Abnormal glucose metabolism in non-diabetic patientspresenting with an acute stroke: prospective study andsystematic review

J.A. DAVE1, M.E. ENGEL2, R. FREERCKS1, J. PETER1, W. MAY1, M. BADRI2,L. VAN NIEKERK1 and N.S. LEVITT1

From the 1Division of Diabetic Medicine and Endocrinology and 2Department of Medicine, Groote

Schuur Hospital, 7925 Cape Town, South Africa

Address correspondence to Dr J.A. Dave, Division of Diabetic Medicine and Endocrinology, Department ofMedicine, J-floor, Old Main Building, Groote Schuur Hospital, Anzio Road, Observatory, 7925, Cape Town,South Africa. email: joel.dave@uct.ac.za

Received 21 August 2009 and in revised form 30 November 2009

Summary

Background: Non-diabetic patients presenting withan acute stroke often have hyperglycaemia. In mostpopulations it is unknown whether the hypergly-caemia is transient and due to the acute stressresponse or whether it represents undiagnosedabnormal glucose metabolism.Aim: To evaluate the prevalence and predictors ofpersistent hyperglycaemia in non-diabetic patientswith an acute stroke.Design: Prospective observational study.Methods: Non-diabetic patients over 40 years oldwith an acute stroke were enrolled over a 2-yearperiod. On admission patients were evaluated withan HbA1c and a 75 g oral glucose tolerance test(OGTT). The OGTT was repeated 3 months later.A meta-analysis was performed to interpret ourresults in the context of published data.Results: One hundred and seven patients were ana-lysed. On admission 26 (24%) patients had diabetes,

39 (37%) had impaired glucose tolerance and42 (39%) had normal glucose tolerance. Forty-four(68%) patients with hyperglycaemia on admissionwere re-investigated at least 3 months afterdischarge. Of these, 6 (14%) had diabetes,12 (27%) had impaired glucose tolerance and26 (59%) had normal glucose tolerance. A 2-hpost-load glucose value 10mmol/l predicted per-sistent hyperglycaemia with 72.2% sensitivity,65.4% specificity and a positive predictive valueand negative predictive value of 59.1 and 77.3%,respectively. A meta-analysis of prevalence data ofimpaired glucose metabolism in non-diabetic indi-viduals 3 months after having had an acute strokerevealed a combined prevalence of 58% (95%confidence interval 25.490.5%).Conclusion: In this study hyperglycaemia in thesetting of an acute stroke was transient in themajority of patients.

Introduction

There is a considerable global burden of diabetes. In

the year 2000, an estimated 171 million people

were affected by diabetes, whilst the excess global

mortality attributable to diabetes was 2.9 million.

This accounted for 5.2% of all deaths.1 This excess

mortality was primarily due to cardiovascular dis-

ease (CVD), and is likely to rise as an estimated

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366 million people will have diabetes by the year

2030.2 Diabetes also increases the risk of ischaemicstroke and is associated with a less favourable out-

come than in people without diabetes. The import-

ance of early initiation and maintenance ofglycaemic control on all-cause mortality and

myocardial infarction in people with diabetes has

recently been demonstrated, adding to the

well-recognized benefit of such control on micro-vascular complications.35 Given these data, ideally

diabetes should be diagnosed early, and treatment

instituted prior to presentation with complications.

Unfortunately this is often not the case. In a numberof studies 5060% of people who presented with an

acute myocardial infarction were found to have un-

diagnosed diabetes.6,7 In addition, many peoplewith newly diagnosed diabetes have pre-existing

CVD as demonstrated in the ADDITION-

Cambridge screening and intervention study, inwhich 19% of screen positive people with diabeteshad pre-existing CVD.8

Patients without known diabetes commonly have

hyperglycaemia at presentation of an acute stroke,

making the diagnosis of diabetes difficult as thehyperglycaemia may occur as an acute stress re-

sponse,912 may represent previously undiagnosed

impaired glucose metabolism1316 or may be a

marker of infarct size.8,17,18 Although there is noevidence that rendering these patients euglycaemic

is beneficial from the point of view of mortality and

morbidity from the stroke, there is evidence that pre-venting persistent hyperglycaemia in patients with

diabetes reduces microvascular disease and

CVD.3,4,19 It is therefore clinically important to rec-

ognize these patients on admission so that they maybenefit from long-term treatment with glucose low-

ering agents. However, there is a paucity of data on

predictors of persistent hyperglycaemia in patients

presenting with an acute stroke who are notknown to have diabetes. We therefore investigated

the prevalence and predictors of persistent hypergly-

caemia in these patients. Furthermore, since there iscurrently no systematic review of the published lit-

erature on the prevalence of persistent hypergly-

caemia in non-diabetic patients who have had an

acute stroke, we analysed our results in the contextof published data through a meta-analysis.

