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The Impact of Diabetes Mellitus on Mortality From All Causes and Coronary Heart Disease in Women
20 Years of Follow-up
Frank B. Hu, MD;
Meir J. Stampfer, MD;
Caren G. Solomon, MD;
Simin Liu, MD;
Walter C. Willett, MD;
Frank E. Speizer, MD;
David M. Nathan, MD;
JoAnn E. Manson, MD
Arch Intern Med. 2001;161:1717-1723.
ABSTRACT
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Background Few data are available on the long-term impact of type 2 diabetes mellitus
on total mortality and fatal coronary heart disease (CHD) in women.
Methods We examined prospectively the impact of type 2 diabetes and history
of prior CHD on mortality from all causes and CHD among 121 046 women
aged 30 to 55 years with type 2 diabetes in the Nurses' Health Study who were
followed up for 20 years from 1976 to 1996.
Results During 20 years of follow-up, we documented 8464 deaths from all causes,
including 1239 fatal CHD events. Compared with women with no diabetes or CHD
at baseline, age-adjusted relative risks (RRs) of overall mortality were 3.39
(95% confidence interval [CI], 3.08-3.73) for women with a history of diabetes
and no CHD at baseline, 3.00 (95% CI, 2.50-3.60) for women with a history
of CHD and no diabetes at baseline, and 6.84 (95% CI, 4.71-9.95) for women
with both conditions at baseline. The corresponding age-adjusted RRs of fatal
CHD across these 4 groups were 1.0, 8.70, 10.6, and 25.8, respectively. Multivariate
adjustment for body mass index and other coronary risk factors only modestly
attenuated the RRs. Compared with nondiabetic persons, the multivariate RRs
of fatal CHD across categories of diabetes duration ( 5, 6-10, 11-15, 16-25,
>25 years) were 2.75, 3.63, 5.51, 6.38, and 11.9 (P<.001
for trend), respectively. The combination of prior CHD and a long duration
of clinical diabetes (ie, >15 years) was associated with a 30-fold (95% CI,
20.7-43.5) increased risk of fatal CHD.
Conclusions Our data indicate that among women, history of diabetes is associated
with dramatically increased risks of death from all causes and fatal CHD.
The combination of diabetes and prior CHD identifies particularly high-risk
women.
INTRODUCTION
TYPE 2 DIABETES mellitus is a well-established risk factor for coronary
heart disease (CHD).1 Diabetic women are at
particularly high risk of CHD2; diabetes eliminates
the usual female advantage for coronary disease mortality. Women with type
2 diabetes, compared with age-matched nondiabetic women, have a 5- to 7-fold
higher rate of CHD death, with an event rate similar to that observed in men
with type 2 diabetes.3 Two recent analyses4-5 have suggested that the magnitude of
diabetes-related CHD mortality rivals the excess risk conferred by prior CHD.
This finding challenges the National Cholesterol Education Program, which
recommends more aggressive lipid-lowering therapy for people with prior CHD
than for those with diabetes.6 However, these
studies were relatively small and did not consider duration of diabetes. Also,
the results for diabetic men and women were combined, although it is known
that diabetes confers a particularly high risk of CHD in women.2
The present study, with 20 years of follow-up, examines the impact of
type 2 diabetes on mortality from all causes and from CHD among women in the
Nurses' Health Study. In particular, we compared the risk of fatal CHD and
total mortality among diabetic women without clinical CHD with that of women
diagnosed as having CHD but not diabetes. We also examined the impact of duration
of clinical diabetes on CHD risk.
PARTICIPANTS AND METHODS
STUDY POPULATION
The Nurses' Health Study cohort was established in 1976 when 121 700
female registered nurses, aged 30 to 55 years and residing in 11 large states,
completed a mailed questionnaire about their medical history and lifestyle.
Every 2 years, follow-up questionnaires have been sent to update information
on potential risk factors and to identify newly diagnosed cases of CHD and
other illness. After excluding the relatively few women (n = 343) whose diabetes
was diagnosed at 30 years or younger (since they were most likely to have
type 1 diabetes mellitus) and those with missing data on date of diagnosis
of diabetes, the final population for analyses included 121 046 women.
