Diabetic macroangiopathy, atherosclerosis secondary to diabetes mellitus (DM), causes cerebro-cardiovascular diseases, which are major causes of death in patients with DM and significantly reduce their quality of life. The alterations in vascular homeostasis due to endothelial and vascular smooth muscle cell dysfunction are the main features of diabetic macroangiopathy. Although multiple metabolic abnormalities that characterize diabetes are involved in the progression of atherosclerosis in patients with DM, it may be said that prolonged exposure to hyperglycemia and insulin resistance clustering with other risk factors such as obesity, arterial hypertension, and dyslipidemia play crucial roles. Laboratory and clinical researches in the past decades have revealed that major biochemical pathways involved in the development of diabetic macroangiopathy are as follows: overproduction of reactive oxygen species, increased formation of advanced glycation end-products (AGEs) and activation of the AGEs-receptor for AGE axis, polyol and hexosamine flux, protein kinase C activation, and chronic vascular inflammation. Among them, oxidative stress is considered to be a key factor.

Brachial-ankle pulse wave velocity (baPWV) is a method to estimate arterial stiffness, which reflects the stiffness of both the aorta and peripheral artery; it would be applicable to general practice, since its measurementis automated. The aim of this study was to evaluate whether baPWV can be predictors of future cardiovascular events (CVE) in diabetic patients. We prospectively evaluated the association between baPWV or carotid intima-media thickness (carotid IMT) at baseline and new onset of CVE in 1040 type 2 diabetic patients without CVE. The predictability of baPWV and/or carotid IMT for identifying patients at high risk for CVE was evaluated by time-dependent receiver-operating-characteristic (ROC) curve analysis. During a median follow-up of 7.5 years, 113 had new CVD events. The cumulative incidence rates of CVE were significantly higher in patients with high baPWV values (≥1550 cm/s) as compared to those with low baPWV values (<1550 cm/s) (p < 0.001, log-rank test). Similarly, the cumulative incidence rate of CVE was significantly higher in patients with higher maximum carotid IMT (maxIMT) values (≥1.0 mm) as compared to those with lower maxIMT values (<1.0 mm) (p < 0.001, log-rank test). Subjects with both high PWV and high IMT had a significantly higher risk of developing CVE as compared to those with either high PWV or high IMT, as well as those with neither. A multivariate Cox proportional hazards regression model revealed that both baPWV (HR = 1.30, [95%CI: 1.07-1.57]; p = 0.009) and maxIMT (HR = 1.20, [95%CI: 1.01-1.41]; p = 0.033) were independent predictors for CVE, even after adjustment for the conventional risk factors. Time-dependent ROC curve analyses revealed that the addition of maxIMT to the Framingham risk score resulted in significant increase in AUC (from 0.60 [95%CI: 0.54-0.67] to 0.63 [95%CI: 0.60-0.82]; p = 0.01). Notably, the addition of baPWV to the Framingham risk score and maxIMT resulted in further and significant (p = 0.02) increase in AUC (0.72 [95%CI: 0.67-0.78]). Evaluation of baPWV, in addition to carotid IMT and conventional risk factors, improved the ability to identify the diabetic individuals with high risk for CVE.

Aim: It remains unclear whether measures used in carotid ultrasonography such as the intima–media thickness (IMT) and ultrasonic tissue characterization of the carotid using the gray-scale median (GSM) can add prognostic information beyond the conventional cardiovascular risk markers in patients with diabetes.Methods: This study employed a combined analysis of data obtained in five longitudinal studies including a total of 3263 patients with diabetes but without apparent cardiovascular disease (CVD) at baseline. The associations between carotid ultrasonography measures and the first occurrence of CVD (488 cases), which were defined as cardiovascular death, coronary artery diseases, stroke, or peripheral artery disease, were analyzed.Results: Common carotid artery (CCA)-mean-IMT, CCA-max-IMT, Max-IMT, plaque-GSM, and the presence of low-GSM echolucent plaques at baseline were prognostic factors for CVD even after adjustment for conventional risk factors. Time-dependent receiver-operating-characteristic (ROC) curve analysis indicated that the use of CCA-mean-IMT, CCA-max-IMT, and Max-IMT in addition to the conventional risk factors improved significantly the prediction of occurrence of CVD. Increments in the CCA-mean-IMT (hazard ratio [HR] 2.37 for every 0.1-mm/year increment [95% confidence interval [CI]: 1.63–3.47], p＜0.001), Max-IMT (HR 1.51 for every 0.1-mm/year increment [95% CI: 1.07–2.14], p=0.020), and Mean-GSM (HR 0.22 for every 10-U/year increment [95% CI: 0.06–0.76], p=0.016) during the observation period were also prognostic factors for CVD even after adjusting for the baseline value of the respective measure.Conclusions: Addition of carotid ultrasonography measures to conventional risk factors significantly improved the stratification of patients by cardiovascular risk. Changes over time in carotid ultrasonography measures may be used as therapeutic outcome measures.

