Epidemiology/Health Services Research

O R I G I N A L A R T I C L E

Diabetes, Fasting Glucose Levels, and Risk

of Ischemic Stroke and Vascular Events
Findings from the Northern Manhattan Study (NOMAS)
BERNADETTE BODEN-ALBALA, MPH, DRPH1,2 TATJANA RUNDEK, MD4 of cardiovascular outcomes, including in-
SAM CAMMACK, MS1 MITCHELL S.V. ELKIND, MD, MS1 cident myocardial infarction and mortal-
JI CHONG, MD1 MYUNGHEE C. PAIK, PHD3 ity (1,2). Similarly, diabetes has been
CULING WANG, PHD3 RALPH L. SACCO, MD, MS4 associated with an increased risk of stroke
CLINTON WRIGHT, MD, MS1 with relative risks (RRs) ranging from 1.8
to 6 (35).
Despite the public health significance
OBJECTIVE There is insufficient randomized trial data to support evidence-based recom- of diabetes, there is a paucity of data em-
mendations for tight control of fasting blood glucose (FBG) among diabetic subjects in primary phasizing tight control of fasting blood
stroke prevention. We explored the relationship between FBG among diabetic subjects and risk
of ischemic stroke in a multiethnic prospective cohort.
glucose (FBG) as a stroke prevention mea-
sure. According to the American Heart
RESEARCH DESIGN AND METHODS Medical and social data and FBG values were Association Guidelines for the Primary
collected for 3,298 stroke-free community residents: mean age SD was 69 10 years; 63% Prevention of Stroke, there is insufficient
were women, 21% were white, 24% were black, and 53% were Hispanic; and follow-up was 6.5 randomized trial data to support glycemic
years. Baseline FBG levels were categorized: 1) elevated FBG: history of diabetes and FBG 126 control among diabetic subjects as a
mg/dl (7.0 mmol/l); 2) target FBG: history of diabetes and FBG 126 mg/dl (7.0 mmol/l); or 3) stroke prevention measure (6). American
no diabetes/reference group. Cox models were used to calculate hazard ratios (HRs) and 95% CI Heart Association recommendations
for ischemic stroke and vascular events.
based on the UK Prospective Diabetes
RESULTS In the Northern Manhattan Study, 572 participants reported a history of diabe- Study (UKPDS) support glycemic control
tes and 59% (n 338) had elevated FBG. Elevated FBG among diabetic subjects was associated among individuals with diabetes to re-
with female sex (P 0.04), Medicaid (P 0.01), or no insurance (P 0.03). We detected 190 duce microvascular complications, ne-
ischemic strokes and 585 vascular events. Diabetic subjects with elevated FBG (HR 2.7 [95% CI phropathy, and retinopathy, as well as
2.0 3.8]) were at increased risk of stroke, but those with target FBG levels (1.2 [0.72.1]) were peripheral neuropathy (6,7). In the UK-
not, even after adjustment. A similar relationship existed for vascular events: elevated FBG (2.0 PDS, tight glycemic control of a prospec-
[1.6 2.5]) and target FBG (1.3 [0.9 1.8]. tive cohort of individuals with newly
diagnosed diabetes did not significantly
CONCLUSIONS This prospective cohort study provides evidence for the benefits of
tighter glucose control for primary stroke prevention. reduce stroke risk (7).
The current obesity epidemic and
Diabetes Care 31:11321137, 2008 associated increasing prevalence of diabe-
tes, especially among minority popula-
tions, warrants further investigation of

D
iabetes is a major public health
problem. In the U.S. today, more
than 18.2 million people have dia-
betes. The prevalence of diabetes in-
creases with age, and certain populations,
including minority groups, may be more
vulnerable. According to the American
Diabetes Association, one of every four
African-American and Hispanic individu-
als 65 years of age has diabetes. In ad-
dition, it is estimated that another 10
15% of the U.S. population has elevated
blood glucose levels and may be consid-
ered to have pre-diabetes. Diabetes is a
major risk factor for cardiovascular dis-
ease and is associated with a 2-fold risk
whether tight control of FBG is associated
with decreased stroke risk. The aim of this
study was to explore the relationship be-
tween FBG levels among diabetic subjects
and the risk of ischemic stroke as well as
other vascular events in a multiethnic
prospective cohort

From the 1Department of Neurology, Columbia University College of Physicians and Surgeons, New York, RESEARCH DESIGN AND
New York; the 2Department of Sociomedical Science, Columbia University Mailman School of Public Health, METHODS
New York, New York; the 3Department of Biostatistics, Columbia University Mailman School of Public
Health, New York, New York; and the 4Department of Neurology, University of Miami, Miami, Florida.
