Relationship between plasma 8-OH-deoxyguanosine and cardiovascular disease and survival in type 2 diabetes mellitus: Results from the ADVANCE trial

Background—8-Oxo-2ʹ-deoxyguanosine (8-oxo-2ʹ-dG) is a biomarker of oxidative DNA damage that is associated with cardiovascular disease and premature mortality in the general population. Although oxidative stress has a proven role in cardiovascular complications in diabetes mellitus, evidence for a relationship between plasma 8-oxo-2ʹ-dG and major cardiovascular outcomes in diabetes mellitus is weak. Methods and Results—A case-cohort study was performed in 3766 participants with prevalent diabetes mellitus in the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial (ClinicalTrials.gov number NCT00145925). The hazard ratios for mortality and major acute cardiovascular events were derived using Cox regression models. During a median of 5 years of follow-up, 695 (18.4%) participants in this enriched cohort died (including 354 deaths from cardiovascular disease). Individuals with higher levels of 8-oxo-2ʹ-dG were more likely to die. After adjusting for cardiovascular disease risk factors, the hazard ratio for a 1-SD increase in plasma 8-oxo-2ʹ-dG was 1.10 (95% confidence interval, 1.01-1.20; P=0.03). This was driven by an independent association between plasma 8-oxo-2ʹ-dG and cardiovascular death (hazard ratio, 1.23; 95% confidence interval, 1.10-1.37 [P<0.001]). By contrast, no association was seen between 8-oxo-20-dG and noncardiovascular disease death (of which cancer was the major single cause). 8-Oxo-2ʹ-dG was also not significantly associated with either nonfatal myocardial infarction or nonfatal stroke. Conclusions—In adults with type 2 diabetes mellitus, increased levels of 8-oxo-2ʹ-dG are independently associated with all-cause mortality and cardiovascular mortality in adults with longstanding type 2 diabetes mellitus who participated in the ADVANCE trial, consistent with the role of oxidative damage in the development and progression of cardiovascular decompensation in diabetes mellitus.