Lupus (1999) 8, 351±355

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PAPER

Loss of the female advantage with cardiovascular disease for

women with diabetes
C Leibson1*
1
Department of Health Sciences Research, Mayo Clinic Foundation, Rochester, MN, USA

Background: The relative risk of cardiovascular disease (CVD) associated with diabetes is greater
for women than men, and diabetic women did not experience temporal declines in CVD mortality
observed for the general population and diabetic men.
Objective: To examine sex differences in CVD risk factors for persons with diabetes over time.
Design: Population-based historical cohort study.
Methods: The provider-linked medical records of all Rochester, MN, residents assigned a clinical
diagnosis of diabetes were reviewed to con®rm case status and assign diagnosis date. Data on
fasting glucose, obesity, persistent proteinuria, smoking, hypertension, and dyslipidemia were
obtained at diagnosis for con®rmed incidence cases.
Results: There were 1330 diabetes cases 1970 ± 1989. Compared to men, women at diagnosis were
older and more likely hypertensive, had similar levels of fasting glucose and persistent proteinuria,
and less likely to smoke. Among persons diagnosed at younger ages, women were more likely than
men to be obese. Comparison with published data for the Rochester population revealed the excess
obesity and hypertension associated with diabetes were highest for women < age 55 y. Temporal
trends in CVD risk factors did not differ between diabetic men and women.

Keywords: diabetes; obesity; epidemiology; hypertension; cardiovascular disease

Introduction why the excess risk of CVD mortality associated with

Persons with diabetes are at increased risk of
cardiovascular disease (CVD) morbidity and mortal-
ity; the excess risks are greater for women than
men.1 ± 3 The disparity is especially high for younger
women. The risk of premature ischemic heart disease
death associated with diabetes is nine-fold for women
and only four-fold for men;3 of all women who die
from heart disease before age 55, approximately one-
third have diabetes.4
Temporal trends reveal that the prevalence of
diabetes has increased for both women and men; the
increase is due to rising incidence5,6 rather than
improved survival; and declines in CVD mortality
observed for the general population over the past three
decades were shared more by diabetic men than
diabetic women.5,7 Thus, it is important to investigate
*Correspondence: C Leibson, Department of Health Sciences
Research, Mayo Clinic Foundation, Rochester, MN55905, USA.
diabetes is greater for women than men, and why the
excess risk increased for women.
This study uses the previously established 1970 ±
1989 Rochester diabetes incidence cohort to compare
men and women at diagnosis for the prevalence of
CVD risk factors and to examine temporal trends in
these risk factors. Some of the data are preliminary.
Methods
Rochester, MN, is relatively isolated from other urban
centers and is home to the Mayo Clinic, a large
tertiary care medical center. Therefore, local residents
receive essentially all medical care from very few
providers. Also, information from every contact for
Mayo patients, including hospital, of®ce, or ER visits;
correspondence; death certi®cate; and autopsy is
contained within a unit medical record. An indexing
system that codes and enters diagnoses assigned at
each encounter into continuously updated computer
®les has been expanded to include non-Mayo
providers of care to local residents.8

