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Blood glucose and its prognostic implications in patients hospitalised with acute myocardial infarction
MIKHAIL KOSIBOROD
Abstract levated blood glucose and its potential link with adverse outcomes in patients with acute myocardial infarction (AMI) has been the subject of intense study over more than 40 years. The numerous observational studies performed to date have addressed some of the questions in this field, but many critically important questions are still poorly understood, and remain subjects of debate. This review summarises current epidemiological data on the prevalence of hyperglycaemia in the AMI patient population and its relationship to patient outcomes, and addresses some of the existing controversies in the field. Diabetes Vasc Dis Res 2008;5:26975 doi:10.3132/dvdr.2008.039 ~110 mg/dL (> 6.1 mmol/L ), ~120 mg/dL (> 6.7 mmol/L), ~140 mg/dL (> 8.0 mmol/L), ~180 mg/dL (> 10.0 mmol/L) and ~200 mg/dL (> 11.0 mmol/L).4 In some of the largest observational studies to date, as well as in epidemiological analyses of randomised clinical trials, initial, mean 24-hour and mean hospitalisation glucose levels above ~120140 mg/dL (6.78.0 mmol/L) appear to be associated with the greatest increase in short-term mortality risk, when the entire cohort of patients (including those with and without established diabetes) is considered.2,27-29 Furthermore, glucose levels below ~140 mg/dL (8.0 mmol/L) during AMI hospitalisation in patients who are hyperglycaemic on admission appear to be associated with a decrease in the risk of short-term mortality.30 Based on these data, and our knowledge of normal ambient blood glucose levels in normal, non-hospitalised individuals, it appears reasonable to consider random glucose levels > 140 mg/dL (8.0 mmol/L) as the definition of hyperglycaemia in the acute MI setting. This definition has also been suggested in the recent American Heart Association Scientific Statement on Hyperglycemia and Acute Coronary Syndrome.31 However, an important caveat to this definition should be acknowledged. Many prior studies have observed that the nature of the relationship between initial glucose levels and short-term mortality differs between patients with and without diabetes.2,15,21,29,30,32 The risk of mortality rises gradually once glucose levels exceed ~110120 mg/dL (6.16.6 mmol/L) in patients without diabetes, whereas in patients with established diabetes the risk does not increase substantially until glucose levels exceed ~200 mg/dL (11.0 mmol/L).2,29 Thus, different definitions of hyperglycaemia may be appropriate according to whether established diabetes is present. Prevalence The prevalence of hyperglycaemia in older studies varies with the definition used but the largest observational studies demonstrate that hyperglycaemia on admission (glucose > 140 mg/dL [7.7 mmol/L]) is very common, occurring in 5158% of patients who present with AMI.2,29 Some patients experience resolution of hyperglycaemia during their hospital course, although persistent hyperglycaemia is highly prevalent during many such hospitalisations. A recent analysis of nearly 17,000 patients hospitalised with AMI showed that 41% of AMI patients have persistent hyperglycaemia (mean hospitalisation glucose > 140 mg/dL [7.7 mmol/L]), and about 14% have persistent severe hyperglycaemia (mean hospitalisation glucose > 200 mg/dL [11.0 mmol/L]).29 The

Key words: acute myocardial infarction, diabetes, epidemiology, glucose, insulin, outcomes, review.

Introduction The initial observation that elevated glucose is a common finding in patients with acute myocardial infarction (AMI) was first made more than 40 years ago.1 Numerous studies have since established definitively that hyperglycaemia is highly prevalent and that it is associated with increased risk of death and in-hospital complications in patients with AMI.2-26 However, many controversies remain, including the exact definition of hyperglycaemia, the mechanisms linking glucose and adverse outcomes, the optimal methods to measure and monitor glucose levels during hospitalisation for AMI, and the role of glucose-lowering therapy and its impact on clinical outcomes. This review will summarise the current state of knowledge in this evolving field, and will offer perspectives on some of the controversies and future directions. Hyperglycaemia definition No uniform definition of hyperglycaemia in the setting of AMI exists. Prior studies used various definitions, including