The Northern Manhattan Study (NOMAS)
Corresponding author: Bernadette Boden-Albala, DrPH, Neurological Institute, 710 W. 168 St., New is a prospective population-based cohort
York, NY 10032. E-mail: bb87@columbia.edu. study designed to study incidence, risk
Received for publication 24 April 2007 and accepted in revised form 4 March 2008. factors, and prognosis of stroke in
Published ahead of print at http://care.diabetesjournals.org on 13 March 2008. DOI: 10.2337/dc07-0797. a multiethnic urban community. Based
Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/
dc07-0797. in Northern Manhattan, an area of
Abbreviations: ARIC, Atherosclerosis Risk in Communities; CPMC, Columbia-Presbyterian Medical 260,000 people, with 104,000 individ-
Center; FBG, fasting blood glucose; NOMAS, Northern Manhattan Study; UKPDS, UK Prospective Diabetes uals aged 39 years of age, this study
Study. has a unique race-ethnicity distribution
2008 by the American Diabetes Association.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby of 63% Hispanic, 20% black, and
marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 15% white. The methodology for

1132 DIABETES CARE, VOLUME 31, NUMBER 6, JUNE 2008


NOMAS has been described previously
and is summarized briefly below (8).
Selection of prospective cohort
A total of 3,298 subjects were recruited
and enrolled between 1993 and 2001.
Participants were eligible if they 1) had
never had a stroke, 2) were aged 40
years, and 3) had resided for at least 3
months in a household with a telephone
in Northern Manhattan. Subjects were
identified by random digit dialing by us-
ing dual frame sampling, and bilingual in-
terviews were conducted (9). The
telephone response rate was 91% (9% re-
fused to be screened), and 87% of those
eligible indicated willingness to partici-
pate. This study was approved by the lo-
cal governing institutional review board,
and written consent was obtained.
Baseline evaluation
Subjects were recruited from the tele-
phone sample to have an in-person base-
line interview and assessment. The
enrollment response rate was 75% with
an overall response rate of 68% (tele-
phone response enrollment response).
Standardized questions regarding medi-
cal history were adapted from the Centers
for Disease Control and Prevention Be-
havioral Risk Factor Surveillance System
(10). Race-ethnicity was based upon self-
identification.
Glucose levels
To examine the impact of FBG on stroke
risk among diabetic subjects, we divided
baseline FBG levels into three categories:
1) elevated FBG: a history of diabetes and
FBG 126 mg/dl (7.0 mmol/l); 2) target
FBG: a history of diabetes and FBG 126
mg/dl (7.0 mmol/l); or 3) no diabetes/
reference group, including those with no
history of diabetes. Fasting serum glucose
was measured according to standard pro-
cedures using a glucose dehydrogenase
method (11).
Other baseline assessments
Hypertension was defined as either sys-
tolic blood pressure levels 140 mmHg,
diastolic blood pressure levels 90
mmHg, or a history of hypertension. Car-
diac disease included history of angina,
myocardial infarction, coronary artery
disease, or valvular heart disease. Obesity
was defined using BMI. Smoking was cat-
egorized as never, former, and current
smoker. Moderate alcohol use was de-
fined as current drinking of 1 drink per
month and 2 drinks per day. Physical
DIABETES CARE, VOLUME 31, NUMBER 6, JUNE 2008
activity was defined as engaging in leisure
activity versus not over the 10 days before
baseline enrollment. Social resources
were defined by educational level and
health insurance status. Education was
dichotomized into those who had com-
pleted high school versus those who had
not. Health insurance was separated into
three mutually exclusive groups: 1) indi-
viduals who had Medicaid or Medicaid/
Medicare or no insurance; 2) individuals
who had private insurance or private/
Medicare; and 3) individuals with Medicare
only (reference group). We combined the
no insurance group with the Medicaid
group on the basis of a similar risk ratio in
these groups, as well as the very low preva-
lence (7%) of noninsured individuals in this
cohort.
