Impaired Glucose Tolerance Increases Stroke Risk in
Nondiabetic Patients With Transient Ischemic Attack or
Minor Ischemic Stroke
Sarah E. Vermeer, MD, PhD; Willemijn Sandee, MSc; Ale Algra, MD, FAHA;
Peter J. Koudstaal, MD, PhD; L. Jaap Kappelle, MD, PhD; Diederik W.J. Dippel, MD, PhD;
on behalf of the Dutch TIA Trial Study Group
Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017
Background and Purpose—Impaired glucose tolerance, an intermediate metabolic state between normal glucose and
diabetes characterized by nonfasting glucose levels between 7.8 to 11.0 mmol/L, is associated with an increased stroke
risk in patients with coronary heart disease. Whether impaired glucose tolerance increases the risk of stroke in patients
with transient ischemic attack (TIA) or minor ischemic stroke is unknown.
Methods—In total, 3127 patients with a TIA or minor ischemic stroke participated in the Dutch TIA Trial, testing 2
different doses of aspirin and atenolol versus placebo. We estimated the risk of stroke and the risk of myocardial
infarction or cardiac death in relation to baseline nonfasting glucose levels (mean 6.0, SD 2.2 mmol/L) with Cox
proportional hazards regression analysis, adjusted for cardiovascular risk factors.
Results—During 2.6 years follow-up, 272 patients (9%) experienced a stroke and 200 (6%) a myocardial infarction or
cardiac death. We found a J-shaped relationship between baseline nonfasting glucose levels and stroke risk. Stroke risk
was nearly doubled in patients with impaired glucose tolerance (glucose 7.8 to 11.0 mmol/L) compared with those with
normal glucose levels (hazard ratio [HR] 1.8, 95% CI, 1.1 to 3.0) and nearly tripled in diabetic patients (glucose
ⱖ11.1 mmol/L; HR 2.8, 95% CI, 1.9 to 4.1). Patients with low glucose levels (⬍4.6 mmol/L) had a 50% increased
stroke risk (HR 1.5, 95% CI, 1.0 to 2.2) compared with those with normal glucose levels. There was no association
between glucose levels and risk of myocardial infarction or cardiac death.
Conclusion—Impaired glucose tolerance is an independent risk factor for future stroke in nondiabetic patients with TIA
or minor ischemic stroke. (Stroke. 2006;37:1413-1417.)
Key Words: glucose 䡲 glucose intolerance 䡲 risk 䡲 transient ischemic attack
C
ardiovascular disease is the leading cause of death and
morbidity in diabetic patients.1 The presence of diabetes
increases the risk of stroke 2- to 5-fold.2,3 Recently, impaired
glucose tolerance, an intermediate metabolic state between normal
glucose tolerance and diabetes mellitus, is also found to be associated with an increased stroke risk in patients with coronary heart
disease.4 It is unknown whether the risk of stroke is increased in
patients with impaired glucose tolerance who had a transient
ischemic attack (TIA) or minor ischemic stroke. Approximately one
quarter of patients with a history of TIA or minor ischemic stroke
have an impaired glucose tolerance.5 If there is an association
between impaired glucose tolerance and (recurrent) stroke in patients with TIA or minor ischemic stroke, this might offer new
options for secondary prevention. We therefore investigated the
relationship between nonfasting glucose levels, the risk of (recurrent) stroke and the risk of myocardial infarction or cardiac death in
patients with a history of TIA or minor ischemic stroke.
Methods
Patients
The study population comprised all participants of the Dutch TIA
Trial, a secondary prevention trial that took place in 1986 to 1990.
The original cohort consisted of 3150 patients, who had had a TIA or
minor disabling ischemic stroke in the past 3 months (modified
Rankin Scale of ⱕ3).6 Patients with cerebral ischemia resulting from
other causes than arterial thrombosis or arterial embolism were
excluded from the study. Twenty-three patients were incorrectly
diagnosed at the time of randomization, and they were excluded from
the analyses, leaving 3127 patients in the study. They were randomized by means of a 2⫻2 factorial design to 2 different doses of
aspirin (30 or 283 mg) and 50 mg atenolol or placebo.7 The trial
showed no differences in effects of aspirin and no efficacy of
atenolol.8,9 All patients received information about the study (written
and oral) and gave their consent to participate in the trial. The
medical ethics committees of the participating centers approved the
study protocol.