Cardiovascular disease (CVD) remains the main cause of death in diabetic patients, and once it has developed, diabetic patients have a worse outcome as compared with non‐diabetic patients. One reason for this is the difficulty of early diagnosis of atherosclerotic change in these patients. Although cardiovascular risk assessment based on conventional risk factors is recommended for predicting cardiovascular risk, validation studies showed only moderate performance. In contrast, it is unrealistic to screen for subclinical or silent atherosclerosis by sophisticated modalities, such as myocardial perfusion scintigraphy, coronary computed tomography angiography or conventional angiography in all diabetic patients, as these tests are limited by the potential of significant adverse effects, technical difficulty, availability and high cost. Therefore, a non‐invasive and inexpensive tool for risk prediction of subclinical atherosclerosis is required for identifying individuals at high risk of CVD. Recently, a number of studies have shown close associations between carotid atherosclerosis and cerebrovascular or coronary artery disease. Carotid ultrasonography has allowed clinicians to visualize the characteristics of the carotid wall and lumen surfaces to quantify the severity of atherosclerosis. Carotid intima‐media thickness (IMT) is an especially useful marker of the progression of atherosclerosis throughout the body, and is an excellent predictor of cardiovascular events. As a simple and non‐invasive procedure, measurement of carotid IMT is one of the most appropriate screening methods to specify high‐risk individuals in subjects with and without diabetes. Therefore, it is expected that carotid ultrasonography will become a potent tool for better clinical practice of atherosclerosis in diabetic patients.

Background: This study aimed to investigate the preventive effects of tofogliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, on atherosclerosis progression in type 2 diabetes (T2DM) patients without apparent cardiovascular disease (CVD) by monitoring carotid intima-media thickness (IMT).Methods: This prospective, randomized, open-label, blinded-endpoint, multicenter, parallel-group, comparative study included 340 subjects with T2DM and no history of apparent CVD recruited at 24 clinical units. Subjects were randomly allocated to either the tofogliflozin treatment group (n = 169) or conventional treatment group using drugs other than SGLT2 inhibitors (n = 171). Primary outcomes were changes in mean and maximum common carotid IMT measured by echography during a 104-week treatment period.Results: In a mixed-effects model for repeated measures, the mean IMT of the common carotid artery (mean-IMT-CCA), along with the right and left maximum IMT of the CCA (max-IMT-CCA), significantly declined in both the tofogliflozin (− 0.132 mm, SE 0.007; − 0.163 mm, SE 0.013; − 0.170 mm, SE 0.020, respectively) and the control group (− 0.140 mm, SE 0.006; − 0.190 mm, SE 0.012; − 0.190 mm, SE 0.020, respectively). Furthermore, the tofogliflozin and the conventional treatment group did not significantly differ in the progression of the mean-IMT-CCA (mean change (95% CI) 0.008 (− 0.009, 0.025) mm, P = 0.34), along with the right (mean change (95% CI) 0.027 (− 0.005, 0.059) mm, P = 0.10) and the left max-IMT-CCA (mean change (95% CI) 0.020 (− 0.030, 0.070), P = 0.43). Similar findings were obtained even after adjusting for traditional CV risk factors and/or administration of drugs at baseline. Relative to the control treatment effects, tofogliflozin significantly reduced the HbA1c, blood glucose level, body weight/body mass index, abdominal circumference, and systolic blood pressure, and significantly increased the HDL-C. The total and serious adverse events incidences did not significantly vary between the treatment groups.Conclusions/interpretation: No IMT changes were observed between the tofogliflozin and the conventional treatment groups. However, tofogliflozin is a safe and effective treatment option for managing primary CVD risk factors in this population.Clinical Trial RegistrationUMIN000017607 (https://www.umin.ac.jp/icdr/index.html).

Carotid ultrasonography is a non‐invasive, simple and inexpensive modality to assess the severity of atherosclerosis. This article reviews related articles, summarizes the rationale for the application of carotid ultrasonography in clinical practice, and addresses the features and the limitations of carotid ultrasonography in cardiovascular risk prediction. Numerous large studies have confirmed that various carotid ultrasound measures, such as carotid intima‐media thickness, the presence or absence of carotid plaque, plaque number and plaque area, can be independent predictors of cardiovascular diseases in individuals with and without diabetes mellitus. Furthermore, many studies showed that the use of carotid intima‐media thickness (especially maximum intima‐media thickness, including plaque thickness) and/or carotid plaque in addition to traditional risk factors significantly improved the prediction of the occurrence of cardiovascular diseases, while controversy remains. Several studies showed that the progression of carotid intima‐media thickness also can be a surrogate end‐point of cardiovascular events. However, the accumulated evidence has not been sufficient. Further study with sufficient power should be carried out. As plaque disruption, which plays a crucial role in the pathogenesis of cardiovascular events, is dependent on the content of lipid in the atheroma and the thickness of the fibrous cap, tissue characterization of a plaque might be useful for determining its fragility. Interestingly, recent studies have shown that ultrasonic tissue characterization of carotid lesions could improve the prediction ability of future cardiovascular diseases. Thus, carotid ultrasonography is a useful modality for better clinical practice of atherosclerosis in patients with diabetes.