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Background The clustering of arterial stiffness with microvascular disease (MD) and their effects on the clinical outcome of patients with type 2 diabetes (T2D) remains not fully clarified. Methods In a prospective study of 414 patients with T2D, we investigated the prognostic value of arterial stiffness and MD for clinical outcomes. Participants were assessed for the presence of MD (ie diabetic retinopathy, nephropathy and neuropathy) and arterial stiffness by pulse wave velocity (PWV) and followed‐up for a median of 30 (range 1‐60) months. The primary endpoint of the study was the composite endpoint of major adverse cardiovascular events, that is, cardiovascular and non‐cardiovascular mortality and non‐fatal myocardial infarction/stroke. Results A total of 146 (35.3%) patients had evidence of MD at baseline. In cox regression models, MD and PWV were independently associated with the composite clinical endpoint; for MD hazard ratio (HR), 3.24, 95%CI, 1.10‐9.54, P=.032, and for PWV HR, 1.20, 95%CI, 1.06‐1.36, P=.004) after adjustment for traditional risk factors, and enhanced risk discrimination and reclassification. The subgroup of patients with MD and high PWV was associated with increased incidence of the composite clinical endpoint (20.9% vs 1.8% in those with no MD & low PWV, P=.001). Importantly, absence of MD at baseline was associated with no mortality events during the follow‐up period. PWV at baseline was not associated with MD progression during follow‐up. Conclusions These findings support that screening for arterial stiffness and MD in the routine clinical assessment of patients with T2D may enhance prognostication and cardiovascular risk reclassification.

Diabetic foot (DF) syndrome is the most common lower-extremity complication of poorly controlled type 2 diabetes (T2D) (1). DF affects the quality of life of T2D patients and is associated with increased morbidity (2). T2D-related mechanisms induce endothelial dysfunction and adverse effects on vascular biology (3). We have recently shown that measurements of endothelial function and arterial stiffness are strongly associated with diabetic retinopathy (4), but their association with DF has not been explored yet.To examine this, we enrolled 284 consecutive T2D subjects visiting our outpatient diabetes clinic and 196 age-and sex-matched healthy control subjects without evidence of diabetes or cardiovascular or other disease. Subjects with known malignancy, hepatic impairment, or acute or chronic inflammatory disease were excluded from the study. Study protocol was approved by the institutional ethics committee. Endothelial function was assessed by the flow-mediated dilation (FMD) of the brachial artery and carotid-femoral pulse wave velocity (PWV) and augmentation index (AIx) were assessed by SphygmoCor (AtCor Medical) as previously described (4).Prevalence of DF was 24.6% among T2D patients. There were no significant differences in age, sex, cardiovascular risk factors (such as smoking, hypertension, and hyperlipidemia), and HbA 1c % between T2D with DF and no DF (NDF) (P 5 NS for all). However, DF patients had significantly increased T2D duration compared with NDF patients (19.5 6 1.1 vs. 12.0 6 0.6 years, P 5 0.001). As expected, T2D was associated with lower FMD and increased PWV and AIx compared with subjects without diabetes, while DF was associated with further adverse effects on endothelial function and arterial stiffness within the group of T2D patients (Fig. 1A-C). Staging of DF (according to the University of Texas diabetic wound classification system) was significantly associated with log[FMD] (r 5 20.165, P 5 0.006), AIx (r 5 0.200, P , 0.05), and log[PWV] (r 5 0.234, P , 0.05), suggesting further exacerbation of endothelial dysfunction and arterial stiffening with increasing severity of DF syndrome. Interestingly, T2D duration was positively associated with both PWV and AIx but only modestly with FMD ( Fig. 1D-F), suggesting that arterial stiffening is a gradual and ongoing process in patients with diabetes. On the other hand, log[HbA 1c %] was not associated with FMD, PWV, or AIx (P 5 NS for all), suggesting that vascular dysfunction may not be reversible by strict glycemic control. In the multivariate logistic regression analysis, including as independent variables those that were associated with DF in bivariate analysis, the only independent predictors of DF were log Peripheral neuropathy, impaired wound healing, local inflammation, and decreased nitric oxide bioavailability may all affect local microcirculation environment and contribute to DF (1). Herein, we provide the first evidence that DF in T2D is associated with endothelial dysfunction and increased stiffness of large arteries. We observed...