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 Cardiovascular disease for women with diabetes
C Leibson
352
Identi®cation of diabetes cases
The complete community-based medical records,
including glucose values, of all Rochester residents
assigned a clinical diagnosis of diabetes or diabetes-
like condition 1945 ± 1990 were reviewed to con®rm
that individuals met National Diabetes Data Group
criteria9 and determine residency. Adjustments were
made for temporal changes in laboratory glucose
methods.10 Persons treated with insulin or oral agents
also quali®ed as cases, irrespective of glucose values.
A detailed description of case ascertainment is
provided elsewhere.5
Data on CVD risk factors
The present study includes 1970 ± 1989 diabetes
incidence cases with age at diagnosis  30 y. The
records of all cases were reviewed for fasting blood
glucose; obesity, that is body mass index (weight in
kilograms=height in meters2)  27.3 for women and
 27.8 for men;11 and prevalence of persistent
proteinuria at diagnosis. Persistent proteinuria was
de®ned as  2 consecutive urinalyses with grade 1 or
greater protein and no subsequent negative values;
exceptions were a single negative value in a string of
positives and values following dialysis or transplant.12
As part of a pilot study, a random sample of 400 of
the 1970 ± 1989 incidence cases were identi®ed to
assess the feasibility of obtaining additional CVD risk
factors. Records were reviewed at diagnosis two
years for evidence of hypertension, that is two
ambulatory blood pressure readings  140 mm Hg
systolic and=or 90 mm Hg diastolic or evidence of
antihypertensive medication, as determined by a
neurologist; smoking status; and all cholesterol and
triglyceride values.
Statistical analysis
Comparisons between sexes and, within each sex,
between calendar periods (1970 ± 79 vs 1980 ± 89) are
presented as means  standard deviation (s.d.) for
continuous variables or as odds ratios (OR) and 95%
con®dence intervals (CI) for dichotomous variables.
Tests for signi®cant differences used Student's t (or
rank sum) and chi-square. Multivariable regression
was used to estimate the independent effects of sex
and year of diagnosis, after adjusting for age and other
CVD risk factors as appropriate. The question of
whether temporal trends differed between the sexes
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over time was addressed by testing for interactions
between sex and year of diagnosis.
Univariate statistics were used to compare esti-
mates of the prevalence of hypertension and body
mass index at diabetes diagnosis with published
estimates for a random sample of the Rochester
population prospectively surveyed in 1986
(n ˆ 2122).13
Results
The 1970 ± 1989 Rochester diabetes incidence cohort
consisted of 1330 individuals age  30 y at diagnosis
(50% male). The proportion of individuals for whom
data at diagnosis were available was very high for
each risk factor under consideration (Table 1), with
the exception that 33% of individuals were missing
triglyceride and cholesterol values at diagnosis  two
years; these latter factors were excluded from
analyses.
Mean age at diagnosis was greater for women than
men (63.8  14.1 vs 60.4  12.7, P < 0.01). Mean
fasting glucose values did not differ between women
and men (220 91 mg=dl vs 222 88 mg=dl,
P ˆ 0.78). As shown in Table 1, diabetic women
were less likely than men to smoke. There were no
differences between women and men in the proportion
with prevalent persistent proteinuria or in the propor-
tion that were obese. The likelihood of having two
blood pressures that quali®ed as hypertensive was
signi®cantly higher for women than men. When
persons on anti-hypertensives were included, 85% of
women and 75% of men (P ˆ 0.02) were hyperten-
sive.
Tests for interactions in multivariable regression
analyses revealed differences in smoking between
women and men were less at younger ages; and at
younger ages, women were more often obese than
men. The prevalence of hypertension was greater in
obese than non-obese persons (OR ˆ 3.74, 95%
CI ˆ 2.22 ± 6.32, P < 0.01). After adjusting for age
and obesity, the effect of female gender on hyperten-
sion no longer reached signi®cance (OR ˆ 1.56, 95%
CI ˆ 0.92 ± 2.64, P ˆ 0.09).
Between 1970 ± 79 and 1980 ± 89, there were
signi®cant declines in the prevalence of persistent
proteinuria (53% for women, 50% for men) and
signi®cant increases in the prevalence of obesity (16%
for both women and men) (Table 2). The prevalence
of hypertension declined 2% for women and increased
6% for men; the prevalence of smoking declined 10%
for women and 19% for men; none of the differences
 Cardiovascular disease for women with diabetes
C Leibson
353
Table 1 The prevalence of cardiovascular disease risk factors at diagnosis of diabetes by sex among members of the 1970 ± 1989
Rochester, MN, diabetes incidence cohort*
No. of records % of reviewed % of data available
CVD risk factor reviewed records with data available that are positive for risk factor OR (95% CI) P-value

Qualifying blood pressures{

(Dx 2 y)
Women 186 97% (181=186) 83% (150=181) 1.93 (1.18 ± 3.16) < 0.01
Men 205 98% (200=205) 72% (143=200)
Obesity
(Dx 6 months)
Women 660 99% (652=660) 59% (386=652) 1.08 (0.87 ± 1.35) 0.47
Men 670 99% (664=670) 57% (380=664)
Persistent proteinuria{
(prior to Dx)
Women 624 99% (620=624) 6.0% (37=620) 0.90 (0.57 ± 1.42) 0.64
Men 627 99% (620=627) 6.6% (41=620)
Smoking status{
(Dx 2 y)
Women 186 91% (169=186) 19% (32=169) 0.41 (0.26=0.67) < 0.01
Men 205 95% (194=205) 36% (70=194)

*Age at diagnosis  30 y, n ˆ 1330 y.

{400 individuals were randomly selected from the 1330 for a pilot study. Nine refused consent for medical records research (53% male, mean age ˆ 64 13
for women, 61 13 for men, P ˆ 0.02).
{Data were collected for a separate study that was limited to 1970 ± 1989 incidence cases with age ˆ 40 y at diagnosis (n ˆ 1251).

