levels of MMP-9 (P\u0026thinsp;=\u0026thinsp;0.001) and lower levels of TIMP-1\u0026ensp;(P\u0026thinsp;=\u0026thinsp;0.008) were significantly associated with larger aortic diameter and are suggestive of a matrix degradation profile. In addition, lower\u0026ensp;OPG (P\u0026thinsp;=\u0026thinsp;0.043) was independently related to greater progression. The final model explained about 47% of the variation of ascending aortic dilatation (adjusted R\u0026sup2;= 0.47), indicating strong predictive ability of both clinical and biochemical factors in the determination of aortic structural abnormalities in patients with\u0026ensp;T2D. Multivariable logistic regression\u0026ensp;model Multivariate logistic regression model was built to determine independent predictors for aortic arch diameter progression, defined as 24-month diameter increase\u0026ensp;\u0026ge;1.0 mm. The\u0026ensp;response variable was dichotomous (1\u0026thinsp;=\u0026thinsp;progression, 0\u0026thinsp;=\u0026thinsp;stability or decrease). The ultimate model also adjusted for clinical covariates (age, sex, systolic blood pressure, baseline HbA1c, statin use), changes in circulating biomarkers (ΔMMP-9, ΔTIMP-1,\u0026ensp;ΔCRP, ΔOPG), and metabolic features (decrease in BMI and in HbA1c during the follow-up). In this model, aortic dilatation progression was independently associated with a significant reduced odds of treatment with GLP-1 receptor agonists (OR\u0026ensp;0.69, 95% CI 0.14\u0026ndash;0.97, P\u0026thinsp;=\u0026thinsp;0.010) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). An independent protective effect was also\u0026ensp;noted for MMP-9; OR: 1.002 per unit change (95% CI: 1.000\u0026ndash;1.005; P\u0026thinsp;=\u0026thinsp;0.099). TIMP-1 was also\u0026ensp;not independently associated with aortic outcomes (OR: 0.999; 95% CI: 0.982; 1.017; P\u0026thinsp;=\u0026thinsp;0.927). Reductions in BMI and HbA1c during follow-up displayed a tendency towards a higher risk of fracture: with each 1 kg/m\u0026sup2; decline in BMI, the OR determined was 1.106 (95% CI: 0.996\u0026ndash;1.228; P\u0026thinsp;=\u0026thinsp;0.060), and for a 0.5%\u0026ensp;decline in HbA1c it was 1.317 (95% CI: 0.613\u0026ndash;2.830; P\u0026thinsp;=\u0026thinsp;0.480), neither of which was statistically significant. Baseline HbA1c and statin were not significant in the\u0026ensp;multivariable model. Model calibration and\u0026ensp;discrimination were confirmed and no multicollinearity was observed among covariates.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eMultivariate Linear Regression \u0026ndash; Predictors of Ascending Aorta Progression\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eβ Coefficient\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e95% CI\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP Value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGLP-1 RA therapy (yes vs. no)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u0026minus;0.72\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(\u0026minus;\u0026thinsp;0.94 to \u0026minus;\u0026thinsp;0.51)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge (years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e+\u0026thinsp;0.010\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(\u0026minus;\u0026thinsp;0.004 to +\u0026thinsp;0.024)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.16\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale sex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e+\u0026thinsp;0.092\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(\u0026minus;\u0026thinsp;0.074 to +\u0026thinsp;0.258)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.27\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBMI (kg/m\u0026sup2;)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e+\u0026thinsp;0.014\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(\u0026minus;\u0026thinsp;0.007 to +\u0026thinsp;0.035)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.19\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBaseline aortic diameter (mm)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e+\u0026thinsp;0.046\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(+\u0026thinsp;0.017 to +\u0026thinsp;0.075)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.004\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHbA1c (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e+\u0026thinsp;0.081\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(+\u0026thinsp;0.018 to +\u0026thinsp;0.144)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.015\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSystolic BP (mmHg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e+\u0026thinsp;0.005\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(\u0026minus;\u0026thinsp;0.002 to +\u0026thinsp;0.013)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.13\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLDL cholesterol (mg/dL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e+\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(\u0026minus;\u0026thinsp;0.004 to +\u0026thinsp;0.006)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.72\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStatin use (yes vs. no)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u0026minus;0.039\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(\u0026minus;\u0026thinsp;0.185 to +\u0026thinsp;0.108)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.60\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMMP-9, ng/mL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e+\u0026thinsp;0.004\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(+\u0026thinsp;0.001 to +\u0026thinsp;0.006)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTIMP-1, ng/mL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u0026minus;0.006\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(\u0026minus;\u0026thinsp;0.010 to \u0026minus;\u0026thinsp;0.002)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.008\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCRP, mg/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e+\u0026thinsp;0.020\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(\u0026minus;\u0026thinsp;0.006 to +\u0026thinsp;0.046)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.13\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOPG, ng/mL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e\u0026minus;0.028\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(\u0026minus;\u0026thinsp;0.056 to \u0026minus;\u0026thinsp;0.001)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.043\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003cem\u003eAbbreviations: GLP-1 RA\u0026thinsp;=\u0026thinsp;glucagon-like peptide-1 receptor agonist; BMI\u0026thinsp;=\u0026thinsp;body mass index; BP\u0026thinsp;=\u0026thinsp;blood pressure; LDL\u0026thinsp;=\u0026thinsp;low-density lipoprotein; HbA1c\u0026thinsp;=\u0026thinsp;glycated hemoglobin; MMP-9\u0026thinsp;=\u0026thinsp;matrix metalloproteinase-9; TIMP-1\u0026thinsp;=\u0026thinsp;tissue inhibitor of metalloproteinases-1; CRP\u0026thinsp;=\u0026thinsp;C-reactive protein; OPG\u0026thinsp;=\u0026thinsp;osteoprotegerin; CI\u0026thinsp;=\u0026thinsp;confidence interval.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eSensitivity Analyses.\u003c/b\u003e To assess the robustness of our findings, several sensitivity analyses were performed. When considering ascending aortic diameter as a continuous variable, the adjusted mean difference between groups remained statistically significant (β = \u0026minus;0.62 mm; 95% CI \u0026minus;\u0026thinsp;0.73 to \u0026minus;\u0026thinsp;0.50; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The effect persisted when applying alternative cut-off thresholds for progression. Using a more sensitive threshold (\u0026ge;\u0026thinsp;0.5 mm increase), progression was observed in 28.1% of the GLP-1 RA group and 71.4% of controls (OR\u0026thinsp;=\u0026thinsp;0.19; 95% CI 0.09\u0026ndash;0.38; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Exclusion of biomarker changes from the multivariate models yielded consistent results (OR\u0026thinsp;=\u0026thinsp;0.21; 95% CI 0.10\u0026ndash;0.44; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), reducing the potential for overadjustment bias. Moreover, inverse probability weighting based on a propensity score incorporating demographic and metabolic covariates confirmed the association between GLP-1 RA therapy and reduced aortic dilatation (β=\u0026minus;0.58 mm; 95% CI \u0026minus;\u0026thinsp;0.70 to \u0026minus;\u0026thinsp;0.45; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). These findings support the robustness of the observed association across different analytic strategies.\u003c/p\u003e\u003cp\u003e\u003cb\u003eCardiac\u0026ensp;Safety and Efficacy.\u003c/b\u003e There were no statistically significant MACE during the moderating follow-up period\u0026ensp;in the GLP-1 RA group. On the contrary, only four events were recorded in the\u0026ensp;control group: 2 non-fatal myocardial infarctions, 1 ischemic stroke and a hospitalization for heart failure (5.7 vs 0%; P\u0026thinsp;=\u0026thinsp;0.045). There were no deaths in\u0026ensp;either group. GLP-1 RA was well tolerated with mild gastrointestinal side effects (nausea, early satiety) present\u0026ensp;in 14.0% of patients; discontinuation of therapy was not necessary in any of them.