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

Abstract

OBJECTIVECirculating 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 METHODSWe 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.RESULTSsRAGE 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.CONCLUSIONSHigher levels of sRAGE and esRAGE are associated with incident CHD but not stroke in type 2 diabetes.

Protein biomarkers for the prediction of cardiovascular disease in type 2 diabetes

“…Thus, it is likely that IL-6 will not add a great amount of information to a model in the presence of CRP. sRAGE has not been studied in many prospective studies of type 2 diabetes; we previously showed that higher levels were associated with an increased risk of CHD but little difference in stroke risk in clinical trials [31]. The inverse association between sRAGE and CVD found here, which is only apparent once it has been adjusted for eGFR and other biomarkers, is contradictory and requires further exploration in other cohorts.…”

The soluble form of the receptor of advanced glycation endproducts increases after bariatric surgery in morbid obesity

“…Remarkably, in that study RAGE levels were identical in cases and CO subjects for CV diseases. 20 However, when coronary heart disease was considered separately, sRAGE levels were higher in cases than in control subjects adjusted for age and sex. There are additional controversial results regarding sRAGE levels in atherosclerosis.…”

“…33 In the recent analysis of the CARDS study, 20 the hazard ratio for sRAGE and stroke was 0.66, but it did not reach levels of significance owing to the relatively low number (n ¼ 44) of stroke events. Remarkably, in that study RAGE levels were identical in cases and CO subjects for CV diseases.…”

“…16 The existing data about sRAGE and cardiovascular (CV) risk are rather controversial, but there is one finding that is consistent in all studies-an inverse correlation between sRAGE levels with BMI. [17][18][19][20][21] However, up to now nearly all studies about sRAGE were done in a crosssectional setting. [4][5][6]13 Morbid obesity (MO) is a pandemic, worldwide disease with still increasing numbers, 22 and bariatric surgery is one of the most frequent surgeries in the Western World.…”

Soluble RAGE levels in plasma of patients with cerebrovascular events

“…In that case-control study of middle-aged, Italian, non-diabetic men, plasma sRAGE levels were lower in men with Coronary Artery Disease (CAD) than in those without CAD, indicating the anti-inflammatory role of sRAGE. Most human studies have shown that the plasma levels of RAGE are lowers in subjects with cerebrovascular dementia, or individuals at high risk of cardiovascular disease [11][12][13][14], but contradiction data have also been reported [15][16][17][18][19]. In our previous work, CAD patients presenting with Peripheral Artery Disease (PAD) have lower sRAGE levels than CAD patients without peripheral atherosclerosis showing that stable atherosclerotic lesions in different vascular districts are inversely related to soluble levels of decoy receptor sRAGE [20].…”