Mid America Heart Institute of Saint Lukes Hospital, 4401 Wornall Road, Kansas City, MO 64111, US. Mikhail Kosiborod, Assistant Professor and Clinical Scholar Correspondence to: Dr Mikhail Kosiborod Mid America Heart Institute of Saint Lukes Hospital, 4401 Wornall Road, Kansas City, MO 64111, US. Tel: +1 816 932 3445; Fax: +1 816 932 5613 E-mail: mkosiborod@cc-pc.com

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Figure 1. The relationship between admission glucose and mortality in AMI

50 45 40 35 30 25 20 15 10 5 0 < 110 > 110 to 140 > 140 to 170 > 170 to 240 > 240 Mortality rate (%) 30-day mortality One-year mortality

Figure 3. Direct comparison of risk-adjusted 30-day mortality between AMI patients with and without known diabetes across the range of admission glucose values
1.0 0.9 0.8 Mortality rate 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 70 120 170 220 270 320 370 Patients without diabetes Patients with diabetes

Key: AMI = acute myocardial infarction To convert glucose values from mg/dL to mmol/L, multiply by 0.055 Analysis from the Cooperative Cardiovascular Project2

Figure 2. The nature of the relationship between admission glucose and mortality differs in AMI patients with and without known diabetes
45 40 Mortality rate (%) 35 30 25 20 15 10 5 0 Patients without diabetes Patients with diabetes

Key: AMI = acute myocardial infarction To convert glucose from mg/dL to mmol/L, multiply by 0.055 Analysis from the Cooperative Cardiovascular Project2

prevalence of persistent hyperglycaemia is considerably higher in patients with established diabetes (78%) than in those without known diabetes (26%).33

The relationship between admission hyperglycaemia and mortality Numerous studies have documented the association between higher admission glucose levels and increased risk of mortality and complications in patients with AMI.2-26 Most of the older and smaller studies (predominantly from the 1980s and 90s) were summarised in the meta-analysis by Capes et al.4 These combined results demonstrated that the relative risk of in-hospital mortality in non-diabetic AMI patients with admission glucose > 110 mg/dL (6.1 mmol/L) was 3.9, as compared with non-diabetic AMI patients who were normoglycaemic. Among AMI patients with diabetes,

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Admission glucose groups (mg/dL)

Admission glucose groups (mg/dL)

Key: AMI = acute myocardial infarction To convert glucose from mg/dL to mmol/L, multiply by 0.055 Analysis from the Cooperative Cardiovascular Project2

< 110

> 110 to 140

> 140 to 170

> 170 to 240

> 240

Admission glucose groups (mg/dL)

those with admission glucose > 180 mg/dL (10.0 mmol/L) had a 70% increase in the relative risk of in-hospital mortality, as compared with diabetic patients with normal admission glucose. More recent studies have confirmed these findings, showing significant increases in the risk of short- and long-term mortality, as well as heart failure, in hyperglycaemic AMI patients both with and without known diabetes.15,21 These findings extend to the entire range of acute coronary syndromes, including ST-elevation MI, non-ST elevation MI and unstable angina.5 Furthermore, studies utilising myocardial contrast echocardiography have also demonstrated that the risk of periprocedural complications such as the no reflow phenomenon is significantly higher in AMI patients with elevated glucose levels after successful percutaneous coronary reperfusion.6 The largest epidemiological study to evaluate the relationship between admission glucose levels and mortality in AMI patients was the analysis from the Cooperative Cardiovascular Project.2 In a cohort of 141,680 elderly patients, a clear, linear relationship was demonstrated between the admission glucose levels and both 30-day and one-year mortality (figure 1) when the entire cohort was analysed. This study also found a marked difference in the nature of this relationship between patients with and without established diabetes. Both short- and long-term mortality increased in a linear fashion with higher admission glucose in patients without known diabetes. However, among those with established diabetes, only patients with severe hyperglycaemia (admission glucose > 240 mg/dL [13.2 mmol/L]) experienced a statistically significant increase in mortality (figure 2). Close analysis and direct comparison of risk-adjusted mortality rates showed that while patients with normal glucose levels and without known diabetes had lower 30-day mortality than corresponding patients with diabetes, their risk increased more steeply at higher glucose levels, surpassing the risk of patients with diabetes at ~140 mg/dL (8.0 mmol/L) (figure 3).