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this prospective study, we provide the first evidence that GLP-1 RAs treatment is independently associated with a decreased progression of aortic arch dilatation\u0026ensp;in T2DM. In patients\u0026ensp;under GLP-1 RA therapy neither structural enlargement of the aortic arch (measured by contrast-enhanced CTA) nor changes of circulating biomarkers related to vascular remodelling and inflammation increased over 24 months. Our most novel finding is to show that GLP-1 RA treatment, known to work effectively for glycemic\u0026ensp;control and for reducing CVD risk, might produce direct structural advantages on the thoracic aorta. This is in addition to the evidence derived from trials of cardiovascular outcome trials (CVOTs), such as LEADER, SUSTAIN-6 and\u0026ensp;REWIND, which demonstrated the lower rates of MACE in patients treated with GP-1 RA (\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Though these trials have focused on anti-atherosclerotic and merely endothelial-stabilising, our finding might extend to exposure\u0026ensp;of a stringent endpoint involving aortic wall integrity and structural progression. Crucially, the structural improvements detected in our study were mechanistically associated to a discriminate biomarker profile indicative of anti-inflammatory and\u0026ensp;anti-remodelling properties. In particular, GLP-1 RA treatment was associated with a reduction in plasma levels of MMP-9 and CRP, and an increase\u0026ensp;in TIMP-1 and OPG. These molecular alterations are particularly pertinent to the\u0026ensp;pathogenesis of aortic dilatation. MMP-9 is a matrixin peptidase derived\u0026ensp;by zinc component that involves in the extracellular matrix proteolysis and is directly linked with aneurysm development and passing away in both the infrarenal and thoracic aortas (\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). In contrast, TIMP1, a natural MMP\u0026ensp;inhibitor is known to have a function to stabilize the vessel extracellular matrix (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). The balance between MMP-9/TIMP-1 is\u0026ensp;thus considered to be essential for VSMC remodelling during vascular injury. In our multivariate analysis lower MMP-9 and\u0026ensp;higher levels of TIMP-1 at follow-up were independent predictors of lesser aortic progression supporting the notion that inhibition of matrix degradation is a major pathway for reducing vascular dilatation. Likewise, CRP, a classic acute phase protein and a circulating systemic inflammatory \u0026ensp;mar ker, was markedly reduced with GLP-1 RA treatment, reinforcing the anti-inflammatory beneficial effect of this therapeutic class. The contribution of chronic low-grade inflammation in the progression of aortic dilatation is\u0026ensp;gradually being appreciated; indeed CRP levels have been proven to be associated with aortic stiffness, medial degeneration, and elastin fragmentation (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Of interest, the biomarker OPG, part of the TNF receptor superfamily, also raised during GLP-1 RA\u0026ensp;treatment. While OPG functions in both the pro- and anti- vascular\u0026ensp;biology process, it also has immune regulatory effects. In this case,\u0026ensp;higher OPG levels could also represent a compensatory vascular protective mechanism (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). (biomarker Measures\u0026ensp;of plasma levels of GLP-1 RA Here, biomarker findings were in line previous preclinical studies having shown that treatment with a GLP-1 RA apartment of aortic aneurysm in mice, in part through the regulation of MMP scales and by preventing free of NF-κB-driven inflammatory (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). However, until\u0026ensp;now, there has been a lack of human data in this regard. Our work offers new clinical evidence of remodeling of the thoracic aorta according to the use of\u0026ensp;GLP-1 RA. It contributes to an expanding literature in\u0026ensp;favor of the vascular effect of this therapeutic category. The consequences of these observations are\u0026ensp;profound. Aortic arch dilatation is a precursor for potentially catastrophic events, which are aneurysm\u0026ensp;rupture and dissection. Even incremental changes in diameter, such as the ones found in the control group in the present\u0026ensp;study (+\u0026thinsp;1.13 mm over 2 years), are associated with increased aortic stiffness, left ventricular afterload, and the risk of subsequent heart failure as well in diabetic subjects (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). Accordingly, treatments which influence aortic remodelling may exert\u0026ensp;considerable life long cardiovascular benefit. Our findings support that GLP-1 RAs might have a unique potential to provide such protection independently of their effects on glycemia or body\u0026ensp;weight. Of note, whilst both GLP-1 RA and control groups received\u0026ensp;beneficial effects on traditional cardiometabolic parameters (HbA1c, blood pressure, LDL cholesterol), only recipients of GLP-1 RA consistently improved on structural/marker-level. This underscores the possibility of direct vasodilatory\u0026ensp; effects of GLP-1 RAs that is independent of conventional risk factor modification. Indeed, GLP-1 RA use was a strong independent predictor of reduced aortic progression in multivariable regression models adjusting for baseline MRA (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e), HbA1c, and statin therapy,\u0026ensp;as well as for blood pressure and LDL cholesterol. Clinically this could have an impact upon future risk stratification and treatment of patients with subclinical aortic\u0026ensp;dilatation and T2DM. At present, there are no drugs that are\u0026ensp;specifically recommended for the prevention of formation of thoracic