Glycaemic Control and Protection of the Vasculature from Glucose Toxicity

Abstract

Diabetes, notably type 2 diabetes, is a major and prevalent health problem with a minimal current estimate of 250 million sufferers worldwide, a prediction of 366 million by 2030 and, based on the evidence of numerous reports, we can also anticipate an excessive morbidity and mortality rate in this population primarily as a result of cardiovascular disease (Kannel & McGee, 1979; Wild et al., 2004). As reflected by the data from the 1991 United Kingdom Prospective Diabetes Study, UKPDS, with 5102 subjects with type 2 diabetes, and the 1993 Diabetes Control and Complications Trial, DCCT, with 1441 type 1 diabetics, the established dogma for the best form of management for patients with diabetes is tight glycaemic control (DCCT 1993; UKPDS 1991, 1998). Such conclusions have been re-emphasised as reflected by a report by Standl and colleagues (2009) indicating that the incidence of cardiovascular events associated with diabetes is reduced by 10-15% per 1% reduction in absolute glycated haemoglobin, HBA1c, levels. In addition, the Emerging Risk Factors Collaboration (ERFC) study, a collaborative meta-analysis of 102 prospective studies, made the observation that the pre-existence of diabetes enhanced the risk of vascular disease more than two fold (ERFC, 2010). Furthermore, the ERFC study of 820,900 participants also concluded that a 50-year-old with diabetes died approximately 6 years earlier than a person without diabetes and that diabetes was moderately associated (but not necessarily causality) with death from certain cancers such as liver, pancreas, bladder, breast, colorectal, lung and ovary as well as other causes including infectious diseases, degenerative disorders and others (ERFC, Seshasai et al 2011). Nonetheless, a ‘glucocentric’ approach to the treatment of diabetes was delivered a setback with the results, released in 2007, from the Action to Control Cardiovascular Risk in Diabetes, ACCORD study of 10,251 patients. The intensified glucose lowering arm of the ACCORD study with 5,128 patients targeted glycated haemoglobin, HBA1c, of <6% was discontinued when it became apparent that such an intensive regimen resulted in a significantly higher all-cause risk of death of 22% and a 35% increase in cardiovascular mortality (Gerstein et al., ACCORD, 2008). In contrast, data from the Action in Diabetes and Vascular Disease, ADVANCE, that was released shortly after that from the ACCORD study provided no evidence of an increased mortality amongst the 11,140 high-risk patients who were randomly assigned to either standard or intensive glucose control (HbA1c of 6.5 or less) in the study, but also reported a 10% reduction in combined microand macrovascular events (ADVANCE 2008). Similarly for the Investigators in the Veterans Affairs Diabetes Trial,