The Euro Heart Survey Diabetes 2007 examined the correlation between acute coronary syndromes and diabetes. It has provided evidence that diabetes is particularly common in patients with chest pain in the intensive coronary care unit (ICCU). Patients with a normal blood glucose level account for only one third of the patients admitted to the ICCU. Another third is made up patients with known diabetes, whereas the remaining patients have newly diagnosed diabetes, i.e. diagnosed on admission, or an impaired glucose tolerance .
The world prevalence of diabetes among adults (aged 20–79years) is approximately 6.4%, affecting 285 million adults in 2010 and is predicted to rise to 7.7%, affecting 439 million adults by 2030. Between 2010 and 2030, there will be a 69% increase in number of adults with diabetes in developing countries and a 20% increase in developed countries. Globally, diabetes is likely to be the fifth leading cause of death .
With CHD ranking as the number one cause of death worldwide, with diabetes increasing by two to three times the risk of CHD, and with diabetes and the often preceding metabolic syndrome dramatically increasing their prevalence, diabetologists and cardiologists have started to join their forces to improve the management of the millions of patients suffering from both diseases .
Aim of the work
This study was designed to validate the hypothesis that intensive blood glucose control with intravenous insulin infusion could reduce short term in hospital mortality and 30day mortality, re-infarction, stroke and re-hospitalization for congestive heart failure in critically ill hyperglycemic patients admitted to an intensive care unit (ICU) with acute coronary syndrome.
Patients and methods
Fifty critically ill adult patients admitted to the ICU with acute coronary syndromes within 6h of presentation with admission hyperglycemia “RBS>140mg/dl” with or without previously known diabetes mellitus were enrolled in this study.
Patients were divided into two groups; 25 patients in each group, where group A received intensive insulin therapy in the form of insulin infusion for 24h in order to maintain blood glucose in the range of 80–130mg/dl.
Patients in group B received reperfusion therapy with the standard anti ischemic therapy and standard glycemic control with sliding scale insulin if glucose exceeded 180mg/dl, targeting in hospital glycemic control with blood glucose<140mg/dl.
Full history taking, clinical examination, ECG analysis quantitatively and qualitatively, cardiac enzymes serial analysis, transthoracic two-dimensional, M-mode and color flow Doppler imaging echocardiography was done before discharge stressing on the following: segmental wall motion abnormalities (SWMA) with calculation of segmental wall motion score and on left ventricular ejection fraction (calculated by two-dimensional echocardiography using modified Simpson's method).
Random blood sugar was measured hourly and corrected accordingly with modulation of the dose of insulin infusion for group A in order to achieve the targeted level of glycemic control between 80 and 130mg/dl. Serum K was repeated every 2h and as needed according to the assessment of the attending physician in order to avoid incidence of hypokalemia and hypoglycemia and in order to treat accordingly. Then in hospital glycemic control was maintained by sliding scale subcutaneous insulin four times daily in order to maintain this level of tight glycemic control along with reperfusion therapy with the standard anti ischemic therapy as well.
All patients were closely monitored for the incidence of in hospital complications in the form of in-hospital death, re-infarction, arrhythmias, heart failure or hemodynamic instability or stroke.
Incidence of out of hospital mortality, re-infarction, heart failure and any coincident complication was followed up for 1month.
Comparison between studied groups regarding that demographic data revealed that there was no significant difference in the proportions between male and females in both groups (Table 1).
Mean age was 55.12±8.03 for group A and 59.68±11 for group B with non-significant difference as shown in Table 1.
Each group was composed of 25 patients of whom eight (32%) patients were diagnosed as having: non ST-segment elevation acute coronary syndromes “Unstable angina+Non STEMI”, 10 (40) patients were diagnosed as having inf. STEMI”, seven (28%) patients were diagnosed as having anterior STEMI. Both groups were identical regarding diagnosis as shown in Table 2.
The aim of tight glycemic control in the intensive insulin therapy arm group A was successfully achieved. The range of glycemic control during the 1st 24h as well as during the rest of ICU stay was significantly lower in group A (Table 3 and Fig. 1).
Cardiac enzymes: There was no significant difference regarding CK-MB on admission, but after 12h it was insignificantly higher in group B. There was no significant difference between both groups regarding troponin on admission, although the number of cases converting to positive being higher in group B as shown in Table 4, Figs. 2 and 3.