Methods

Patients

Patients without known diabetes who were admittedto two participating hospitals with a diagnosis of

acute stroke at specific times between July 2004

and 2006 were approached for participation in thisstudy. Exclusion criteria included: being

with an upper range of 6.0%. Insulin was measuredusing a radioimmunoassay (Roche Modular E170).

Statistical analysis

Normality assumption was tested using ShapiroWilks test. Variables failing this assumption weretransformed when appropriate. These variables arepresented as median [interquartile range (IQR)] andwere analysed using the non-parametric MannWhitney U-test. Categorical variables are presentedas frequency (percentage) and were compared usingthe 2 or Fischers exact test. The relationships be-tween 3-month glycaemic status and biochemicalparameters as explanatory variables were assessedusing multiple and or logistic regression techniques.A receiver operating characteristic (ROC) curve wasplotted to determine the cut-points for predictors ofdysglycaemia and their sensitivity, specificity, andpredictive values. Statistical analyses were per-formed using SPSS (version 16.0.1) for Windows(SPSS Inc.) and STATA (version 10.0).

Systematic review and meta-analysis

Review inclusion and exclusion criteria

Prospective cohort studies investigating the preva-lence of dysglycaemia assessed according toWHO and American Diabetes Association (ADA)criteria in non-diabetic individuals with acutestroke were eligible for inclusion.22,23 Studies withmissing admission data or having follow-up data

hypoglycaemic agents (Table 2). The remaining 21patients were not re-assessed due to death after dis-charge [13 (20%) patients: eight patients with dia-betes and five patients with pre-diabetes] andinadequate contact details [8 (12%) patients].Eighteen (41%) of the 44 patients re-investigated re-mained dysglycaemic [6 (14%) had diabetes, 12(27%) had pre-diabetes] and 26 (59%) had NGT(Table 2). The three patients on oral hypoglycaemicagents were considered to have diabetes as sup-ported by their elevated FPG and HbA1c despitetreatment (Patient A: FPG 6.6mmol/l, HbA1c 6.7%;patient B: FPG 6.8mmol/l, HbA1c 6.6%; patient C:FPG 6.8mmol/l, HbA1c 6.3%). Of the 26 patientsclassified with diabetes during the acute admission,5 (19%) remained diabetic, 6 (23%) hadpre-diabetes and 6 (23%) had NGT (Table 3). Inthe 39 patients with pre-diabetes during the acuteadmission, 1 (3%) developed diabetes, 6 (15%)remained with pre-diabetes and 20 (51%) revertedto NGT (Table 3). Patients with dysglycaemia had ahigher median HbA1c (5.95%, IQR 5.56.4 vs.5.5%, IQR 5.26.1; P=0.04) and median homeosta-sis model assessment of insulin resistance

(HOMA-IR) (3.5, IQR 2.74.7 vs. 1.4, IQR 0.92.2;P 0.001) than those with NGT, but age, gender,past history of hypertension or dyslipidaemia,family history of diabetes, current/previous smoking,body mass index (BMI), waist circumference, BP,triglycerides and high-density lipoprotein (HDL)did not differ between those with NGT ordysglycaemia.On admission, patients that subsequently

died had a significantly higher FPG thanthose alive at follow-up (10.43.9mmol/l, 95%CI: 8.8; 12 vs. 8.6 3.3mmol/l, 95% CI: 7.9; 9.3,P=0.043) but there was no significant difference inHbA1c.Logistic regression analysis revealed the 2-h

post-load glucose value on admission to be theonly significant predictor of persistent dysglycaemia3 months after discharge. A 2-h post-load glucosevalue 10mmol/l predicted dysglycaemia with72.2% sensitivity, 65.4% specificity and gave a posi-tive predictive value (PPV) and negative predictivevalue (NPV) of 59.1 and 77.3%, respectively(Table 4). The area under the ROC curve was 0.76(95% CI: 0.610.90).

