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

Abstract

Background8‐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 ResultsA 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 (http://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.ConclusionsIn 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.

Effect of Dipeptidyl-Peptidase 4 Inhibitors on Circulating Oxidative Stress Biomarkers in Patients with Type 2 Diabetes Mellitus

“…AOPP levels were also higher in hypertensive patients and in particular, in those with renal complications [43]. In a prospective study, oxidative DNA damage, measured as 8-hydroxy-2-deoxyguanosine (8-OHdG), predicted micro and macrovascular complications in T2DM patients [44]. Experimental studies also highlighted the pathological role of some of these markers: by binding to their common receptor RAGE, AOPP and AGEs activate inflammatory and apoptotic pathways leading to oxidative stress, inflammation and cell death both on cardiomyocytes and renal cells [45][46][47].…”

Regulation of Vascular Function and Inflammation via Cross Talk of Reactive Oxygen and Nitrogen Species from Mitochondria or NADPH Oxidase—Implications for Diabetes Progression

“…A meta-analysis of 12 studies revealed that supplementation with vitamin E was associated with reduced blood glucose and glycated hemoglobin and administration of vitamins C as well as E were associated with lower MDA levels and higher GPx as well as SOD activity [109]. The ADVANCE Trial revealed that 8-oxo-2'-deoxyguanosine levels were correlated with all-cause and cardiovascular mortality in adults with type 2 diabetes mellitus (T2DM) (n = 3766) [110]. Likewise, an independent prospective cohort study revealed a correlation of RNA oxidation with all-cause and cardiovascular mortality risk in patients with T2DM [111].…”

The Role of Oxidative Stress in Common Risk Factors and Mechanisms of Cardio-Cerebrovascular Ischemia and Depression

“…Whereas a study emphasized the protection of glucagon-like peptide 1 (GLP-1) agonists against oxidative and apoptotic damage in a diabetic mouse model [89], another study supported the role of metformin in improving neurological functions and OS status via the AMPK/mTOR signaling pathway in acute stroke patients with type 2 diabetes [90]. In heart disease, a clinical trial enrolling 3766 adults with prevalent diabetes mellitus illustrated that increased levels of 8-oxo-2′-deoxyguanosine, a biomarker of oxidative DNA damage, were independently associated with elevated cardiovascular mortality [91]. In depression, recent studies have proposed that one possible mechanism linking diabetes and depression was the increase in lipid peroxidation and decrease in antioxidant activity in the hippocampal and prefrontal cortices, which are the areas of the brain associated with mood [92,93].…”