The ECG was qualitatively and quantitatively analyzed for each patient in both groups and comparison between both groups at admission and at 24h from admission and upon discharge showed no significant difference between studied groups regarding most of the ECG variables but the sum of ST-segment depression in inferior leads was significantly higher in group B at ECGs done 24h after admission and the sum of ST-segment elevation in I and aVL at discharge was higher in group B (Table 5 and Fig. 4).
Echocardiographic parameters: E.F was higher in group A yet the difference did not reach statistical significance, whereas regional wall motion abnormality score index was significantly lower in group A as shown in Table 6.
In our study; there was no significant difference between the studied groups regarding the incidence of re-infarction where only one case in group B suffered from re-infarction while no cases in group A. The incidence of heart failure was higher in group B; five cases (20%) compared to only one case (4%) in group A (P value 0.08) (Table 7).
During 30days follow up of patients in both groups, there was a non-significant increase in the incidence of heart failure in group B compared to group A (3 vs. 6, P value 0.27). There was an insignificant increase in the incidence of out of hospital mortality in group B (three cases 12% vs. no cases in group A) as shown in Table 8.
The incidence of major adverse cardiac events was lower in group A but the level was not significant (6 vs. 10, P value 0.23) as shown in Table 9.
The presence of major adverse cardiac events was lower in case of good glycemic control in both groups regardless of the use of insulin infusion as shown in Table 10.
The main role of insulin in the heart under physiological conditions is obviously the regulation of substrate utilization. Indeed, insulin promotes glucose uptake and its utilization via glycolysis. Insulin, promoting glucose as the main cardiac energy substrate, reduces myocardial O2 consumption and increases cardiac efficiency .
Moreover, insulin seems to augment cardiomyocyte contraction, while it affects favorably myocardial relaxation, increases ribosomal biogenesis and protein synthesis, stimulates vascular endothelial growth factor (VEGF) and thereby angiogenesis, suppresses apoptosis, promotes cell survival and finally ameliorates both myocardial microcirculation and coronary artery resistance, leading to increased blood perfusion of myocardium. Thus, insulin acts directly on heart muscle, and this action is mediated principally through PKB/Akt signal pathway .
Under pathological conditions, such as type 2 diabetes, myocardial ischemia, and cardiac hypertrophy, insulin signal transduction pathways and action are clearly modified .
It should be noted that the anti-apoptotic and anti-inflammatory effects of insulin are attenuated in the presence of insulin resistance; moreover, evidence suggests that myocardial ischemia especially in the presence of hyperglycemia is associated with an important insulin resistance. Therefore, it is conceivable that the beneficial effects of insulin during myocardial infarction in the presence of hyperglycemia are attenuated .
The direct effects of endogenous or infused insulin and the effects of preventing hyperglycemia on cardiac changes of apoptosis and inflammation cannot be differentiated because both occurred concomitantly .
In our study, there was a significant difference in glycemic control during the 1st 24h and during the rest of ICU stay with RBS being significantly higher in group B which is of special importance taking into account the results of a recent prospective study that confirms that: a persistent increase of fasting glucose during hospitalization for acute myocardial infarction has greater prognostic effect than baseline fasting glucose. Changes in fasting glucose during hospitalization are simple and sensitive indicators of dynamic changes in long term mortality risk .
Meijering et al. evaluated insulin protocols in 24 studies (including six with AMI patients). The best results were found using a dynamic scale protocol for continuous intravenous insulin infusion, combined with frequent blood glucose measurement and taking into account changes in glucose levels rather than single values . And that was similar to the protocol we used during our study.
As for cardiac enzymes in our study while there was no significant difference regarding CK-MB on admission it was higher in group B after 12h. There was no difference between both groups regarding troponin on admission; with the number of cases converting to positive being higher in group B.
This is in agreement with the study by Raffaele Marfella at 2009 that showed that hyperglycemia was associated with higher troponin I levels and larger infarct size as well as myocardial TNF-α, NFκB-activated, caspase-3, and nitrotyrosine levels compared with normoglycemic patients .
In our study; E.F was lower in group B but statistically non-significant. Regional wall motion abnormality score index was highly significantly lower in group A.
This is in agreement with a study by Raffaele Marfella that demonstrated that the reduction in glucose levels in the first period after AMI might improve cardiac function. After adjusting for baseline glucose and other clinical predictors, they found that, for every 10-mg/dl drop in glucose level between baseline and 6days, there was an 11% relative decrease in the infarct segment length, 13% in the troponin levels, 11% in the wall motion scores, and a 12% decrease in the MPI as well as an 11% relative increase in the ejection fraction in hyperglycemic patients .
