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Strong epidemiological evidence indicates that diabetes is a major risk factor for cardiovascular disease (CVD), and despite advances in the treatment of CVD, outcomes in patients with diabetes mellitus (DM) remain suboptimal. In the European prospective investigation into cancer in Norfolk (EPIC–NORFOLK) study,1 the risk of CVD and total mortality associated with haemoglobin A1c (HbA1c) concentrations increased continuously through the sample distribution. An increase in HbA1c of 1 percentage point was associated with a relative risk of death from any cause of 1.24 (95% CI 1.14 to 1.34; p<0.001) in men and with a relative risk of 1.28 (95% CI 1.06 to 1.32; p<0.001) in women. Several meta-analyses2–4 arrived at similar conclusions, setting the stage for the conduct of randomised controlled trials exploring the effect of glycaemic control on CVD outcomes.
Several plausible mechanisms underlie the relationship of DM and CVD, all of which lend themselves to the development of specific treatment targets, although the lowering of glucose per se appears to be an appropriate and potentially beneficial intervention. Obesity is characterised by an expanding adipose tissue mass and the development of an inflammatory state caused by the increased secretion of cytokines and adipokines from adipose tissue.5 The hyperglycaemic state causes oxidative stress and increased glycation of proteins in the body, leading to the formation of advanced glycation end products.6 These in turn contribute to exacerbation of the proinflammatory state, activation of macrophages and vascular smooth muscle cells, low-density lipoprotein oxidation and accelerated atherogenesis.
It thus seems logical that a reduction in blood glucose to near normal would result in a reduction in CVD events. Although clinical trials have shown that intensive glucose control reduces the risk of microvascular complications among patients with type 2 DM, its effect …