Intra-plaque vascularization assessed in contrast-enhanced ultrasound predicts cardiovascular events in type 2 diabetes with no significant carotid atherosclerotic stenosis: a prospective study with therapeutic implications for SGLT2 inhibitor use.

Aims: Patients with type 2 diabetes mellitus (T2DM) and no significant carotid stenosis are often considered at moderate cardiovascular risk. However, some may harbour biologically active plaques. Intra-plaque vascularization (IPV), detectable in contrast-enhanced ultrasound (CEUS), reflects plaque vulnerability and may enhance risk stratification. We assessed the prognostic value of CEUS-derived IPV and the effects of SGLT2 inhibitors (SGLT2i) on cardiovascular outcomes and inflammatory markers. Methods and results: In this 6-year prospective cohort study, 251 asymptomatic T2DM patients with carotid atherosclerosis <50% stenosis were enrolled. IPV was quantified by CEUS and stratified by tertiles. The primary endpoint was major adverse cardiovascular events (MACE: CV death, non-fatal MI, non-fatal stroke, or heart failure hospitalization). Secondary endpoints included changes in VEGF, IL-6, and TNF-α levels. Patients were also stratified by chronic SGLT2i use. High IPV was associated with greater MACE incidence (32.5%) compared with low IPV (7.4%; HR 3.84, 95% CI 1.89-7.78; P < 0.001). SGLT2i-treated patients showed reduced MACE incidence (12.1% vs. 26.3%, P = 0.004), particularly in the high-IPV subgroup (23.1% vs. 38.9%; HR 0.48, 95% CI 0.25-0.91; P = 0.026). Treatment was also linked to significant VEGF (-52.4 vs. -18.6 pg/mL) and IL-6 (-1.9 vs. -0.6 pg/mL) reductions (P < 0.001 for both). Conclusion: CEUS-detected IPV predicts cardiovascular events in T2DM patients without significant stenosis. SGLT2i may reduce risk by modulating plaque inflammation and angiogenesis. CEUS combined with biomarker profiling may support personalized prevention strategies in diabetes.