ASSESSMENT OF HISTORY OF CHD
At baseline and every 2 years during follow-up, we asked the women to
report whether they had angina pectoris, coronary bypass surgery or angioplasty,
and/or myocardial infarction (MI). In this study, only report of a prior MI
was considered as history of CHD. In 1976, 394 women reported a history of
MI. During the follow-up from 1976 to 1994, 2473 women reported newly diagnosed
MI. The confirmation of self-reported MI through medical record review according
to strict diagnostic criteria was approximately 68% before 1984.7
This increased to 82% between 1990 and 1996 (unpublished data). Most of the
nonconfirmed cases had coronary disease but did not meet the criteria for
MI.
CONFIRMATION OF DIABETES MELLITUS
In 1976, 1715 women reported physician-diagnosed diabetes (limited to
diagnosis at age >30 years). During the follow-up periods, 6046 women reported
newly diagnosed diabetes mellitus. A supplementary questionnaire regarding
symptoms, diagnostic tests, and hypoglycemic therapy was mailed to women who
indicated on any biennial questionnaire that they had been diagnosed as having
diabetes. A case of diabetes was considered confirmed if at least 1 of the
following was reported on the supplementary questionnaire: (1) 1 or more classic
symptoms (excessive thirst, polyuria, weight loss, hunger, pruritus) plus
fasting plasma glucose level of at least 140 mg/dL (7.8 mmol/L) or random
plasma glucose level of at least 200 mg/dL (11.1 mmol/L); (2) at least 2 elevated
plasma glucose concentrations on different occasions (fasting glucose level
of at least 140 mg/dL or random plasma glucose level of at least 200 mg/dL
and/or a concentration at least 200 mg/dL after 2 hours or more on oral glucose
tolerance testing) in the absence of symptoms; or (3) treatment with hypoglycemic
medication (insulin or oral hypoglycemic agent). The validity of this questionnaire
has been verified in a subsample of this study population.8
Among a random sample of 84 women classified by the questionnaire as having
type 2 diabetes, 71 gave permission for their medical records to be reviewed
and records were available for 62. An endocrinologist (J.E.M.), blinded to
the information reported on the supplementary questionnaire, reviewed the
records according to National Diabetes Data Group (NDDG) criteria.9 The diagnosis of type 2 diabetes was confirmed in
61 (98%) of 62 women. Our primary analyses were based on self-reported diabetes.
A secondary set of analyses was conducted that included only women with "definite"
type 2 diabetes by the NDDG criteria. We used the NDDG diagnostic criteria
because the analytic cohort preceded the American Diabetes Association's diagnostic
guidelines published in 1997.10
ASCERTAINMENT OF END POINTS
The primary end points included deaths from all causes and fatal CHD
that occurred after the return of the 1976 questionnaire but before June 1,
1996. Deaths were reported by next of kin and the postal system or ascertained
through the National Death Index. We estimate that follow-up for the deaths
was more than 98% complete.11 We obtained copies
of death certificates and medical records and determined causes of death (classified
according to the categories of the International Classification
of Diseases, Ninth Revision [ICD-9]).
Fatal CHD was confirmed by hospital records or autopsy or if CHD was
listed as the cause of death on the death certificate and evidence of previous
CHD was available. Probable fatal CHD cases were designated where CHD was
the underlying cause on the death certificate, but no records were available.
These cases constituted 14.7% of fatal CHD cases. We also included sudden
deaths (12.3% of fatal CHD). Deaths owing to all cardiovascular disease included ICD-9 codes 390 through 459 and 795.
STATISTICAL ANALYSIS
We conducted 2 sets of analyses, one comparing deaths from all causes
and fatal CHD according to reported diabetes and CHD diagnoses at baseline
(1976) and the other according to reported diagnoses either at baseline or
during follow-up (updated every 2 years). Person-time for each participant
was calculated from the date of return of the 1976 questionnaires to the date
of confirmed fatal CHD, death from other causes, or June 1, 1996, whichever
came first.
We calculated rates of fatal CHD for women with prior diabetes, CHD,
or both by dividing the number of incident cases by the number of person-years
of follow-up. The relative risk (RR) was computed as the rate among women
with prior diabetes, CHD, or both divided by the rate among women with neither
condition, with adjustment for 5-year age categories. For the analysis of
overall mortality, person-time was calculated from the date of the 1976 questionnaire
to the date of death from any cause or June 1, 1996. Duration of clinical
diabetes was calculated as years since first diagnosis of diabetes and the
variable was divided into 5 categories (5, 6-10, 11-15, 16-25, >25 years).
