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

Abstract

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.

Keywords: SGLT2 inhibitors; VEGF; cardiovascular outcomes; carotid plaque; contrast-enhanced ultrasound; inflammation; intra-plaque vascularization; type 2 diabetes.

Graphical Abstract

Figure 1

Baseline levels of inflammatory and angiogenic biomarkers by IPV tertile (panel A) and treatment group (panel B). Box plots show VEGF, IL-6, and TNF-α concentrations, with superimposed individual values. In panel A, patients in the highest tertile (Tertile 3) showed significantly higher levels of all biomarkers compared with Tertile 1 and Tertile 2 (P < 0.001 for all comparisons). In panel B, baseline biomarker levels were significantly higher in untreated control patients compared with those treated with SGLT2 inhibitors (P < 0.001 for all).

Figure 2

Temporal trends in metabolic and inflammatory parameters during the 72-month follow-up period. Line plots show mean values (±SD) of HbA1c, LDL cholesterol, HDL cholesterol, and triglycerides (top row) and inflammatory biomarkers (bottom row), stratified by treatment group (SGLT2i vs. control). Metabolic parameters remained stable over time in both groups. In contrast, VEGF, IL-6, and TNF-α levels decreased significantly more in the SGLT2i group compared with controls (P < 0.001 for all comparisons).

Figure 3

Temporal trends of metabolic parameters during the 72-month follow-up in SGLT2i-treated patients' vs. controls. Mean values (±SD) of HbA1c, LDL cholesterol, HDL cholesterol, and triglycerides are shown over time for the two treatment groups. No significant longitudinal changes were observed in either group, and no time-by-treatment interaction was detected.

Figure 4

MACE outcomes by treatment group and interaction with IPV tertiles. Panel A displays Kaplan–Meier survival curves showing a significantly lower MACE incidence in patients treated with SGLT2 inhibitors compared with controls (log-rank P = 0.004). Panel B shows the distribution of MACE incidence by treatment group across IPV tertiles, with the largest difference observed in Tertile 3 (23.1% vs. 38.9%). Panel C includes the adjusted Cox regression model for treatment effect, indicating that SGLT2i therapy was associated with a 51% reduction in MACE risk (HR 0.49, 95% CI 0.27–0.88, P = 0.018), most pronounced in the highest tertile (HR 0.48, 95% CI 0.25–0.91, P = 0.026). No significant interaction was detected between treatment effects.