Table 1 Characteristics of the study population during the acute admission

Parameter NGT Dysglycaemia P

Socio-demographic characteristics

Age (years) 59 (4969) 62 (5371) 0.23

Male gender 29 (69) 28 (43)

Systematic review and meta-analysis

The search strategy yielded 935 citations. Records

were screened by title after which 48 articles were

deemed to be potentially relevant. Abstracts were

evaluated by two observers working independently

and 43 studies were excluded; following full-text

scrutiny, one publication was excluded, while for

a further two, the full text was unavailable.

Reasons for exclusion were known diabetics

included (n=3), no glycaemic data provided

(n=5), no admission OGTT and no follow-up data

at3 months (n=35).

Characteristics of the included studies

One publication (Vancheri) satisfied our inclusion

criteria (Table 5). Together with our unpublished

data, the eligible studies pertained to two distinct

study populations comprising 213 participants with

median ages of 71.0 and 61.0 years, respectively.

The proportions of men were 61 and 53%,

Table 2 Characteristics of the subjects that were dysglycaemic on admission and who were re-tested after 3 months

Parameter NGT Dysglycaemia P

n 26 18

Age (years) 64.0 (5272) 65 (5373) 0.95

Female gender 13 (50) 13 (72) 0.14

Previous hypertension 18 (69) 12 (67) 0.86

History of smoking 11 (42) 11 (61) 0.22

Previous dyslipidaemia 2 (8) 1 (6) 0.64a

Family history of diabetes mellitus 7 (27) 5 (28) 0.95

Admission

BMI (kg/m2) 26 (2329) 27 (2430) 0.33

Waist circumference (cm) 93 (7899) 93 (87100) 0.90

Systolic BP (mmHg) 167 (150191) 159 (140210) 0.70

Diastolic BP (mmHg) 94 (85104) 87 (76104) 0.21

HbA1c (%) 5.5 (5.26.1) 6.0 (5.56.4) 0.04

OGTT

FPG (mmol/l) 5.7 (5.36.3) 6.4 (5.86.8) 0.15

2-h plasma glucose (mmol/l) 9.1 (8.210.3) 10.9 (9.414.4) 0.004

Total cholesterol (mmol/l) 5.5 (4.96.0) 5.3 (4.76.1) 0.69

Triglyecrides (mmol/l) 1.3 (1.11.5) 1.5 (1.22.3) 0.12

HDL (mmol/l) 1.1 (0.91.3) 1.1 (0.81.2) 0.39

LDL (mmol/l) 3.5 (3.04.1) 3.3 (2.93.9) 0.65

3 monthsOGTT

FPG (mmol/l) 5.0 (4.85.3) 6.0 (5.66.6)

respectively. For the outcome of interest, a total of

125 subjects were included in the analysis. Bothwere observational studies conducted in Italy and

South Africa, respectively and both classified im-

paired glucose metabolism according to WHO andADA criteria.Meta-analysis of prevalence data of dysglycaemia

in non-diabetic individuals 3 months after havinghad an acute stroke revealed a combined preva-

lence of 58% (95% CI: 25.490.5%) (Table 5).

Statistically significant heterogeneity [heterogeneity2 significant (P< 0.01), I2>90%] was found acrossthe studies.

Discussion

In this prospective study, the second to evaluate glu-cose homeostasis in patients without a prior diagno-

sis of diabetes and an acute stroke, using a FPG and

OGTT on admission and again within 312 monthsafter discharge, 61% of patients were found to bedysglycaemic (24% had diabetes and 36%pre-diabetes) on admission. However, by 312months after discharge the majority (59%) hadNGT leaving an overall prevalence of persistent dys-glycaemia of 21% (7% with diabetes and 14% withpre-diabetes). The 2-h post-load blood glucose onadmission was most predictive of dysglycaemia at3 months.Although the prevalence of dysglycaemia on ad-

mission was high in this study, it was lower than thatreported in the only other study using a FPG andOGTT to evaluate glucose homeostasis on admis-sion and again at least 3 months later.16 In thatstudy, the prevalence of dysglycaemia on admissionwas 84.3% (45.8% had diabetes and 38.5% IGT).The higher prevalence may be due to the older ageof their patients (69.6 years, IQR 63.276.7 vs.61 years, IQR 51.071.0). Interestingly, the majority

Table 4 Sensitivity, specificity and predictive values of the 2-h post-load glucose on admission for predicting dysglycaemiaat 3 months after discharge

Two-hour post-load

glucose (mmol/l)

on admission

Sensitivity (%) Specificity (%) PPV (%) NPV (%)

