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Explaining the Sex Difference in Coronary Heart Disease Mortality Among Patients With Type 2 Diabetes Mellitus
A Meta-analysis
Alka M. Kanaya, MD;
Deborah Grady, MD, MPH;
Elizabeth Barrett-Connor, MD
Arch Intern Med. 2002;162:1737-1745.
ABSTRACT
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Background Most studies suggest that diabetes is a stronger coronary heart disease
(CHD) risk factor for women than men, but few have adjusted their results
for classic CHD risk factors: age, hypertension, total cholesterol level,
and smoking.
Objective To establish an accurate estimate of the odds ratio for fatal and nonfatal
CHD due to diabetes in both men and women.
Methods We compared the summary odds ratio for CHD mortality and the absolute
rates of CHD mortality in men and women with diabetes. We searched the MEDLINE
and Cochrane Collaboration databases and bibliographies of relevant articles
and consulted experts. Studies that included a nondiabetic control group and
provided sex-specific adjusted results for CHD mortality, nonfatal myocardial
infarction, and cardiovascular or all-cause mortality were included. Of 4578
articles identified, 232 contained primary data, and 182 were excluded. Two
reviewers recorded data on study characteristics, quality, and outcomes from
50 studies.
Results Sixteen studies met all inclusion criteria. In unadjusted and age-adjusted
analyses, odds of CHD death were higher in women than men with diabetes. From
8 prospective studies, the multivariate-adjusted summary odds ratio for CHD
mortality due to diabetes was 2.3 (95% confidence interval, 1.9-2.8) for men
and 2.9 (95% confidence interval, 2.2-3.8) for women. There were no significant
sex differences in the adjusted risk associated with diabetes for CHD mortality,
nonfatal myocardial infarction, and cardiovascular or all-cause mortality.
Absolute CHD death rates were higher for diabetic men than women in every
age strata except the very oldest.
Conclusions The excess relative risk of CHD mortality in women vs men with diabetes
was absent after adjusting for classic CHD risk factors, but men had more
CHD deaths attributable to diabetes than women.
INTRODUCTION
TYPE 2 diabetes mellitus is associated with an increased risk of coronary
heart disease (CHD), cerebrovascular disease, and peripheral vascular disease.1 Estimates of CHD mortality in diabetic men have varied
from 1- to 3-fold the rate in nondiabetic men,2-11
whereas estimates in diabetic women have ranged from 2- to 5-fold the rate
in nondiabetic women.3, 6, 9, 11-13
The variation in relative risk estimates of cardiovascular disease makes it
difficult to evaluate the strength of diabetes as a risk factor for either
sex. Two previous meta-analyses that included studies that did not adjust
for major cardiac risk factors concluded that diabetes is a stronger risk
factor for CHD mortality in women than men.14-15
However, it is unclear whether these reported sex differences in CHD risk
are real or attributable to differences between men and women with diabetes
with respect to other major risk factors for CHD.
We systematically reviewed the results from published studies and aimed
to establish an accurate estimate of the odds ratio (OR) for fatal and nonfatal
CHD due to diabetes in both men and women. We compared the sex-specific risk
of CHD mortality, nonfatal myocardial infarction (NFMI), and cardiovascular
or all-cause mortality between diabetic men and women. We also calculated
absolute CHD death rates attributable to diabetes for each sex. Our main analyses
included only studies that provided multivariate-adjusted comparisons to determine
the independent association between diabetes and cardiovascular disease outcomes.
METHODS
DATA SOURCES
We performed a computerized search using MEDLINE and the Cochrane Collaboration
database for all studies published from January 1966 through February 2000
using the keywords diabetes and cardiovascular disease,
myocardial infarction, or ischemic heart disease. Additional studies were identified by review of bibliographies in
relevant articles and consultation with experts. We limited our search to
peer-reviewed articles. English language and non–English language articles
were included. In the case of multiple publications from a single study, we
used the most comprehensive or recent publication.
