© Borgis - New Medicine 4/2009, s. 109-113
*Calin Pop1, Marcel Pop2, Lavinia Pop1
Hyperglycaemia in Acute Coronary Syndrome: an unsolved problem in clinical medicine
1 „Vasile Goldis” Vest University, Faculty of Medicine, Arad, Romania
Head: Prof. Aurel Ardelean, rector
2 Semmelweis University, Faculty of Health Science, Budapest, Hungary
Head: Prof. Judit Meszaros, PhD
Acute or stress hyperglycaemia represents the transient elevation of the blood glucose level due to the activation of neurohormonal mechanisms in organisms exposed to stress. An abnormal prevalence of glycosuria in patients with acute coronary syndrome (ACS) had been reported as early as 1931 but it was only in 1975 that an abnormally high level of glycaemia following acute myocardial infarction (AMI) was noted to represent an aggravating factor affecting prognosis.
Acute hyperglycaemia induced hazards regarding ACS prognosis can be explained by the prevalence of insulin resistance syndrome in these patients, irrespective of the presence or absence of diabetes mellitus (DM), while clinical trials clearly highlight the fact that intensive glycaemic control reduces mortality rate in patients with a critical state of different illnesses, lessens the deterioration of renal function and cuts cardiovascular risk in patients with ACS. Glycaemic control in hyperglycaemia patients with ACS can be carried out by using a metabolic mixture containing a glucose-insulin-potassium mixture (GIK) independent of the glucose level status, or better by optimized insulin therapy. Proper achievement of the standardized protocol is imperative for obtaining optimal glycaemic levels and minimizing hypoglycaemia risks, especially in patients who develop ACS. Ongoing studies and trials will provide new elements and information that will improve the evolution and prognosis of patients with ACS and hyperglycaemia.
Acute or stress hyperglycaemia represents the transient elevation of the blood glucose level due to the activation of neurohormonal mechanisms in organisms exposed to stress.
The first data about the presence of hyperglycaemia in patients with critical illnesses were described by Claude Bernard in 1855. Since then a number of studies have demonstrated that in 5-30% of the cases these illnesses are accompanied by stress hyperglycaemia (1, 2).
Acute hyperglycaemia also induces imminent hazards regarding the evolution and prognosis of patients developing acute coronary syndrome (ACS), partially explainable by the increased prevalence of insulin resistance syndrome (3).
For better medical practice in this exciting field it is imperative that answers be found to a number of questions related to:
1. The prevalence and the risks induced by acute hyperglycaemia in ACS.
2. Whether elevated blood glucose is a marker or a mediator of more severe myocardial damage.
3. Whether acute treatment is going to have a significant impact or not; whether it can reduce short-term or long-term mortality and morbidity rate following ACS.
Prevalence and risks associated with acute hyperglycaemia in ACS
An abnormal prevalence of glycosuria in patients with ACS was reported as early as 1931, but it was only in 1975 that attention was directed to abnormally high glycaemia following acute myocardial infarction (AMI) representing an aggravating factor for prognosis (4, 5).
The influence of hyperglycaemia in patients free from diabetes mellitus
The first meta-analysis regarding the topic was published in 2000 by Capes et al. It comprised 15 cohort studies and clinical trials gathering 1856 patients free from DM, hospitalized for AMI. The relative risk (RR) of mortality was 3.9 times higher in patients with glucose>110 mg/dl (95% confidence interval [CI]:2.5-5.4) while in patients with glucose>144 mg/dl cardiogenic shock and congestive heart failure (CHF) it had a high prevalence. In their subsequent studies Wahab (6), Stranders (7) and Meier (8) successively demonstrated the existence of a larger necrotic area and a 4% higher mortality rate for each 18 mg/dl increase of glucose level in patients with AMI and admission hyperglycaemia, independent of the prior presence or absence of DM. In 2005 Ainla et al. (9) presented a study on 775 hospitalized patients with AMI in whom the mortality rate was 4 times higher in the subgroup with glucose level ≥ 200 mg/dl, 47% vs. 14%, compared with normoglycaemic patients. The Cooperative Cardiovascular Project (CCP), the most comprehensive study yet, evaluated 141,680 patients with AMI, and highlighted that depending on the admission glucose level (≥ 100 mg/dl up to ≥ 240 mg/dl) cardiovascular mortality rate increased from 13 to 77% at 30 days and 7 to 46% at 1 year.(10) Mortality risk was not influenced by the presence or absence of DM, but in patients with the same blood glucose level and free from DM the mortality rate showed a linear increase with glucose level ≥ 110 mg/dl. Mortality risk and CHF showed similar results starting with glucose level ≥ 200 mg/dl, irrespective of the diabetes status (11).
