Association of Serum Markers of Oxidative Stress With Incident Major Cardiovascular Events, Cancer Incidence, and All-Cause Mortality in Type 2 Diabetes Patients: Pooled Results From Two Cohort Studies

Abstract

OBJECTIVE Oxidative stress plays an important role in the pathophysiology of type 2 diabetes mellitus (T2DM). However, associations of biomarkers of oxidative stress with diabetes complications have not yet been addressed in large cohort studies. RESEARCH DESIGN AND METHODS Derivatives of reactive oxygen metabolites (d-ROMs) levels, a proxy for the reactive oxygen species burden, and total thiol levels (TTLs), a proxy for the reductive capacity, were measured in 2,125 patients with T2DM from two German cohort studies of almost equal size at baseline and 3–4 years later. Multivariable adjusted Cox proportional hazards models with time-dependent modeled d-ROMs levels and TTLs were used to assess the associations with incident major cardiovascular events (MCE), cancer incidence, and all-cause mortality. RESULTS In total, 205, 179, and 394 MCE, cancer, and all-cause mortality cases were observed during 6–7 years of follow-up, respectively. Both oxidative stress biomarkers and the d-ROMs-to-TTL ratio were statistically significantly associated with all-cause mortality in both cohorts, and the pooled hazard ratios (HRs) and 95% CIs for top versus bottom tertiles were 2.10 (95% CI 1.43, 3.09) for d-ROMs levels, 0.59 (0.40, 0.87) for TTLs, and 2.50 (1.86, 3.36) for d-ROMs-to-TTL ratio. The d-ROMs-to-TTL ratio was also statistically significantly associated with incident MCE for top versus bottom tertile (1.65 [1.07, 2.54]), but this association did not persist after additional adjustment for chronic diseases. No associations with cancer were detected. CONCLUSIONS The observed strong associations of both biomarkers with mortality suggest an important contribution of an imbalanced redox system to the premature mortality of patients with diabetes.