Prevalence of abnormal glucose tolerance following a transient ischemic attack or ischemic stroke.

Abstract

Despite current preventive therapies, patients with transient ischemic attack (TIA) and ischemic stroke remain at high risk for recurrent brain disease and cardiovascular events. In an effort to develop new therapies, abnormal glucose tolerance has recently been proposed as an interventional target. Among persons not otherwise known to be diabetic, impaired glucose tolerance (IGT) and diabetic glucose tolerance (DGT) are each associated with an increased risk for incident vascular disease, vascular disease mortality, and all-cause mortality. We conducted this study to determine if IGT and DGT are sufficiently common among patients with TIA and ischemic stroke to warrant therapeutic trials of antihyperglycemic agents.
Men and women older than 45 years were recruited from 3 hospitals in south central Connecticut. Eligibility criteria included a recent TIA or nondisabling ischemic stroke, no history of physician-diagnosed diabetes mellitus, and a fasting plasma glucose level less than 126 mg/dL (<7.0 mmol / L). After an overnight fast, subjects were admitted to a clinical research center for a standard 75-g oral glucose tolerance test. Impaired glucose tolerance was defined by a 2-hour plasma glucose value of 140 to 199 mg/dL (7.8-11.0 mmol / L) and DGT by a value of 200 mg/dL or greater (> or =11.1 mmol/L).
Between June 2000 and August 2003, we enrolled 98 eligible patients. The average time from TIA or stroke to measurement of glucose tolerance was 105 days (range, 24-180 days) and the median age was 71 years. Twenty-seven subjects (28%) had IGT and 24 (24%) had diabetes. In a forward stepwise logistic regression model, only a fasting plasma glucose level of 110 mg/dL or greater (> or =6.1 mmol / L) and lower waist circumference were associated with an increased risk for IGT or DGT.
Impaired glucose tolerance and DGT are present in most persons with a recent TIA or ischemic stroke who have no history of diabetes and a fasting plasma glucose level less than 126 mg/dL (<7.0 mmol / L). Our findings bring new urgency to the initiation of research to examine the effectiveness of antihyperglycemic therapies among patients with cerebrovascular disease and abnormal glucose tolerance.

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ORIGINAL INVESTIGATION
Prevalence of Abnormal Glucose Tolerance
Following a Transient Ischemic Attack
or Ischemic Stroke
Walter N. Kernan, MD; Catherine M. Viscoli, PhD; Silvio E. Inzucchi, MD; Lawrence M. Brass, MD;
Dawn M. Bravata, MD; Gerald I. Shulman, MD, PhD; James C. McVeety, MD
Background:Despitecurrentpreventivetherapies,pa-
tients with transient ischemic attack (TIA) and ische-
mic stroke remain at high risk for recurrent brain dis-
ease and cardiovascular events. In an effort to develop
new therapies, abnormal glucose tolerance has recently
been proposed as an interventional target. Among per-
sons not otherwise known to be diabetic, impaired glu-
cosetolerance(IGT)anddiabeticglucosetolerance(DGT)
are each associated with an increased risk for incident
vascular disease, vascular disease mortality, and all-
cause mortality. We conducted this study to determine
if IGT and DGT are sufficiently common among pa-
tients with TIA and ischemic stroke to warrant thera-
peutic trials of antihyperglycemic agents.
Methods:Menandwomenolderthan45yearswerere-
cruited from 3 hospitals in south central Connecticut.
Eligibility criteria included a recent TIA or nondis-
abling ischemic stroke, no history of physician-
diagnosed diabetes mellitus, and a fasting plasma glu-
coselevellessthan126mg/dL(?7.0mmol/L).Afteran
overnight fast, subjects were admitted to a clinical re-
search center for a standard 75-g oral glucose tolerance
test.Impairedglucosetolerancewasdefinedbya2-hour
plasma glucose value of 140 to 199 mg/dL (7.8-11.0
mmol/L) and DGT by a value of 200 mg/dL or greater
(?11.1 mmol/L).