We collapsed the last 2 categories in the analysis of duration of diabetes
stratified by prior CHD. Test for trend was conducted by treating the original
duration variable as a continuous variable.
We used pooled logistic regression to adjust estimated incidence rate
ratios simultaneously for potential confounding variables. In this approach,
independent 2-year blocks of person-time of follow-up are pooled for regression
analysis, and the dependence of the incidence rates on time is modeled nonparametrically
with indicator variables. D'Agostino et al12
have showed that the pooled logistic model is asymptotically equivalent to
the Cox regression when the time intervals are short and the probability of
outcome in the intervals is low (both assumptions are satisfied by our data);
examples comparing the 2 methods were given by Cupples et al.13
Our covariates included age (5-year categories); body mass index, a measure
of weight in kilograms divided by the square of height in meters (<21,
21-22.9, 23-24.9, 25-28.9, 29-31.9,  32); cigarette smoking (never, past,
and current smoking of 1 to 14, 15 to 24, and 25 cigarettes per day);
menopausal status (premenopausal, postmenopausal without hormone replacement,
postmenopausal with past hormone replacement, postmenopausal with current
hormone replacement); and parental history of MI before the age of 60 years.
We did not adjust for history of hypertension or hypercholesterolemia because
they are considered intermediate variables in the biological pathway. Secondary
analysis further adjusting for these variables did not materially change the
RRs for total mortality but somewhat attenuated the RRs for fatal CHD. All
covariates except parental history of MI were updated every 2 years. Alcohol
use and physical activity were first assessed in 1980. Because further analyses
adjusting for these 2 variables did not alter the results, we did not include
them in the final model. As preplanned, we conducted stratified analyses according
to age group, history of hypertension, high cholesterol levels, and parental
history of MI.
RESULTS
During 20 years of follow-up from 1976 to 1996 (2 341 338
person-years), we documented 8464 deaths from all causes, including 1239 cases
of fatal CHD. A total of 1892 deaths were ascribed to cardiovascular disease
and 6572 were attributed to other causes (mainly cancer). Table 1 presents characteristics of the participants in the middle
year (1986) of the follow-up. Women who had both diabetes and CHD were more
likely to have hypertension and high cholesterol levels and less likely to
use postmenopausal hormone therapy and vitamin E supplements. Women with a
history of CHD, regardless of their diabetes status, were older and more likely
to have a family history of CHD. On the other hand, women with a history of
diabetes, regardless of CHD status, were heavier and drank less alcohol. Women
with both diabetes and CHD were more likely to be treated with insulin than
those with diabetes alone. Dietary intakes of fiber, fat, and cholesterol
did not differ appreciably across the groups.
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Table 1. Distribution of Potential Coronary Risk Factors According
to History of Diabetes and Coronary Heart Disease (CHD) in 1986*
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ANALYSES ACCORDING TO HISTORY OF DIABETES AND CHD AT BASELINE (1976)
At baseline in 1976, 1437 women reported diagnoses of diabetes (all
these women were older than 30 years at diagnosis) and 394 reported diagnoses
of MI. Table 2 shows RRs of death
from all causes, all cardiovascular disease, and fatal CHD according to diabetes
and CHD status at baseline. The age-adjusted RR of all-cause mortality was
approximately 7 times higher for women who had both diabetes and CHD compared
with those with neither condition. The age-adjusted RR of death was 3.39 for
women with a history of diabetes and no CHD compared with 3.00 for women with
a history of CHD and no diabetes. Multivariate adjustment for smoking, body
mass index, and other covariates somewhat attenuated these RRs. The multivariate-adjusted
RRs of fatal CHD were similar for women with prior CHD (RR, 8.15; 95% confidence
interval [CI], 6.25-10.6) and those with diabetes alone (RR, 7.48; 95% CI,
6.30-8.89). Women with both conditions were approximately 18 times more likely
to die of CHD than those with neither conditions at baseline (multivariate
RR, 17.6; 95% CI, 10.5-29.4).
