blood glucose and its prognostic

8/13/2019 Blood Glucose and Its Prognostic

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VOLUME 5 ISSUE 4 . NOVEMBER 2008 269

Abstract

Elevated blood glucose and its potential link withadverse outcomes in patients with acute myocar-dial infarction (AMI) has been the subject of

intense study over more than 40 years. The numerousobservational studies performed to date have addressedsome of the questions in this field, but many critically

important questions are still poorly understood, andremain subjects of debate. This review summarises cur-rent epidemiological data on the prevalence of hyper-glycaemia in the AMI patient population and its rela-tionship to patient outcomes, and addresses some ofthe existing controversies in the field.Diabetes Vasc Dis Res 2008;5:26975doi:10.3132/dvdr.2008.039

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

IntroductionThe initial observation that elevated glucose is a commonfinding in patients with acute myocardial infarction (AMI) wasfirst made more than 40 years ago.1 Numerous studies havesince established definitively that hyperglycaemia is highlyprevalent and that it is associated with increased risk of deathand in-hospital complications in patients with AMI.2-26

However, many controversies remain, including the exactdefinition of hyperglycaemia, the mechanisms linking glucoseand adverse outcomes, the optimal methods to measure andmonitor glucose levels during hospitalisation for AMI, and therole of glucose-lowering therapy and its impact on clinicaloutcomes. This review will summarise the current state of

knowledge in this evolving field, and will offer perspectiveson some of the controversies and future directions.

Hyperglycaemia definitionNo uniform definition of hyperglycaemia in the setting ofAMI exists. Prior studies used various definitions, including

~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 largestobservational studies to date, as well as in epidemiologicalanalyses of randomised clinical trials, initial, mean 24-hourand 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, whenthe entire cohort of patients (including those with and with-out established diabetes) is considered.2,27-29 Furthermore,glucose levels below ~140 mg/dL (8.0 mmol/L) during AMIhospitalisation in patients who are hyperglycaemic onadmission appear to be associated with a decrease in the riskof short-term mortality.30 Based on these data, and ourknowledge of normal ambient blood glucose levels in nor-mal, non-hospitalised individuals, it appears reasonable toconsider 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 recentAmerican Heart Association Scientific Statement on

Hyperglycemia and Acute Coronary Syndrome.31 However,an important caveat to this definition should be acknowl-edged. Many prior studies have observed that the nature ofthe relationship between initial glucose levels and short-termmortality differs between patients with and withoutdiabetes.2,15,21,29,30,32 The risk of mortality rises gradually onceglucose levels exceed ~110120 mg/dL (6.16.6 mmol/L) inpatients without diabetes, whereas in patients with estab-lished diabetes the risk does not increase substantially untilglucose levels exceed ~200 mg/dL (11.0 mmol/L).2,29 Thus,different definitions of hyperglycaemia may be appropriateaccording to whether established diabetes is present.

PrevalenceThe prevalence of hyperglycaemia in older studies varies withthe definition used but the largest observational studiesdemonstrate that hyperglycaemia on admission (glucose> 140 mg/dL [7.7 mmol/L]) is very common, occurring in5158% of patients who present with AMI.2,29 Some patientsexperience resolution of hyperglycaemia during their hospi-tal course, although persistent hyperglycaemia is highlyprevalent during many such hospitalisations. A recent analy-sis of nearly 17,000 patients hospitalised with AMI showedthat 41% of AMI patients have persistent hyperglycaemia(mean hospitalisation glucose > 140 mg/dL [7.7 mmol/L]),

and about 14% have persistent severe hyperglycaemia (meanhospitalisation glucose > 200 mg/dL [11.0 mmol/L]).29 The

REVIEW

Blood glucose and its prognosticimplications in patients hospitalised with

acute myocardial infarctionMIKHAIL KOSIBOROD

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 KosiborodMid America Heart Institute of Saint Lukes Hospital, 4401 Wornall Road,Kansas City, MO 64111, US.Tel: +1 816 932 3445; Fax: +1 816 932 5613E-mail: [email protected]