STUDY SELECTION
Studies were included if they met all of the following criteria: (1)
the study population included both men and women and the outcomes were stratified
by sex; (2) a control group of nondiabetic subjects was included (studies
that used historical controls or standardized mortality ratios were excluded);
(3) outcomes included CHD mortality, NFMI, and cardiovascular or all-cause
mortality; (4) follow-up was at least 6 months; and (5) results were adjusted
at least for age, hypertension, hypercholesterolemia, and smoking. In the
event that results were not adjusted for these variables, we contacted the
corresponding authors to request the results of adjusted analyses. We excluded
studies that primarily followed up patients with prior myocardial infarction
(MI). We planned to repeat the main comparisons in subgroups defined by race
or ethnicity (white, black, Latino, Japanese American, and native American)
and study design (prospective cohort or cross-sectional analyses).
Diabetes was defined by self-report, use of a diabetic medication, physician
documentation in medical records, or fasting or 2-hour postchallenge glucose
criteria. Most studies used the 1985 World Health Organization criteria for
classification of diabetes. Most studies used age as a continuous variable
in their multivariate analysis, but a few categorized age by 5- or 10-year
increments. Most studies dichotomized smoking into current vs never or past
use, whereas only 1 study considered number of cigarettes smoked per day as
a continuous variable in their model. Total cholesterol level was considered
a continuous variable by most studies, but some dichotomized the variable
(by  240 mg/dL or >6.2 mmol/L cut points), whereas one study used quartiles
of total cholesterol in their final model. Hypertension was managed more heterogeneously.
Some studies used a combination of elevated systolic (140 mm Hg, >150
mm Hg, or >160 mm Hg) and diastolic (90 mm Hg or >95 mm Hg) blood pressures
or an antihypertensive medication to define a dichotomous hypertension variable
for the multivariable analysis. Other studies used a continuous systolic blood
pressure measurement or categorized systolic blood pressure by increments
of 5 or 10 mm Hg or used quartiles of systolic blood pressure for their model.
In all included studies, CHD mortality was defined by the International Classification of Diseases, Ninth Revision (ICD-9) codes 410 through 414 or by physician documentation of sudden
cardiac death. Nonfatal myocardial infarction was defined by definite electrocardiographic
criteria using the Minnesota code, enzyme levels consistent with MI, self-report
(with or without Rose questionnaire criteria), or medical record documentation.
We excluded outcomes that included both fatal and nonfatal coronary events
aggregated in one estimate from the analysis. Cardiovascular mortality was
defined by ICD-9 codes 389 through 459.
DATA EXTRACTION AND SYNTHESIS
One author reviewed titles and abstracts of articles retrieved from
the search and excluded case reports, letters, comments, reviews, and reports
without primary data. Two trained data abstractors (A.M.K. and Lily Chaput,
MD) reviewed the 50 remaining manuscripts to determine study eligibility.
Data were extracted on study quality, participant characteristics, length
of follow-up, and outcomes (CHD mortality, NFMI, and cardiovascular or all-cause
mortality). Discrepancies between reviewers were resolved by consensus.
We calculated summary estimates of the adjusted ORs and 95% confidence
intervals (CIs) using a random-effects model16
with a general variance–based method17
that retains adjustment for confounding. We used an Excel-based (Microsoft
Inc, Redmond, Wash) meta-analysis program developed by the University of California,
San Francisco, for our analyses. We examined the heterogeneity of study findings
using standard  2 analyses with a criterion for statistical
significance of .10. Summary estimates for men and women were compared using
the z test, with a 2-tailed level of significance
of P .05.
QUALITY ASSESSMENT AND SENSITIVITY ANALYSIS
We also performed analyses based on study quality. A study was rated
high quality if it had a prospective cohort design, used a fasting plasma
glucose or oral glucose tolerance test to define diabetes, and adjusted for
covariates in addition to the 4 specified for inclusion. Since the mean follow-up
years from the pooled prospective cohort studies was 14 years, we also required
that high-quality studies have at least 14 years of follow-up with a less
than 10% loss to follow-up. Intermediate-quality studies were adjusted for
age, hypertension, hypercholesterolemia, and smoking but were of shorter duration
or were cross-sectional and did not use laboratory tests in defining diabetes.
A third category of studies did not meet inclusion criteria for our meta-analysis
because the analyses were not adjusted for age, hypertension, smoking, and
total cholesterol level (termed unadjusted studies).
We analyzed the available crude or age-adjusted ORs from these unadjusted
studies as a part of our quality analysis. We performed a separate sensitivity
analysis using age-adjusted and unadjusted estimates from our included studies
that provided CHD mortality outcomes. If studies did not report unadjusted
risk estimates, we used the crude rates of CHD mortality to calculate relative
risk estimates and 95% CIs.
