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

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.Receptor for advanced glycation end products (RAGE) is a cell-surface molecule that binds many ligands, including advanced glycation end products (AGEs) (1,2). This binding results in diverse responses, including altered gene expression and cell migration and proliferation, in pathways that are considered to play a pivotal role in the pathogenesis of atherosclerosis, heart failure, and other diabetes complications. The involved pathways relevant to atherosclerosis are diverse; for example, blocking ligand binding to RAGE in mice reduced diabetes-induced inflammation and atherosclerotic plaque formation and reduced vascular smooth muscle proliferation and migration and extracellular matrix production in response to injury (3). A circulating soluble form of RAGE has been proposed as a potentially useful biomarker of cardiovascular disease (CVD) in diabetes. This soluble RAGE (total sRAGE) likely comprises both the extracellular domain of wild-type, full-length RAGE, which results from proteolytic cleavage at the cell surface, and an endogenous secreted isoform lacking a transmembrane domain (RAGE-V1 or esRAGE) that can also be measured separately (4–6). RAGE antagonists are in clinical development as therapeutics for diabetes complications and Alzheimer disease. An important question, therefore, is the usefulness of circulating total sRAGE (hereafter termed sRAGE) and esRAGE as potential biomarkers of diabetes complications and need for therapy.The published literature on esRAGE and sRAGE prediction of complications in patients with diabetes is sparse and conflicting (6–8). sRAGE levels have been found to be higher in coronary disease cases, or those with higher atherosclerotic burden, than control subjects in some studies (7–12) but lower in others (13). esRAGE levels have been mostly reported to be lower in case subjects, or those with greater atherosclerosis burden, than control subjects (11,14–16). However prospective data are essential to fully understand the relationship between sRAGE and CVD. Two recent prospective studies showed that higher levels of sRAGE were associated with CVD in type 1 diabetes (8,12). There are no prospective studies that have examined both esRAGE and sRAGE as predictors of CVD in type 2 diabetes with adjustment for other risk factors. There is also need for more clinical data on the relationship of circulating esRAGE and sRAGE with other factors in diabetes.The primary purpose of this analysis was to examine the relationship of serum esRAGE and sRAGE to incident cardiovascular events. We also explored the relationship of esRAGE and sRAGE with each other and with other risk factors in type 2 diabetes. We examined these questions using samples and data from a randomized controlled clinical trial of statin therapy in type 2 diabetic patients without prior CVD (the Collaborative Atorvastatin Diabetes Study [CARDS]) (17).