Results: Between June 2000 and August 2003, we en-
rolled98eligiblepatients.TheaveragetimefromTIAor
stroketomeasurementofglucosetolerancewas105days
(range, 24-180 days) and the median age was 71 years.
Twenty-sevensubjects(28%)hadIGTand24(24%)had
diabetes.Inaforwardstepwiselogisticregressionmodel,
onlyafastingplasmaglucoselevelof110mg/dLorgreater
(?6.1mmol/L)andlowerwaistcircumferencewereas-
sociated with an increased risk for IGT or DGT.
Conclusions: Impaired glucose tolerance and DGT are
present in most persons with a recent TIA or ischemic
strokewhohavenohistoryofdiabetesandafastingplasma
glucose level less than 126 mg/dL (?7.0 mmol/L). Our
findings bring new urgency to the initiation of research
toexaminetheeffectivenessofantihyperglycemicthera-
piesamongpatientswithcerebrovasculardiseaseandab-
normal glucose tolerance.
Arch Intern Med. 2005;165:227-233
A
tality, and all-cause mortality.1,2In a re-
cent pooled analysis including 22514
persons enrolled in 10 European cohort
studies, blood glucose concentration 2
hours after an oral glucose challenge was
a better predictor of death from all causes
and cardiovascular disease than was fast-
ing plasma glucose (FPG) level.2Among
subjectsnotpreviouslydiagnosedwithdia-
betes in this analysis, those with impaired
glucose tolerance (IGT) (blood glucose
valueof140-199mg/dL[7.8-11.0mmol/L]
at 2 hours) were 34% more likely to die of
strokeorheartdisease(hazardsratio,1.34;
95% confidence interval, 1.14-1.57) com-
BNORMAL GLUCOSE TOLER-
ance among persons not
otherwise known to have
diabetes is associated with
an increased risk for inci-
dentvasculardisease,vasculardiseasemor-
paredwithpersonswithnormalglucosetol-
erance. Those with diabetic glucose toler-
ance (DGT) (blood glucose value ?200
mg/dL [?11.1 mmol/L] at 2 hours) were
55% more likely to die of stroke or heart
disease (hazards ratio, 1.55; 95% confi-
dence interval, 1.20-2.01).
Themechanismsfortheassociationbe-
tween IGT and increased risk for vascular
disease are not fully understood, but it is
knownthattheprevalenceofmetabolicrisk
factors (eg, low high-density lipoprotein
cholesterollevelandelevatedsystolicblood
pressure) increase linearly according to
postchallenge glucose concentration.3Hy-
perglycemia,furthermore,isassociatedwith
insulinresistance,adisordercharacterized
byendothelialdysfunction,vascularinflam-
mation,hypertension,dyslipidemia,abnor-
malfibrinolysis,andacceleratedatheroscle-
rosis.4,5In addition to the adverse vascular
Author Affiliations:
Departments of Internal
Medicine (Drs Kernan, Viscoli,
Inzucchi, Bravata, and
Shulman), Neurology
(Drs Brass and McVeety),
Epidemiology and Public
Health (Dr Brass), and Cellular
& Molecular Physiology
(Dr Shulman), Yale School of
Medicine, New Haven, Conn;
Veterans Affairs Connecticut
Healthcare System, West Haven
(Drs Brass and Bravata); and
Howard Hughes Medical
Institute, New Haven
(Dr Shulman).
Financial Disclosure:
Dr Inzucchi has received
honoraria from and served as a
consultant for Takeda
Pharmaceuticals, which partly
funded this study.