Received October 12, 2005; final revision received January 19, 2006; accepted March 2, 2006.
From the Department of Neurology (S.E.V., W.S., P.J.K., D.W.J.D.), Erasmus Medical Center, Rotterdam; and the Department of Neurology (A.A.,
L.J.K.), University Medical Center Utrecht, The Netherlands.
Correspondence to S.E. Vermeer, MD, PhD, Erasmus Medical Center, Department of Neurology, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
E-mail [email protected]
© 2006 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
DOI: 10.1161/01.STR.0000221766.73692.0b
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Stroke
June 2006
Glucose Measurement and Other
Baseline Variables
In the Dutch TIA trial, we used a checklist in plain language to
obtain information about symptoms, medical history, smoking and
drug use. All patients underwent a computed tomography (CT) scan,
except those with transient monocular blindness. Nonfasting venous
plasma glucose levels were measured at baseline, with a mean
interval of 3 weeks to the preceding event. Glucose measurements
were not available for 17 participants because of failure to obtain a
sample or some other error in the blood collection process. We
defined diabetes mellitus as a previous diagnosis of diabetes, the use
of oral antidiabetic drugs or insulin, or a nonfasting plasma glucose
level of ⱖ11.1 mmol/L. We considered patients to have an impaired
glucose tolerance if they had nonfasting plasma glucose levels
between 7.8 and 11.0 mmol/L.10 Blood pressure was measured at
study entry as a part of the physical examination. Hypertension was
defined as the self-reported history of hypertension with or without
use of antihypertensive drugs, a systolic blood pressure of
160 mm Hg or over, or a diastolic blood pressure of 95 mm Hg or
over at baseline.
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Follow-Up
Patients were seen every 4 months by a neurologist or, if that was not
possible, by their general practitioner. We collected information
about outcome events, TIAs, surgical procedures, blood pressure and
degree of disability using the modified Rankin Scale by means of a
standardized questionnaire. An ECG was made every 2 years (for
most patients it came to 1 or 2 ECGs). All surviving patients had
their last follow-up visit in 1990. The mean follow-up was 2.6 years.
No patient was lost to follow-up.
Outcome Events
We examined vascular events in general, with special attention to
stroke and myocardial infarction or cardiac death. We defined stroke,
both fatal or nonfatal, as a new infarct or bleeding visible on CT,
together with matching symptoms lasting for ⬎24 hours. If CT scan
was normal, an increase in disability of at least 1 grade on the
modified Rankin Scale was sufficient for the diagnosis of stroke.
Myocardial infarction was defined as the presence of at least 2 of the
following criteria: a history of chest pain, changes in cardiac
enzymes more than twice the upper range of normal, or relevant
changes visible on ECG. Cardiac death included death from myocardial infarction, heart failure, and sudden death.
Statistical Analysis
We categorized patients based on quintiles of glucose levels, with the
upper quintile further divided based on standardized criteria of
impaired glucose tolerance and diabetes mellitus,10 into the following groups: ⬍4.6, 4.6 to 5.0, 5.1 to 5.7, 5.8 to 7.7, 7.8 to 11.0, and
ⱖ11.1 mmol/L. The highest category also comprised patients with
known diabetes mellitus with lower glucose measurements. We used
the Kaplan-Meier method to estimate the vascular event rate for each
glucose category. The follow-up time was calculated from the date of
study entry until the date of a (recurrent) stroke, myocardial
infarction, death, or end of follow-up, whichever came first. We
estimated the relative risk of vascular events in relation to nonfasting
glucose levels with Cox proportional hazards regression analysis
with 95% CI, adjusted for cardiovascular risk factors (age, sex,
smoking, hypertension, and minor ischemic stroke in history). The
reference group consisted of patients with a nonfasting glucose level
of 5.8 to 7.7 mmol/L.
