Total Soluble and Endogenous Secretory Receptor for Advanced Glycation End Products as Predictive Biomarkers of Coronary Heart Disease Risk in Patients With Type 2 Diabetes
An Analysis From the CARDS Trial
- Helen M. Colhoun1⇓,
- D. John Betteridge2,
- Paul Durrington3,
- Graham Hitman4,
- Andrew Neil5,
- Shona Livingstone1,
- Valentine Charlton-Menys3,
- Weihang Bao6,
- David A. DeMicco6,
- Gregory M. Preston6,
- Harshal Deshmukh1,
- Kathryn Tan7 and
- John H. Fuller8
- 1Medical Research Institute, University of Dundee, Dundee, U.K.
- 2Department of Medicine, Royal Free and University College Medical School, London, U.K.
- 3Cardiovascular Research Group, University of Manchester, Manchester, U.K.
- 4Centre for Diabetes, Barts and the London School of Medicine and Dentistry, London, U.K.
- 5Nuffield Department of Clinical Medicine, University of Oxford, Oxford, U.K.
- 6Pfizer Ltd., New York, New York
- 7Department of Medicine, University of Hong Kong, Hong Kong, China
- 8Department of Epidemiology and Public Health, University College London, London, U.K.
- Corresponding author: Helen M. Colhoun, .
OBJECTIVE Circulating levels of soluble receptor for advanced glycation end products (sRAGE) likely comprise both a secreted isoform (esRAGE) and wild-type RAGE cleaved from the cell membrane. Both sRAGE and esRAGE have been proposed as biomarkers of cardiovascular disease (CVD), but prospective data are limited. We examined the relationship of sRAGE and esRAGE to incident coronary heart disease (CHD) and stroke in type 2 diabetic patients followed for 3.9 years in a trial of atorvastatin: the Collaborative Atorvastatin Diabetes Study (CARDS).
RESEARCH DESIGN AND METHODS We used a nested case-control design sampling all incident cases of CVD with available plasma and randomly selecting three control subjects, who were free of CVD throughout follow-up, per case. Analysis was by Cox regression with adjustment for treatment allocation and relevant covariates.
RESULTS sRAGE and esRAGE were strongly correlated (ρ = 0.88) and were both higher in those with lower BMI (P < 0.001), higher adiponectin (P < 0.001), lower estimated glomerular filtration rate (P = 0.009), and white ethnicity (P < 0.001). Both sRAGE and esRAGE were associated with incident CHD events, independently of treatment allocation and the above factors; hazard ratio (HR) = 1.74 (95% CI 1.25–2.41; P = 0.002) for a doubling of the sRAGE level; HR = 1.45 (1.11–1.89; P = 0.006) for a doubling of the esRAGE level. There was no significant association with stroke; HR for sRAGE = 0.66 (0.38–1.14). Atorvastatin, 10 mg daily, did not alter sRAGE.
CONCLUSIONS Higher levels of sRAGE and esRAGE are associated with incident CHD but not stroke in type 2 diabetes.
- Received March 2, 2011.
- Accepted June 10, 2011.
- © 2011 by the American Diabetes Association.
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