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and metabolic effects of IGT, persons with this condition
developdiabetes,includingDGT,atamuchhigherratethan
personswithnormalglucosetolerance.6,7Diabetes,ofcourse,
isawell-establishedriskfactorforatherosclerosis,stroke,
andheartdisease.8-10Mechanismsbywhichdiabetesleads
to vascular disease are probably the same as those previ-
ously listed for IGT.11
Because of the adverse health consequences of IGT,
severaltherapeutictrialshavebeenconducted.IntheUS
Diabetes Prevention Program, an intensive lifestyle in-
tervention among persons with IGT reduced the inci-
denceofdiabetesby58%comparedwithplacebo.12Simi-
lar findings were reported among obese northern
European subjects who participated in the Finnish Dia-
betes Prevention Study.13Pharmacologic interventions
thatpreventdiabetesinhigh-riskindividualsincludethia-
zolidinediones,14?-glucosidase inhibitors,15and bigua-
nides.12TheSTOP–Noninsulin-DependentDiabetesMelli-
tus(STOP-NIDDM)trialinvestigatorshavereportedthat
acarbose, an ?-glucosidase inhibitor that specifically re-
duces postprandial hyperglycemia, reduced major car-
diovascular events (coronary heart disease, cardiovas-
cular death, congestive heart failure, transient ischemic
attack[TIA],stroke,andperipheralvasculardisease)by
49% compared with placebo among persons with IGT.16
Prevention studies have not focused on patients who
have both a normal FPG level and DGT. They already
have diabetes, so prevention of this end point is moot.
Theirriskforvasculardisease,however,exceedstherisk
amongpersonswithIGT,2andpreventionofthisendpoint
wouldbeveryimportant.PersonswithanormalFPGlevel
and DGT usually do not require medications to achieve
diabetes treatment goals and, therefore, would be can-
didates for enrollment in randomized, placebo-
controlled clinical trials of antihyperglycemic medica-
tions to prevent vascular end points.
Theforegoingepidemiologicandexperimentaldatasug-
gestthatantihyperglycemictreatmentofIGTandDGTmay
representanimportantnewtherapyforpatientswithahis-
toryofTIAorstroke.Despitetheuseofantiplateletagents
andotherproventherapies,patientswithsymptomaticcere-
brovasculardiseasearestillathighriskforrecurrentvas-
cularevents.Onaverage,within5yearsoftheinitialevent,
25%ofpatientswillhavearecurrentstroke,10%willhave
amyocardialinfarction,and12%willdiefromoneofthese
conditions.17-21ThepotentialimpactoftreatmentforIGT
and DGT will depend on the prevalence of these condi-
tions, which is currently unknown. Both can only be de-
tectedafteranoralglucosetolerancetest(OGTT).Inprac-
tice,physiciansrarelyperformanOGTTafterstroke,and
therehasbeennosubstantialresearchinthisarea.Theaim
ofthisstudy,therefore,wastoascertaintheprevalenceof
IGTandDGTamongacohortofpatientswithsymptom-
atic cerebrovascular disease.
METHODS
STUDY PARTICIPANTS
We studied men and women older than 45 years with no his-
tory of diabetes who were admitted to 1 of 3 participating hos-
pitals between June 2000 and August 2003 for TIA or nondis-
abling ischemic stroke. All subjects were originally recruited
for participation in studies on the prevalence of insulin resis-
tance among patients with a recent TIA or ischemic stroke or
thetemporaltrendininsulinresistanceafterischemicstroke.22,23
A nondisabling stroke was recognized when a patient was able
to communicate verbally, take 3 steps with or without the as-
sistance of another person, and ride in a car. We enrolled only
persons with nondisabling events to minimize the contribu-
tion of stroke-related inactivity to the measured insulin sensi-
tivity.24Patients were excluded if their cerebrovascular event
was related to trauma, medical instrumentation, or embolism
fromanartificialheartvalve.Patientswerealsoexcludedifthey
were taking oral corticosteroids, had irreversible medical con-
ditions that were likely to affect short-term survival or ability
toparticipateinthestudyprotocol,orhadanFPGvalueof126
mg/dL or greater (?7.0 mmol/L).
