Association between advanced glycation end products (AGEs) and diabetic complications: A systematic review and...

Diabetes mellitus is characterized by chronic hyperglycemia, which accelerates the accumulation of advanced glycation end products (AGEs), contributing to vascular complications through oxidative stress and inflammation, though clinical evidence remains heterogeneous. This systematic review and meta-analysis searched PubMed, Embase, Scopus, and Web of Science for observational studies evaluating AGEs in diabetes. To resolve methodological variations, analyses were stratified by modality: tissue-bound AGEs via skin autofluorescence (sAF) and circulating isoforms, specifically N^ε-carboxymethyllysine (CML). Fifteen studies (6,288 participants) were included. Patients with complications had significantly higher AGE levels than those without (pooled MD = 0.29 AU; 95% CI: 0.23-0.36; I² = 71%). Subgroup analyses revealed that tissue-bound sAF was consistently elevated across all microvascular and macrovascular subtypes. Conversely, circulating CML demonstrated a highly selective, robust association with macrovascular outcomes (MD = 20.24 µmol/mol lys; 95% CI: 7.19-33.29) but no significant link with microvascular angiopathy. Overall, elevated AGEs are consistently associated with diabetic complications. Tissue-bound sAF serves as a versatile clinical biomarker for global end-organ damage, whereas circulating CML acts as a distinct indicator of macrovascular risk.