aortic enlargement in diabetic patients. Our data kind of support the idea to consider GLP-1 RAs\u0026ensp;in this scenario, especially in patients with borderline aortic diameters and raised biomarkers of matrix degradation. Moreover, our study included several sensitivity analyses to address potential biases inherent to the observational design. Specifically, the association between GLP-1 RA therapy and attenuated aortic dilatation remained significant across multiple definitions of progression (\u0026ge;\u0026thinsp;0.5 mm and \u0026ge;\u0026thinsp;1.0 mm increase), supporting the consistency of the findings. Furthermore, the effect persisted when adjusting for relevant clinical confounders and when excluding changes in circulating biomarkers to reduce the risk of overadjustment bias. Importantly, a propensity score\u0026ndash;weighted regression confirmed that GLP-1 RA use remained independently associated with reduced aortic enlargement after accounting for differences in baseline characteristics, including age, BMI, glycemic control, and lipid profile. These additional analyses reinforce the robustness and validity of the observed association, although causality cannot be inferred. Future randomized controlled trials are warranted to further delineate the mechanistic pathways and to determine whether these structural benefits translate into improved cardiovascular outcomes.Nonetheless, several limitations warrant consideration. First, while our sample size and follow-up duration are among the largest to date for imaging-based studies in this area, the cohort remains relatively modest and from a single centre. Second, although we adjusted for multiple confounders, residual bias cannot be excluded in this observational design. Third, our study focused exclusively on thoracic (ascending aorta) dilatation; whether similar benefits would be observed in the abdominal aorta remains unknown. Future research should aim to validate our findings in larger, multi-centre cohorts and assess whether GLP-1 RAs can prevent clinical aortic events, such as aneurysm rupture or need for surgical repair. Serial imaging of both the thoracic and abdominal aorta in response to GLP-1 RA therapy may provide a more comprehensive understanding of vascular remodelling dynamics in diabetes. In addition, mechanistic studies exploring the impact of GLP-1 RAs on endothelial function, vascular smooth muscle cell phenotype, and collagen/elastin architecture may yield important insights to add to current knowledge (\u003cspan additionalcitationids=\"CR29\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Ultimately, these results highlight the importance of integrating imaging and biomarker strategies in assessing vascular health in diabetes. The simultaneous assessment of structural and molecular changes offers a powerful platform for monitoring disease progression and therapeutic response.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;This study was supported by PRIN 2020 – Prot: 2020LM8WNW, Ministry of University and Research (Italy).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest:\u003cbr\u003e\u003c/strong\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;Conceptualisation: Celestino Sardu, Raffaele Marfella\u003cbr\u003e\u0026nbsp;Methodology: Celestino Sardu, Ferdinando Carlo Sasso, Maria Luisa Balestrieri\u003cbr\u003e\u0026nbsp;Investigation: Ludovica Vittoria Marfella, Carlo Fumagalli, Luca Rinaldi, Domenico Cozzolino, Cristiana Sellitto\u003cbr\u003e\u0026nbsp;Data Curation: Caterina Carusone, Marianna Abitabile, Luciana Meo, Concetta Aprea\u003cbr\u003e\u0026nbsp;Formal Analysis: Andrea Padula, Lorenza Marfella, Nunzia D’Onofrio\u003cbr\u003e\u0026nbsp;Writing – Original Draft: Celestino Sardu, Ludovica Vittoria Marfella\u003cbr\u003e\u0026nbsp;Writing – Review \u0026amp; Editing: Raffaele Marfella, Maria Luisa Balestrieri\u003cbr\u003e\u0026nbsp;Supervision: Raffaele Marfella, Ferdinando Carlo Sasso\u003cbr\u003e\u0026nbsp;All authors have read and approved the final version of the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eZhou M, Wang X, Li J, et al. 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A long-acting glucagon-like peptide-1 analogue attenuates induction of plasminogen activator inhibitor type-1 and vascular adhesion molecules. J Endocrinol. 2009;201(1):59\u0026ndash;66.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLiu H, Hu Y, Simpson RW, Dear AE. Glucagon-like peptide-1 attenuates tumour necrosis factor-alpha-mediated induction of plasminogen activator inhibitor-1 expression. J Endocrinol. 2008;196(1):57\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eArakawa M, Mita T, Azuma K, et al. Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a glucagon-like peptide-1 receptor agonist, exendin-4. Diabetes. 