Oxidative and Advanced Glycation End-Products Biomarkers and Their Association with the Risk of Cardiovascular Disease Outcomes in Type 1 Diabetes in DCCT/EDIC

Background: Type 1 diabetes confers a significant risk of cardiovascular disease (CVD), and new biomarkers of risk are needed for early detection. We have investigated the predictive value of oxidation products (OPs) and advanced glycation end-products (AGEs) for CVD events in the Diabetes Control and Complications Trial and the follow-up Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. Methods: Using a case-control design, we measured plasma OPs including methionine sulfoxide [MetSO] and the AGE carboxyethyllysine [CEL] by LC/mass spectrometry in 459 participants (93 CVD cases and 366 controls) at three time points during DCCT, and at year 1-2 of EDIC. Cox proportional hazards models assessed the association between biomarkers as fixed or time-dependent covariates and the risk of subsequent CVD events. Prediction improvement was assessed using the C-statistic. Findings: Baseline CEL was associated with CVD (p=0·03, HR 1·15) when fully adjusted for age, HbA1c, BMI, HDL, LDL, sex, systolic and diastolic blood pressure, while MetSO at beginning of EDIC and as a time-dependent covariate, was strongly inversely associated with CVD outcomes (p < 0·001 and HR 0·58 and 0·61, respectively). MetSO also significantly increased the predictive c-statistic from 0·711 to 0·783 (p<0·001) when added to the other covariates. Interpretation: High levels of MetSO, a product of the free oxygen radical scavenger methionine, are associated with lower incidence of a primary CVD event during DCCT/EDIC· MetSO also significantly improved the predictive value over traditional risk factors, which may allow more timely institution of preventive therapies. Trial Registrations: NCT00360893, NCT00360815. Funding Statement: The DCCT/EDIC has been supported by cooperative agreement grants (1982-1993, 2012- 2017), and contracts (1982-2012) with the Division of Diabetes Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Disease (current grant numbers U01 DK094176 and U01 DK094157), and through support by the National Eye Institute, the National Institute of Neurologic Disorders and Stroke, the General Clinical Research Centers Program (1993-2007), and Clinical Translational Science Center Program (2006-present), Bethesda, Maryland, USA. Declaration of Interests: None for JML and IB as noted below. PJB and Scott Howell have the following Declarations of interest: PJB is Chief Scientific Officer and Scott Howell is the Laboratory Director of PreventAGE Healthcare LLC (PHC), and PJB prepared and submitted the SBIR that funded the study in PHC’s name. PHCs goal is to develop precise biomarkers that can predict diabetic complications. Although no commercialization of the content of this manuscript has taken place, it is possible that this could occur in the future. Further detail on this relationship is contained in the enclosed ICJME form and in the “declaration of interests” section. Ethics Approval Statement: All appropriate written consents, permissions, and releases have been obtained from the participants by the DCCT/EDIC central overview committee.