The influence of hyperglycaemia in patients with diabetes mellitus
The prevalence of DM in patients hospitalized for ACS is 20-25% but acute hyperglycaemia occurrence is more frequent and is present in 50% of them, even in those without a history of diabetes (3, 4, 6, 12, 13).
Isihara et al. (14) monitored 1,253 patients with AMI and DM who underwent emergency angioplasty (PTCA) and in whom the mortality rate was significantly higher (10% vs. 5%) as well as the procedural complications, having glucose level ≥ 200 mg/dl.
In a subsequent study Cao et al. (15) pointed out that mortality risk was 5 times higher in patients with blood glucose level ≥ 300 mg/dl and 2.6 times higher in those with blood glucose level ≥ 218 mg/dl, compared with blood glucose level ≥ 160 mg/dl, the reference value in the study.
DIGAMI [Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction (16)] clinical trials CREATE–ECLA [Clinical Trial of Reviparin and Metabolic Modulation in Acute Myocardial Infarction Treatment (17)] and HI-5 [Hyperglycemia Intensive Insulin Study in Infarction (18)] also highlighted a higher mortality rate (14-26%) in the long run in patients with AMI and DM.
The trials and the studies conducted so far suggest a different impact for acute hyperglycaemia in patients with ACS, depending on the presence or absence of DM. Thus some patients with hyperglycaemia but free from known DM could well have had an unidentified diabetes status, forming an extremely high risk group. It is also possible that a higher grade of severity of the disease or a higher level of stress resulted in the same level of hyperglycaemia in patients free from DM, although there is a tendency to administer intensive treatment to patients with hyperglycaemia and known DM.
Definition of admission hyperglycaemia
Hospital admission hyperglycaemia target values differ according to different studies. Moreover, there is no consensus about the definition of abnormal blood glucose values, methods to monitor blood glucose levels, the benefits of treatment, and the target values for blood glucose. A recent clarification on the subject matter has been issued by Deedwania et al. (19), who, irrespective of the metabolic status of patients developing ACS, suggest for hyperglycaemia an admission plasmatic glucose level ≥ 140 mg/dl, while for severe hyperglycaemia with a very high risk of poor outcome a value of ≥ 180 mg/dl is considered the lower limit. It is highly recommended to test plasma glucose levels compared to capillary glucose levels as plasma glucose levels tend to show 10% higher values (20).
Cardiovascular effects of acute hyperglycaemia in patients with ACS
In different studies hyperglycaemia was associated with a high incidence of coronary artery occlusions, with an unsatisfactory reestablishment of coronary artery blood flow type TIMI 0-2 [OR=2.6091.50-4.50)] and the occurrence and persistence of the so-called "no-reflow” phenomenon (21,22). Iwakura et al. published the results of a study carried out on 146 patients with AMI who underwent PTCA and among whom 52% of those having blood glucose level ≥ 160 mg/dl frequently suffered from the "no-reflow” phenomenon vs. 14% of normoglycaemic subjects. Isihara et al. (14) described a similar situation with a more frequent incidence of the "no-reflow” phenomenon in hyperglycaemic patients, 17% vs. 9%, as well as in those with known DM, 26% vs. 12%, whose blood glucose level was ≥ 200 mg/dl. In the same study hyperglycaemia was associated with more reduced values of ejection fraction (EF), 51% vs. 56%, associated with a delay of the reestablishment of contractile function, evaluated by the "Wall Motion Score Index” (delta WMS) in the study reported by Iwakura et al. (23). The afore-mentioned correlations are extremely important as the "no-reflow” phenomenon has been associated with a significant increase of mortality rate, while EF value is an important marker of long-term prognosis in patients with AMI (8, 24).
