Blockade of the advanced glycation end products (AGEs) and their receptor (RAGE) system is a possible mechanism for sustained beneficial effects of multifactorial intervention on mortality in type 2 diabetes

Steno-2 Study has previously shown that intensified multifactorial intervention reduces the risk of nonfetal cardiovascular disease in patients with type 2 diabetes. Further, in the recent follow-up study, intensive therapy was found to have sustained beneficial effects on cardiovascular events and death in this population. A similar outcome was reported in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT-EDIC) Research, which revealed that original intensive therapy reduced the risk of cardiovascular events to about 50% of that of conventional treatment in type 1 diabetic patients 11 years after the end of the trial, although glycosylated hemoglobin values in the two groups had almost converged during the follow-up periods. These two clinical studies strongly suggest that so-called 'metabolic memory' causes chronic vascular damage in diabetic patients, that are not easily reversed, even by subsequent, relatively good control of metabolic risk factors. Potential mechanisms for propagating this 'metabolic memory' are the non-enzymatic glycation of proteins. Indeed, the formation and accumulation of advanced glycation end products (AGEs) have been known to progress at an accelerated rate under diabetes, and there is accumulating evidence that AGEs-their receptor RAGE interaction elicits oxidative stress generation and subsequently evokes vascular inflammation, thus being involved in the pathogenesis of accelerated atherosclerosis in diabetes. Since renin-angiotensin system inhibitors or a lipid-lowering agent, atorvastatin, not only inhibit the AGE-signaling to inflammation, but also reduce serum levels of AGEs in type 2 diabetic patients, it is conceivable that the carry-over beneficial effects of multifactoriat intervention on cardiovascular events and death in the follow-up Steno-2 Study could be ascribed, at least in part, to its inhibitory effects on AGE formation and/or the downstream-signaling pathways. Therefore, it is interesting to clarify whether circulating or skin AGE levels at the closure of Steno-2 Study could predict cardiovascular events at the end of the trial.