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20

15 Odds ratio

No diabetes All patients Diabetes

Adjusted hazard ratio for mortality (95% confidence interval)

Figure 4. The relationship between mean hospitalisation glucose and risk-adjusted in-hospital mortality in AMI patients with and without known diabetes, after multivariable adjustment

Figure 5. The relationship between mean 24-hour glucose and death at three days in the CREATE-ECLA study
4

10

5 1 0

Key: AMI = acute myocardial infarction; BG = blood glucose To convert glucose from mg/dL to mmol/L, multiply by 0.055 Data from Kosiborod29

The relationship between persistent hyperglycaemia and mortality Most prior studies have focused predominantly on the prognostic value of admission glucose principally as a matter of convenience, since only admission glucose values are usually available in many retrospective studies. However, the glucose value on hospital admission represents only a single measurement in time, and does not reflect the overall exposure to hyperglycaemia. While several smaller studies have suggested that persistent hyperglycaemia is prognostically important,23,25,30,34 the definitive evidence for this concept comes from a recent analysis of nearly 17,000 patients hospitalised with AMI.29 Results from this study have demonstrated clearly a powerful relationship between average glucose during hospitalisation and in-hospital mortality. There was a statistically significant, gradual increase in the risk of in-hospital mortality as the mean hospitalisation glucose level rose above the threshold of ~120 mg/dL (6.6 mmol/L) (figure 4). Again, a marked difference in the nature of the relationship between mean hospitalisation glucose and mortality was observed in patients with and without known diabetes. The risk of death associated with higher mean glucose rose steeply in patients without recognised diabetes above 120 mg/dL (6.6 mmol/L). However, among patients with known diabetes, the curve was much less steep, and only those diabetic patients with severe, sustained hyperglycaemia (mean hospitalisation glucose > 200 mg/dL [11.0 mmol/L]) had significantly higher risk of death compared with those whose mean glucose levels were <110 mg/dL (6.1 mmol/L). Similar to the prior findings involving admission glucose, normoglycaemic patients without known diabetes had a lower mortality rate than corresponding patients with diabetes: their risk increased to a much greater degree at higher glucose levels, surpassing the risk of patients with diabetes at ~130 mg/dL (7.2 mmol/L). Even more importantly, average hospitalisation glucose was shown to be a much better discriminator of in-hospital mor-

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Mean BG (mg/dL)

70 < 80 to < 70 90 to 8 10 to < 0 < 9 110 to 1 0 0 120 to < 1 0 0 13 to < 110 2 0 14 to < 1 0 0 < 3 15 to 1 0 0 < 4 16 to 1 0 5 0 17 to < 1 0 6 0 18 to < 1 0 7 190 to < 1 0 0 20 to < 180 0 < 9 21 to 2 0 0 < 0 22 to 210 < 230 to 2 0 0 < 2 24 to 2 0 < 3 250 to 2 0 260 to < 40 2 0 27 to < 250 0 < 60 28 to 2 7 290 to < 2 0 0 < 80 to 2 < 90 3 > 00 30 0

< 126

126144 Mean 24-hour glucose (mg/dL)

> 144

Key: To convert glucose from mg/dL to mmol/L, multiply by 0.055 Data from Diaz et al.28

tality than admission glucose (C statistic 0.70 vs. 0.62, p<0.0001). Epidemiological analyses from randomised clinical trials of glucose-insulin-potassium (GIK) therapy (CREATE-ECLA)28 and studies of intensive glucose control in AMI (the Hyperglycemia: Intensive Insulin Infusion in Infarction study, HI-5)27 also clearly confirmed the relationship between persistent hyperglycaemia and increased mortality risk. In the CREATE-ECLA population (figure 5), for example, patients with mean 24-hour glucose > 144 mg/dL (7.9 mmol/L) experienced a markedly increased risk of death at three days compared to patients with mean glucose <126 mg/dL (6.9 mmol/L).