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270 DIABETES AND VASCULAR DISEASE RESEARCH

prevalence of persistent hyperglycaemia is considerably high-

er in patients with established diabetes (78%) than in thosewithout known diabetes (26%).33

The relationship between admission hyperglycaemiaand mortalityNumerous studies have documented the associationbetween higher admission glucose levels and increased riskof mortality and complications in patients with AMI.2-26 Mostof the older and smaller studies (predominantly from the1980s and 90s) were summarised in the meta-analysis byCapes et al.4 These combined results demonstrated that therelative risk of in-hospital mortality in non-diabetic AMIpatients with admission glucose > 110 mg/dL (6.1 mmol/L)

was 3.9, as compared with non-diabetic AMI patients whowere normoglycaemic. Among AMI patients with diabetes,

those with admission glucose > 180 mg/dL (10.0 mmol/L)had a 70% increase in the relative risk of in-hospital mortal-ity, as compared with diabetic patients with normal admis-sion glucose. More recent studies have confirmed these find-ings, showing significant increases in the risk of short- andlong-term mortality, as well as heart failure, in hypergly-caemic AMI patients both with and without known dia-betes.15,21 These findings extend to the entire range of acutecoronary syndromes, including ST-elevation MI, non-ST ele-vation MI and unstable angina.5 Furthermore, studies utilis-

ing myocardial contrast echocardiography have also demon-strated that the risk of periprocedural complications such asthe no reflow phenomenon is significantly higher in AMIpatients with elevated glucose levels after successful percu-taneous coronary reperfusion.6

The largest epidemiological study to evaluate the rela-tionship between admission glucose levels and mortality inAMI patients was the analysis from the CooperativeCardiovascular Project.2 In a cohort of 141,680 elderlypatients, a clear, linear relationship was demonstratedbetween the admission glucose levels and both 30-day andone-year mortality (figure 1) when the entire cohort was

analysed. This study also found a marked difference in thenature of this relationship between patients with and withoutestablished diabetes. Both short- and long-term mortalityincreased in a linear fashion with higher admission glucose inpatients without known diabetes. However, among thosewith established diabetes, only patients with severe hypergly-caemia (admission glucose > 240 mg/dL [13.2 mmol/L])experienced a statistically significant increase in mortality (fig-ure 2). Close analysis and direct comparison of risk-adjustedmortality rates showed that while patients with normalglucose levels and without known diabetes had lower30-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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Figure 1. The relationship between admission glucose andmortality in AMI

50

Mortatyrate(%)

45

40

35

3025

20

15

10

5

0< 110 > 110

to 140> 140to 170

> 170 to 240 > 240

Admission glucose groups (mg/dL)

One-year mortality

30-day mortality

Key:AMI = acute myocardial infarctionTo 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 admissionglucose and mortality differs in AMI patients with andwithout known diabetes

Mortalityrate(%)

45

40

35

30

25

20

15

10

5

0< 110 > 110

to 140> 140to 170

> 170to 240

> 240


Patients with diabetes

Patients without diabetes

Key:AMI = acute myocardial infarctionTo convert glucose from mg/dL to mmol/L, multiply by 0.055


Figure 3. Direct comparison of risk-adjusted 30-daymortality between AMI patients with and without knowndiabetes across the range of admission glucose values

Mortalityrate

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.070 120 170 270 320


Patients with diabetes

Patients without diabetes

220 370

1.0

Key:AMI = acute myocardial infarctionTo convert glucose from mg/dL to mmol/L, multiply by 0.055



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The relationship between persistent hyperglycaemiaand mortalityMost prior studies have focused predominantly on the prog-nostic value of admission glucose principally as a matter ofconvenience, since only admission glucose values are usual-ly available in many retrospective studies. However, the glu-cose value on hospital admission represents only a singlemeasurement in time, and does not reflect the overall expo-sure to hyperglycaemia.

