Retinal arteriolar tortuosity and fractal dimension are associated with long-term cardiovascular outcomes in people with type 2 diabetes.

AIMS/HYPOTHESIS: Our aim was to determine whether quantitative retinal traits in people with type 2 diabetes are independently associated with incident major cardiovascular events including CHD and stroke. METHODS: A total of 1066 men and women with type 2 diabetes, aged 65-74 years, were followed up over 8 years in the population-based Edinburgh Type 2 Diabetes Study. Using retinal photographs taken at baseline and specialist software, a number of quantitative retinal traits were measured, including arteriolar and venular widths and tortuosity as well as fractal dimension (a measure of the branching pattern complexity of the retinal vasculature network). Incident CHD events occurring during follow-up included fatal and non-fatal myocardial infarction, first episodes of angina and coronary interventions for CHD. Incident cerebrovascular events included fatal and non-fatal stroke or transient ischaemic attack. Cox proportional hazard regression analyses were performed to identify the association of the retinal traits with cardiovascular events in the population with retinal data available (n = 1028). RESULTS: A total of 200 participants had an incident cardiovascular event (139 CHD and 61 cerebrovascular events). Following adjustment for age and sex, arteriolar tortuosity and fractal dimension were associated with cerebrovascular events (HR 1.27 [95% CI 1.02, 1.58] and HR 0.74 [95% CI 0.57, 0.95], respectively), including with stroke alone (HR 1.30 [95% CI 1.01, 1.66] and HR 0.73 [95% CI 0.56, 0.97], respectively). These associations persisted after further adjustment for established cardiovascular risk factors (HR 1.26 [95% CI 1.01, 1.58] and HR 0.73 [95% CI 0.56, 0.94], respectively). Associations generally reduced in strength after a final adjustment for the presence of diabetic retinopathy, but the association of fractal dimension with incident cerebrovascular events and stroke retained statistical significance (HR 0.73 [95% CI 0.57, 0.95] and HR 0.72 [95% CI 0.54, 0.97], respectively). Associations of retinal traits with CHD were generally weak and showed no evidence of statistical significance. CONCLUSIONS/INTERPRETATION: Arteriolar tortuosity and fractal dimension were associated with incident cerebrovascular events, independent of a wide range of traditional cardiovascular risk factors including diabetic retinopathy. These findings suggest potential for measurements of early retinal vasculature change to aid in the identification of people with type 2 diabetes who are at increased risk from stroke.

N-terminal pro-brain natriuretic peptide and risk of cardiovascular events in older patients with type 2 diabetes: the Edinburgh Type 2 Diabetes Study.

AIMS/HYPOTHESIS: The aim of this study was to investigate the association of N-terminal pro-brain natriuretic peptide (NT-proBNP) with traditional cardiovascular risk factors and incident cardiovascular events in older people with type 2 diabetes. METHODS: In the prospective phase of the Edinburgh Type 2 Diabetes Study, 1066 men and women aged 60 to 75 years with type 2 diabetes mellitus were followed for 4 years; 112 participants had an incident cardiovascular event. At baseline, cardiovascular risk factors, pre-existing cardiovascular disease and levels of NT-proBNP were evaluated. RESULTS: Raised plasma NT-proBNP levels were associated with these classical cardiovascular risk factors: increased duration of diabetes, use of insulin, raised BMI, reduced HDL-cholesterol, reduced renal function and use of lipid-lowering and anti-hypertensive medication (all p < 0.05). In the prospective analysis, NT-proBNP was strongly associated with subsequent risk of all cardiovascular disease events (HR per one SD increase in NT-proBNP 1.39; 95% CI 1.10, 1.75), independent of cardiovascular risk factors traditionally used to predict vascular events. NT-proBNP was also independently associated with incident coronary artery disease events (1.48, 95% CI 1.10, 1.98). The addition of NT-proBNP to multivariate models improved the C-index by 0.019 for the 'hard' cardiac endpoint (fatal and non-fatal myocardial infarction). CONCLUSIONS/INTERPRETATION: In older people with type 2 diabetes, NT-proBNP is associated with the development of coronary and cerebrovascular events, independent of a wide range of other vascular and metabolic risk factors, and may prove a useful addition to current vascular risk scores in diabetes populations.

Decreased iron stores are associated with cardiovascular disease in patients with type 2 diabetes both cross-sectionally and longitudinally.