Results
The Table shows the baseline characteristics of the study
population. The nonfasting plasma glucose levels ranged from
2.6 to 25.1 mmol/L. In total, 165 (5%) had impaired glucose
tolerance and 284 (9%) patients had diabetes mellitus. Of this
latter group, 112 had acceptable or well-controlled glucose
Baseline Characteristics of All Patients of the Dutch TIA Trial
n⫽3127
Age, y
65.1⫾10.0
Women
1085 (35%)
Current smoking
1399 (45%)
Hypertension
2132 (68%)
Qualifying event
Minor stroke
TIA
History of myocardial infarction
Nonfasting plasma glucose, mmol/L
2130 (68%)
997 (32%)
315 (10%)
6.0⫾2.2
Diabetes mellitus
284 (9%)
Use of antidiabetic medication
188 (6%)
Values are unadjusted means⫾SD or No. of patients (percentages).
levels (⬍11.1 mmol/L), 48 low glucose levels (⬍4.6 mmol/L),
and 124 diabetic glucose levels (ⱖ11.1 mmol/L), despite
antidiabetic therapy. Patients with impaired glucose tolerance
were significantly older (mean age 67.8 years) than those
with normal glucose tolerance (mean age 65.6 years). Patients
with low nonfasting glucose levels (⬍4.6 mmol/L) were
significantly younger (mean age 63.7 years), more often male
(31% women) and less frequently had hypertension (64%)
compared with patients with normal glucose tolerance. Compared with all other glucose categories (mean weight normal
glucose 75.4 kg, impaired glucose tolerance 75.4 kg, diabetes
mellitus 75.3 kg), patients with low nonfasting glucose levels
weighed less (mean weight 73.5 kg). The qualifying event of
the diabetic patients more often was of lacunar subtype (65%,
P⫽0.08), although this was not statistically different from the
other glucose categories (mean 57%).
During 2.6 years follow-up, 272 patients (9%) experienced
a fatal or nonfatal stroke and 200 patients (6%) had a
myocardial infarction or cardiac death. Nineteen (12%) of the
patients with impaired glucose tolerance had a stroke during
follow-up and another 9 patients (6%) a myocardial infarction
or cardiac death. Fifty (18%) of the diabetic patients experienced a stroke and 31 (11%) a cardiac event. After 2.6 years,
82% of the diabetic patients were stroke-free, compared with
94% of those with normal glucose tolerance and 88% of the
patients with impaired glucose tolerance (Figure 1).
The relationship between nonfasting glucose levels and
stroke risk was J-shaped (Figure 2A). Patients with low
nonfasting glucose levels had a 50% increased risk of stroke
compared with those with normal glucose tolerance (hazard
ratio [HR] 1.5, 95% CI, 1.0 to 2.2), after adjustment for
cardiovascular risk factors. The adjusted risk of stroke was
nearly doubled in patients with impaired glucose tolerance
(HR 1.8, 95% CI, 1.1 to 3.0) and nearly tripled in diabetic
patients (HR 2.8, 95% CI, 1.9 to 4.1). Further adjustment for
history of myocardial infarction did not alter these associations. There was no association between impaired glucose
tolerance and myocardial infarction or cardiac death (Figure
2B). The relative risk of myocardial infarction or cardiac
death was doubled in diabetic patients (HR 2.0, 95% CI, 1.3
to 3.2). Diabetic patients had a 2.5-fold increased risk of
Vermeer et al
Impaired Glucose Tolerance Increases Stroke Risk
1415
Figure 1. Kaplan-Meier curve of cumulative
stroke incidence stratified by nonfasting glucose levels (in mmol/L). Diabetic patients
are included in the highest category
(ⱖ11.1 mmol/L). The normal glucose categories 4.6 to 7.7 mmol/L are pooled for
visual convenience.
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having a vascular event (95% CI, 1.9 to 3.4) and patients with
impaired glucose tolerance a borderline significant risk of 1.4
(95% CI, 0.9 to 2.2; Figure 2C). Patients with glucose levels
⬍4.6 mmol/L had a relative risk of 1.4 (95% CI, 1.0 to 1.9)
compared with those with normal glucose tolerance.
Discussion
We found a J-shaped relationship between glucose levels and
(recurrent) stroke risk in patients with a recent TIA or minor
ischemic stroke. The risk of stroke not only was increased in
patients with diabetes mellitus and impaired glucose tolerance, but also in those with low nonfasting glucose levels
(⬍4.6 mmol/L). There was no association between impaired
glucose tolerance and the risk of myocardial infarction or
cardiac death.
