Higher Plasma Levels of Advanced Glycation End Products Are Associated With Incident Cardiovascular Disease and All-Cause Mortality in Type 1 Diabetes

A 12-year follow-up study

  1. Coen D. Stehouwer, MD, PHD1,2
  1. 1Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands
  2. 2Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, the Netherlands
  3. 3Care and Public Health Research Institute (CAPHRI), Maastricht University Medical Centre, Maastricht, the Netherlands
  4. 4Steno Diabetes Center, Gentofte, Denmark
  5. 5Department of Clinical Epidemiology and Medical Technology Assessment, Maastricht University Medical Centre, Maastricht, the Netherlands
  6. 6Department of Medical Endocrinology, Rigshospitalet, Copenhagen, Denmark
  7. 7Faculty of Health Science, Aarhus University, Aarhus, Denmark
  1. Corresponding author: Johanna W. Nin, j.nin{at}maastrichtuniversity.nl.
  1. J.W.N. and A.J. contributed equally to this work.

Abstract

OBJECTIVE To investigate the associations of plasma levels of advanced glycation end products (AGEs) with incident cardiovascular disease (CVD) and all-cause mortality in type 1 diabetes and the extent to which any such associations could be explained by endothelial and renal dysfunction, low-grade inflammation, and arterial stiffness.

RESEARCH DESIGN AND METHODS We prospectively followed 169 individuals with diabetic nephropathy and 170 individuals with persistent normoalbuminuria who were free of CVD at study entry and in whom levels of Nε-(carboxymethyl)lysine, Nε-(carboxyethyl)lysine, pentosidine and other biomarkers were measured at baseline. The median follow-up duration was 12.3 (interquartile range 7.6–12.5) years.

RESULTS During the course of follow-up, 82 individuals (24.2%) died; 85 (25.1%) suffered a fatal (n = 48) and/or nonfatal (n = 53) CVD event. The incidence of fatal and nonfatal CVD and of all-cause mortality increased with higher baseline levels of AGEs independently of traditional CVD risk factors: hazard ratio (HR) = 1.30 (95% CI = 1.03–1.66) and HR = 1.27 (1.00–1.62), respectively. These associations were not attenuated after further adjustments for markers of renal or endothelial dysfunction, low-grade inflammation, or arterial stiffness.

CONCLUSIONS Higher levels of AGEs are associated with incident fatal and nonfatal CVD as well as all-cause mortality in individuals with type 1 diabetes, independently of other risk factors and of several potential AGEs-related pathophysiological mechanisms. Thus, AGEs may explain, in part, the increased cardiovascular disease and mortality attributable to type 1 diabetes and constitute a specific target for treatment in these patients.

Footnotes

  • Received June 8, 2010.
  • Accepted November 6, 2010.

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