The association between fasting glucose during AMI hospitalisation and mortality Several studies have also documented a clear relationship between elevated fasting glucose during AMI hospitalisation and increased mortality risk.25,32,35,36 Unlike the random glucose level on admission, elevated fasting glucose may be a better reflection of abnormalities in underlying glucose metabolism, and thus may be a better predictor both of short-term and long-term outcomes. In one of the earlier studies on this issue, Suleiman et al. demonstrated that while both admission and fasting glucose levels predicted 30-day mortality in non-diabetic patients with AMI, fasting glucose was the better discriminator.25 In a subsequent study by the same group, using a larger patient sample and a longer follow-up period, fasting glucose was shown to also be a strong predictor of long-term mortality (mean follow-up 24 months) and left ventricular systolic function post-AMI. Fasting glucose also added significantly to the discriminating ability of the Global Registry of Acute Coronary Events (GRACE) risk score (a validated tool used to estimate allcause mortality risk in patients with acute coronary syndromes).32 At least two additional studies have documented the relationship between elevated fasting glucose and increased risk of mortality and heart failure post-AMI.35,36 As with the previously discussed studies of admission and mean glucose, the relationship between fasting glucose and

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Table 1. Comparison of various glucose metric time window combinations using C statistics Time window Admission Admission 24 hours 48 hours Hospitalisation p-value for overall comparison across time windows 0.619 N/A N/A N/A Glucose metric Mean TAG N/A 0.643 0.659 0.70 <0.0001 N/A 0.643 0.658 0.704 <0.0001 p-value for overall comparison across glucose metrics N/A 0.0001 <0.0001 0.0002

HGI N/A 0.647 0.664 0.708 <0.0001

Key: TAG = time-averaged glucose; HGI = hyperglycaemic index Data from Kosiborod29

mortality was much stronger in patients without known diabetes than in those with established diabetes.

Glucometrics in patients with AMI: which measure is the best predictor of risk? While glycosylated haemoglobin (HbA1C) is useful in assessing average glucose control, and has clear prognostic implications in the outpatient setting,37 its value in predicting outcomes in the setting of hospitalisation for AMI is limited.20,38 Therefore, there is a need for a summary measure of inpatient glucose control (in-hospital HbA1C) that would take into account multiple and random glucose measurements obtained at various times and intervals, representing various nutritional conditions, and have a demonstrated impact on patient outcomes. As noted above, various glucose measures have been shown to be associated with increased risk of mortality and in-hospital complications among patients with AMI, including admission, mean 24-hour, mean hospitalisation and fasting glucose. Several other (and more sophisticated) measures of glucose control have been proposed in other studies, such as time-averaged glucose (TAG, area under the glucose curve)34 and hyperglycaemic index (HGI)39 both of which take into consideration not only the glucose values themselves, but also the time period over which these values were recorded. In one of the largest studies to date, several of these metrics were directly compared for their ability to discriminate AMI survivors from non-survivors (table 1).29 Specifically, three different measures of glucose control over time (mean, TAG and HGI) were each evaluated over three time periods (24 hours, 48 hours and the entire hospitalisation) and compared with admission glucose. While higher glucose values were strongly associated with increased risk of in-hospital mortality for all glucose metrics, measures of persistent hyperglycaemia performed significantly better than admission glucose alone. There was a gradual, statistically significant increase in the discriminating ability of these glucometrics as the time window increased. Specifically, the C index values for any summary measure of glucose over the entire hospitalisation were better than the C indices for glucometrics over 48 and 24 hours. While the most sophisticated metric of glucose during hospitalisation (HGI) had the highest C index, the overall differences between mean glu-

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14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 Categories of 24-h change in glucose (baseline glucose minus 24-h glucose level) Mortality at 30 days (%) > 1.7 mmol/L (30 mg/dL) i.e. large drop in glucose in the first 24 h > 0 mmol/L, i.e. no change to moderate drop in glucose in the first 24 h < 0 mmol/L, i.e. actual increase in glucose in the first 24 h 2/68 2.9 1/54 2/114 1.9 1.8 5/208 2.4 1/205 0/25 0.5 0.0 < 6.9 (< 125) > 6.9, < 7.8 (> 125, < 140)

Figure 6. The relationship between baseline glucose, 24-hour change in glucose and 30-day mortality in the CARDINAL study

6/55 10.9 5/58 8.6 4/55 7.3 13/332 3.9

3/108 2.8 3/187 1.6

> 7.8, < 9.4 (> 140, < 170)