Table 2 The prevalence of cardioavscular disease risk factors at diagnosis of diabetes by sex and decade of diagnosis among members
of the 1970 ± 1989 Rochester, MN, diabetes incidence cohort*
Women Men

CVD risk factor 1970 ± 1979 1980 ± 1989 OR (95% CI) P-value 1970 ± 1979 1980 ± 1989 OR (95% CI) P-value

% with qualifying blood 84% (61=72) 82% (89=109) 0.80 (0.36 ± 1.80) 0.59 69% (63=91) 73% (80=109) 1.23 (0.66 ± 2.50) 0.52
pressures values (Dx 2 y)
% obese (Dx 2 y) 54% (152=280) 63% (234=372) 1.43 (1.04 ± 1.96) 0.03 52% (144=275) 61% (236=389) 1.40 (1.03 ± 1.92) 0.02
% with persistent proteinuria{ 8.5% (23=272) 4.0% (14=348) 0.45 (0.23 ± 0.90) 0.02 9.3% (24=257) 4.7 (17=363) 0.48 (0.25 ± 0.91) 0.02
(prior to Dx)
% currently smoking (Dx 2 y) 20% (12=59) 18% (20=110) 0.87 (0.39 ± 1.93) 0.73 40% (34=84) 33% (36=110) 0.72 (0.40 ± 1.29) 0.26
Mean age, y (s.d.) (at Dx) 64.9 (13.2) 62.9 (14.7) ± 0.06 60.1 (12.7) 60.6 (12.7) ± 0.65
Mean fbg, mg=dl (s.d.) (at Dx) 222 (97) 219 (88) ± 0.66 226 (93) 219 (84) ± 0.36

*Age at diagnosis  30 y, n ˆ 1330.

{400 individuals were randomly selected from the 1,330 for a pilot study. Nine refused consent for medical records research (53% male, mean
age ˆ 64 13 for women, 61 13 for men, P ˆ 0.02).
{Data were collected for a separate study that was limited to 1970 ± 1989 incidence cases with age ˆ 40 y at diagnosis (n ˆ 1251).

reached statistical signi®cance. There were no sig-
ni®cant differences between time periods in age or
fasting glucose for either women or men.
Multivariable regression analyses were performed
for women and men separately to estimate the effect
of year of diagnosis on the prevalence of CVD risk
factors, adjusted for age. The results were unchanged
from the ®ndings in Table 2. When women and men
were included together in the models, tests for
interactions revealed no difference between the sexes
with respect to temporal trends in the prevalence of
CVD risk factors (data available on request).
Age- and sex-speci®c estimates of mean body mass
index (BMI) for all members of the 1970 ± 1989
diabetes incidence cohort reveal the difference
between diabetic women and men was greatest for
persons diagnosed before age 45 y (mean
BMI ˆ 35.2  10.1 vs 30.2  7.2, difference ˆ 4.5,
P < 0.01) (Figure 1). Figure 1 also provides published
estimates for the 1986 Rochester population, age
 45.13 The greatest difference in BMI between
diabetic persons and the general population occurred
for women age < 55 y (mean BMI ˆ 32.2 vs 24.8,
difference ˆ 7.4). A decline in BMI with increasing