The strengths of this study are the large number of patients,
the prospective design of the Dutch TIA Trial, the meticulous
follow-up, and adjudication of outcome events that was
blinded to the treatment assignment but also to the glucose
level at baseline. Because the original study was a large and
randomized clinical trial, we do not expect any confounding
by treatment regimen. However, there are some methodological limitations. We measured nonfasting venous plasma
glucose levels. Randomly taken glucose samples do not meet
the definition of impaired glucose tolerance. Some patients
might have been in a fasting state at the time of glucose
measurement, resulting in lower glucose levels than if it was
a postprandial measurement. The glucose levels were measured without knowledge of other risk factors and outcome
events that were diagnosed blinded to all other data as well.
Therefore, any misclassification will be random and result in
an underestimation of the strength of the risk associations.
Furthermore, the interval between baseline glucose measurement and preceding event differed among patients, with a
range of ⬍1 week to 3 months. Glucose levels can be
increased in the first hours of acute stroke.11 However, the
vast majority had their glucose levels measured ⬎1 week
after the acute event, when glucose levels are normalized. If
anything, misclassification will again result in an attenuation
of the associations. Finally, the use of a single glucose
measurement to classify patients may have underestimated
the strength of any associations attributable to regression
dilution. Another limitation is that we did not have insulin
measurements, which would have given more information
and could strengthen this study.
Generalizability of the results might be limited by patient
selection. With exclusion of patients with cardiac sources of
emboli from the trial, the mean age and presence of cardiovascular risk factors, such as hypertension, will differ from
that of a general TIA population. Old age and hypertension
are known risk factors for stroke. However, because the
relationship of glucose levels and stroke risk was consistent
over all age strata and we adjusted for cardiovascular risk
factors, we do not think that this would have materially
altered the conclusions of the present study. Another limitation might be that this trial was conducted more than a decade
ago. During that period, treatment with blood pressure- and
cholesterol-lowering drugs was less common. Nowadays, we
treat patients far more aggressively with antihypertensive
drug and statins, that each have been shown to lead to a stroke
reduction up to 30% in diabetic patients.12–14 This does not
necessarily mean that these drugs will alter the effect estimate
of diabetes mellitus or impaired glucose tolerance itself. The
risk reduction with antihypertensive medication is significantly larger in diabetic patients than in nondiabetics with
hypertension. It is unknown, however, whether the effect of
antihypertensive therapy also differs among the nondiabetic
glucose categories. Statins are both effective in diabetic and
nondiabetic patients. A meta-analysis of 14 randomized
controlled trials among cardiovascular patients with diabetes
mellitus, impaired fasting glucose and normal glucose levels,
showed no difference in risk reduction of vascular events
1416
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June 2006
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Figure 2. HRs for stroke (A), myocardial infarction or cardiac
death (B), and vascular events (C) by nonfasting glucose categories, adjusted for age, sex, hypertension, smoking, and minor
stroke. Diabetic patients are included in the highest category
(ⱖ11.1 mmol/L). Bars represent 95% CI.
with statin therapy among these 3 glucose groups.15 Therefore, we do not think this will hamper external validity of our
results.
The magnitude of the relative stroke risk estimate associated with impaired glucose tolerance in our study is similar to
that found in a secondary prevention trial among patients with
coronary heart disease.4 They also observed a J-shaped association between fasting glucose levels and stroke risk. The
increased stroke risk in patients with impaired glucose tolerance could be explained by a similar metabolic mechanism
that leads to vascular complications in diabetes mellitus.16
The cardiovascular risk profile (obesity, hypertension, dyslipidemia, insulin resistance) is already worsening in this
intermediate metabolic state, leading to a higher risk of stroke
and other vascular events.17,18
We found no association between impaired glucose tolerance and myocardial infarction or cardiac death. A study
among patients with a recent myocardial infarction found a
strong relationship between impaired glucose tolerance and
vascular events, including myocardial infarction, but they did
not examine the association with myocardial infarction separately.19 In the earlier mentioned secondary prevention trial
among patients with coronary heart disease, impaired fasting
glucose was related with a worse clinical outcome, but again
no association with recurrence of myocardial infarction was
observed.20 Disturbances in glucose metabolism may affect
brain tissue more than myocardial tissue. The brain totally
depends on glucose for its metabolic demands, whereas
myocardial tissue can generate energy from other sources. In
a normal, healthy situation, the brain is protected against
disturbances in the glucose level by a counterregulatory
mechanism.21 When this mechanism fails to maintain a
normal glucose level during hypo- or hyperglycemia, the
brain will be damaged. This might explain our finding that the
intermediate metabolic stage of impaired glucose tolerance is
associated with stroke and not with myocardial infarction or
cardiac death. Furthermore, that the risk estimate for stroke in
diabetic patients is higher than for myocardial infarction
supports our findings as well.22
In line with our results, previous studies found an increased
risk of vascular disease in patients with low fasting glucose
levels.4,23 One explanation might be frailty of these patients,
which is supported by our finding that patients with low
glucose levels weighed less than those with normal glucose
levels. Furthermore, hypoglycemia is associated with focal
and global brain damage and dysfunction.24 This again
illustrates the vulnerability of the human brain compared with
the heart.