> 9.4 (> 170)

Baseline glucose in mmol/L (mg/dL)

Data from Goyal30

cose, TAG and HGI were small. Overall, mean hospitalisation glucose appeared to be the most practical metric of glucose control during AMI hospitalisation, due to the combination of its discriminating power and ease of calculation and clinical implementation. Fasting glucose has also been demonstrated to be a better predictor of patient outcomes than admission glucose.25 While metrics of average glucose control during hospitalisation (mean, TAG and HGI) were never directly compared with fasting glucose, what appears clear is that the prognostic impact of elevated glucose values extends (and is compounded) throughout AMI hospitalisation. Thus, glucose values throughout AMI hospitalisation are important, should be monitored, and may be used in clinical practice for prognosis and performance assessment, and possibly (if intervention is demonstrated to improve outcomes) as a therapeutic target. Is there evidence that glucose lowering during AMI hospitalisation impacts patient outcomes? Prior studies have definitively demonstrated the prognostic association between elevated glucose and adverse patient

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outcomes in AMI, but these findings cannot answer the critical question: is hyperglycaemia a direct mediator of increased mortality and complications, or is it just a marker of greater disease severity and co-morbidity burden? To answer this question definitively, well designed, randomised clinical trials of target-driven intensive glucose control in hospitalised AMI patients will be required, and some are underway. In the interim, epidemiological data (though scarce so far) can help us to evaluate whether changes in glucose levels during hospitalisation are associated with changes in prognosis, whether specific therapies such as insulin used for glucose lowering during hospital stay can impact patient outcomes, and whether information about specific target levels can be gleaned from epidemiological data and subsequently tested in future randomised trials. The best epidemiological analysis of the relationship between change in glucose levels during hospitalisation and outcomes in AMI patients comes from the retrospective analysis of 1,469 patients in the CARDINAL study (figure 6).30 Among patients with baseline glucose of > 140 mg/dL (7.8 mmol/L), a drop in glucose of > 30 mg/dL (1.65 mmol/L) during the first 24 hours of hospitalisation was associated with lower risk of 30-day mortality, while no change or an increase in glucose values were associated with significant increase in the risk of death. As in other studies, the relationship between change in glucose and mortality was observed in non-diabetic, but not in diabetic, patients. Importantly, due to data limitations, this study was unable to determine whether decreases in 24-hour glucose levels occurred following initiation of insulin therapy or happened spontaneously, and whether administration of glucose-lowering therapy impacted patient prognosis. It was also unable to identify the specific range of post-admission glucose values associated with optimal patient outcomes. Additional epidemiological studies are underway and will offer further insights into these questions. There are few epidemiological data regarding the impact of in-hospital insulin therapy on outcomes in hyperglycaemic AMI patients. Insulin clearly remains the most effective method of glucose lowering in the in-patient setting. Small, mechanistic studies have suggested that insulin may have anti-inflammatory, pro-fibrinolytic and anti-apoptotic properties, and that it can inhibit generation of reactive oxygen species and improve myocardial blood flow.40-48 However, whether insulin therapy is associated with any clinical benefit in AMI above and beyond its associated glucose-lowering effect remains a subject of debate. One observational study demonstrated that patients with severe hyperglycaemia on admission (> 11.0 mmol/L [~200 mg/dL]) and no prior history of diabetes had a 56% relative risk increase in mortality at seven days (and a 51% increase in mortality at 30 days) if they did not receive insulin during hospitalisation, as compared with similar patients who did receive insulin therapy.49 However, the study was unable to determine whether patients who received insulin actually had better glucose control during hospitalisation. Furthermore, patients treated with insulin appeared to have a lower burden of co-morbidity; and the study findings may, in part, reflect a degree of unmeasured confounding.