While several smaller studies have suggested that persis-

tent hyperglycaemia is prognostically important,23,25,30,34 thedefinitive evidence for this concept comes from a recentanalysis of nearly 17,000 patients hospitalised with AMI.29

Results from this study have demonstrated clearly a power-ful relationship between average glucose during hospitalisa-tion and in-hospital mortality. There was a statistically signif-icant, gradual increase in the risk of in-hospital mortality asthe mean hospitalisation glucose level rose above the thresh-old of ~120 mg/dL (6.6 mmol/L) (figure 4). Again, a markeddifference in the nature of the relationship between meanhospitalisation glucose and mortality was observed inpatients with and without known diabetes. The risk of death

associated with higher mean glucose rose steeply in patientswithout recognised diabetes above 120 mg/dL (6.6 mmol/L).However, among patients with known diabetes, the curvewas much less steep, and only those diabetic patients withsevere, sustained hyperglycaemia (mean hospitalisation glu-cose > 200 mg/dL [11.0 mmol/L]) had significantly higherrisk of death compared with those whose mean glucose lev-els were 144

Mean 24-hour glucose (mg/dL)

Key: To convert glucose from mg/dL to mmol/L, multiply by 0.055

Data from Diaz et al.28


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

Glucometrics in patients with AMI: which measureis the best predictor of risk?While glycosylated haemoglobin (HbA1C) is useful in assess-ing average glucose control, and has clear prognostic impli-cations in the outpatient setting,37 its value in predicting out-comes in the setting of hospitalisation for AMI is limited.20,38

Therefore, there is a need for a summary measure of in-patient glucose control (in-hospital HbA1C) that wouldtake into account multiple and random glucose measure-ments obtained at various times and intervals, representingvarious nutritional conditions, and have a demonstratedimpact on patient outcomes.

As noted above, various glucose measures have been

shown to be associated with increased risk of mortality andin-hospital complications among patients with AMI, includ-ing admission, mean 24-hour, mean hospitalisation and fast-ing glucose. Several other (and more sophisticated) measuresof glucose control have been proposed in other studies, suchas time-averaged glucose (TAG, area under the glucosecurve)34 and hyperglycaemic index (HGI)39 both of whichtake into consideration not only the glucose values them-selves, but also the time period over which these values wererecorded. In one of the largest studies to date, several ofthese metrics were directly compared for their ability to dis-criminate AMI survivors from non-survivors (table 1).29

Specifically, three different measures of glucose control overtime (mean, TAG and HGI) were each evaluated over threetime periods (24 hours, 48 hours and the entire hospitalisa-tion) and compared with admission glucose. While higherglucose values were strongly associated with increased risk ofin-hospital mortality for all glucose metrics, measures of per-sistent hyperglycaemia performed significantly better thanadmission glucose alone. There was a gradual, statisticallysignificant increase in the discriminating ability of these glu-cometrics as the time window increased. Specifically, the Cindex values for any summary measure of glucose over theentire hospitalisation were better than the C indices for glu-cometrics over 48 and 24 hours. While the most sophisti-

cated metric of glucose during hospitalisation (HGI) had thehighest C index, the overall differences between mean glu-

cose, TAG and HGI were small. Overall, mean hospitalisa-tion glucose appeared to be the most practical metric of glu-cose control during AMI hospitalisation, due to the combi-nation of its discriminating power and ease of calculationand clinical implementation.

Fasting glucose has also been demonstrated to be a bet-ter predictor of patient outcomes than admission glucose.25

While metrics of average glucose control during hospitalisa-tion (mean, TAG and HGI) were never directly comparedwith fasting glucose, what appears clear is that the prognos-tic impact of elevated glucose values extends (and is com-pounded) throughout AMI hospitalisation. Thus, glucose val-ues throughout AMI hospitalisation are important, should bemonitored, and may be used in clinical practice for progno-sis and performance assessment, and possibly (if interventionis demonstrated to improve outcomes) as a therapeutic tar-get.

Is there evidence that glucose lowering during AMIhospitalisation impacts patient outcomes?

