Background: Sodium–glucose transporter 2 inhibitors (SGLT2-I) could modulate atherosclerotic plaque progression, via down-regulation of inflammatory burden, and lead to reduction of major adverse cardiovascular events (MACEs) in type 2 diabetes mellitus (T2DM) patients with ischemic heart disease (IHD). T2DM patients with multivessel non-obstructive coronary stenosis (Mv-NOCS) have over-inflammation and over-lipids’ plaque accumulation. This could reduce fibrous cap thickness (FCT), favoring plaque rupture and MACEs. Despite this, there is not conclusive data about the effects of SGLT2-I on atherosclerotic plaque phenotype and MACEs in Mv-NOCS patients with T2DM. Thus, in the current study, we evaluated SGLT2-I effects on Mv-NOCS patients with T2DM in terms of FCT increase, reduction of systemic and coronary plaque inflammation, and MACEs at 1 year of follow-up. Methods: In a multi-center study, we evaluated 369 T2DM patients with Mv-NOCS divided in 258 (69.9%) patients that did not receive the SGLT2-I therapy (Non-SGLT2-I users), and 111 (30.1%) patients that were treated with SGLT2-I therapy (SGLT2-I users) after percutaneous coronary intervention (PCI) and optical coherence tomography (OCT) evaluation. As the primary study endpoint, we evaluated the effects of SGLT2-I on FCT changes at 1 year of follow-up. As secondary endpoints, we evaluated at baseline and at 12 months follow-up the inflammatory systemic and plaque burden and rate of MACEs, and predictors of MACE through multivariable analysis. Results: At 6 and 12 months of follow-up, SGLT2-I users vs. Non-SGLT2-I users showed lower body mass index (BMI), glycemia, glycated hemoglobin, B-type natriuretic peptide, and inflammatory cells/molecules values (p < 0.05). SGLT2-I users vs. Non-SGLT2-I users, as evaluated by OCT, evidenced the highest values of minimum FCT, and lowest values of lipid arc degree and macrophage grade (p < 0.05). At the follow-up end, SGLT2-I users vs. Non-SGLT2-I users had a lower rate of MACEs [n 12 (10.8%) vs. n 57 (22.1%); p < 0.05]. Finally, Hb1Ac values (1.930, [CI 95%: 1.149–2.176]), macrophage grade (1.188, [CI 95%: 1.073–1.315]), and SGLT2-I therapy (0.342, [CI 95%: 0.180–0.651]) were independent predictors of MACEs at 1 year of follow-up. Conclusions: SGLT2-I therapy may reduce about 65% the risk to have MACEs at 1 year of follow-up, via ameliorative effects on glucose homeostasis, and by the reduction of systemic inflammatory burden, and local effects on the atherosclerotic plaque inflammation, lipids’ deposit, and FCT in Mv-NOCS patients with T2DM.

The aim was to assess the impact of glucagon-like peptide-1 receptor agonists (GLP-1 RA) treatment on the progression of ascending aorta dilatation in patients with type 2 diabetes mellitus (T2DM). A total of 127 T2DM patients with subclinical ascending aortic dilatation (35–45 mm) were prospectively enrolled. Fifty-seven initiated GLP-1 RA therapy (liraglutide, semaglutide, or dulaglutide), while 70 continued on standard care. Ascending aortic diameter was measured by computed tomography angiography (CTA) at baseline and 24 months, alongside circulating markers of vascular remodeling: matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinases-1 (TIMP-1), C-reactive protein (CRP), and osteoprotegerin (OPG). Progression of aortic dilatation was significantly lower in the GLP-1 RA group compared with controls (+0.36 ± 0.20 mm vs. +1.05 ± 0.28 mm; p < 0.001). 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. GLP-1 RA therapy was associated with reduced progression of ascending aortic dilatation in T2DM, supporting a potential vasoprotective role beyond glucose lowering.