In our study; there was no significant difference between the studied groups regarding the incidence of re-infarction while only one case in group B suffered from re-infarction vs. no cases in group A. The incidence of heart failure was higher in group B; five cases (20%) in comparison to only one case (4%) in group A (P value 0.08).
In accordance with these data, the HI-5 (Hyperglycemia Intensive Insulin Infusion in Infarction) study evidenced that, although insulin infusion therapy did not reduce the primary end point of mortality, it did reduce the secondary end points of heart failure (12.7%) compared with control subjects (22.8%; P=0.04) as well as re-infarction at 3months (2.4% vs. 6.1%; P=0.05) . In our study; the incidence of hemodynamic instability during the ICU stay was near significantly higher in group B (7 cases 28% vs. 2 cases 8%, P value 0.06) in group A.
This again is in agreement with the study by Raffaele Marfella which evidenced that tight glycemic control in the immediate post-infarcted period, for almost 3days, was associated with significantly less need for inotropic support and lower incidence of atrial fibrillation and pneumonia . In our study, no cases suffered from cerebrovascular accidents in the two groups. Only one case in group B suffered from death during the ICU stay. But during 30days follow up of patients in both groups, there was lower incidence of heart failure; (three cases 12% vs. six cases 24%, P value 0.27) in group A.
This again is in agreement with the HI-5 (Hyperglycemia Intensive Insulin Infusion in Infarction) study . In our study, there was no significant difference regarding the incidence of other complications with the incidence of renal impairment in one case in group B vs. no cases in group A. There was only one case of cerebral hemorrhage in group B vs. no cases in group A.
In our study, there was a trend in the incidence of out of hospital mortality in group B (three cases 12% vs. no cases) in group A.
This again is in agreement with the more recent HI-5 study did find a lower mortality at 3 and 6months in favor of intensive glucose lowering, which is consistent with DIGAMI-1, although this was not statistically significant. The mortality rates in the HI-5 study were markedly lower than those in the DIGAMI studies .
In a study by Raffaele Marfella, although the investigators did not observe a significant reduction in overall mortality in patients receiving the insulin infusion, they suggested that “it remains possible that tight glycemic control with insulin therapy after acute myocardial infarction improves outcomes.” .
Two other studies support the concept that glucose control matters in diabetic patients with CVD. In the Munich registry, optimization of care in diabetic patients with AMI was investigated. Part of the intervention studied was an I.V. insulin infusion aiming at normalizing hyperglycemia within 12h. In-hospital mortality in diabetic patients with ACS dropped from 29% to 17% with optimized care .
Data from MINAP (observational Myocardial Infarction National Audit Project) show that patients without known diabetes, presenting with ACS and admission glucose >11mmol/L treated with intravenous insulin have a mortality rate approximately 50% lower than similar patients not receiving insulin. Thus, contemporary evidence suggests that increased blood glucose in acute MI patients with or without diabetes is associated with a worse outcome and that insulin treatment may be associated with reduced mortality .
Similarly, the CARDINAL trial database, showed that in non-diabetic patients, higher baseline glucose predicted higher mortality [hazards ratio (HR) 1.12, per 0.6mmol/L (11mg/dL) increase], and a greater 24h change in glucose predicted lower mortality (HR 0.91, for every 0.6mmol/L drop in glucose in the first 24h) at 30days. At multivariable analysis, baseline glucose and 24h changes remained significant mortality predictors at 180days in non-diabetic patients. However, using a multivariable 30-day mortality model, neither baseline glucose nor the 24h change in glucose predicted mortality in diabetic patients .
Accordingly, the epidemiological analysis from the DIGAMI-2 study  together with information from the study on patients in intensive care by van den Berghe strongly support the concept that a meticulous glucose control rather than insulin treatment or the insulin dose might be an important factor to improve cardiac outcome in hyperglycemic patients .
The data from our study support the hypothesis that tight glycemic control in patients with acute coronary syndrome presenting with hyperglycemia at admission whether known or not known to be diabetic is beneficial in reducing both in hospital and out of hospital incidence of complications especially heart failure and hemodynamic instability with a decrease in wall motion score index and some improvement in the ejection fraction at echocardiography examination. The incidence of mortality was also lower in the group of better glycemic control although not statistically significant.
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