HYPOGLYCEMIA AND INPATIENT GLUCOSE CONTROL
Hyperglycemia is common in acutely ill patients and is associated with an increased morbidity and mortality (33). This has subsequently led to a large number of trials using various intensive insulin protocols to control inpatient blood glucose. However, results from these trials have increased the controversy over the risks versus benefit of tight inpatient glycemic control. Van den Berghe et al. (34) demonstrated that intensive insulin therapy in critically ill patients reduced morbidity and mortality. The DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) study found that insulin-glucose infusion followed by intensive subcutaneous insulin in diabetic patients with acute myocardial infarction improved long-term survival (35). Conversely, the DIGAMI 2 study did not confirm superiority of insulin versus conventional treatment, but reaffirmed the importance of good glycemic control in prevention of cardiovascular events (36). The recently published NICE-SUGAR (Normoglycemia in Intensive Care Evaluation–Survival Using Glucose Algorithm Regulation) study found that intensive glucose control increased mortality among adults in the ICU (37). The Glucose Insulin in Stroke Trial (GIST)-U.K. looked at tight control of glucose in patients with acute stroke using an intensive insulin infusion protocol and found no benefit (38). The GIST-UK trial was underpowered to draw any firm conclusions. However, the sub-analysis of the mean change in glucose at 24 h showed that patients who had a decrease in plasma glucose of ≥2 mmol/l had a mortality rate of 34 versus 22% for those who had a <2 mmol/l decrease (38). This raises the question of hypoglycemia having a role in increased mortality in the inpatient setting.
Some recent studies looking at using intensive insulin infusions such as the volume and insulin therapy in severe sepsis and septic shock (VISEP) showed that the incidence of hypoglycemia was higher in the intensively treated group (39). A study by Kosiborod et al. (40), looking at 16,871 patients admitted with myocardial infarction, found that a J-shaped relationship existed between glucose and mortality. Incremental increases above 120 mg/dl and incremental declines below 70 mg/dl were found to be strongly associated with increased mortality. The slopes of these relationships were even steeper in patients with diabetes, suggesting hypoglycemia could contribute to increased mortality, especially in diabetic patients. In another study, a pooled analysis of over 4,200 patients from various myocardial infarction intervention studies, death occurred in 4.6% of the patients with hypoglycemia versus 1% of those who were considered euglycemic (81–199 mg/dl) (41). In contrast, a sub-analysis of the DIGAMI 2 data did not show hypoglycemia to be an independent risk factor for future morbidity or mortality in patients with type 2 diabetes and myocardial infarction (42).
Thus, the role of hypoglycemia in cardiovascular mortality in the inpatient setting is still controversial. Much of the variability in results is due to the different protocols used, differences in definition of hypoglycemia, as well as methodology of its detection and report, presence or absence of safeguards against hypoglycemia in the protocols, local training level of the personnel administering the protocols, and selected patient population. Hence, carefully constructed clinical trails to research this question are required. However, it is prudent to conclude from the available data that severe hypoglycemia should be avoided as much as possible in the inpatient setting.
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MECHANISMS BY WHICH HYPOGLYCEMIA MAY AFFECT CARDIOVASCULAR EVENTS
Hypoglycemia induces several counterregulatory responses. They include a decrease in pancreatic β-cell insulin secretion, an increase in pancreatic α-cell glucagon secretion, an increased sympathoadrenal response with acute plasma increase in adrenaline and norepinephrine (in addition to its elevated tissue turnover), as well as an increased secretion of ACTH/glucocorticoids. Besides these classical responses, there are several indirect changes induced by hypoglycemia that affect inflammatory cytokine secretion, endothelial function, coagulation, and fibrinolysis. All of these responses have potential adverse effects on cardiovascular morbidity and mortality and will be discussed in this section (Fig. 1).
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