Shifting the Disease Management Paradigm From Glucose

W ith the worldwide growing prevalence of obesity and type 2 diabetes, cardiovascular disease (CVD), diabetic nephropathy, retinopathy, and neuropathy as principal complications of diabetes are expected to become a major public health challenge. Diabetes accounts for at least double the number of death rates compared with otherwise healthy individuals. Hyperglycemia represents the hallmark of diabetic metabolic changes, but whether antihyperglycemic treatment alone is sufficient to prevent cardiovascular and other organic complications in type 2 diabetes is a matter of debate. A recent meta-analysis of epidemiological studies reported an 18% increase in CVD risk for every 1% increase in A1C (1). Two major studies have underlined the importance of optimal glycemic control in reducing diabetes-related complications. The U.K. Prospective Diabetes Study (UKPDS) showed that intensive glycemic control (mean A1C below 7%) by means of insulin or oral agents in type 2 diabetic patients reduces the relative risk for microvascular outcomes by 25% over a period of 10 years (relative risk reduction). The reduction in macrovascular end points (myocardial infarction) was of borderline significance (16% relative risk reduction, P 0.052) (2). The Diabetes Control and Complications Trial/ Epidemiology of Diabetes Intervention and Complications (DCCT/EDIC) trial reported a 50% reduction in CVD outcomes in type 1 diabetic patients treated intensively over a period of 6.5 years and followed for a further 12 years (3). In contrast to these data, the intensive glucose-lowering arm of the Action to Control Cardiovascular Risk (ACCORD) trial—a major trial in type 2 diabetic patients— has been recently stopped because of increased mortality in this group (4). The ACCORD trial was set up to test three complementary medical treatment strategies for type 2 diabetes to reduce CVD morbidity and mortality. Aggressive reduction of A1C below 6%, combined increase in HDL cholesterol, and reduction of LDL cholesterol and lowering of blood pressure (BP) were the main therapeutic targets. Because of safety concerns after concise review of the available data and recommendation by the safety monitoring board, the intensive blood glucose (BG)-lowering treatment arm was halted in February 2008. There was a higher death rate in the intensively treated group, although a lower rate of primary outcome events such as nonfatal myocardial infarction was detected. The BPand lipid-lowering trials will be continued until June 2009. The unexpected high mortality in the group undergoing a treatment targeting an A1C below 6% was attributed to hypoglycemic episodes in older and plurimorbid patients, or to the adverse effects of a particular drug or drug combination. These data are not isolated, since the 2-year feasibility phase of the Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type II Diabetes Mellitus (VA-CSDM) found a nonsignificant increase in the risk for cardiovascular events in the intensively treated group (5). Moreover, some combinations of drugs (such as metformin and sulfonylureas) have previously been considered to be responsible for increased mortality, suggesting that hyperglycemia should not be lowered at any price (6). Overall, at least three conclusions can be drawn from these data: 1) lowering of BG in elderly and plurimorbid patients should be performed with caution, 2) combination therapies should be rigorously considered, and 3) there may be a certain threshold beyond which lowering of BG may be detrimental. One further aspect that is under debate in diabetes treatment is which of the two aspects of hyperglycemia should be mainly addressed: the preprandial or the postprandial hyperglycemia? Several studies have found that postprandial BG correlates better with CV risk than does fasting BG (7). The possible mechanisms have been reviewed elsewhere (8). Consistent with these findings, treatment of postprandial hyperglycemia with acarbose in people with type 2 diabetes resulted, according to a meta-analysis of seven randomized studies, in a reduction of CVD development by 35% (9). Evidence from large interventional studies is still lacking and the results of ongoing trials are expected. From all the aforementioned data, it is obvious that controversy still exists as to whether postprandial or fasting BG should be targeted, and it is not exactly known at which point the benefit of lowering BG stops and the harm begins. However, there is also another factor beyond hyperglycemia that jeopardizes the cardiovascular system of diabetic patients during the postprandial phase. Recently, it has been shown that dietary toxins significantly impair endothelial function in the postabsorptive state in people with type 2 diabetes, an effect that went beyond hyperglycemia and hypertriglyceridemia (10). Food toxins generated by heating consist of advanced glycation end products (AGEs) and lipoxidation end products, as well as other ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●