Plasma advanced glycation endproducts 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)

  1. Casper G. Schalkwijk1
  1. 1CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, the Netherlands
  2. Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands 2Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht
  3. 3The Netherlands 3The National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
  1. Corresponding author: Casper G. Schalkwijk, C.Schalkwijk{at}


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 Nε-(carboxymethyl)lysine (CML), Nε-(carboxyethyl)lysine (CEL) and pentosidine were measured with liquid-chromatography. AGEs were loge-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.

  • Received December 10, 2013.
  • Accepted May 1, 2014.

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