Patients were identified by review of discharge logs from all
participating hospitals and by weekly contact with stroke clini-
cians who volunteered to assist with surveillance. For patients
dischargedwithInternationalClassificationofDiseases,NinthRe-
vision,ClinicalModificationcodes433though436(occlusionand
stenosis precerebral arteries, occlusion cerebral arteries, tran-
sient cerebral ischemia, and acute but ill-defined cerebrovascu-
lardisease),weobtainedpermissionforcontactdirectlyfromper-
sonalphysicians.Aneffortwasmadetodeterminetheeligibility
of every patient with an appropriate discharge diagnosis, al-
thoughcompleterecordswerenotmaintainedtodocumentrea-
sonsforexclusionofallnonenrolledpotentialsubjects.Thisstudy
wasapprovedbytheinvestigationalreviewboardateachpartici-
pating hospital (Yale-New Haven Hospital, New Haven, Conn;
Hospital of St Raphael, New Haven; and West Haven Veterans
AdministrationMedicalCenter,WestHaven,Conn),andallpa-
tients provided written informed consent.
PATIENT ASSESSMENT
Patients who passed a telephone screening for eligibility were
invited to the General Clinical Research Center of Yale-New
Haven Hospital for an interview, physical examination, and
OGTT (all completed on the same day). The interview com-
prised questions about medical conditions and current medi-
cations. The physical examination comprised anthropomor-
phic measures (weight, waist-hip circumference, and height)
and blood pressure. Waist circumference was measured at the
midpointbetweenthelowerborderoftheribcageandtheiliac
crest.25
The OGTT was performed according to standard proce-
dures modified to permit calculation of the Composite Insulin
SensitivityIndex(CompositeIndex)describedbyMatsudaand
DeFronzo.26After baseline measures, subjects consumed 75 g
oforalglucose.TheCompositeIndexwascalculatedasthefol-
lowing:
10000/[(FPG Value in Milligrams per Deciliter ? Fasting
PlasmaInsulinValueinMicrounitsperMilliliter)?(MeanPlasma
GlucoseConcentrationinMilligramsperDeciliter?MeanPlasma
Insulin Concentration in Microunits per Milliliter)]1/2.
Meanplasmaglucoseandinsulinvalueswereobtainedfrom
measures made at 30, 60, 90, and 120 minutes after glucose
administration.Higherindexvaluesindicategreaterinsulinsen-
sitivity.Asanadditionalmeasureofinsulinsensitivity,wealso
calculated the Homeostasis Model Assessment of Insulin Re-
sistance, which is estimated as the following27:
[(FPG Value in Millimoles per Liter) ? (Fasting Plasma
Insulin Value in Microunits per Liter)]/22.5.
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Higher values indicate greater insulin resistance. As a mea-
sure of ?-cell function, we calculated the Homeostasis Model
Assessment of ?-cell function.27
Plasma glucose concentrations were measured by a glu-
cose oxidation method (Glucose Analyzer II; Beckman
Instruments, Palo Alto, Calif). Plasma insulin was measured
using a commercial radioimmunoassay kit (Linco Research,
St Charles, Mo) that does not cross-react with human proin-
sulin.
STATISTICAL ANALYSIS
Baselinefeaturesofthestudypopulationweredescribedbysimple
percentages.Hypertensionwasdefinedbyself-reporthistoryand
current use of an antihypertension drug, or by a blood pressure
greaterthan160/100mmHg.Myocardialinfarctionwasdefined
byself-reportofphysiciandiagnosisofmyocardialinfarctionfor
which the patient was hospitalized for more than 1 day. Carotid
stenosis was based on carotid duplex ultrasonography obtained
atthetimeofthecerebrovascularevent.Atrialfibrillationwasclas-
sifiedbyanelectrocardiogramobtainedduringtheinitialhospi-
talizationforcerebrovascularsymptomsoratthetimeoftheglu-
cose tolerance test. Obesity was defined according to standard
criterion of a body mass index over 30 (calculated as weight in
kilogramsdividedbythesquareofheightinmeters).28Abdomi-
nal obesity was defined as a value greater than 102 cm for men
and greater than 88 cm for women.29
Glucose tolerance was classified according to criteria estab-
lished by the American Diabetes Association.30Normal toler-
ance is defined by a plasma glucose value less than 140 mg/dL
(?7.8 mmol/L) 2 hours after 75 g of oral glucose. Impaired
glucose tolerance is defined by values of 140 mg/dL or greater
(?7.8 mmol/L) and less than 200 mg/dL (?11.1 mmol/L).