Acute hyperglycaemia determines endothelial dysfunction and inflammatory phenomena as a result of vasoconstriction. There is a prothrombotic state facilitated by the modification of plaquetary function and diminished fibrinolysis associated with the pro-inflammatory state induced by activation of κβ transcriptional intranuclear factor and metalloproteinase accumulation and the PAI-1 plasminogen activator inhibitor factor, favouring fissure and rupture of the atherosclerotic plaque. Insulin deficiency and excessive catecholamine release reduce ischaemic myocardium glucose utilization promoting glycogenosis with the stimulation of lipolysis and the increase in circulation of free fatty acids having pro-arrhythmogenic effects. Hyperglycaemia had formerly been associated with apoptosis and the reduction of collateral blood flow, the increase in necrotic area and the abolition of ischaemic preconditioning, associated with QT interval prolongation and a remarkable increase in arterial pressure in human volunteers with>270 mg/dl induced glucose level (25-32).
The relationship between all these physiopathological mechanisms seem to be ensured by the insulin-resistance phenomenon which in the SAN ANTONIO Heart Trial was associated with a 2.5 increase of mortality rate and major cardiovascular events even after multivariable analysis adjustment for the main cardiovascular risk factors (33).
The role and benefits of intensive hyperglycaemia management in ACS
Glycaemic control in hyperglycaemic patients with ACS can be carried out in two ways: by using a metabolic mixture containing a glucose-insulin-potassium mixture (GIK) irrespective of the blood glucose level, or by the optimized administration of insulin exclusively in patients with acute hyperglycaemia.
The concept of administering GIK has been based on the study carried out by the Sodi–Pallares team, who suggested that the GIK infusion could protect the ischaemic myocardium by reducing the oxidized free fatty acids and by ameliorating metabolic glucose utilization (34). This was followed by the CREATE–ECLA randomized trial conducted on 20,201 patients with AMI – the trial did not demonstrate any beneficial effect of GIK, thus tempering any kind of former enthusiasm about the idea. The results showed an increase in the blood glucose level of the respective patients during the first 6 hours after administration, a decrease in the placebo group and an especially high mortality rate, 14% vs. 6% in the group of patients with high blood glucose level when compared with the normal level (17).
In contrast with GIK administration in different studies and trials the normalization of the blood glucose level after intravenous administration of insulin, critical status patients´ prognosis was found to ameliorate. This was a reference trial conducted by Berghe et al. (35) on a batch of 1,548 patients with critical post-surgery status. These patients were exposed to 80–110 mg/dl tight glycaemic control through a pseudo-physiological intensive insulin therapy (basal–bolus). In the active batch the intensive care unit in-hospital mortality rate decreased significantly from 8% to 4.6% and from 10.9% to 7.2% throughout the entire period of hospitalization.
The aforementioned results cannot be extrapolated in a simple way to ACS patients, and 3 clinical trials have tested the way in which tight glycaemic control through insulin therapy significantly reduces the mortality rate and in-hospital complications in hyperglycaemic patients with ACS (16, 18, 36).
The DIGAMI study was the first and most important to monitor the effects of intensive insulin therapy (a continuous infusion followed by multi-dose subcutaneous administration) versus the standard treatment, in 620 patients with AMI and known type II DM and/or>200 mg/dl admission blood glucose level (16). The glycaemic control was superior in the intensive treatment batch, 173 mg/dl vs. 210 mg/dl, and was associated with a significant decrease of mortality rate in the respective group; one-year mortality was 19% vs. 26% and the follow-up was extended to 3.4 years. The respective trial continues to be the only one in the field which has succeeded in reducing blood glucose level significantly and which demonstrated that accurate tight glycaemic control is correlated with a better prognosis for survival in hyperglycaemic patients with ACS.
The DIGAMI-2 trial directed the study towards three ways of insulin therapy (a 24-hour continuous infusion treatment followed by a ≥ 3 months intensive multi-dose regimen therapy, a 24-hour continuous infusion treatment followed by conventional regimen, and the conventional insulin regimen) – on a batch of 1,253 randomized patients with AMI and known type II DM and/or>200 mg/dl admission blood glucose level (36). The study evidenced no difference in survival among the 3 groups, explainable by the fact that the goal of long-term glycaemic control in the intensive treatment group (90-126 mg/dl) has never been achieved. A similarity between the two DIGAMI studies was that patients with DM were included, none of them with acute hyperglycaemia free from DM, who in fact represented the highest mortality AMI risk group associated with hyperglycaemia.
