Glucose control, macro- and microvascular disease, and the Food and Drug Administration: let's keep our eye on the ball.

The increase in prevalence of diabetes worldwide continues unabated with recent estimates in the United States alone being24million,amountingto8%ofthepopulation.Themajor concern with the growing number of diabetes cases is the resulting micro- and macrovascular complications resulting in significant morbidity and mortality for more individuals and their families.Thus,developmentofnewapproachesthatincorporate both pharmacology and lifestyle factors that will lead to prolonged and better life is desperately needed. It is noteworthy that the last few years have seen the release of a wealth of new information regarding glycemia and diabetes complications, with much attention focused on glucose control and macrovascular disease. Although epidemiological analyses suggest that each 1% increase in hemoglobin A1c increases the risk for cardiovascular disease (CVD) by approximately 18%, the unanswered question for diabetes management was whether treating patients to near normal levels for hemoglobin A1c reduced CVD events (1). As such, both primary analyses on macrovascular outcomes from long-term clinical trials examining the effect of improved glucose control on CVD per se and secondary analyses of data obtained during studies of glucose-lowering medications have been attempted. In the process of considering these observations, there has also been debate about the veracity of the approachesusedtoreachsomeoftheconclusions.Thenetresulthas been a great deal of consternation in the clinic, and significant confusion for the provider, as to what constitutes the best therapeutic regimen for the diabetic patient who has significant cardiovascular risk factors. So where are we currently in our understanding of the role of glucose control in reducing macrovascular disease events? Findings in the United Kingdom Prospective Diabetes Study (UKPDS) suggested that improved glucose control may benefit those with type 2 diabetes (2). This was supported by the epidemiological follow-up of the cohort of type 1 diabetic patients intheDiabetesControlandComplicationsTrialinwhoma42% reductionintheriskofanyCVDeventwasstillpresent10yrafter the end of the aggressive control period (3). These data provided reasonable assurance that it was just a matter of time before definitive clinical data could be obtained demonstrating conclusively that intensive glucose control, in addition to effective lipid and blood pressure management, reduced CVD events in individuals with type 2 diabetes. However, with the release over the last few months of the findings of three large clinical trials in patients with type 2 diabetes, the results have not clarified the situation but, if anything, appeared to have muddied the waters! In early 2008, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study was terminated prematurely due to a 22% increase in all-cause mortality (4). A closer look demonstrates there were inconsistencies in the direction of components of the composite outcome. Although the intensively treated group had significantly greater overall mortality and cardiovasculardeath,nonfatalmyocardialinfarctionwassignificantlyless forintensivetreatment,ascomparedwithstandardtherapy,suggesting a benefit for improved glycemia. Nonfatal stroke and