Impaired glucose tolerance is like diabetes mellitus, an
independent risk factor for stroke in nondiabetic patients with
TIA or minor ischemic stroke. Low nonfasting glucose levels
(⬍4.6 mmol/L) are also associated with an increased stroke
risk. Intensive glucose control in both type 1 and type 2
diabetic patients seems to reduce stroke and other macrovascular events.25–27 New secondary prevention trials should be
initiated to investigate whether intensive glucose control
reduces stroke incidence in these patients.
Vermeer et al
Impaired Glucose Tolerance Increases Stroke Risk
Acknowledgments
The Netherlands Heart Foundation (grants 84.089 and 88.210) and
the Praeventiefonds (grant 28-1732) supported the Dutch TIA Trial.
References
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1. Howard BV, Rodriguez BL, Bennett PH, Harris MI, Hamman R, Kuller
LH, Pearson TA, Wylie-Rosett J. Prevention Conference VI: Diabetes
and Cardiovascular Disease: Writing Group I: Epidemiology. Circulation. 2002;105:e132–137.
2. Goldstein LB, Adams R, Becker K, Furberg CD, Gorelick PB,
Hademenos G, Hill M, Howard G, Howard VJ, Jacobs B, Levine SR,
Mosca L, Sacco RL, Sherman DG, Wolf PA, del Zoppo GJ. Primary
prevention of ischemic stroke: a statement for healthcare professionals
from the Stroke Council of the American Heart Association. Circulation.
2001;103:163–182.
3. Kissela BM, Khoury J, Kleindorfer D, Woo D, Schneider A, Alwell K,
Miller R, Ewing I, Moomaw CJ, Szaflarski JP, Gebel J, Shukla R,
Broderick JP. Epidemiology of ischemic stroke in patients with diabetes:
the greater Cincinnati/Northern Kentucky Stroke Study. Diabetes Care.
2005;28:355–359.
4. Tanne D, Koren-Morag N, Goldbourt U. Fasting plasma glucose and risk
of incident ischemic stroke or transient ischemic attacks: a prospective
cohort study. Stroke. 2004;35:2351–2355.
5. Kernan WN, Viscoli CM, Inzucchi SE, Brass LM, Bravata DM, Shulman
GI, McVeety JC. Prevalence of abnormal glucose tolerance following a
transient ischemic attack or ischemic stroke. Arch Intern Med. 2005;165:
227–233.
6. van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients.
Stroke. 1988;19:604 – 607.
7. The Dutch TIA trial: protective effects of low-dose aspirin and atenolol in
patients with transient ischemic attacks or nondisabling stroke. The Dutch
TIA Study Group. Stroke. 1988;19:512–517.
8. A comparison of two doses of aspirin (30 mg vs 283 mg a day) in patients
after a transient ischemic attack or minor ischemic stroke. The Dutch TIA
Trial Study Group. N Engl J Med. 1991;325:1261–1266.
9. Trial of secondary prevention with atenolol after transient ischemic attack
or nondisabling ischemic stroke. The Dutch TIA Trial Study Group.
Stroke. 1993;24:543–548.
10. Report of the expert committee on the diagnosis and classification of
diabetes mellitus. Diabetes Care. 2003;26 (Suppl 1):S5–S20.
11. Gray CS, Hildreth AJ, Alberti GK, O’Connell JE. Poststroke hyperglycemia: natural history and immediate management. Stroke. 2004;35:
122–126.