Diabetes is defined by a value of 200 mg/dL or greater (?11.1
mmol/L).
Unadjusted odds ratios were calculated for the occurrence
of IGT or DGT (2-hour plasma glucose concentration of 140
mg/dLorgreater[?7.8mmol/L])amongpatientswithandwith-
out specific clinical features. P values for these bivariate asso-
ciationswerecalculatedfromthe?2statistic.Anadjustedanaly-
sis was performed using a forward stepwise logistic regression
model (with P values for entry and retention, .10) that consid-
eredallsubjectfeatureswithasignificantbivariateassociation
with 2-hour plasma glucose concentration of 140 mg/dL or
greater (?7.8 mmol/L) (P?.10). All statistical analyses were
performedusingSASstatisticalsoftware(SASversion8.0;SAS
Institute Inc, Cary, NC).
RESULTS
Between June 2000 and August 2003, we enrolled 102
subjects.FoursubjectswereexcludedbecausetheirFPG
level exceeded 125 mg/dL (6.9 mmol/L), leaving 98 eli-
gible subjects who were included in the analysis for this
report.TheaveragetimefromTIAorstroketotheOGTT
was 105 days (range, 24-180 days).
The clinical features of the participants are given in
Table 1. The median age was 71 years. The minority
werefemale(39/98;40%),82(84%)werewhite,10(10%)
were African American, and 4 (4%) were Hispanic. The
index event was a stroke (vs TIA) for 83 participants
(85%), and 9 (10%) had carotid stenosis of more than
70%. The self-reported medical conditions were typical
for patients with cerebrovascular disease. Eighteen par-
ticipants (18%) were obese according to body mass in-
dex, and 45 (46%) had abdominal obesity according to
waist measurements.
AccordingtotheOGTTresults,27participants(28%)
had IGT, 24 (24%) had DGT, and 51 (52%) had either
oneoftheseabnormalities(Table2).Thestratifiedanaly-
sis in Table 2 demonstrates that persons with an im-
pairedfastingglucose(IFG)level(ie,110-125mg/dL[6.1-
6.9mmol/L]),comparedwithsubjectswithanormalFPG
level(ie,?110mg/dL[?6.1mmol/L]),weremorelikely
tohaveDGT(59%vs17%;P=.001).HemoglobinA1ctests
were available for 18 of 24 patients with DGT. The me-
dian value was 5.5% with a range of 4.6% to 6.7% (nor-
mal range, 4.2%-5.8%); 6 subjects had elevated read-
ings.
Bivariate associations between selected baseline vari-
ables and risk for IGT or DGT are displayed in Table 3.
Table 1. Baseline Features for 98 Patients
With a Recent TIA or Ischemic Stroke, a Fasting Plasma
Glucose Level Less Than 126 mg/dL, and
No History of Diabetes
FeatureValue*
Sociodemographic characteristic
Age, y
Female sex
Race
White
African American
Hispanic
Other
Clinical characteristic†
Myocardial infarction
Atrial fibrillation
Hypertension
Systolic blood pressure, mm Hg
Diastolic blood pressure, mm Hg
Obesity
BMI
Abdominal obesity
Waist circumference, cm
Fasting plasma glucose, mg/dL
Homeostasis Model Assessment–
insulin resistance
Homeostasis Model Assessment–?-cell
Insulin Sensitivity Index
Neurological characteristic†
Index stroke (vs TIA)
Lacunar pathophysiology
History of stroke
Carotid stenosis ?70%‡
71 (48-90)
39 (40)
82 (84)
10 (10)
4 (4)
2 (2)
13 (13)
4 (4)
61 (62)
140 (101-195)
80 (58-110)
18 (18)
26 (18-44)
45 (46)
98 (69-138)
97.5 (76.0-124.0)
3.0 (0.5-10.4)
125 (19-808)
2.5 (0.4-10.2)
83 (85)
22 (23)
12 (12)
9 (10)
Abbreviations: BMI, body mass index (calculated as weight in kilograms
divided by the square of height in meters); DBP, diastolic blood pressure;
SBP, systolic blood pressure; TIA, transient ischemic attack.