6 100.0 (82.4100) 3.8 (0.718.9) 41.9 (28.456.7) 100.0 (20.7100)7 100.0 (82.4100) 7.7 (2.124.1) 42.9 (29.157.8) 100.0 (34.2100)8 94.4 (74.299.0) 15.4 (6.233.5) 43.6 (29.359.0) 80.0 (37.696.4)9 88.9 (67.296.9) 50.0 (32.167.9) 55.2 (37.671.6) 86.7 (62.196.3)10 72.2 (49.187.5) 65.4 (46.280.6) 59.1 (38.876.7) 77.3 (56.689.9)11 50.0 (29.071.0) 84.6 (66.5093.9) 69.2 (42.487.3) 71.0 (53.483.9)12 38.9 (20.361.4) 88.5 (71.096.0) 70.0 (39.789.2) 67.7 (50.880.9)13 38.9 (20.361.4) 96.2 (81.199.3) 87.5 (52.997.8) 69.4 (53.182.0)14 27.8 (12.550.9) 96.2 (81.199.3) 83.3 (43.797.0) 65.8 (49.978.8)15 22.2 (9.045.2) 96.2 (81.199.3) 80.0 (37.696.4) 64.1 (48.477.3)

Table 5 General characteristics of studies included in the systematic review and meta-analysis

Vancheri n (%) Dave n (%) Combined

ES (95% CI)

n at start 106 107

n at follow-up 81 (76) 44a (41)

n (male) 65 (61) 57 (53)

Region Italy South Africa

Source Hospital Hospital

Normoglycaemia at admission 15 (16) 42 (39)

Dysglycaemia at admission 81 (84) 65 (61)

Normoglycaemia at 3 months 21 (26) 26 (59)Dysglycaemia at 3 months 60 (74) 18 (41) 0.58 (0.25; 0.90)Missing/excluded/died 10 (10) 21 (32)

n: number; ES: effect size.aOnly patients that were dysglycaemic at admission were re-evaluated.

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(74%) of their patients with dysglycaemia on admis-sion remained dysglycaemic when re-tested3 months after discharge (43% had diabetes and31% IGT) leaving their overall prevalence of dysgly-caemia at 65% (37.5% with diabetes and 27.1%with IGT), suggesting a pre-existent abnormality ofglucose metabolism in the majority of their patients.On the other hand, the majority of dysglycaemicpatients in our study reverted to euglycaemia, indi-cating that the hyperglycaemia on admission waslikely to be due to the acute stress response. It hasbeen debated whether the acute stress responseplays a significant physiological role, nevertheless,it is well-documented that the diabetogenic hor-mones cortisol and catecholamines are elevated insome patients with an acute stroke.11,12,24 Whilsteven in a population-based survey in ruralTanzania 80% of subjects with IGT reverted toNGT within 5 days, partly attributable to the orient-ing reflex in BP measurements in a population un-familiar with blood testing.25

Patients in developing countries present later inthe course of their illness, which in the case of anacute stroke may result in a larger infarct area andhigher blood glucose. The causal relationshipbetween hyperglycaemia and larger infarcts remainsunknown, but is speculated to be due to increasedoxidative stress and inflammation found in the set-ting of hyperglycaemia.26 Interestingly, the patientsin this study that died had a higher fasting bloodglucose level on admission than those that survivedyet there was no difference in HbA1c, suggestingpre-stroke euglycaemia and possibly larger andmore severe cerebral infarcts. This is consistentwith the study by Murros et al. that showed thatpre-stroke hyperglycaemia (as suggested by anincreased HbA1c) did not have any predictivevalue concerning stroke outcome but thatpost-stroke fasting hyperglycaemia correlatedstrongly with stroke severity and predicted strokeoutcome.27 They suggest that a high fasting bloodglucose after a stroke reflects a stress response to amore severe ischemic brain lesion. Other studies inanimals and humans have shown an associationbetween hyperglycaemia and worse outcomeafter stroke in terms of both mortality andmorbidity.18,2830