Annual prospective follow-up
Subjects were screened annually by tele-
phone interview to determine any change
in vital status, detect neurological and
cardiac symptoms and events, review any
interval hospitalizations, review risk fac-
tor status, review changes in medication,
and determine changes in functional sta-
tus. Phone assessment served as a screen
for events. The telephone interview sim-
ple stroke question (Since your last visit
have you been diagnosed with a stroke?)
had a sensitivity of 92% and specificity of
95%. Moreover, a 10% random sample of
the cohort was followed annually in per-
son for 5 years to evaluate for any tele-
phone false-negative results and evaluate
for serial changes in baseline measures. In
between follow-up interviews, subjects
and family members were reminded to
notify us in the event of stroke, myocar-
dial infarction, or death.
Subjects who screened positive by
telephone were scheduled for an in-
person assessment. All affirmative re-
sponses to neurological symptoms and
conditions required a review and exami-
nation by the study neurologists. In addi-
tion, ongoing hospital surveillance of
admission and discharge ICD-9 codes
provided data on mortality and morbidity
that may not have been captured during
the annual telephone follow-up.
Outcome classifications (ischemic
stroke, myocardial infarction, or
vascular death)
For these analyses, two outcome mea-
sures were 1) first ischemic stroke and 2)
first vascular event, defined as either first
ischemic stroke or first myocardial infarc-
tion or vascular death. Stroke was defined
Boden-Albala and Associates
as rapidly developing clinical signs of fo-
cal (at times global) disturbance of cere-
bral function, lasting 24 h or leading to
death with no apparent cause other than
that of vascular origin (12). Subjects who
are hospitalized for stroke at Columbia-
Presbyterian Medical Center (CPMC)
have systematic evaluations during their
hospitalization, which include standard
diagnostic tests: admission serological
studies, head computed tomography,
carotid duplex Doppler, transcranial
Doppler, echocardiography, electrocardi-
ography, magnetic resonance imaging,
and angiography. The diagnostic evalua-
tion by neurologists at non-Northern
Manhattan hospitals is difficult to control,
but any participant who needs vascular
noninvasive tests can have these done as
part of their in-person follow-up visit at
CPMC. Subjects who are suspected of
having a stroke and have not had a prior
diagnostic evaluation have one completed
either through their primary care physi-
cian, the CPMC neurology clinic, or the
Clinical Research Center. If a patient has
been hospitalized, then medical records
will be reviewed to verify details.
More than 98% of these patients with
stroke outcomes had at least one form of
imaging, predominately a computed to-
mographic scan. Although our surveil-
lance system captured both hemorrhagic
and ischemic stroke, for the purposes of
this study we are reporting only on isch-
emic stroke outcomes. Hemorrhagic
stroke accounted for 9% of all stroke, and
we did not have the ability to examine this
stroke subtype separately. More than 70%
of the patients with stroke were hospital-
ized at the Columbia University Medical
Center.
Myocardial infarction was defined by
criteria adapted from the Lipid Research
Clinics Coronary Primary Prevention
Trial (13) and required at least two of the
following three criteria: 1) ischemic car-
diac pain determined to be typical angina;
2) cardiac enzyme abnormalities defined
as abnormal creatinine phosphokinase
MB fraction or troponin values; and 3)
electrocardiogram abnormalities.