12. Curb JD, Pressel SL, Cutler JA, Savage PJ, Applegate WB, Black H,
Camel G, Davis BR, Frost PH, Gonzalez N, Guthrie G, Oberman A,
Rutan GH, Stamler J. Effect of diuretic-based antihypertensive treatment
on cardiovascular disease risk in older diabetic patients with isolated
systolic hypertension. Systolic Hypertension in the Elderly Program
Cooperative Research Group. JAMA. 1996;276:1886 –1892.
1417
13. Tuomilehto J, Rastenyte D, Birkenhager WH, Thijs L, Antikainen R,
Bulpitt CJ, Fletcher AE, Forette F, Goldhaber A, Palatini P, Sarti C,
Fagard R. Effects of calcium-channel blockade in older patients with
diabetes and systolic hypertension. Systolic Hypertension in Europe Trial
Investigators. N Engl J Med. 1999;340:677– 684.
14. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA,
Livingstone SJ, Thomason MJ, Mackness MI, Charlton-Menys V, Fuller JH.
Primary prevention of cardiovascular disease with atorvastatin in type 2
diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364:685–696.
15. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C,
Kirby A, Sourjina T, Peto R, Collins R, Simes R. Efficacy and safety of
cholesterol-lowering treatment: prospective meta-analysis of data from
90 056 participants in 14 randomised trials of statins. Lancet. 2005;366:
1267–1278.
16. Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA. 2002;287:2570–2581.
17. Wagenknecht LE, D’Agostino RB Jr, Haffner SM, Savage PJ, Rewers M.
Impaired glucose tolerance, type 2 diabetes, and carotid wall thickness:
the Insulin Resistance Atherosclerosis Study. Diabetes Care. 1998;21:
1812–1818.
18. Temelkova-Kurktschiev TS, Koehler C, Leonhardt W, Schaper F, Henkel
E, Siegert G, Hanefeld M. Increased intimal-medial thickness in newly
detected type 2 diabetes: risk factors. Diabetes Care. 1999;22:333–338.
19. Bartnik M, Malmberg K, Norhammar A, Tenerz A, Ohrvik J, Ryden L.
Newly detected abnormal glucose tolerance: an important predictor of
long-term outcome after myocardial infarction. Eur Heart J. 2004;25:
1990 –1997.
20. Arcavi L, Behar S, Caspi A, Reshef N, Boyko V, Knobler H. High fasting
glucose levels as a predictor of worse clinical outcome in patients with
coronary artery disease: results from the Bezafibrate Infarction Prevention (BIP) study. Am Heart J. 2004;147:239 –245.
21. Gerich JE. Lilly lecture 1988. Glucose counterregulation and its impact
on diabetes mellitus. Diabetes. 1988;37:1608 –1617.
22. Kannel WB, Wilson PW, Zhang TJ. The epidemiology of impaired
glucose tolerance and hypertension. Am Heart J. 1991;121:1268 –1273.
23. Wei M, Gibbons LW, Mitchell TL, Kampert JB, Stern MP, Blair SN.
Low fasting plasma glucose level as a predictor of cardiovascular disease
and all-cause mortality. Circulation. 2000;101:2047–2052.
24. Malouf R, Brust JC. Hypoglycemia: causes, neurological manifestations,
and outcome. Ann Neurol. 1985;17:421– 430.
25. Intensive blood-glucose control with sulphonylureas or insulin compared
with conventional treatment and risk of complications in patients with
type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS)
Group. Lancet. 1998;352:837– 853.
26. Effect of intensive blood-glucose control with metformin on complications in
overweight patients with type 2 diabetes (UKPDS 34). UK Prospective
Diabetes Study (UKPDS) Group. Lancet. 1998;352:854–865.
27. Intensive diabetes treatment and cardiovascular disease in patients with
type 1 diabetes. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study
Research Group. N Engl J Med. 2005;353:2643–2653.
Impaired Glucose Tolerance Increases Stroke Risk in Nondiabetic Patients With Transient
Ischemic Attack or Minor Ischemic Stroke
Sarah E. Vermeer, Willemijn Sandee, Ale Algra, Peter J. Koudstaal, L. Jaap Kappelle and
Diederik W.J. Dippel
on behalf of the Dutch TIA Trial Study Group
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Stroke. 2006;37:1413-1417; originally published online April 20, 2006;
doi: 10.1161/01.STR.0000221766.73692.0b
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