Impaired insulin secretion and insulinstimulated glucose uptake

glucose oxidation requires less oxygen than FFA oxidation to maintain ATP production. Thus, myocardial energy use is more efficient during the increased dependence on glucose oxidation with ischemia (approximately 11% more ATP is generated from glucose oxidation as compared with FFA oxidation). In the setting of relative insulinopenia (insulin resistance or frank DM) that is exacerbated by the stress of AMI, the ischemic myocardium is forced to use FFAs more than glucose for an energy source because myo-cardial glucose uptake is impaired acutely. Thus, despite acute hyperglycemia, a metabolic crisis may ensue as the hypoxic myocardium becomes less energy efficient in the setting of frank DM or insulin resistance.

Insulin augments the translocation of GLUT-1 and GLUT-4 receptors to the sarcolemma and can diminish FFA release from myocytes and adipocytes [27]. Thus, the extent to which the myocardium expresses an intact response to insulin, therapeutic augmentation of oxidative glucose metabolism by way of exogenous insulin, or improved insulin sensitivity may play a useful role for improving outcomes in patients who have hyperglycemia and relative insulinopenia as the result of an insulin-resistant state. The concept of a metabolic cocktail to promote glucose oxidation and reduce FFA levels to protect the ischemic myocardium dates back to Sodi-Pallares et al [28]. Early studies yielded promising results; a subsequent meta-analysis of 1932 patients who had AMI suggested that therapy with glucose-insulin-potassium (GIK) reduced mortality by 28% [29]. Mortality was reduced by 48% in a subgroup of patients who received high-dose GIK to suppress FFA levels maximally. A prominent Latin American Study [30] further suggested that GIK in the setting of acute reperfusion (predominantly thrombolysis) for patients who had AMI reduced in-hospital mortality by 66%. There was a remarkable reduction in absolute mortality of 10% (15.2% to 5.2%) in GIK-treated reperfused patients versus controls.

Despite nearly a half century of study and its low cost and minimal side-effect profile, acceptance of the GIK metabolic cocktail in AMI has not been forthcoming. The lack of enthusiasm over the use of GIK in AMI seems to stem from the lack of large randomized trials, controversy over low- versus high-dose therapy, and a cumbersome mode of delivery that requires a large volume load. Collectively, clinical studies suggest that the dose of insulin must be optimized to confer benefit; little effect is seen with low-dose GIK protocols [30-31]. In addition, GIK studies have contained only a small number of high-risk patients who had congestive heart failure or cardiogenic shock.

Recently, Van der Horst et al [32] reported the results of the largest study to date of GIK in combination with acute reperfusion with primary angioplasty. Overall, in this 940-patient Dutch study, there was no difference in mortality between those who received GIK and those who received placebo (4.8% versus 5.8%; P = 0.5). In 856 patients who did not have heart failure, mortality was reduced 72% with GIK as compared with placebo (1.2% versus 4.2%; P < 0.005). There was a nonsignificant trend toward benefit in the diabetic subgroup. The prevalence of the highest quartile of infarct size also was reduced among subjects who received GIK (22% versus 29%; P < 0.005), with a trend toward a lower prevalence of ejection fractions less than 30% (13% versus 17%; P = 0.2) in subjects who received GIK compared with subjects who did not.

GIK was not beneficial, however, in patients who had congestive heart failure in the Dutch study, as compared with a trend toward benefit in the Latin American trial. The sample size of patients who had heart failure was small in both studies and the infusion rate was twice as fast in the Dutch study; this resulted in more than 2 L of fluid being delivered in the first 8 hours. Additionally, successful reperfusion was accomplished in only a modest number of patients who had heart failure in both studies. Outcomes were remarkably similar in GIK-treated patients who did not have heart failure in the aforementioned studies, despite a wide range in the duration of symptoms before GIK therapy (2.5 to 11 hours). To help to address the issues that surround GIK therapy, a large, randomized trial of GIK therapy in AMI is currently in progress (GIK II: http://

In the Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI) trial [14-16], acute treatment for at least 24 hours with intravenous GIK until blood sugar was controlled, coupled with aggressive subacute treatment with subcutaneous insulin, resulted in a 29% relative reduction in 1-year mortality in a cohort of patients that predominantly had type 2 DM. As compared with 43% of control patients, 87% of GIK-treated patients were discharged on insulin. Patients who had previous insulin use and a low CV risk profile had the most promising results (58% reduction in in-hospital mortality and 52% reduction in 1-year mortality). Hypoglycemia occurred in 15% of patients who received insulin infusion; however, only 10% of patients required discontinuation of their insulin infusion.

Recently, the results of the DIGAMI-2 trial further highlighted the importance of glucose lowering in AMI. However, this pivotal trial, which was released at the 2004 European Association for the Study of Diabetes, failed to show an improvement in total mortality in diabetic patients with AMI undergoing intensive insulin therapy. The trial was initially designed to include 3000 subjects but was stopped at 1253 subjects due to poor enrollment. DIGAMI-2 compared acute insulin-glucose infusion followed by an insulin-based long-term glucose control with insulin-glucose infusion followed by standard glucose control or routine metabolic management in the third group according to physician discretion.

The results of the DIGAMI-2 trial were confounded by several factors. The actual mortality was significantly lower than the estimated mortality for the group at 2 years, and the mean hemoglobin A1c at the time of enrollment in all three groups was relatively low at 7.3%. The glucose goal was not reached in the intensive therapy group; 41% of patients in the control group with routine care received extra insulin in the hospital, and 14% received insulin infusions. Multidose insulin for glucose lowering was given to only 42% of patients chronically in the intensively managed group (compared with 13%-15% in the two remaining groups). Glucose control over the duration of the study was similar in the three groups (mean hemoglobin A1c: 6.8%). The mortality ranged between 19.3% and 23.4% between the three groups, which was not statistically significant.

There was appropriate use of cardioprotective drugs during AMI in the DIGAMI-2 trial. At hospital discharge, beta-blockers were given to over 80% of the patients, aspirin was given to nearly 90% of the patients, and angiotensin-converting enzyme (ACE) inhibitors and statin therapy were given to approximately 65% of the patients. The overall 2-year mortality of approximately 20%, although significantly lower than the 30% noted in the DIGAMI-1 trial, is evidence that there is still much work to do. Overall these results suggest that the mode of glucose therapy may not matter as much as aggressive glucose control. Because all three groups reached a similar mean A1c of below 7%, the hypothesis of the trial was not fully tested. Additionally, there was significant crossover with the use of both acute intravenous insulin therapy and chronic insulin therapy in the three groups, complicating the analysis of insulin-based therapy compared with the routine use of oral hypoglycemic agents after myocardial infarction.

Acutely GIK therapy decreases lipolysis and improves glucose oxidation; aggressive metabolic therapy also is associated with a myriad of effects in ischemic/reperfused myocardium and in non-infarcted myocardium that is exposed to increased afterload stress (Box 3). FFA levels rapidly increase in AMI as a result of the lipolysis that is secondary to catecholamine excess (and the presence of heparin). FFAs are directly toxic to the myocardium, promote arrhythmogenesis, and, are inefficient as a metabolic substrate. GIK shifts oxidative metabolism from FFA to glucose, lowers circulating FFA levels, and seems to protect myocytes from increasing intracellular calcium levels that are associated with ischemia [33].

Box 3. Acute benefits of insulin and glucose therapy in acute myocardial infarction

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