Relationship Between Plasma 8-OH-Deoxyguanosine and Cardiovascular Disease and Survival in Type 2 Diabetes Mellitus: Results From the ADVANCE Trial

Abstract

Background: 8-Oxo-2'-deoxyguanosine (8-oxo-2'-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-2'-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-2'-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-2'-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-2'-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-2'-dG and noncardiovascular disease death (of which cancer was the major single cause). 8-Oxo-2'-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-2'-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.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00145925.

Keywords: cardiovascular outcomes; mortality; oxidative stress; survival analysis; type 2 diabetes mellitus.

Figure 1

Cumulative survival curves for all primary outcomes by quarter of 8‐oxo‐2′‐deoxyguanosine (8‐oxo‐2′‐dG), adjusted as in model 3 in Table 1. Blue, red, and green lines correspond, in this order, to increasing tertiles of 8‐ox‐dG. CVD indicates cardiovascular disease.

Figure 2

Hazard ratios (with 95% confidence intervals [CIs]) for all‐cause and cardiovascular death by predefined subgroups, adjusted as in model 3 in Table 1. eGFR indicates estimated glomerular filtration rate; HbA1c, glycated hemoglobin.