Glucose metabolism and acute myocardial infarction.

For over 50 years, efforts have been made to develop beneficial glycometabolic support strategies for patients with myocardial ischaemia and infarction. The concept of providing maximal metabolic support to injured myocardial cells is elegant, and has led to relatively simple and low-cost interventions. Glucose–insulin–potassium (GIK) therapy focuses on infusion of high doses of glucose to halt free fatty acid production, and various schemes have been studied over the past decades. Clinical results of GIK infusion have been mixed, with results varying from impressive survival benefits to excess mortality. The CREATE-ECLA study, in which 20 201 patients were randomized to GIK infusion or standard treatment after ST-segment elevation myocardial infarction, showed no benefit of GIK infusion (hazard ratio for 30-day mortality, 1.03; 95% CI, 0.95–1.13). GIK also showed a neutral effect on secondary endpoints. This result, together with a number of other recent studies, supports the current opinion that GIK does not give a clinically significant benefit in acute myocardial infarction (AMI). The traditional GIK scheme often induces hyperglycaemia, as the insulin component is not titrated to maintain normoglycaemia. In the article, Goyal et al. report on elevated glucose levels in patients with AMI and the prognostic value of these levels for adverse outcome (30and 180-day mortality). Goyal et al. have analysed the glucose values collected in the CARDINAL (Complement and ReDuction of INfarct size after Angioplasty or Lytics) studies. In a cohort of 1469 patients, glucose levels were determined at baseline and 24 h thereafter. More than half of the patients had a baseline glucose level higher than 7.8 mmol/L. Of these patients, one-third showed no or only moderate decrease in glucose during the first 24 h. Moreover, a considerable number of patients who presented with a baseline glucose lower than 7.8 mmol/L had a rising glucose level during the first 24 h. Although a large number of reports have described the association between hyperglycaemia at admission and adverse outcome, data on glucose levels at later moments after infarction are scarce. The association between hyperglycaemia at admission and adverse outcome was confirmed by Goyal et al., but more importantly, the change in glucose in the first 24 h was shown to be an independent predictor of adverse outcome. There are three straightforward explanations for this association. First, the change in glucose may be a marker of clinical condition. As the multivariate prognostic model only included baseline characteristics, the change in glucose was the only parameter that contained information about the clinical course of a patient during the first 24 h. Adverse developments during this important initial period, for example unsuccessful reperfusion therapy, may prevent a drop in glucose level. Second, the failure of glucose to drop may be a result of pre-existing glycometabolic dysregulation, either subclinical or frank previously undiagnosed diabetes, which is known to negatively affect prognosis. The third possibility is most interesting from an intervention-oriented point of view: hyperglycaemia might be causally related to adverse outcome, and treatment may therefore improve outcome. Unfortunately, this retrospective study cannot discern the respective contributions of these explanations. Indeed, retrospective studies cannot answer the question whether insulin therapy to treat persistent hyperglycaemia will be beneficial in AMI patients. In critically ill patients admitted to a predominantly cardiosurgical intensive care unit, a large randomized clinical trial has evaluated intensive insulin therapy aiming for normoglycaemia. In a cohort of 1548 patients, insulin therapy markedly reduced mortality during the stay on the intensive care unit (8.0 vs. 5.8%, P, 0.04). A number of complications related to critical illness occurred significantly less frequently with intensive insulin therapy. Although the exact mechanisms that have led to these impressive results of intensive insulin therapy still need more study, a number of mechanisms that may play a role have been identified. Some of these mechanisms may also apply to patients with AMI. For instance, hyperglycaemia is associated with a pro-inflammatory and pro-thrombotic state, and interferes with normal endothelial function. Insulin not only antagonizes these negative aspects of hyperglycaemia, but may also boast intrinsic beneficial effects, such as improved glucose utilization and increased myocardial perfusion. In contrast, evident differences between patients