SI conversion factor: To convert glucose to millimoles per liter, multiply by
0.0555.
*Data are given as median (range) or number (percentage) of patients.
†Definitions: myocardial infarction, self-report of hospitalization for more
than 1 day for myocardial infarction; hypertension, self-report of physician
diagnosis of hypertension and current use of hypertension medication or
baseline blood pressure higher than 160/100 mm Hg; obesity, BMI greater
than 30; abdominal obesity, greater than 102 cm for men and greater than
88 cm for women; Homeostasis Model Assessment, see “Methods” section;
Composite Insulin Sensitivity Index, see “Methods” section; history of
stroke, self-report of prior hospitalization for more than 1 day for stroke.
‡Eight subjects had missing data.
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Higher FPG level, lower waist circumference, lower
?-cell function (ie, lower value for the Homeostasis
Model Assessment of ?-cell function), and lacunar cause
of stroke were each associated with an increased risk for
2-hour plasma glucose concentration of 140 mg/dL or
greater (?7.8 mmol/L). Of these, only FPG level and
lower waist circumference entered the forward stepwise
logistic regression analysis (adjusted odds ratio for glu-
cose, 1.08 for each milligram-per-deciliter change
[P=.002]; adjusted odds ratio for waist circumference,
0.95 for each centimeter change [P=.005]). When
plasma glucose was defined as a dichotomous variable,
the odds ratio for a value of 110 mg/dL or greater (?6.1
mmol/L) was 5.55 (P=.01). The association between
waist circumference and risk for 2-hour plasma glucose
concentration of 140 mg/dL or greater (?7.8 mmol/L)
did not change after sequentially forcing potential con-
founding variables into the multivariable model, includ-
ing hypertension, lacunar cause, sex, and age.
COMMENT
OurfindingsindicatethatIGTorDGTarepresentinmore
thanhalfofpatientswitharecentTIAorischemicstroke
who do not carry a prior diagnosis of diabetes and have
an FPG level less than 126 mg/dL (?7.0 mmol/L). Not
surprisingly,prevalenceisincreasedamongpatientswith
IFG(ie,110-125mg/dL[6.1-6.9mmol/L]),althoughre-
liance on FPG level alone would have missed 73% (37/
51)ofpatientswithanabnormal2-hourplasmaglucose
concentrationduringtheOGTT.Inourpopulation,sev-
eral established risk factors for hyperglycemia (ie, older
age,obesity,andincreasedwaistcircumference)werenot
predictiveofabnormalglucosetolerance.Infact,agreater
waist circumference appeared to be protective. Limited
statistical power probably explains our failure to detect
an effect of age.
The finding for waist circumference was not ex-
pectedandwasnotexplainedbyconfoundingvariables.
Potentialexplanationsfortheassociationincludechance,
bias, and biology. Chance is quantified by the bivariate
P value (.05), which must be interpreted in consider-
ationofthemultipleriskfactorsweexamined.Biasseems
unlikely, although we cannot be certain that an unrec-
ognized confounding variable did not affect the ob-
served odds ratio. An additional source of bias may be
patient selection. If larger patients at risk for stroke (ie,
those with a larger waist circumference) are more com-
monlyscreenedfordiabetesthanaresmallerpatients,then
the larger patients in our cohort may represent a re-
sidualgroupwithbetterglucosemetabolism.Totestthis
theory, we examined the prevalence of abnormal glu-
cose tolerance according to quintile of waist circumfer-
enceinourcohort.Ourfindingsupportedthetheorythat
prevalence was similar in the first 4 quintiles but lowest
in the fifth (data not shown). Biological factors may be
at work if lower waist circumference in this older co-
hort indicates a lower lean body mass and, therefore, re-
ducedcapacityforglucoseclearanceintoskeletalmuscle.