ABSOLUTE RISK
To ascertain the effect of diabetes on the absolute numbers of deaths
from CHD (ICD-9 codes 410-414), we used the 1998
US Vital Statistics data for coronary death rates for each sex and all races/ethnicities
stratified by age.18 We calculated the expected
death rate among men and women by multiplying the observed death rate by the
summary OR due to diabetes in men and women. We then calculated the excess
death rate by subtracting these 2 estimates.
RESULTS
The MEDLINE and Cochrane Collaboration search located 4578 articles.
Of the 234 articles that contained primary data, 50 were duplicative publications,
46 studies did not include a nondiabetic control group, 44 did not provide
information about the outcomes of interest, and 26 did not perform analyses
based on diabetes status. Another 9 did not provide data stratified by sex,19-27
7 were hospital-based studies with follow-up of less than 6 months,28-34
and 9 were studies of patients with prior MI.35-43
Another 7 studies were excluded since their study population consisted of
a single sex only.44-50
Of the 36 remaining studies, 10 studies met all of our inclusion criteria.13, 22, 51-58
Twenty-two did not publish fully adjusted risk estimates,5-6,59-78
2 did not report 95% CIs or P values for their adjusted
results,3, 9 and 2 provided only
combined outcomes of nonfatal and fatal CHD.12, 79
We contacted the corresponding authors of these 26 articles twice; authors
of 6 studies64-65,72, 74-75,77
provided the data necessary to satisfy inclusion criteria. Some authors were
unable to recreate their original analyses,5, 12, 73, 78
some did not have the necessary variables in the data set,63, 66, 76
and others did not provide the requested data.3, 6, 9, 59-62,67-71,79
We compared the crude summary estimates from 8 of these excluded studies that
reported unadjusted risks to evaluate the effect of adjustment for age and
multiple covariates on the summary ORs.61-62,66, 68-71,73
Thus, after receiving additional information from authors, 16 studies
fulfilled all of our inclusion requirements; 12 were prospective cohort studies13, 22, 51-58,74, 77
and 4 were cross-sectional analyses64-65,72, 75
(Table 1). We included the results
of separate reports based on the same cohort only when the type of outcome
reported was different51, 57 or
additional information about ethnicity was provided.55-56
For example, one publication56 from the Chicago
Heart Association Detection Project in Industry provided information on women,
whereas another reported data stratified by ethnicity.55
Altogether, the meta-analysis includes adjusted findings of 13 distinct study
populations.
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Table 1. Characteristics of Studies of Coronary Heart Disease Risk
in Diabetic vs Nondiabetic Subjects
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Follow-up time in the 12 prospective cohort studies ranged from 5 to
32 years (mean, approximately 14 years). Most of the studies enrolled middle-aged
participants with one notable exception: the Bernalillo County study72 included subjects older than 65 years. There were
6235 diabetic participants included in the studies (48% women) and 71 306
nondiabetic control subjects (52% women).
Table 2 presents the multivariate-adjusted
ORs by sex and ethnicity for CHD mortality, NFMI, cardiovascular mortality,
and/or all-cause mortality for each included study. Adjusted ORs for CHD mortality
due to diabetes range from 0.8 to 5.3 for men and 1.3 to 20.7 for women. Of
the 8 studies that reported CHD mortality outcomes, most show a higher OR
for women compared with men. Two exceptions are the National Health and Nutrition
Examination Survey I54 cohort and the Reykjavik
study,13 which found fairly similar odds of
CHD mortality for men and women. Among the 4 studies that report NFMI outcomes,
most show higher ORs for women than men except for the King County study.64-65 The data for cardiovascular and all-cause
mortality are mixed, with approximately half of the studies showing a higher
OR for women than men.
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Table 2. Adjusted Odds Ratios (95% Confidence Intervals) for Coronary
Heart Disease (CHD) Mortality, Nonfatal Myocardial Infarction (NFMI), Cardiovascular
Mortality, and All-Cause Mortality by Sex
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Overall, the summary OR for CHD mortality due to diabetes from 8 prospective
cohort studies was 2.3 (95% CI, 1.9-2.8) for men and 2.9 (95% CI, 2.2-3.8)
for women for all race/ethnic groups combined, without heterogeneity in findings
(Table 3) (Figure 1A and B).
