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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.

SUBMITTER: Thomas MC

PROVIDER: S-EPMC6064915 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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

Thomas Merlin C MC Woodward Mark M Li Qiang Q Pickering Raelene R Tikellis Christos C Poulter Neil N Cooper Mark E ME Marre Michel M Zoungas Sophia S Chalmers John J

Journal of the American Heart Association 20180630 13

<h4>Background</h4>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.<h4>Methods and results</h4>A case-cohort study was performed in 3766 participants with pr ...[more]

PMID: 29960985

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Project description:IntroductionThe diagnosis of diabetes mellitus is based on suitable cut-off values of specific biomarkers, such as the concentration of glucose in plasma. The German Diabetes Association has very recently published a clinical practice guideline on the definition, classification and diagnosis of diabetes mellitus that recommends measurements of plasma glucose concentration have an imprecision defined as a minimal difference (MD) of at a fasting plasma glucose concentration of 7.0 mmol/L. To obtain reliable values for the MD, we investigated long-term and short-term measurement uncertainty.MethodsThe imprecision was determined by two approaches: (1) a long-term dataset with imprecision based on the Guideline of the German Medical Association on Quality Assurance in Medical Laboratory Examinations (Rili-BAEK), in a medical laboratory operating 24/7, using internal quality control (IQC) data for four concentrations during a 10-year period; and (2) a detailed short-term dataset with imprecision assessed by hourly measurements of control materials. These datasets were used to calculate the MD cut-off (MDcut-off) as: [Formula: see text] = 2 [Formula: see text], where SD is the standard deviation and k = 2 represents a confidence level of 95%.ResultsThe MDcut-off of ≤ 0.7 mmol/L at a fasting plasma glucose concentration of 7.0 mmol/L (MDcut-off 7.0) for the long-term and the short-term approaches were 0.44 and 0.40 mmol/L, respectively. The MDcut-off 7.0 from both approaches was therefore below the recommended value of 0.7 mmol/L. It was noted that the variability in performance within and between instruments can be covered by reporting the long-term MDcut-off 7.0 across all connected instruments. In this study, stable results for the MDcut-off 7.0 were obtained after 1 year.ConclusionImprecision as measured by IQC data is remarkably stable over many years of operation. Current imprecision assessment usually focuses on only single instruments, whereas clinicians perceive the measurement as the result of the combined analytical performance of all instruments used for a certain assay. In the clinical setting, the MD may be a more useful measure of imprecision, and we suggest deriving the MDcut-off combined from all instruments and control cycles that are used in the patient care setting for a given analyte.

Project description:Background Pathologic angiogenesis is a hallmark of type 2 diabetes mellitus (T2DM) microvascular complications and may modulate adipogenesis and precede the onset of clinical diabetes mellitus; however, longitudinal data are unavailable. Placental growth factor is a potent proangiogenic factor that stimulates the formation of mature and durable vessels but is understudied in human diseases. Methods and Results We conducted a prospective case-cohort study of baseline placental growth factor and incident T2DM within the WHS (Women's Health Study). A random sample of incident T2DM cases (n=491) occurring over a 15-year follow-up period was selected and compared with a reference subcohort (n=561). Case subjects were matched to the reference risk set on 5-year age groups and race. All subjects in this analysis were required to have a hemoglobin A1c <6.5% at WHS enrollment. Median baseline levels of placental growth factor were higher in case subjects compare to the reference subcohort (18.0 pg/mL versus 17.2 pg/mL) but were only weakly correlated with glycemic measures and not associated with obesity. The risk of diabetes mellitus increased across placental growth factor quartile in the base model (hazard ratios, 1.00, 1.14, 1.46, and 2.14; P-trend<0.001) and in multivariable-adjusted models accounting for clinical T2DM risk factors (hazard ratios, 1.00, 1.17, 1.45, and 2.61; P-trend<0.001). These findings were not substantially altered by further adjustment for high-sensitivity C-reactive protein, hemoglobin A1c, or fasting insulin and remained robust in sensitivity analyses excluding those diagnosed within 2 years of enrollment and those with baseline hemoglobin A1c ≥6.0%. Conclusions Elevated placental growth factor levels are associated with future T2DM independent of traditional risk factors, measures of glycemia, insulin resistance, and high-sensitivity C-reactive protein. These prospective data suggest that pathologic angiogenesis may occur well before the clinical onset of T2DM and thus may have relevance to vascular complications of this disease. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000479.

Dataset Information

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

Publications

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

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