Had we adjusted the glucose dose for lean body mass, it
is possible that waist circumference would no longer be
associated with increased risk for IGT. Such adjust-
ment, however, is not standard procedure.
To our knowledge, this is the first study of OGTT
among patients with symptomatic cerebrovascular dis-
Table 3. Bivariate ORs for the Association
Between Selected Baseline Features and Risk of 2-Hour
Glucose ?140 mg/dL Among 98 Subjects
Feature
OR
(P Value)
Sociodemographic characteristics
Age
Female
African American
Clinical characteristics
Myocardial infarction
Hypertension history
SBP
DBP
BMI
Waist circumference
Neurological characteristics
Index stroke (vs TIA)
Lacunar cause
Prior history of stroke
Carotid stenosis (?70%)
Atrial fibrillation
Laboratory measures
Fasting plasma glucose
HOMA–insulin resistance
HOMA–?-cell
1.03 (.16)
1.34 (.48)
0.91 (.17)
0.76 (.65)
1.24 (.60)
1.01 (.46)
0.99 (.57)
0.93 (.10)
0.97 (.05)
1.29 (.65)
2.45 (.08)
0.41 (.18)
0.67 (.57)
0.92 (.93)
1.05 (.01)
1.03 (.81)
0.99 (.04)
Abbreviations: BMI, body mass index; DBP, diastolic blood pressure;
HOMA, Homeostasis Model Assessment; OR, odds ratio; SBP, systolic blood
pressure; TIA, transient ischemic attack.
Table 2. Results of Oral Glucose Tolerance Testing Overall and by Fasting Plasma Glucose Category
Subjects
All
Fasting plasma glucose, mg/dL
?110
110-125
No. of Patients
98
No. (%) of Subjects According to 2-Hour Plasma Glucose Concentration*
?140 mg/dL
47 (48)
140-199 mg/dL
27 (28)
?200 mg/dL
24 (24)
81
17
44 (54)
3 (18)
23 (28)
4 (24)
14 (17)
10 (59)
SI conversion factor: To convert glucose to millimoles per liter, multiply by 0.0555.
*?2=14.0; P=.001.
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ease. Previous research on impaired glucose metabo-
lismafterstrokehascharacterizedpatientsusingtheFPG
orhemoglobinA1cvalueobtainedduringacute-carehos-
pitaladmission.Estimatesforunrecognizeddiabetesrange
from 14% using the older glucose criterion (FPG level
?140 mg/dL [?7.8 mmol/L])31to 22% using the cur-
rentcriterion(fastingplasmaglucose?126mg/dL[?7.0
mmol/L]).30,32Wewerenotabletolocateanyreliablere-
search in which patients were classified based on test-
ing performed after discharge from the acute-care hos-
pitalization.
In comparison with the paucity of data on IGT after
stroke, more data are available for healthy persons and
persons with other vascular disease (Table 4). Among
2583persons,withameanageof54years,intheFraming-
ham offspring study, 13% had IGT and 5% had DGT.3
Similarvalueswerefoundamongalargecohortofhealthy
Europeans.2Amongcommunity-dwellingpersonsolder
than65years,however,therateswereconsiderablyhigher:
32% had IGT and 14% had DGT.1Even higher preva-
lence values were observed among persons with a re-
cent myocardial infarction: 40% and 25%, respec-
tively.33When considered with our findings, the results
fromotherstudiessuggestthatratesofIGTandDGTare
highamongolderAmericansandevenhigheramongthose
with clinical vascular disease.
