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Background
Diabetes mellitus, essentially a disorder of chronic hyperglycaemia, is a condition that is prevalent in about 5-7% of the adult population.[1] Despite considerable progress in the treatment of hyperglycaemia and hypertension, the presence of vascular complications of diabetes is still around 20-25% among patients with diabetes of more than 5 years' duration. There is a strong link between diabetes and cardiovascular disease, with nearly 80% of deaths associated with diabetes being due to cardiac complications.[2] Prolonged hyperglycaemia is now recognized as a primary cause of diabetic complications.[3]
There is an increasing body of evidence implicating advanced glycation end-products (AGEs) as one of the major causes of diabetic complications. AGEs are formed by a complex chain of reactions involving reducing sugars such as glucose and proteins, resulting in the formation of multimeric complexes that trigger several pathological events.[4] In vivo accumulation of AGEs over time is associated with important structural and functional changes in the cardiovascular system, including increased vascular and cardiac stiffening with atherosclerotic plaque formation, which manifests clinically as hypertension, diastolic dysfunction and atherosclerosis.[5] In the extracellular environment, AGEs modification of proteins has been shown to lead to cross-linking of extracellular matrix (ECM) proteins, particularly collagen and elastin, resulting in increased vascular stiffness and diminished arterial and myocardial compliance.[6] AGEs have been shown to quench nitric oxide (NO), thereby mediating a defective endothelium-dependent vasodilation.[7] Clinical studies have demonstrated increased levels of AGEs on low-density lipoproteins (LDLs) in diabetic compared with non-diabetic individuals.[2] Glycated LDL is more susceptible to oxidative modification, a critical step in the initiation of atherogenesis. Intracellular formation of AGEs leads to functional derangement of macromolecules. Interaction of AGEs with their receptors present on several cell types, including endothelial cells, smooth muscle cells and macrophages, causes increased oxidative stress and induces the production of pro-inflammatory cytokines and growth factors.[2] Studies show that type 2 diabetes is associated with low-grade inflammation and endothelial dysfunction, which correlate with an increased risk of cardiovascular mortality.[8] Interventions that reduce AGEs have been shown to ameliorate the development and/or progression of cardiovascular disease and extend life.[5]
Alagebrium chloride (formerly known as ALT-711) [4,5-dimethyl-3-(2-oxo-2-phenylethyl)-thiazolium chloride] belongs to a novel class of thiazolium derivatives that are thought to act via cleavage of preformed AGE protein cross-links in...