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Table 2. Relative Risks of Death From All Causes, CHD, and All Cardiovascular
Disease According to History of Diabetes and Prior CHD at Baseline in 1976:
The Nurses' Health Study, 1976-1996*
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ANALYSES ACCORDING TO UPDATED STATUS OF DIABETES AND CHD
During the follow-up periods, an additional 6046 women reported newly
diagnosed diabetes (all these women were older than 30 years at diagnosis),
and 2473 women reported newly diagnosed CHD. Table 3 shows RRs of all-cause mortality, fatal CHD, and cardiovascular
death according to diabetes and CHD diagnoses at baseline and during follow-up
(updated every 2 years). Compared with women with neither diabetes nor CHD,
multivariate RRs of all-cause mortality were 2.44 for women with diabetes
alone, 2.58 for women with CHD alone, and 5.82 for women with both conditions.
Compared with women with neither conditions, women with both diabetes and
prior CHD were 20 times more likely to die from any cardiovascular disease
and 25 times more likely to die from CHD. In contrast to results from Table 2, the RRs of cardiovascular death
and fatal CHD were substantially greater for women with CHD alone than those
with diabetes alone. The multivariate RRs of fatal CHD were 10.7 (95% CI,
9.03-12.6) for women with CHD alone compared with 5.65 (95% CI, 4.83-6.60)
for women with diabetes alone. Restriction of the analyses to only patients
with diabetes confirmed by the supplementary questionnaires did not appreciably
alter the results. (The age-adjusted RRs of fatal CHD were 12.0 for women
with CHD alone and 6.19 for women with diabetes alone.)
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Table 3. Relative Risks of Death From All Causes, CHD, and All Cardiovascular
Disease According to the Status of Diabetes and CHD at Baseline and During
Follow-up: The Nurses' Health Study, 1976-1996*
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In subgroup analyses, the excess risk of fatal CHD associated with diabetes
alone, prior CHD alone, or both was significant in all subgroups stratified
by age group, history of hypertension, history of high cholesterol levels,
or parental history of MI (Table 4).
Compared with younger women (<55 years) with neither condition, the RR
of fatal CHD for older women (65 years) with both diabetes and existing
CHD was 159.5 (95% CI, 111.1-229.1). As expected, history of hypertension
and parental history of MI augmented the elevated RRs associated with diabetes
alone or prior CHD. Interestingly, for women who had diabetes or CHD, high
cholesterol levels did not appear to further increase the risk of fatal CHD.
One possible explanation is that cholesterol-lowering treatment may have already
reduced the risk among those patients.
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Table 4. Multivariate Relative Risks (95% Confidence Intervals) of
CHD Death According to the Status of Diabetes and CHD at Baseline and During
Follow-up: Subgroup Analysis*
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THE IMPACT OF DURATION OF CLINICAL DIABETES
The risk of CHD mortality increased monotonically with increased duration
of clinical diabetes (Figure 1).
Compared with nondiabetic women, the RRs of fatal CHD across categories of
duration of diabetes (5, 6-10, 11-15, 16-25, >25 years) were 2.75, 3.63,
5.51, 6.38, and 11.9 (P<.001 for trend). In the
same multivariate model, the RR of fatal CHD for women with vs without prior
CHD was 5.49. The increased risk of fatal CHD with longer duration of diabetes,
especially among those with diabetes for 15 years or more, was persistent
in women with or without prior CHD (Figure
2). Women with prior CHD alone had a RR of 8.61 (95% CI, 7.08-10.5),
which was similar to that among women with diabetes for more than 15 years
(RR, 8.66; 95% CI, 6.87-10.9). A combination of CHD and a long duration of
diabetes (ie, >15 years) identifies a particularly high-risk group for fatal
CHD (RR, 30.0; 95% CI, 20.7-43.5).
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Figure 1. Multivariate relative risks and
95% confidence intervals of fatal coronary heart disease (CHD) associated
with duration of diabetes mellitus (DM) and a prior history of CHD. Adjusted
for the same covariates as in Table 2.
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Figure 2. Multivariate relative risks of
fatal coronary heart disease (CHD) according to duration of diabetes mellitus
(DM) stratified by a prior history of CHD. Adjusted for the same covariates
as in Table 2.
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In contrast to the monotonic increased risk of fatal CHD with longer
duration of diabetes, the risk of fatal CHD increased dramatically in the
first several years after onset of an MI and then remained relatively stable;
compared with women without a prior MI, the multivariate RRs of fatal CHD
across categories of number of years after first MI (5, 6-10, 11-20, >20
years) were 4.70, 6.05, 6.12, and 6.74, respectively.