Prior studies have definitively demonstrated the prognosticassociation between elevated glucose and adverse patient

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

Mortalityat30days(%)

012

3456789

1011121314

< 6.9(< 125)

> 6.9, < 7.8(> 125, < 140)

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

> 9.4(> 170)

Baseline glucose in mmol/L (mg/dL)

0/250.0

1/2050.5

5/2082.4

2/682.9

2/1141.8

1/541.9 3/187

1.6

3/1082.8

5/588.6

13/3323.9

4/557.3

6/5510.9

Categories of 24-h change in glucose(baseline glucose minus 24-h glucose level)

> 1.7 mmol/L (30 mg/dL) i.e. largedrop in glucose in the first 24 h

> 0 mmol/L, i.e. no change to moderatedrop in glucose in the first 24 h

< 0 mmol/L, i.e. actual increase inglucose in the first 24 h

Data from Goyal30

Table 1. Comparison of various glucose metric time window combinations using C statistics

Time window Glucose metric p-value for overallAdmission Mean TAG HGI comparison across glucose metrics

Admission 0.619 N/A N/A N/A N/A

24 hours N/A 0.643 0.643 0.647 0.000148 hours N/A 0.659 0.658 0.664


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outcomes in AMI, but these findings cannot answer the crit-ical question: is hyperglycaemia a direct mediator ofincreased mortality and complications, or is it just a markerof greater disease severity and co-morbidity burden? Toanswer this question definitively, well designed, randomisedclinical trials of target-driven intensive glucose control in hos-

pitalised AMI patients will be required, and some are under-way. In the interim, epidemiological data (though scarce sofar) can help us to evaluate whether changes in glucose lev-els during hospitalisation are associated with changes inprognosis, whether specific therapies such as insulin used forglucose lowering during hospital stay can impact patient out-comes, and whether information about specific target levelscan be gleaned from epidemiological data and subse-quently tested in future randomised trials.

The best epidemiological analysis of the relationshipbetween change in glucose levels during hospitalisation andoutcomes in AMI patients comes from the retrospectiveanalysis 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 associatedwith lower risk of 30-day mortality, while no change or anincrease in glucose values were associated with significantincrease in the risk of death. As in other studies, the relation-ship between change in glucose and mortality was observedin non-diabetic, but not in diabetic, patients. Importantly,due to data limitations, this study was unable to determinewhether decreases in 24-hour glucose levels occurred fol-lowing initiation of insulin therapy or happened sponta-neously, and whether administration of glucose-loweringtherapy impacted patient prognosis. It was also unable to

identify the specific range of post-admission glucose valuesassociated with optimal patient outcomes. Additional epi-demiological studies are underway and will offer furtherinsights into these questions.

There are few epidemiological data regarding the impactof in-hospital insulin therapy on outcomes in hypergly-caemic AMI patients. Insulin clearly remains the most effec-tive method of glucose lowering in the in-patient setting.Small, mechanistic studies have suggested that insulin mayhave anti-inflammatory, pro-fibrinolytic and anti-apoptoticproperties, and that it can inhibit generation of reactive oxy-gen species and improve myocardial blood flow.40-48

However, whether insulin therapy is associated with anyclinical benefit in AMI above and beyond its associated glu-cose-lowering effect remains a subject of debate. One obser-vational study demonstrated that patients with severe hyper-glycaemia on admission (> 11.0 mmol/L [~200 mg/dL])and no prior history of diabetes had a 56% relative riskincrease in mortality at seven days (and a 51% increase inmortality at 30 days) if they did not receive insulin duringhospitalisation, as compared with similar patients who didreceive insulin therapy.49 However, the study was unable todetermine whether patients who received insulin actuallyhad 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.

Nevertheless, the study findings are in accord with resultsfrom the original Diabetes Mellitus: Insulin Glucose Infusionin Acute Myocardial Infarction (DIGAMI) trial,50 whichshowed significantly lower mortality in severely hypergly-caemic AMI patients who were treated with target-driveninsulin-glucose infusion. Clearly, more observational data

and randomised clinical trial data are needed to establishwhether target-driven glucose lowering with insulinimproves outcomes in hyperglycaemic patients with AMI.Until then, a reasonable initial approach is to consider inten-sive glucose control in critically ill AMI patients who have sig-nificant hyperglycaemia on admission (> 180 mg/dL, 9.9mmol/L), as outlined in the recent statement by theAmerican Heart Association.31