For subjects who died, the date of
death was recorded along with cause of
death. Deaths were classified as vascular
or nonvascular on the basis of informa-
tion obtained from the family and physi-
cians and validated with medical records
and death certificates. Causes of vascular
death included ischemic stroke, myocar-
dial infarction, heart failure, pulmonary
embolus, cardiac arrhythmia, and other
1133
FBG and risk of stroke in diabetic subjects

Table 1Baseline sociodemographic characteristics of the Northern Manhattan Study cohort of fasting glucose and those with better
fasting glucose levels.
Prevalence (%) During a mean of 6.5 years of follow-
up, 190 ischemic strokes and 585 vascu-
Nondiabetic Diabetic lar events were detected. Among the
Overall subjects subjects P value diabetic group, 62 ischemic stroke events
n 3,298 2,724 574 were documented (14 in the controlled
Sociodemographics diabetes group and 48 in the uncontrolled
Age (years) 69 10 69 11 68 8 NS diabetes group) In a multivariable Cox
Men 1,224 (37) 1,008 (37) 216 (38) NS model with no diabetes as the reference,
White 691 (21) 624 (23) 67 (12) 0.0001 elevated FBG levels (HR 2.7 [95% CI 1.9
Black 803 (25) 647 (24) 156 (28) NS 3.8]) were significantly associated with
Hispanic 1,725 (54) 1,384 (52) 341 (60) 0.0003 increased risk of stroke, whereas target
Completed high school 1,511 (46) 1,304 (48) 206 (36) 0.0001 FBG levels (1.2 [0.72.1]) did not signif-
Medicaid only 1,432 (44) 1,123 (41) 309 (55) 0.0001 icantly increase stroke risk after ad-
Vascular risk factors justment for age, race-ethnicity, sex, in-
Hypertension 2,425 (74) 1,939 (71) 486 (85) 0.0001 surance status, education, hypertension,
Any physical activity 1,943 (59) 1,627 (60) 316 (55) NS coronary artery disease, lipid levels, obe-
Cardiac disease 787 (24) 608 (22) 179 (31) 0.0001 sity, physical inactivity, alcohol intake,
Current smoking 508 (15) 419 (15) 89 (16) NS and smoking. A similar relationship ex-
Mild/moderate alcohol 1,074 (33) 944 (35) 130 (23) 0.0001 isted for risk of any vascular events: ele-
BMI 29 kg/m2 1,124 (34) 884 (32) 240 (42) 0.0001 vated FBG (2.0 [1.6 2.5]) and target FBG
HDL 35 mg/dl 741 (22) 581 (21) 160 (28) 0.0005 (1.3 [0.9 1.8]). In a separate analysis to
Data are means SD.
determine whether the effect of elevated
FBG was significantly different from tar-
get FBG, we found that they were signifi-
vascular causes. Nonvascular causes of ethnicity, education, and insurance status cantly different (P 0.03).
death included accident, cancer, pulmo- were considered as sociodemographic We further explored the dose-
nary disorders (pneumonia, chronic ob- factors, and models were adjusted for hy- response model for levels of FBG for isch-
structive pulmonary disease, and others) pertension, obesity, dyslipidemia, cardiac emic stroke, vascular death, and any
and other nonvascular causes. All vascu- disease, smoking, physical inactivity, and vascular event. We found that FBG levels
lar outcomes were reviewed and validated alcohol consumption. 126 but 150 were associated with a
in a manner similar to that for stroke out- HR of 4.1 [95% CI 2.37.2] and FBG lev-
comes by our team of three study els 150 were associated with a HR of 2.7
cardiologists. RESULTS A cohort of 3,298 com- [1.8 3.9], after controlling for age, race-
munity residents were enrolled. At base- ethnicity, sex, education, and physical
Statistical analyses line, mean SD age was 69 10 years, activity.
