Role of Systemic Factors in Improving the Prognosis of Diabetic Retinal Disease and Predicting Response to Diabetic Retinopathy Treatment.

Topic: To review clinical evidence on systemic factors that might be relevant to update diabetic retinal disease (DRD) staging systems, including prediction of DRD onset, progression, and response to treatment. Clinical relevance: Systemic factors may improve new staging systems for DRD to better assess risk of disease worsening and predict response to therapy. Methods: The Systemic Health Working Group of the Mary Tyler Moore Vision Initiative reviewed systemic factors individually and in multivariate models for prediction of DRD onset or progression (i.e., prognosis) or response to treatments (prediction). Results: There was consistent evidence for associations of longer diabetes duration, higher glycosylated hemoglobin (HbA1c), and male sex with DRD onset and progression. There is strong trial evidence for the effect of reducing HbA1c and reducing DRD progression. There is strong evidence that higher blood pressure (BP) is a risk factor for DRD incidence and for progression. Pregnancy has been consistently reported to be associated with worsening of DRD but recent studies reflecting modern care standards are lacking. In studies examining multivariate prognostic models of DRD onset, HbA1c and diabetes duration were consistently retained as significant predictors of DRD onset. There was evidence of associations of BP and sex with DRD onset. In multivariate prognostic models examining DRD progression, retinal measures were consistently found to be a significant predictor of DRD with little evidence of any useful marginal increment in prognostic information with the inclusion of systemic risk factor data apart from retinal image data in multivariate models. For predicting the impact of treatment, although there are small studies that quantify prognostic information based on imaging data alone or systemic factors alone, there are currently no large studies that quantify marginal prognostic information within a multivariate model, including both imaging and systemic factors. Conclusion: With standard imaging techniques and ways of processing images rapidly evolving, an international network of centers is needed to routinely capture systemic health factors simultaneously to retinal images so that gains in prediction increment may be precisely quantified to determine the usefulness of various health factors in the prognosis of DRD and prediction of response to treatment. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Higher HbA1c variability is associated with increased arterial stiffness in individuals with type 1 diabetes.

BACKGROUND: Both long-term glycaemic variability and arterial stiffness have been recognized as cardiovascular risk factors. This study aims to investigate whether an association between these phenomena exists in individuals with type 1 diabetes. METHODS: This cross-sectional study included 673 adults (305 men, 368 women) with type 1 diabetes and combined available retrospective laboratory data on HbA1c from the preceding 10 years with outcome data on arterial stiffness and clinical variables from a comprehensive study visit. HbA1c variability was calculated as adjusted standard deviation (adj-HbA1c-SD), coefficient of variation (HbA1c-CV) and average real variability (HbA1c-ARV). As measures of arterial stiffness, carotid-femoral pulse wave velocity (cfPWV; n = 335) and augmentation index (AIx; n = 653) were assessed using applanation tonometry. RESULTS: The study population had a mean age of 47.1 (± 12.0) years and a median duration of diabetes of 31.2 (21.2-41.3) years. The median number of HbA1c assessments per individual was 17 (12-26). All three indices of HbA1c variability were significantly correlated with both cfPWV and AIx after adjustment for sex and age (p < 0.001). In separate multivariable linear regression models, adj-HbA1c-SD and HbA1c-CV were significantly associated with cfPWV (p = 0.032 and p = 0.046, respectively) and AIx (p = 0.028 and p = 0.049, respectively), even after adjustment for HbA1c-mean. HbA1c-ARV was not associated with cfPWV or AIx in the fully adjusted models. CONCLUSIONS: An association independent of HbA1c-mean was found between HbA1c variability and arterial stiffness, suggesting a need to consider multiple HbA1c metrics in studies assessing cardiovascular risk in type 1 diabetes. Longitudinal and interventional studies are needed to confirm any causal relationship and to find strategies for reducing long-term glycaemic variability.

Carotid intima-media thickness and arterial stiffness in relation to cerebral small vessel disease in neurologically asymptomatic individuals with type 1 diabetes.

AIMS: To determine if arterial functional and structural changes are associated with underlying cerebral small vessel disease in neurologically asymptomatic individuals with type 1 diabetes. METHODS: We enrolled 186 individuals (47.8% men; median age 40.0, IQR 33.0-45.0 years) with type 1 diabetes (median diabetes duration of 21.6, IQR 18.2-30.3 years), and 30 age- and sex-matched healthy controls, as part of the Finnish Diabetic Nephropathy (FinnDiane) Study. All individuals underwent a biochemical work-up, brain magnetic resonance imaging (MRI), ultrasound of the common carotid arteries and arterial tonometry. Arterial structural and functional parameters were assessed by carotid intima-media thickness (CIMT), pulse wave velocity and augmentation index. RESULTS: Cerebral microbleeds (CMBs) were present in 23.7% and white matter hyperintensities (WMHs) in 16.7% of individuals with type 1 diabetes. Those with type 1 diabetes and CMBs had higher median (IQR) CIMT 583 (525 - 663) µm than those without 556 (502 - 607) µm, p = 0.016). Higher CIMT was associated with the presence of CMBs (p = 0.046) independent of age, eGFR, ApoB, systolic blood pressure, albuminuria, history of retinal photocoagulation and HbA1c. Arterial stiffness and CIMT were increased in individuals with type 1 diabetes and WMHs compared to those without; however, these results were not independent of cardiovascular risk factors. CONCLUSIONS: Structural, but not functional, arterial changes are associated with underlying CMBs in asymptomatic individuals with type 1 diabetes.

Arterial Stiffness Predicts Mortality in Individuals With Type 1 Diabetes.

OBJECTIVE: Type 1 diabetes is accompanied by a significant burden of cardiovascular disease (CVD), which is poorly explained by traditional risk factors. We therefore aimed to explore whether arterial stiffness estimated by the augmentation index (AIx) predicts mortality in individuals with type 1 diabetes. RESEARCH DESIGN AND METHODS: After baseline examination comprising pulse wave analysis by applanation tonometry alongside assessment of traditional cardiovascular risk factors, 906 individuals with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study were followed up for a median of 8.2 years (interquartile range 5.7-9.7). Associations between baseline hemodynamics, including AIx, and all-cause mortality as well as a composite of cardiovascular and/or diabetes-related mortality were investigated using multivariable Cox regression models. RESULTS: The 67 individuals who died during follow-up had higher baseline AIx (median 28% [interquartile range 21-33] vs. 19% [9-27]; P < 0.001) compared with those alive. This association was independent of conventional risk factors (age, sex, BMI, HbA1c, estimated glomerular filtration rate [eGFR], and previous CVD event) in Cox regression analysis (standardized hazard ratio 1.71 [95% CI 1.10-2.65]; P = 0.017) and sustained in a subanalysis of individuals with chronic kidney disease. Similarly, higher AIx was associated with the composite secondary end point of cardiovascular and diabetes-related death (N = 53) after adjustments for sex, BMI, eGFR, previous CVD event, and height (standardized hazard ratio 2.30 [1.38-3.83]; P = 0.001). CONCLUSIONS: AIx predicts all-cause mortality as well as a composite cardiovascular and/or diabetes-related cause of death in individuals with type 1 diabetes, independent of established cardiovascular risk factors.