COMMENT
In this large prospective cohort of women, type 2 diabetes mellitus
was associated with dramatically increased mortality from all causes and fatal
CHD among women. We observed a strong monotonic relationship between duration
of clinical diabetes and CHD mortality, independent of history of CHD. The
combination of a long duration of diabetes and preexisting CHD identifies
a particularly high-risk group.
Several previous studies have compared the magnitude of CHD risk associated
with history of diabetes or prior CHD. Haffner et al4
followed up 2432 Finnish men and women aged 45 to 64 years for 7 years and
found that the risk of fatal CHD was as high among diabetic patients without
prior CHD as it was among nondiabetic patients who had experienced prior CHD.
Because the study involved only 69 nondiabetic patients with prior CHD, the
power of the study to detect differences between the 2 groups was limited.
Also, the small sample size did not allow separate analyses by sex or stratification
by duration of diabetes. In a 5-year follow-up of 91 285 US male physicians
aged 40 to 84 years, Lotufo et al14 found that
for all-cause mortality, the magnitude of excess risk conferred by diabetes
was similar to that conferred by prior CHD. For fatal CHD, however, prior
CHD was a more powerful predictor (age-adjusted RR was 3.3 for diabetic men
without prior CHD vs 5.6 for nondiabetic men with prior CHD). The discrepancy
of the results between the 2 studies may be due to different age distribution
and sex composition of the 2 populations. The duration of diabetes may also
be different in the 2 studies; the average duration of diabetes was 8 years
in the Finnish study, whereas the duration of diabetes was not ascertained
in the Physicians' Health Study. Recently, Malmberg and colleagues5 reported that in a 2-year study diabetic patients
(duration of diabetes was not specified) without prior cardiovascular disease
had rates of coronary morbidity and mortality similar to those for nondiabetic
patients with previous vascular disease.
In our baseline analyses (Table 2), the excess risk of cardiovascular death and fatal CHD conferred
by diabetes alone was similar to that conferred by prior CHD. However, in
the updated analyses (Table 3),
the excess risk of fatal CHD associated with preexisting CHD was substantially
greater than that conferred by diabetes without clinical CHD. Obviously, in
the baseline analyses, only women who had a long duration of diabetes (20
years) were included in the diabetic group, whereas in the updated analyses,
both new and long-standing cases of diabetes were included. Our findings highlight
the importance of considering duration of diabetes when comparing the magnitude
of excess risk of fatal CHD conferred by diabetes alone and prior CHD.
Diabetes has more deleterious effects on women than on men; it eliminates
the usual female advantage for coronary disease mortality. In the Rancho Bernardo
Study,15 diabetic women had CHD mortality rates
similar to both nondiabetic and diabetic men, whereas nondiabetic women had
substantially lower risk. The reason for the accelerated atherogenesis among
diabetic women is not completely understood, but it is at least in part related
to more severe lipid and lipoprotein abnormalities, particularly elevated
levels of triglycerides and reduced levels of high-density lipoprotein, among
diabetic women.16-17 A recent
study3 suggests greater impairment of endothelial
function associated with type 2 diabetes in women than in men. In addition,
the magnitude of increased risk of reinfarction and fatality rate following
an acute MI among diabetic patients compared with nondiabetic patients was
greater in women than in men.18
Our data support current guidelines that recommend aggressive management
of cardiovascular risk factors in diabetic patients, including hypertension,
dyslipidemia, and lifestyle factors (smoking, obesity, and diet).19 The United Kingdom Prospective Diabetes Study showed
that tight control of blood pressure substantially decreased the risk of diabetes-related
deaths and the progression of microvascular complications,20
providing support for tighter control of blood pressure for diabetic individuals
than usually is recommended for nondiabetic individuals with hypertension.