2010;59(4):1030\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSharma AK, Lu G, Jester JV, et al. Experimental abdominal aortic aneurysm formation is inhibited by exendin-4, a glucagon-like peptide-1 receptor agonist. Arterioscler Thromb Vasc Biol. 2013;33(7):1671\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWang Y, Aikawa M, Yang Z, et al. Osteoprotegerin promotes intimal plaque stability through inhibition of matrix metalloproteinases and proinflammatory cytokines. Arterioscler Thromb Vasc Biol. 2005;25(12):2604\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRidker PM, Rifai N, Rose L, et al. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002;347(20):1557\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNakamura M, Yamamuro A, Nishikawa H, et al. Impact of ascending aortic dilatation on left ventricular afterload and remodeling in patients with hypertension. Hypertens Res. 2012;35(9):915\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZhou M, Wang X, Li J, et al. Matrix metalloproteinase-9 expression in aortic aneurysms: a meta-analysis. J Vasc Surg. 2014;59(5):1355\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNewby AC. Metalloproteinase expression in monocytes and macrophages and its relationship to atherosclerotic plaque instability. Arterioscler Thromb Vasc Biol. 2005;25(5):904\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLiu H, Dear AE, Knudsen LB, Simpson RW. A long-acting glucagon-like peptide-1 analogue attenuates induction of plasminogen activator inhibitor type-1 and vascular adhesion molecules. J Endocrinol. 2009;201(1):59\u0026ndash;66.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLiu H, Hu Y, Simpson RW, Dear AE. Glucagon-like peptide-1 attenuates tumour necrosis factor-alpha-mediated induction of plasminogen activator inhibitor-1 expression. J Endocrinol. 2008;196(1):57\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eArakawa M, Mita T, Azuma K, et al. Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a glucagon-like peptide-1 receptor agonist, exendin-4. Diabetes. 2010;59(4):1030\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSharma AK, Lu G, Jester JV, et al. Experimental abdominal aortic aneurysm formation is inhibited by exendin-4, a glucagon-like peptide-1 receptor agonist. Arterioscler Thromb Vasc Biol. 2013;33(7):1671\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWang Y, Aikawa M, Yang Z, et al. Osteoprotegerin promotes intimal plaque stability through inhibition of matrix metalloproteinases and proinflammatory cytokines. Arterioscler Thromb Vasc Biol. 2005;25(12):2604\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRidker PM, Rifai N, Rose L, et al. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002;347(20):1557\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Type 2 diabetes mellitus, ascending aortic dilatation, GLP-1 receptor agonists, computed tomography angiography, vascular biomarkers, inflammation ","lastPublishedDoi":"10.21203/rs.3.rs-7174676/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7174676/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAIMS-To assess the impact of GLP-1 receptor agonist (GLP-1 RA) treatment on the progression of ascending aortic dilatation in patients with type 2 diabetes mellitus (T2DM), investigated with computed tomography angiography (CTA) and circulating biomarkers reflecting vascular remodeling.\u003c/p\u003e\n\u003cp\u003eMETHODS-A total of 127 T2DM patients with subclinical ascending aortic dilatation (diameter 35 mm \u0026lt; and ≤ 45 mm) were prospectively enrolled in this study. All were first-line naïve to GLP-1 RA. Fifty-seven patients started GLP-1 RA treatment (liraglutide, semaglutide, or dulaglutide) and 70 remained in routine care as controls. CTA was performed at baseline and 24 months to measure the ascending aortic diameter. Matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinases-1 (TIMP-1), C-reactive protein (CRP) and osteoprotegerin (OPG) were evaluated from sera at these two time points.\u003c/p\u003e\n\u003cp\u003eRESULTS-The GLP-1 RA recipients, compared with controls, had the more limited progression of aortic dilatation (mean change, +0.36±0.20 mm vs+1.05±0.28 mm; P\u0026lt;0.001) at 24 months. Therapy correlated with decreased MMP-9 and CRP (P\u0026lt;0.01) and increased TIMP-1 and OPG (P\u0026lt;0.05). The use of GLP-1 RA was an independent predictor of low progression, even in multivariate models after adjusting for demographic, metabolic, and biomarker data.\u003c/p\u003e\n\u003cp\u003eCONCLUSIONS-GLP-1 receptor agonist therapy has been associated with reduced ascending aortic dilatation in T2DM, suggesting a vasoprotective action beyond glucose lowering.\u003c/p\u003e","manuscriptTitle":"GLP-1 Receptor Agonists Are Associated With Reduced Ascending Aorta Dilatation in Patients With Type 2 Diabetes: A Prospective Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-28 05:47:41","doi":"10.21203/rs.3.rs-7174676/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ae10b724-1f67-455f-be8b-17264373c0df","owner":[],"postedDate":"July 28th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-08-24T13:08:16+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-28 05:47:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7174676","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7174676","identity":"rs-7174676","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}