Circulating levels of AGEs and soluble RAGE isoforms are associated with all-cause mortality and development of cardiovascular complications in type 2 diabetes: a retrospective cohort study

Abstract

Background Advanced glycation end-products (AGEs) and their interaction with the receptor for advanced glycation end-products (RAGE) play a pivotal role in the development and progression of type 2 diabetes. In this retrospective cohort study, we explored the association of circulating levels of soluble RAGE (sRAGE) isoforms, i.e., endogenous secretory esRAGE and cleaved cRAGE, AGEs and their respective ratios with 15-year all-cause mortality in type 2 diabetes. Methods Baseline AGEs and sRAGE isoforms concentration were measured by ELISA in 362 patients with type 2 diabetes and in 125 age- and gender-matched healthy control subjects (CTR). Independent predictors of mortality were determined using Cox proportional-hazards models and used to build and validate a nomogram for all-cause mortality prediction in type 2 diabetes. Results AGEs, total sRAGE, cRAGE and the AGEs/sRAGE and AGEs/esRAGE ratios were significantly increased in patients with type 2 diabetes compared to CTR (p < 0.001). In CTR subjects, but not in type 2 diabetes patients, a significant negative correlation between cRAGE and age was confirmed (p = 0.003), whereas the AGEs/sRAGE (p = 0.032) and AGEs/cRAGE (p = 0.006) ratios were positively associated with age. At an average follow-up of 15 years (4,982 person-years), 130 deaths were observed. The increase in the AGEs/cRAGE ratio was accompanied by a higher risk of all-cause mortality in patients with type 2 diabetes (HR per each SD increment = 1.30, 95% CI 1.15–1.47; p < 0.001). Moreover, sRAGE was associated with the development of major adverse cardiovascular events (MACE) in type 2 diabetes patients without previous MACE (OR for each SD increase: 1.48, 95% CI 1.11–1.89). A nomogram based on age, sex, HbA1c, systolic blood pressure, and the AGEs/cRAGE ratio was built to predict 5-, 10- and 15-year survival in type 2 diabetes. Patients were categorized into quartiles of the monogram scores and Kaplan-Meier survival curves confirmed the prognostic accuracy of the model (log-rank p = 6.5 × 10− 13). Conclusions The ratio between AGEs and the cRAGE isoform is predictive of 15-year survival in patients with type 2 diabetes. Our data support the assessment of circulating AGEs and soluble RAGE isoforms in patients with type 2 diabetes as predictors of MACE and all-cause mortality.

HbA1c-based rather than fasting plasma glucose-based definitions of prediabetes identifies high-risk patients with angiographic coronary intermediate lesions: a prospective cohort study

“…[ 19 ] reported that circulating AGEs and soluble receptor for AGE (RAGE) isoforms in patients with type 2 diabetes as predictors of MACE and all-cause mortality [ 19 ]. In addition, AGEs can be estimated by the non-invasive skin autofluorescence, and provided additional prognostic information in patients with both type 1 [ 20 ] and type 2 diabetes [ 21 ].…”

Prognostic value of soluble ST2, high-sensitivity cardiac troponin, and NT-proBNP in type 2 diabetes: a 15-year retrospective study

“…The estimated glomerular filtration rate (eGFR) was calculated according to CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation based on serum creatinine, age, sex, and ethnicity. The presence of diabetic complications was established as previously described [ 23 ]. Diabetic retinopathy was assessed by fundoscopy through dilated pupils and/or fluorescence angiography; incipient nephropathy was defined as a urinary albumin excretion rate > 30 mg/24 h and a normal creatinine clearance; neuropathy was established by electromyography; ischemic heart disease was defined by clinical history and/or ischemic electrocardiographic alterations; peripheral artery disease, including atherosclerosis obliterans and cerebrovascular disease based on history, was defined with physical examinations and Doppler velocimetry.…”

Accelerated AGEing: The Impact of Advanced Glycation End Products on the Prognosis of Chronic Kidney Disease

“…In contrast, in DM and CKD. sRAGE levels increase [ 21 , 22 ] have been independently associated with cardiovascular outcome [ 21 , 23 ]. This means that changes in sRAGE levels depend on the clinical setting.…”