The prevalence of sociodemographic, 63% were women, 21% were white, 24% In a separate analysis, we explored
conventional vascular risk factors, and were black, and 53% were Hispanic. factors associated with elevated versus
other baseline variables was calculated. More than 18% (n 572) of the cohort target FBG levels. Three dimensions of
Kaplan-Meier curves of survival free of had reported a diagnosis of diabetes factors were examined: demographics,
ischemic stroke and survival free of vas- (Table 1). Among those with diabetes, risk factors, and social resources. In mul-
cular events (ischemic stroke, myocardial 19% achieved control with diet, 55% tivariable analyses, elevated FBG was sig-
infarction, or vascular death) were calcu- were taking oral hypoglycemic agents, nificantly greater among women (P
lated (Fig. 1 of the online appendix avail- and 26% were taking insulin at the base- 0.04), those with Medicaid (P 0.01), or
able at http://dx.doi.org/10.2337/dc07- line interview. those with no insurance (P 0.03). Vas-
0797). Cox proportional regression Control of FBG in diabetic subjects cular risk burden or prevalence of risk
models were used to calculate hazard ra- was poor, with 59% (338 subjects) of factors was not significantly associated
tios (HRs) and 95% CI for ischemic stroke individuals with diabetes having FBG lev- with elevated versus target FBG levels
and all vascular events (stroke, myocar- els 126 mg/dl. Elevated FGB levels were among those with diabetes.
dial infarction, and vascular death). similar among white, black, and Hispanic
Times to first event among stroke and vas- diabetic subjects. The mean duration of CONCLUSIONS In our multieth-
cular outcomes (ischemic stroke, myocar- diabetes in the cohort was 12 years with a nic prospective community-based stroke-
dial infarction, or vascular death) were median of 8 years. There was no differ- free cohort, we report a strong re-
analyzed as outcomes with censoring at ence in the duration of diabetes among lationship between elevated FBG levels
the time to either nonvascular event or those with target FBG levels (mean 11.3 among diabetic subjects (FBG 126
last follow-up. years and median 8 years) versus elevated mg/dl [7.0 mmol/l]) and increased risk of
In addition, we performed a separate FBG levels (mean 12 years and median 8 incident ischemic stroke as well as vascu-
cross-sectional analysis among those with years). Likewise, the use of oral hypogly- lar events after adjustment for sociodemo-
diabetes to identify factors associated with cemic agents and insulin among diabetic graphic and vascular risk factors. The
elevated FBG versus target FBG levels (Fig. subjects was not statistically different be- increased risk associated with elevated
2 of the online appendix). Age, sex, race/ tween diabetic subjects with poor control FBG was similar whether fasting glucose

1134 DIABETES CARE, VOLUME 31, NUMBER 6, JUNE 2008


Table 2Adjusted HRs of ischemic stroke and vascular events by level of glucose among diabetic subjects
Nondiabetic
subjects
n 2,621
Ischemic stroke Referent
Vascular death Referent
Any vascular event Referent
Data are relative risk (95% CI). All models were adjusted for age, race-ethnicity, sex, education, and physical activity.
was 126 150 mg/dl or greater. In our co-
hort, risk of ischemic stroke among a di-
abetic population with FBG levels within
the target range was associated with a
lower and nonsignificant risk of stroke
and vascular events. Furthermore, there
was a significantly different relationship
in stroke risk between those with elevated
FBG levels and target FBG levels. Few
studies have examined the relationship
between control of FBG levels and isch-
emic stroke risk, and most include stroke
as a combined outcome with cardiovascu-
lar disease. In a meta-analysis, chronic hy-
perglycemia defined by a 1 point increase
in A1C was found to be associated with a
pooled RR of 1.18 [95% CI 1.10 1.26]
for all vascular end points, and a pooled
RR of 1.15 [1.08 1.23] for stroke (14).