The HI-5 trial tried to find a solution to some questions of the DIGAMI study and was the first randomized trial which included patients with hyperglycaemia and unknown diabetes status: included in the study were 244 patients with AMI and type II DM or with>140 mg/dl blood glucose level, who received either a 24-hour intensive insulin infusion treatment or the standard insulin infusion in order to achieve a blood glucose level of 72–180 mg/dl. The trial did not highlight any difference regarding the mortality rate between the two groups, raising the same issues as the DIGAMI–2 study (comparison was made between two insulin regimens, instead of two different intensity variants of glycaemic control); no significant difference was registered regarding blood glucose level median values between the intensive group and the one receiving the standard therapy (18).
As hyperglycaemia had direct detrimental effects on patients, significantly aggravating their prognosis after ACS, further important clarification is necessary: 1) How should hyperglycaemia be treated and what are the goals of the therapy in patients free from DM and those with known DM? 2) What is the period of vulnerability to hyperglycaemia in patients with ACS? and 3) What is the impact of persistent in-hospital hyperglycaemia?
Prognostic value of hypoglycaemia
An important aspect deriving from intensive glycaemic control in patients with ACS is the possibility of occurrence of hypoglycaemia, an important predictor of adverse events. In the Svensson et al. (37) study, <54 mg/dl blood glucose level was associated with an increased mortality rate by 93%. In another study admission hypoglycaemia was correlated with cardiovascular mortality and a high incidence of 30-day reinfarction, in some way related to hyperglycaemia, but it is not clear whether the detrimental effect of hypoglycaemia impact was related to all hypoglycaemic events or was restricted only to the clinically severe ones (38).
The necessity of implementing a standard insulin therapy protocol
Attempts to elaborate a standard insulin therapy protocol in patients with ACS and hyperglycaemia have failed due to the lack of a consensus. The information concerning hyperglycaemia management in patients with ACS is still limited and the existing studies have highlighted the fact that 78% of patients free of DM and 27% of those with DM have not been administered insulin therapy in case of blood glucose level values>240 mg/dl (10). Inzouchi et al. propose an in-hospital management algorithm for hyperglycaemia in patients with critical status, but implementation of it in patients with ACS has been limited by cardiologists´ fear that hypoglycaemic episodes could appear, as the number of qualified personnel who should monitor hyperglycaemic status is reduced and because of the absence of trials which could clearly demonstrate the necessity to achieve normoglycaemic status in these patients.
The most comprehensive guidelines were issued by the AHA Diabetes Committee in 2008 and were presented under the title: Scientific Statement – Hyperglycemia and Acute Coronary Syndromes. These guidelines are based on the premise that no matter how intense and documented, the interdependence between hyperglycaemia and ACS requires further investigation (19)
– In-hospital blood glucose level should be checked in all patients with suspected or confirmed ACS as part of the initial laboratory investigation [Evidence Level A].
– Suspected or confirmed ACS patients admitted to intensive care units for coronary heart disease must undergo tight glycaemic control [Evidence Level B].
– Intensive insulin therapy is recommended for patients whose blood glucose level is ≥180 mg/dl [Evidence Level B], and it is beneficial to keep it within 90-140 mg/dl [Evidence Level C].
– Special attention should be given to patients who are not admitted to intensive care units, with subcutaneous insulin therapy in order to keep their blood glucose level <180 mg/dl [Evidence Level C].
– The efficiency and applicability of insulin therapy is generally recognized in ACS patients, but until a new standardized protocol is developed, efforts should be made for the secure implementation of the existing one, to minimize the risks for hypoglycaemia. [Evidence Level B].
– Hyperglycaemic patients without known DM should be evaluated for the severity of metabolic disturbances [Evidence Level B].
– On leaving the hospital, all hyperglycaemic patients with or without DM should be scheduled for a follow-up metabolic control therapy [Evidence Level C].
Acute hyperglycaemia aggravates the evolution and the prognosis of ACS patients, irrespective of their diabetic status. The clinical trials carried out so far have demonstrated the fact that intensive glycaemic control decreases the mortality rate in patients with critical status illness; it decreases the deterioration of renal function and indicates a reduction in risk for cardiovascular events in patients with ACS. The elaboration of a standardized protocol is imperative to rapidly achieve optimal levels of glycaemia and to minimize hypoglycaemia risks. Ongoing studies and trials will bring new elements and information regarding the benefits and therapeutic options for hyperglycaemia in ACS.
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