Our study differs from most other studies that haveassessed hyperglycaemia in the acute stroke settingin that it was designed a priori to examine the ques-tion of persistent hyperglycaemia. For that reason,only patients with hyperglycaemia on admissionwere re-examined. However, we were only able tore-investigate 68% of the dysglycaemic patients as13 (20%) had died and 8 (12%) were lost tofollow-up. The latter observation is probably due

in large part to patients giving incorrect contactdetails so as to qualify for admission to their hospitalof choice rather than the hospital closest to wherethey live. If one assumes that all those notre-examined became euglycaemic (best casescenario) or that they remained dysglycaemic(worst case scenario) then the lowest and highestprevalences of dysglycaemia are 28 and 60%,respectively. Even at 60%, the worst case scenarioprovides a much lower prevalence than describedby Vancheri et al.16

A dearth of factors examined on admission(including age, gender, smoking, previous historyof hypertension, family history of diabetes, BP,lipids, BMI, waist circumference, HbA1c, fasting in-sulin and HOMA) proved to be predictive of dysgly-caemia at follow-up. Both the present study and thatof Vancheri et al. found the 2-h post-load plasmaglucose on admission to be most predictive of dys-glycaemia at 3 months. This may be somewhat sur-prising as the poor reproducibility of the 2-hpost-load glucose would be expected to cast doubton its ability to be a predictive test. The use of acomposite score including multiple diabetes riskfactors such as waist girth or BMI, family history ofdiabetes, age and levels of physical activity mayprove to be more useful and its utility should beexplored in a larger cohort. This would permitearly introduction of appropriate glucose loweringtherapy and attainment of euglycaemia or close toeuglycaemia immediately after the stroke, with therecognized benefits.We attempted to analyse our results in the context

of existing studies. However this systematic reviewhighlights the lack of well-designed prospective stu-dies utilizing both a FPG and 2-h post-load plasmaglucose to identify dysglycaemic patients (as recom-mended by the WHO and ADA). We believe thatmost studies were likely to have missed patients withabnormal glucose metabolism on admission as theydid not use a FPG and OGTT to diagnose dysgly-caemia. In addition, most studies do not havefollow-up glycaemic data and are therefore unableto assess the prevalence of persistent dysglycaemia.The studies by Kernan et al.14 and Gray et al.31 con-tain follow-up glycaemic data and are similar tothose included in the meta-analysis, but are likelyto have missed patients with abnormal glucose me-tabolism, as no OGTT was done on admission andonly patients whose fasting blood glucose waswithin a specifically defined range were included.Lam et al. report a prevalence of 17 and 26% ofdiabetes and IGT, respectively in Chinese patientswith a stroke and no prior diagnosis of diabetes.28 Astheir report does not contain glycaemic data on ad-mission, it is not possible to determine whether their

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reported prevalence is of persistent dysgycaemia or

whether the dysglycaemia developed in these pa-

tients as a result of the stroke i.e. less physical activ-

ity, weight gain and the use of diabetogenic drugs

such as b-blockers and/or thiazide diuretics. In ourmeta-analysis, the results showed significant hetero-

geneity. Procedurally, the studies were similar in

almost every respect and thus, we suspect that this

variation is due to the difference in the number of

participants for which follow-up data were avail-

able. Nevertheless, a meta-analysis of these studies

is still useful in providing an idea of the overall

prevalence which indicates a combined prevalence

of persistent dysglycaemia of 58%.It is concerning that a significant number of stroke

patients with no prior history of diabetes have their

first clinical presentation of dysglycaemia as an

acute stroke. It seems that opportunistic screening

of individuals with risk factors for diabetes who

attend a health service will allow for earlier diagno-

sis and initiation of therapy and a chance to avert or

delay micro and macrovascular complications.

Indeed, the ADDITION-Cambridge study has

shown that people with screen-detected type 2 dia-

betes have an adverse cardiovascular risk profile

and that a significant absolute reduction in this risk

is achievable through multifactorial therapies.8

Since a proportion of hyperglycaemic non-diabetic

stroke patients will have transient hyperglycaemia

or prediabetes, it is important that these patients

undergo strict lifestyle modification and are

re-assessed with an OGTT at least 3 months after

discharge.In conclusion, we report a high prevalence of

transient dysglycaemia in patients with an acute

stroke. It is concerning that at least 21% of patients

in our study had undiagnosed dysglycaemia. In

agreement with studies post-myocardial infarction

and in the absence of significant predictive factors

we suggest a follow-up OGTT at least 3 months after

discharge in hyperglycaemic acute stroke patients

with no prior history of diabetes.

Acknowledgement

The authors wish to thank Dr Frances Wilson for

helping with the recruitment of patients.

Funding

The Medical Research Council of South Africa and

the University of Cape Town.

Conflict of interest: None declared.

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