Impaired glucose tolerance among stroke patients is
important because it may be a remediable risk factor for
recurrence.Unfortunately,itsstatusasariskfactoramong
strokepatientscanonlybeinferredfromresearchinother
populations;ithasnotbeenadequatelyexaminedamong
stroke survivors. The closest evidence in stroke patients
isfromstudiesinvolvingrandomorFPGmeasurements
obtained during hospitalization for acute stroke.34Hy-
perglycemia(?110mg/dL[?6.1mmol/L])ispresenton
admission in more than 50% of patients with acute
stroke.35,36Inanimalresearch,hyperglycemiaduringacute
ischemic stroke is associated with increased infarct vol-
ume and higher rates of hemorrhagic conversion.37-39In
humanresearch,hyperglycemia(variablydefinedasran-
dom or fasting) is associated with increased risk for in-
hospital mortality and worse functional outcome at 3
months,38,40,41but the effect may be confined to patients
withnonlacunarcauses.42Clinicaltrialsarecurrentlyun-
der way to determine if immediate insulin therapy im-
provestheclinicaloutcomeamongpatientsadmittedwith
an acute ischemic stroke and hyperglycemia.36Similar
trials among critically ill adult patients in intensive care
units have demonstrated that intensive insulin therapy
reduces mortality by more than 40%.43
EvidencethatIGTcanberemediatedalsocomesfrom
researchinnonstrokepopulations,butitisprobablyrea-
sonabletoassumethatthefindingsaregeneralizable.Large
clinical trials among patients with IGT have shown that
glycemia can be improved, vascular risk factors can be
attenuated, and diabetes can be prevented by lifestyle
modification12,13and treatment with metformin,12tro-
glitazone,14and acarbose.15Each of these trials, how-
ever,involvedrelativelyyoungpersons(meanages,50-55
years). New trials among older stroke patients with IGT
could be designed to test simultaneously the effects of
metabolic interventions for prevention of both diabetes
and vascular disease.44
The sampling and classification methods in our re-
searchmaylimititsgeneralizabilityandaccuracy,butwe
believe these limitations are minor. We sampled only a
portion of eligible hospitalized patients in 1 geographic
area. Incomplete enrollment may have resulted in bi-
ased results if, for example, persons who consented to
participatewerehealthierthanpersonswhodidnot.The
effect of this bias, we believe, would have been to un-
derestimatetheprevalenceofIGT;healthierpeoplewho
enrolled in the study, compared with those who did not
enroll,maybemoreactive,lessobese,and,therefore,less
likelytohaveIGT.Thefactthatwesampledpatientsfrom
1 geographic area probably has no significant effect on
generalizabilitybecausepopulationratesofimpairedglu-
cosemetabolismanddiabetesaresimilaracrosstheUnited
States. We classified subjects based on a single OGTT.
We cannot be certain that our results would not have
changedifwehadconfirmeddiabeteswitharepeatedtest,
as recommended by the American Diabetes Associa-
tion.30
Table 4. Prevalence of Impaired Glucose Tolerance and Diabetic Glucose Tolerance
Among Selected Cohorts of Persons Without Previously Diagnosed Diabetes*
Publication
Year
1998
2001
2002
PopulationNo. of Subjects
2583
21718
4014
Mean Age, y
54
53
73
Percentage of Subjects According to 2-Hour
Plasma Glucose Concentration
?140 mg/dL
88
87
54
140-199 mg/dL
13
10
32
?200 mg/dL
Framingham offspring3
Europeans2
US community-dwelling adults with no
clinical vascular disease1
Patients with a recent ischemic stroke
5
3
14
Present
study
2002
98 7048 2824
Patients with a recent acute myocardial
infarction33
1446335 4025
SI conversion factor: To convert glucose to millimoles per liter, multiply by 0.0555.
*Impaired glucose tolerance was defined as 2-hour plasma glucose concentration between 140 and 199 mg/dL; diabetic glucose tolerance was defined as a
2-hour plasma glucose concentration of 200 mg/dL or greater. Studies are ordered by increasing magnitude of prevalence of diabetic glucose tolerance.
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