A recent American Diabetes Association guideline21
recommends the same cholesterol-lowering goal for people with diabetes and
no clinical CHD as for patients with preexisting CHD (ie, a low-density lipoprotein
cholesterol level <100 mg/dL [<2.59 mmol/L]). Two statin trials22-23 among patients with existing CHD
showed similar significant reductions in CHD death in both patients with and
without diabetes. A secondary analysis of the Scandinavian Simvastatin Survival
Study showed that simvastatin therapy was associated with even greater reductions
in risk of major CHD events and total mortality among diabetic patients than
among nondiabetic patients.24 The effects of
tight glycemic control on cardiovascular complications are not yet settled,
although intensive therapy that lowers blood glucose levels has been proved
to reduce risk of microvascular complications in both patients with type 125 and type 226 diabetes.
Our study is one of few epidemiologic studies on diabetes-related cardiovascular
risk among women. The large sample size and long duration of follow-up provide
the opportunity to examine the impact of duration of clinical diabetes on
risk of cardiovascular disease. The follow-up rate of this cohort was high
during 20 years of follow-up (98% for death ascertainment). Thus, our study
results are unlikely to be biased by losses to follow-up. In addition, we
have collected detailed information on cardiovascular risk factors such as
smoking, body mass index, menopausal status, and postmenopausal hormone use
through repeated assessments.
Several limitations of the study should be considered. The data on diagnosed
diabetes and CHD were based on self-reports by the nurses. This may have led
to some misclassification. However, our previous studies7-8
have found self-reporting of these medical conditions to be reliable. To avoid
potential confounding by type 1 diabetes, we included only women reporting
a diagnosis of diabetes at 30 years or older. Moreover, the analysis restricted
to confirmed cases of type 2 diabetes by the supplementary questionnaire yielded
similar results.
Because our "nondiabetic" cohort was not uniformly screened for glucose
intolerance and the onset of diabetes can occur several years before clinical
diagnosis,27 the reported duration of diabetes
in our study may have been underestimated. Also, some cases of diabetes may
have been undiagnosed. This misclassification, however, would have inflated
the cardiovascular risk in the nondiabetic population and led to underestimation
of the RRs among our diabetic population. We believe that the proportion of
undiagnosed diabetes is relatively small in our cohort compared with the general
population because virtually all participants in our study have ready access
to health care. For example, more than 98% of the women in our study visited
a physician for a physical examination, breast examination, mammogram, or
sigmoidoscopy or colonoscopy at least once between 1988 and 1990. Finally,
the diagnostic criteria for type 2 diabetes were changed in 199710
such that lower fasting glucose levels (126 mg/dL [6.99 mmol/L]) would
now be considered diagnostic. We used the criteria proposed by the National
Diabetes Data Group9 because all our cases
were diagnosed before June 1996. If the new criteria were used, some women
in this study classified as nondiabetic would have been reclassified as having
diabetes, and the cardiovascular risk in the reference (nondiabetic) population
would have been even lower.
In conclusion, our data indicate that diabetes is associated with dramatically
increased risk of total mortality and CHD death among women. The excess risk
of fatal CHD for women who had clinical diabetes for more than 15 years was
similar to that conferred by prior CHD. The combination of a long duration
of diabetes and preexisting CHD identifies a particularly high-risk group.
AUTHOR INFORMATION
Accepted for publication January 18, 2001.
This study was supported by research grants DK36798, HL24074, HL34594,
and CA40356 from the National Institutes of Health, Bethesda, Md. Dr Hu's
work is supported by an American Diabetes Association Research Award. Dr Solomon
is supported by an American Heart Association Clinician Scientist Award.
We are indebted to the participants in the Nurses' Health Study for
their continuing outstanding level of cooperation and to Al Wing, MBA, Gary
Chase, Karen Corsano, MSL, Lisa Dunn, Barbara Egan, Lori Ward, Erin Boyd,
and Jill Arnold for their unfailing help.
Corresponding author: Frank B. Hu, MD, Department of Nutrition, Harvard
School of Public Health, 665 Huntington Ave, Boston, MA 02115 (e-mail: Frank.hu{at}channing.harvard.edu).
From the Departments of Nutrition (Drs Hu, Stampfer, and Willett) and
Epidemiology (Drs Stampfer, Willett, and Manson), Harvard School of Public
Health, Channing Laboratory (Drs Stampfer, Willett, Speizer, and Manson) and
Divisions of Women's Health (Dr Solomon) and Preventive Medicine (Drs Liu
and Manson), Department of Medicine, Brigham and Women's Hospital, and Diabetes
Center (Dr Nathan), Massachusetts General Hospital, Harvard Medical School,
Boston.
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