Point : Inpatient Glucose Management

In January 2004, a panel convened by the American College of Endocrinology (ACE) and the American Association of Clinical Endocrinologists (AACE) issued a position statement on the management of glucose in hospitalized patients (1). This panel included representation by the American Diabetes Association (ADA), the Endocrine Society, the American Heart Association, the Society of Critical Care Medicine, the Society of Thoracic Surgeons, The American Association of Diabetes Educators, The American Society of Anesthesiologists, and The Society of Hospital Medicine, all of whom were cosignatories to the ensuing document. The position statement recommended that a preprandial target level of 110 mg/dl (6.0 mmol/l) be set for the plasma glucose level of all hospitalized patients, regardless of the presence or absence of a prior diagnosis of diabetes (1). The impetus for establishment of a position on this issue largely arose from the publication of two major prospective controlled intervention trials that demonstrated significant reductions in serious morbidities and mortality in hospitalized patients in whom glycemia was tightly regulated (2,3). These trials were in turn undertaken to further address the findings of prior observational studies, which showed a strong correlation between hyperglycemia and poor clinical outcomes in a variety of inpatient settings (4–8). Until recently, it seemed intuitively obvious that hyperglycemia manifested under physiologically stressful situations was a consequence of the primary illness and a marker of its severity, rather than directly contributing additional morbidity to it. While the former may indeed be the case, it came as a surprise to many that prospective trials addressing the hyperglycemia alone, or to be more specific, addressing it by the administration of insulin, improved multiple immediate clinical outcomes, including reducing sepsis, renal failure, transfusion requirements, and polyneuropathy (3,9). Moreover, in one study, in-hospital mortality was reduced by 50% (10). Consequent upon the favorable effects on morbidity, there was a reduction in the length of hospital stay and overall cost of care (6). The presence of diabetes as a comorbidity has been calculated to add an average $11,500 to the cost of a hospital admission in 1997 dollars (11), and between 1997 and 2000 its identification increased from 9.5 to 12.4% of hospital admissions or 4.5 million admissions annually (12,13), although this is almost certainly a considerable underestimate of the true prevalence (14). Of additional interest was the finding that long-term outcomes were also improved by the intervention of intensive glycemic control, which reduced mortality by 25% 3 years after the initial treatment in one study (2). Interestingly, mortality was reduced by an even greater extent (45%) in patients who had not previously been treated for diabetes (2). The biochemical and physiologic basis for these beneficial effects is not yet fully understood. Furthermore, it is not clear whether the reduction in plasma glucose or the therapeutic administration of insulin is the major contributor to this treatment effect, since in one study (2), the subgroup with the greatest benefit from the intervention had been treated with oral antidiabetic agents before admission. The multiple metabolic actions of insulin make it an attractive candidate for the mechanism producing the favorable changes. Insulin lowers catecholamine-induced free fatty acid release and acutely regulates the vasomotor function and contractility of the myocardium and the vasculature (15,16), as well as stimulating nitric oxide production, improving endothelial function, and lowering inflammatory and prothrombotic mediators and cytokines (17,18). On the other hand, it has long been known that hyperglycemia per se impairs immune function in several ways: neutrophil function is reduced, complement binding is attenuated, and monocyte phagocytic function is disrupted (19). Moreover, hyperglycemia has been shown to induce a proinflammatory and prothrombotic state in human studies (20 –22). It is therefore possible, and even likely, that the combined effects of increased insulinemia and reduced glycemia act in a complementary, or possibly synergistic, manner at different sites to bring about overall improvements in hemodynamic, immune, and metabolic functioning. As momentum gathers to implement programs designed to achieve intensive glycemic control in hospitalized patients nationwide, it has been pointed out that the favorable impact of tight glycemic regulation with insulin has hitherto been achieved in the artificial setting of unblinded, albeit controlled, clinical trials in high-risk patients in intensive care units (ICUs) in academic medical centers and that the findings are unproven in the nonresearch general clinical care setting. It has even been suggested that the improvements may have resulted from the increased attention and vigilance that is necessarily given to such patients, in whom the potential for insulin administration to cause hypoglycemia, with its own adverse clinical impact, is significant. It has been argued that extrapolation of these data to implementation of widespread clinical interventions in less controlled settings is premature, risky, and expensive. Furthermore, the findings of a recently published major prospective interventional study (Diabetes and InsulinGlucose Infusion in Acute Myocardial Infarction [DIGAMI]-2 [23]) did not reproduce the benefits of the original DIGAMI trial (2). These criticisms have no legitimate basis in fact, since the conclusions primarily derive from randomized controlled trials, which are the only valid method for hypothesis testing and can only be performed in attentive clinical care settings. Results of randomized prospective interventional clinical trials constitute the most widely accepted and rigorous level of evidence leading to acceptance of new therapies into general P o i n t C o u n t e r p o i n t