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 Cardiovascular disease for women with diabetes
C Leibson
354
Figure 1 A comparison of mean body mass index (BMI) for members of
the 1970 ± 1989 Rochester, MN, diabetes incidence cohort (n ˆ 1316) with
mean BMI for a random sample of the 1986 Rochester, MN, population,
by sex and age group.
Figure 2 A comparison of the prevalence of hypertension in a random
sample of individuals (n ˆ 391) identi®ed from the 1970 ± 1989 Rochester,
MN, diabetes incidence cohort with the prevalence of hypertension in a
random sample of the 1986 Rochester, MN, population (n ˆ 2122), by sex
and age group. Data for the Rochester population were obtained from
Phillips SJ. Mayo Clin Proc 1988; 63: 691. Hypertension in the diabetes
study was de®ned as the presence of any two qualifying outpatient blood
pressure values recorded in the medical record at the time of
diagnosis two years. Hypertension in the Rochester study was de®ned
as two qualifying in-home blood pressure values obtained prospectively in
a standardized manner. Qualifying blood pressures were de®ned as
> ˆ 140 mm Hg systolic and=or > ˆ 90 mm Hg diastolic in both studies.
age was most apparent for diabetic women. For
persons diagnosed after age 74 y, the mean BMI was
similar for women (26.2 5.2) and men (26.7  3.7,
P ˆ 0.34); and the difference in mean BMI between
diabetic and Rochester women aged > 74 y
(mean ˆ 23.3, difference ˆ 2.9) was less than half
that between younger and older diabetic women
(difference ˆ 6.0).
The 1986 Rochester survey also collected data on
the prevalence of hypertension.13 As shown in Figure
2, levels of hypertension in the Rochester population
were much lower than levels for diabetic individuals,
for both sexes and at every age. Among Rochester
residents, the prevalence of hypertension was less for
women than for men at younger ages and greater for
women than for men at older ages; this pattern was not
observed for persons with diabetes. The odds
associated with diabetes were highest for women
age < 55 y (OR ˆ 19.7, 95%CI ˆ 9.7 ± 40.2) and
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remained high in every age group (OR for age
> 74 y ˆ 13.6, 95%CI ˆ 4.3 ± 42.9) compared to the
odds associated with diabetes for men (OR for
age < 55 ˆ 7.4, 95%CI ˆ 4.5 ± 12.3; OR for age > 74
ˆ 3.8, 95%CI ˆ 1.7 ± 8.7).
Discussion
This study compares the prevalence of CVD risk
factors at diagnosis of diabetes between women and
men, over time, and with published estimates for
selected risk factors in the 1986 Rochester population.
With the exception of smoking, CVD risk factor levels
for women were either similar to or greater than levels
for men. The high levels of CVD risk compared to the
Rochester population were especially high for young
diabetic women.
The CVD risk factor estimates for diabetic women
and men reported here agree with those from other
studies.4,14 ± 16 The unique contribution of this study is
the comparison of CVD risk factors between diabetic
women and men over time. Data on temporal trends
are needed to inform investigations of why diabetic
women did not exhibit declines in CVD mortality that
were experienced by the general population and
diabetic men in recent decades.5,7 The absence of
any signi®cant sex by calendar year interactions in the
present study argues against between-sex differences
in temporal trends in CVD risk factors as an
explanation.
The present study is limited by the fact that data
were collected retrospectively. Criteria for determin-
ing which and how frequently individuals were
measured were not standardized. Data on several
CVD risk factors, for example exercise, insulin levels,
waist-to-hip ratios, were unavailable. This limitation
is especially problematic for triglyceride and choles-
terol valuesÐthe association between diabetes and
dyslipidemia is well recognized; elevated triglycerides
and LDL to HDL cholesterol ratios are associated
with increased risk of CVD among persons with
diabetes;17,18 and a few studies have reported
between-sex differences in these factors and their
associated risks.15,19,20 The extent to which compar-
isons between the sexes and over time in the present
study were confounded by differences in unmeasured
risk factors is unclear. It is also not known whether
diabetic women and men differed with respect to
temporal trends in these unmeasured factors.
The possibility that the loss of the female
advantage in diabetes is related to differences between
women and men in the relative odds of obesity and

hypertension is encouraging from a public health
perspectiveÐobesity and hypertension are modi®able
risk factors. However, temporal trends in CVD risk
factors observed in this study were less encouraging.
Although there were marked declines in persistent
proteinuria and smaller declines in smoking, the
prevalence of obesity increased over time and the
prevalence of hypertension remained unchanged. The
latter ®nding contrasts with the declines in hyperten-
sion for both sexes and all age groups during the
1970s and 1980s for the US population generally21
and occurred despite obvious room for improvement.
Over half (52% of men and 65% of women) of
diabetic individuals with no treatment for hyperten-
sion in our study had two outpatient blood pressure
readings that quali®ed as hypertensive. These ®ndings
have important clinical implications. High blood
pressure increases the risk of death from coronary
heart disease among young diabetics more than three-
fold;4 and control of hypertension markedly reduces
CVD complications and mortality among persons with
diabetes.22
In conclusion, the relative burden of CVD risk
factors at diabetes diagnosis is greater for women than
men, especially at younger ages. This ®nding is
consistent with the high excess risk of CVD death
observed for premenopausal diabetic women.3,4 But
between-sex differences in temporal trends in mortal-
ity reported earlier for the Rochester diabetes cohort5
were not accompanied by between-sex differences in
temporal trends in CVD risk factors at diagnosis.
Acknowledgements
Funding was provided by SmithKline Beecham
Pharmaceuticals and NIH grant AG08729. Data
collection and analysis were performed by Susan
Helling, Kristine Otto-Higgins, and Jeanine Ransom.
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