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Nevertheless, the study findings are in accord with results from the original Diabetes Mellitus: Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI) trial,50 which showed significantly lower mortality in severely hyperglycaemic AMI patients who were treated with target-driven insulin-glucose infusion. Clearly, more observational data and randomised clinical trial data are needed to establish whether target-driven glucose lowering with insulin improves outcomes in hyperglycaemic patients with AMI. Until then, a reasonable initial approach is to consider intensive glucose control in critically ill AMI patients who have significant hyperglycaemia on admission (> 180 mg/dL, 9.9 mmol/L), as outlined in the recent statement by the American Heart Association.31 Current patterns of hyperglycaemia management in hospitalised AMI patients The specific glucose levels at which treatment should be initiated remain highly debatable but current consensus is that treatment with insulin should be considered in AMI patients with severe hyperglycaemia (>180 mg/dL, 9.9 mmol/L).31 However, available evidence shows that a large proportion of these patients remain untreated. The data from the Cooperative Cardiovascular Project indicated that among patients with severe hyperglycaemia on admission (> 240 mg/dL, 13.2 mmol/L), nearly 80% of patients without a history of diabetes and more than 25% of patients with known diabetes received no insulin during hospitalisation.2 More recent studies confirm these findings. Analysis of nearly 17,000 AMI patients hospitalised in the US between 2000 and 2005 showed that among patients with severe, sustained hyperglycaemia (mean hospitalisation glucose > 200 mg/dL [11.0 mmol/L]), nearly 40% of patients did not receive any insulin therapy, and almost 90% did not receive intravenous insulin infusion. As expected, insulin treatment rates were considerably higher in patients with known diabetes than in those without established diabetes (despite the higher glucose-associated risk of mortality in patients without known diabetes.)33 Moreover, there was substantial variability in insulin treatment rates across the 40 participating medical centres.51 A recent study carried out in the UK also showed that 64% of non-diabetic patients with admission glucose > 11 mmol/L (~200 mg/dL) received no glucoselowering treatments during hospitalisation.49

The prognostic importance of hypoglycaemia in patients with AMI Since therapy of hyperglycaemia in the AMI setting necessitates the use of insulin, concern persists about the short-term and long-term impact of hypoglycaemia. Several prior studies have demonstrated that glucose values in the hypoglycaemic range may impact mortality adversely in AMI. Studies by Svensson et al. and Pinto et al. demonstrated that random glucose values < 55 mg/dL (3.0 mmol/L) and < 81 mg/dL (4.5 mmol/L), respectively, were associated with a marked increase in mortality (with a 93% increase in the adjusted relative risk of two-year mortality in the study by Svensson et al.).23,52 One of the larger observational studies on this issue also demonstrated a clear J-shaped relationship

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between average glucose values during hospitalisation and in-hospital mortality (figure 4).29 Specifically, patients with mean hospitalisation glucose of < 70 mg/dL (3.9 mmol/L) experienced a marked increase in the odds of mortality (OR 6.4, p=0.01) when compared to patients with mean glucose of 100 to < 110 mg/dL (5.56.1 mmol/L). Whether hypoglycaemia directly impacts mortality in AMI by increasing catecholamine levels through activation of the sympathetic nervous system and worsening ischaemic injury, or whether it is merely a marker for the most critically ill patients (with liver insufficiency, sepsis or shock) remains unknown, and future observational studies will offer additional insights into this issue. Summary A large body of data evaluating the nature of the relationship between elevated glucose and adverse outcomes in patients with AMI has been accumulated over more than 40 years of observational research. Some questions in this field have been answered, but many more remain subjects of ongoing debate. It is clear that elevated glucose is a powerful predictor of increased mortality and in-hospital complications, particularly in patients without a prior history of diabetes, and that its adverse prognostic impact lasts throughout the entire AMI hospitalisation. It is also clear that hyperglycaemia is very common in this setting and that it frequently remains untreated. What remains unknown is whether this glucoseassociated mortality risk is modifiable, whether target-driven glucose-lowering interventions will improve patient outcomes, and whether glucose management strategies should be different in patients with and without known diabetes. Until definitive data from future randomised clinical trials become available, a strategy of monitoring glucose levels for risk stratification, and selective administration of intensive glucose control to patients with significant hyperglycaemia (> 180 mg/dL [9.9 mmol/L]) using protocols that minimise hypoglycaemia, is advisable. Conflicts of interest statement MK is supported by the American Heart Association Career Development Award in Implementation Research, has received speaking honoraria from the Vascular Biology Working Group and Diaved, Inc., and has served on the advisory board for Sanofi-Aventis (but received no personal compensation). References
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