When Hyperglycemia Is Not Sweet: Increased Mortality in Patients with ACS...

For patients presenting to the hospital with elevated blood glucose levels and acute coronary syndromes (ACS), with or without preexisting diabetes mellitus, an increase in mortality has been observed in a number of trials. In this excellent American Heart Association (AHA) Scientific Statement from the Diabetes Committee of the Nutrition, Physical Activity, and Metabolism Council, Dr. Deedwania and his colleagues provide the current evidence basis for this AHA Scientific Statement and discuss the pathophysiology of hyperglycemia in patients with ACS. The authors also provide recommendations for glucose management to help reduce in-hospital complications and death in these patients. Finally, areas for further investigation are suggested to bridge the multiple knowledge gaps currently preventing optimal care for patients with ACS and elevated blood glucose levels.[1]

Hyperglycemia on hospital admission is common, ranging from 25% to greater than 50% of patients admitted with ACS, and has been demonstrated to be a significant risk factor for in-hospital complications and mortality. Elevation of the blood glucose level in nondiabetic acute myocardial infarction (AMI) patients greater than 110 mg/dL and in diabetic AMI patients greater than 180 mg/dL is associated with a near-linear increase in left ventricular failure, myocardial infarct size, and death in multiple studies. A relative increase in mortality for one study, the Cooperative Cardiovascular Project, which evaluated 141,680 elderly patients with AMI, was 13-77% at 30 days and 7-46% at 1 year.[2] This association of hyperglycemia and increased risk of death was found in both diabetic and nondiabetic patients based on an admission glucose level. A subsequent analysis by the same group of 16,871 patients with AMI found that persistent hyperglycemia, identified through serial glucose testing during hospitalization, was an even better predictor of mortality than admission glucose alone.[3]

Hyperglycemia in the setting of ACS appears to result in multiple physiologic abnormalities responsible for the higher risk of complications and death observed in this patient population. A decrease in collateral circulation and increased infarct size have been noted in patients with ACS.[4] Patients with an elevated blood glucose have also been shown to have an increased incidence of occlusion of the infarct-related artery in ST-segment elevation myocardial infarction (STEMI) with an increase in 30-day mortality.[5] Hyperglycemia has been shown to increase the binding of inflammatory cells to endothelium and increased inflammatory cytokine production in monocytes as reflected by elevated C-reactive protein, interleukin (IL)-6, and tumor necrosis factor (TNF)-alpha levels.[6] It also disturbs platelet function through the impaired responsiveness of platelets to the antiaggregatory effects of nitric oxide in patients with ACS.[7-9] In addition, elevated glucose levels have been associated with increased free fatty acid concentrations, increased insulin resistance, and impaired glucose utilization, which can potentially worsen ischemia through elevated oxygen consumption.[10]

Because of the multiple deleterious effects of hyperglycemia in the patient with ACS, the benefits of insulin have been intensively studied in the setting of ACS. Insulin has multiple antiinflammatory effects, including a reduction of C-reactive protein and serum amyloid A concentrations and suppression of the generation of reactive oxygen species. It also promotes the release of nitric oxide and the expression of endothelial nitric oxide synthase by the endothelium, serving as a potent vasodilator.[11,12] The use of insulin in hyperglycemic patients with ACS may improve the activity of fibrinolytic agents and decrease the aggregation of platelets by improving their response to nitric oxide. There is also evidence that insulin has an antiapoptotic effect on myocardial cells. It is not clear whether these beneficial effects are due to glucose level normalization or insulin infusion.

Surprisingly, it has been difficult to demonstrate a beneficial effect for control of glucose levels in patients with ACS. A large multinational randomized clinical trial of 20,201 patients with AMI, CREATE-ECLA, showed no difference in patients randomized to receive glucose/insulin/potassium (GIK) versus usual treatment in 30-day mortality, cardiac arrest, or cardiogenic shock. This may have been due to the inclusion of patients with both normal and elevated glucose levels in the study and 24-hour glucose levels that were actually higher in the GIK group (155 mg/dL) than in the control group (135 mg/dL).[13] In an observational study from England and Wales, the National Audit of Myocardial Infarction Project, which enrolled 38,864 patients without known diabetes, 3835 had elevated glucose levels on admission. Treatment with insulin was initiated for these patients, targeting glucose normalization. A significant reduction in mortality was observed at 7 days of 11.6% versus 16.5%, and at 30 days of 15.8% versus 22.1% for patients receiving insulin compared to patients not receiving insulin.[14] Studies by Van Den Berghe and colleagues in both surgical and medical intensive care unit (ICU) patients, using target-driven glucose levels through intensive insulin therapy, demonstrated significant reductions in mortality for the surgical ICU patients and in morbidity in medical ICU patients.[15,16] It is also important to stress that glucose control should not be too aggressive, as hypoglycemia in patients with ACS has also been associated with both an increased short- and long-term risk of mortality. Currently, there are few Registry data available on the treatment of patients with ACS and hyperglycemia across the United States. In the Cooperative Cardiovascular Project, for patients with severe hyperglycemia on admission, 27% of patients with known diabetes and 78% of patients without known diabetes did not receive insulin therapy.[2]

It is important for clinicians to be aware of the increased risk of death and complications for patients with hyperglycemia in the setting of ACS. For cardiologists, emergency physicians, and clinicians, a clearer understanding of the impact of elevated blood glucose on morbidity and mortality in patients with ACS is essential. In this AHA Scientific Statement on Hyperglycemia and Acute Coronary Syndrome, Deedwania and his coauthors appropriately conclude with a number of areas requiring further investigation, preferably through randomized, controlled clinical trials.[1] Ideally, this AHA Scientific Statement will serve as the impetus to drive further studies to elucidate the proper approach to hyperglycemia in the ACS patient. Presumably, these future trials will provide sufficient evidence basis to allow the appropriate integration of proper glucose control into the AHA/American College of Cardiology Guidelines for care of patients with ST-segment elevation and non-ST-segment elevation ACS.