Similarly, in a nested sample from the
Atherosclerosis Risk in Communities
(ARIC) cohort, elevated baseline A1C was
reported to be an independent predictor
of cardiovascular outcomes (1.1 [1.1
1.20]) per 1 percentage point increase in
A1C (15) In a registry cohort of Finnish
diabetic patients, both high plasma glu-
cose levels (13.4 mmol/l) and elevated
A1C (10.7%) were strongly associated
with increased risk of prevalent stroke
(16). In the large prospective ARIC study
in which the relationship between ele-
vated FBG levels and risk of ischemic
stroke was examined, RRs were compared
among two definitions of diabetes. Poor
glycemic control defined as fasting glu-
cose 140 mg/dl or a history of diabetes
conferred a 2.2-fold risk [95% CI 1.6
3.2] of ischemic stroke, and poor glyce-
mic control defined by a history of
diabetes or fasting glucose 126 mg/dl
was associated with a HR of 1.9 [1.32.7]
for ischemic stoke. However, the ARIC
study did not examine the impact of ele-
vated glucose levels among diabetic sub-
jects. Although there appears to be a dose-
response relationship between the
glucose levels and outcomes in the lower
glucose group compared with the mid-
DIABETES CARE, VOLUME 31, NUMBER 6, JUNE 2008
Glucose
126 mg/l
214
1.8 (1.03.1)
1.4 (0.92.2)
1.6 (1.22.3)
range and high-range group, the relative
risks in the mid-range group and the
high-range group are similar. Indeed the
CIs are almost identical. In addition, the
mid-range group (n 73) is small. Nev-
ertheless, the lack of dose response be-
tween the two upper glucose groups may
suggest that damage to organ systems be-
gins in the mid-level group. Other studies
have reported that FBG level is an inde-
pendent risk factor for coronary heart dis-
ease among nondiabetic populations
(3,5). In the ARIC cohort, the relationship
between FBG levels and ischemic stroke
among nondiabetic subjects demon-
strated a slightly increased risk but failed
to reach significance (3). We found simi-
lar results (Table 2).
Only a few randomized trials have
been conducted to examine whether tight
FBG control leads to better vascular out-
comes, and these trials have been criti-
cized for small numbers of subjects and
insufficient follow-up. The University
Group Diabetes Program (UGDP) found
no significant benefit of tight glycemic
control among 400 diabetic subjects (17).
This study, however, suggested that two
agents (tolbutamide and phenformin)
used for glycemic control might actually
be associated with increased cardiovascu-
lar mortality. Another trial of 153 type 2
diabetic men assigned to intensive versus
conventional therapy demonstrated no
difference in cardiovascular events during
22 months of follow-up (18).
The largest randomized clinical trial
examining the relationship between vas-
cular outcomes and tight glycemic control
among type 2 diabetic subjects was the
UKPDS. In the UKPDS, intensive glyce-
mic control reduced the relative risk of
any diabetes-related end point by 12%
and microvascular complications by 25%
(7). However, tight glycemic control was
not significantly associated with de-
creased risk of stroke (HR 1.1 [95% CI
0.8 1.5]) among 5,102 diabetic subjects
randomly assigned to conventional (diet-
Boden-Albala and Associates
Diabetic subjects
Glucose Glucose
126 mg/l and 150 150 mg/l
73 283
5.1 (2.89.3) 3.3 (2.24.8)
3.2 (2.14.0) 2.6 (2.13.8)
3.3 (2.25.1) 2.7 (2.13.5)
controlled only) versus intensive treat-
ment regiments (chlorpropamide,
glyburide, insulin, or metformin among
obese subjects). A strength of the UKPDS
was its meticulous, serial measurement of
glycemic control using A1C techniques.
One limitation of the UKPDS was its def-
inition of stroke as a major stroke with
symptoms or signs lasting 1 month or
longer. This outcome criteria may have
led to an underidentification of cases of
stroke, especially those of small vessel eti-
ology. In addition, the short follow-up pe-
riod associated with clinical trials may
underestimate the control effect,
whereas a FBG value in an observational
study may be an effective indicator of con-
trol over many years. Further, because of
the intent to treat nature of the trial,
80% of the control group required one
or more of the therapies reserved for the
intensive intervention regiment. The NO-
MAS cutoff for glycemic control was 126
mg/dl (7.0 mmol/l), which was actually
higher than target glucose levels in the
UKPDS. Finally, in the UKPDS, none of
the monotherapies were capable of main-
taining target control glucose levels of
108 mg/dl (6.0 mmol/l) (7).