BACKGROUND AND AIMS: The possible contribution of iron to cardiovascular complications of type 2 diabetes (T2D) has been scarcely investigated. We aimed to study whether serum ferritin is linked to prevalent/incident cardiovascular disease (CVD) in T2D. METHODS: The prevalence of coronary heart disease (CHD), cerebrovascular disease (CEVD) and CVD was evaluated in the SIDIAP study (n = 38,617) and prevalence and 7-year incidence were analysed in the Edinburgh Type 2 Diabetes Study (ET2DS) (n = 821). Logistic and Cox regressions were used to describe associations between serum ferritin and CVD adjusting for confounding variables. RESULTS: Increase of 1 SD unit in log-ferritin was associated with lower CVD prevalence in fully-adjusted models (ET2DS odds ratio (OR) 95% confidence interval (CI): 0.81 (0.68-0.96), p = 0.018; SIDIAP study: 0.91 (0.88-0.94), p < 0.001). In ET2DS, ferritin in the highest (vs. the lowest) quintile was associated with lower incidence of CVD (fully adjusted HR 95% CI: 0.46 (0.26-0.83), p = 0.010). This association persisted after removing subjects with CVD at baseline (n = 536) (HR 95% CI: 0.34 (0.14-0.81), p = 0.016). CONCLUSIONS: Low iron status was associated with CVD risk in T2D. This pattern was consistent in populations at different cardiovascular risk. Low iron status seems to be harmful for cardiovascular health in T2D and it may be a target for intervention.

Comparison of non-traditional biomarkers, and combinations of biomarkers, for vascular risk prediction in people with type 2 diabetes: The Edinburgh Type 2 Diabetes Study.

BACKGROUND AND AIMS: We aimed at comparing the impact of multiple non-traditional biomarkers (ankle brachial pressure index (ABI), N-terminal pro-brain natriuretic peptide (NT-proBNP), high sensitivity cardiac troponin (hs-cTnT), gamma-glutamyl transpeptidase (GGT) and four markers of systemic inflammation), both individually and in combination, on cardiovascular risk prediction, over and above traditional risk factors incorporated in the QRISK2 score, in older people with type 2 diabetes. METHODS: We conducted a prospective study of 1066 men and women aged 60-75 years with type 2 diabetes mellitus, living in Lothian, Scotland. RESULTS: After 8 years, 205 cardiovascular events occurred. Higher levels of hs-cTNT and NT-proBNP and lower ABI at baseline were associated with increased risk of CV events, independently of traditional risk factors (basic model). The C statistic of 0.722 (95% CI 0.681, 0.763) for the basic model increased on addition of individual biomarkers, most markedly for hs-cTnT (0.732; 0.690, 0.774)). Models including different combinations of biomarkers had even greater C statistics, with the highest for ABI, hs-cTnT and GGT combined (0.740; 0.699, 0.781). CONCLUSIONS: Individually, hs-cTnT appeared to be the most promising biomarker in terms of improving vascular risk prediction in people with type 2 diabetes, over and above traditional risk factors incorporated in the QRISK2 score. Combining several non-traditional biomarkers added further predictive value, and this approach merits further investigation when developing cost effective risk prediction tools for use in clinical practice.

Association between severe hypoglycemia, adverse macrovascular events, and inflammation in the Edinburgh Type 2 Diabetes Study.

OBJECTIVE: To determine whether a history of severe hypoglycemia was associated with an increased risk of subsequent macrovascular events in people with type 2 diabetes and to explore possible mediation of this association by inflammation. RESEARCH DESIGN AND METHODS: A cohort of 1,066 adults aged 60-75 years with type 2 diabetes was evaluated prospectively. Baseline history of severe hypoglycemia and plasma levels of the inflammatory markers C-reactive protein, fibrinogen, interleukin-6, and tumor necrosis factor-α were recorded. Their association with incident macrovascular events after 4 years was explored. RESULTS: At baseline, 87 participants (8.2%) reported one or more episodes of severe hypoglycemia within the preceding year, and at follow-up 99 participants (9.3%) had suffered a new macrovascular event. Hypoglycemia was associated with increased odds of macrovascular events (odds ratio [OR] 2.11 [95% CI 1.06, 4.21], P = 0.035), including coronary heart events (OR 2.44 [95% CI 1.13, 5.26], P = 0.023), largely due to increased myocardial infarction (OR 4.02 [95% CI 1.54, 10.48], P = 0.004). Hypoglycemia was also associated with increased levels of inflammatory markers, including a general inflammation factor derived using principal-components analysis (P = 0.030, after adjustment for cardiometabolic risk factors). However, the significant association between hypoglycemia and macrovascular events persisted after adjustment for inflammatory markers. CONCLUSIONS: The odds of suffering a macrovascular event were higher in patients with type 2 diabetes who had a history of severe hypoglycemia. There was no evidence that a proinflammatory state had a major role in mediating this association.