Plasma Advanced Glycation End Products Are Associated With Incident Cardiovascular Events in Individuals With Type 2 Diabetes: A Case-Cohort Study With a Median Follow-up of 10 Years (EPIC-NL)

Experimental data suggest a role for advanced glycation endproducts (AGEs) in cardiovascular disease (CVD), particularly in type 2 diabetes (T2DM). However, epidemiological evidence of an association between high plasma AGEs and increased cardiovascular risk remains inconclusive. Therefore, in a case-cohort study comprising 134 cardiovascular cases and a random subcohort of 218 individuals (including 65 cardiovascular cases), all with T2DM and nested in the EPIC-NL study, plasma levels of protein-bound N e -(carboxymethyl)lysine (CML), N e -(carboxyethyl)lysine (CEL) and pentosidine were measured with liquid-chromatography. AGEs were log e -transformed, combined in a z-score and the association with incident cardiovascular events was analysed with Cox-proportional hazard regression, adapted for case-cohort design (Prentice method). After multivariable adjustment (sex, age, cohort status, diabetes duration, total cholesterol to HDL-cholesterol ratio, smoking, systolic blood pressure, BMI, blood pressure-, cholesterol- and glucose-lowering treatment, prior cardiovascular events and triglycerides) higher plasma AGE z-scores were associated with higher risk of incident cardiovascular events in individuals without prior cardiovascular events, (HR: 1.31 (95%CI: 1.06-1.61)). A similar trend was observed in individuals with prior cardiovascular events (HR: 1.37 (95%CI: 0.63-2.98)). In conclusion, high plasma AGEs were associated with incident cardiovascular events in individuals with T2DM. These results underline the potential importance of AGEs in development of CVD.