In a separate analysis, we also exam-
ined associations between FBG levels and
vascular and social risk factors. We report
that health insurance type is an indepen-
dent predictor of elevated FBG levels
among our diabetic patients. Indeed, FBG
targets may be difficult to achieve in clin-
ical practice settings in which continuity
of care and adherence to treatment are not
emphasized. Other studies have shown
similar results. In a retrospective design of
subjects with newly treated diabetes cap-
tured through an administrative claims
database, female sex, preferred provider
organization insurance plans, and use of
insulin were associated with early nonad-
herence as well as treatment discontinua-
tion (19). In a small cross-sectional study,
lower family socioeconomic status and
lower rate of health insurance, but not ed-
1135
FBG and risk of stroke in diabetic subjects
ucation or ethnicity, were associated with
higher A1C levels (20). The UKPDS
showed little difference by race/ethnicity
in glycemic control (21). In our study,
despite differences in the prevalence of
diabetes by race/ethnicity, there were no
significant differences in elevated versus
target glucose levels between whites,
blacks, and Hispanics. The inclusion of a
large multiethnic, older, heterogeneous
cohort with similar geographical access to
the medical center is generalizable to
other multiethnic urban populations and
allows for more valid comparisons across
race/ethnicity categories.
Other strengths include a prospective
population-based design for which both
baseline exposures and outcomes were
well documented. Our aggressive fol-
low-up strategies have resulted in 1%
loss to follow-up. Study participants were
seen in person at both study entry and
follow-up to document outcome events.
One potential limitation in our results is
that ascertainment of outcomes might dif-
fer by diabetes control status. It is possible
that patients with poor control may be
identified earlier because of other related
comorbidities. Overall, 54% of our out-
come information was obtained through
CPMC daily admissions information, and
there was no difference in the proportion
of subjects with controlled and uncon-
trolled diabetes identified this way. Simi-
larly, the proportion of outcome events
reported during follow-up of patient and
family report (43%) did not differ by dia-
betes control status. Finally, 3% of out-
comes were picked up through screening
and examination with no difference by di-
abetes control status.
An important limitation was our use
of a single sample of fasting glucose to
define baseline glycemic control. How-
ever, given its use in previous epidemio-
logical studies and our lack of A1C data,
we felt this measurement of FBG has rea-
sonable utility (4). Most studies have used
A1C as the indicator of better versus poor
long-term regulation of plasma glucose.
Indeed, A1C is thought to reflect long-
term glycemic control and may be a more
accurate and stable measure than fasting
glucose levels (22). Theoretically, A1C re-
flects the average fasting glucose level
throughout the 3-month cycle of the
erythrocyte. In reality, the measure of
A1C is actually a weighted average with
more recent glucose levels contributing
more than earlier levels. Studies also indi-
cate that fasting plasma glucose levels
may underestimate A1C levels, especially
1136
at higher A1C levels (23). Indeed, there
may be a systematic bias toward incor-
rectly assigning persons with a higher
A1C as having a lower FBG (better con-
trol), which would bias results toward the
null hypothesis. Hence, the effect of FBG
on risk of incident stroke may be greater
than what we observed. Other limitations
of this study include our inability to cap-
ture microvascular end points as well as
our nonspecific identification of therapies
for glycemic control.
A number of issues remain unre-
solved regarding elevated versus targeted
FBG among diabetic subjects. Data from
this and other prospective studies provide
evidence that targeted FBG levels among
diabetic subjects are associated with a re-
duction of macrovascular risk including
ischemic stroke and other vascular
events. Ongoing rigorous clinical trials
such as Action to Control Cardiovascular
Risk in Diabetes (ACCORD), a study of
10,000 adults with diabetes, will ulti-
mately provide conclusive evidence re-
garding the importance of glycemic
control in preventing macrovascular dis-
ease including ischemic stroke.
Acknowledgments This work has been
funded by National Institutes of Health Na-
tional Institute of Neurological Disorders and
Stroke NS 29993.
The authors thank Janet DeRosa, MPH,
NOMAS project manager, and the entire
NOMAS research staff for their continued hard
work and dedication. We also thank Lin
Huang for her statistical help.
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