Current patterns of hyperglycaemia management inhospitalised AMI patientsThe specific glucose levels at which treatment should be ini-tiated remain highly debatable but current consensus is that

treatment with insulin should be considered in AMI patientswith severe hyperglycaemia (>180 mg/dL, 9.9 mmol/L).31

However, available evidence shows that a large proportionof these patients remain untreated. The data from theCooperative Cardiovascular Project indicated that amongpatients with severe hyperglycaemia on admission (> 240mg/dL, 13.2 mmol/L), nearly 80% of patients without a his-tory of diabetes and more than 25% of patients with knowndiabetes received no insulin during hospitalisation.2 Morerecent studies confirm these findings. Analysis of nearly17,000 AMI patients hospitalised in the US between 2000and 2005 showed that among patients with severe,sustained hyperglycaemia (mean hospitalisation glucose

> 200 mg/dL [11.0 mmol/L]), nearly 40% of patients did notreceive any insulin therapy, and almost 90% did not receiveintravenous insulin infusion. As expected, insulin treatmentrates were considerably higher in patients with known dia-betes than in those without established diabetes (despite thehigher glucose-associated risk of mortality in patients withoutknown diabetes.)33 Moreover, there was substantial variabili-ty in insulin treatment rates across the 40 participating med-ical centres.51 A recent study carried out in the UK alsoshowed that 64% of non-diabetic patients with admissionglucose > 11 mmol/L (~200 mg/dL) received no glucose-lowering treatments during hospitalisation.49

The prognostic importance of hypoglycaemia inpatients with AMISince therapy of hyperglycaemia in the AMI setting necessi-tates the use of insulin, concern persists about the short-termand long-term impact of hypoglycaemia. Several prior stud-ies have demonstrated that glucose values in the hypogly-caemic range may impact mortality adversely in AMI.Studies by Svensson et al. and Pinto et al. demonstratedthat random glucose values < 55 mg/dL (3.0 mmol/L) and< 81 mg/dL (4.5 mmol/L), respectively, were associated witha marked increase in mortality (with a 93% increase in theadjusted relative risk of two-year mortality in the study by

Svensson et al.).23,52

One of the larger observational studieson this issue also demonstrated a clear J-shaped relationship

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between average glucose values during hospitalisation andin-hospital mortality (figure 4).29 Specifically, patients withmean hospitalisation glucose of < 70 mg/dL (3.9 mmol/L)experienced a marked increase in the odds of mortality (OR6.4, p=0.01) when compared to patients with mean glucoseof 100 to < 110 mg/dL (5.56.1 mmol/L). Whether hypo-

glycaemia directly impacts mortality in AMI by increasingcatecholamine levels through activation of the sympatheticnervous system and worsening ischaemic injury, or whetherit is merely a marker for the most critically ill patients (withliver insufficiency, sepsis or shock) remains unknown, andfuture observational studies will offer additional insights intothis issue.

SummaryA large body of data evaluating the nature of the relationshipbetween elevated glucose and adverse outcomes in patientswith AMI has been accumulated over more than 40 years ofobservational research. Some questions in this field have

been answered, but many more remain subjects of ongoingdebate. It is clear that elevated glucose is a powerful predic-tor of increased mortality and in-hospital complications, par-ticularly in patients without a prior history of diabetes, andthat its adverse prognostic impact lasts throughout the entireAMI hospitalisation. It is also clear that hyperglycaemia isvery common in this setting and that it frequently remainsuntreated. What remains unknown is whether this glucose-associated mortality risk is modifiable, whether target-drivenglucose-lowering interventions will improve patient out-comes, and whether glucose management strategies shouldbe different in patients with and without known diabetes.Until definitive data from future randomised clinical trials

become available, a strategy of monitoring glucose levels forrisk stratification, and selective administration of intensiveglucose control to patients with significant hyperglycaemia(> 180 mg/dL [9.9 mmol/L]) using protocols that minimisehypoglycaemia, is advisable.

Conflicts of interest statementMK is supported by the American Heart Association CareerDevelopment Award in Implementation Research, hasreceived speaking honoraria from the Vascular BiologyWorking Group and Diaved, Inc., and has served on theadvisory board for Sanofi-Aventis (but received no personal

compensation).

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