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Table 3. Summary Odds Ratios (95% Confidence Intervals) for Coronary
Heart Disease Mortality by Sex (Diabetes vs No Diabetes)
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Figure 1. Odds ratios and 95% confidence
intervals for the risk of coronary heart disease mortality for diabetic vs
nondiabetic men (A) and women (B). Summary odds ratios by random-effects model
are presented below individual study results.
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Most studies that reported CHD mortality were performed with white subjects;
therefore, subgroup analysis by race was limited to white participants. Summary
estimates for CHD mortality for white men and women were similar to those
for all ethnicities combined (men: OR, 2.2; 95% CI, 1.8-2.8; women: OR, 2.8;
95% CI, 2.1-3.7).
Although the summary ORs for CHD mortality from diabetes for women were
somewhat higher than those for men overall and for every subgroup, the ORs
were not statistically different. In analyses based on the unadjusted studies
that were not included in the main meta-analysis, the summary OR for women
was significantly higher than for men (10.4 vs 2.2; P
= .02 for the comparison of ORs). Sensitivity analyses that included age-adjusted
estimates for whites from the included studies found a statistically significant
difference between estimates for men and women (2.1 vs 3.4; P = .05). The unadjusted risk estimates from the included studies were
similar to the age-adjusted estimates (2.2 in men vs 3.2 in women), with a
trend toward a statistically significant difference between the sexes. In
analyses based on studies in white race and adjusted for major cardiovascular
risk factors, the difference in relative risk between men and women was smaller
and not statistically significant (2.2 vs 2.8; P
= .20) (Figure 2).
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Figure 2. Summary odds ratios for each sex
are presented by adjustment of study results for white race only. Unadjusted
and age-adjusted summary odds ratio show a trend or significant differences
by sex, whereas multiple-adjusted results (for age, hypertension, total cholesterol
level, and smoking) show no difference by sex. P values are for
comparison of odds ratios between men and women in each category.
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Based on 4 population-based studies, the summary OR for NFMI due to
diabetes was 1.6 (95% CI, 1.1-2.2) for men and 1.7 (95% CI, 1.3-2.3) for women,
a difference that was not statistically significant (Table 4). The summary ORs for cardiovascular mortality due to diabetes
were higher than for CHD mortality or NFMI for both sexes (3.2 in men vs 4.1
in women), but the difference was not statistically different (P = .49). There was also little difference between the summary ORs
for all-cause mortality due to diabetes between men and women (2.1 vs 1.9).
There was heterogeneity among the findings of the individual studies for these
3 outcomes that could not be easily eliminated in subgroup analyses. Only
the unadjusted studies showed significantly higher summary ORs in women than
men for these 3 outcomes as well (data not shown).
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Table 4. Summary Odds Ratios (95% Confidence Intervals) for Nonfatal
Myocardial Infarction, Cardiovascular Mortality, and All-Cause Mortality*
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Despite summarizing estimates from 13 distinct study populations, we
lacked power to perform subgroup analyses by race/ethnicity for cardiovascular
mortality and all-cause mortality and were unable to derive meaningful summary
estimates for CHD mortality in African Americans, Japanese Americans, or native
Americans. We were able to derive summary estimates for NFMI for Latinos only
from 2 cross-sectional analyses.72, 75
Diabetes did not significantly increase risk of NFMI for Latino men (OR, 1.2;
95% CI, 0.6-2.4) or for Latina women (OR, 1.4; 95% CI, 0.9-2.1). The summary
estimates for Latino men and women were lower than those for non-Latino whites
(men: OR, 1.7; 95% CI, 1.1-2.6; women: OR, 2.8; 95% CI, 1.7-4.4).
Table 5 presents the death
rates from coronary disease by sex and age in the US population in 199880 and uses the overall summary OR for CHD mortality
(2.3 for men and 2.9 for women) to calculate the expected coronary death rate
and excess death rate among diabetic men and women. Even though the summary
OR for coronary death due to diabetes is slightly higher in women, the higher
absolute coronary death rate in men results in higher excess deaths due to
diabetes in men at all ages except for the very oldest (>85 years).
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Table 5. US Death Rates per 100 000 Population From Coronary Heart
Disease by Sex and Age*
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COMMENT
Using estimates adjusted for age, hypertension, total cholesterol level,
and smoking, summary ORs for CHD mortality, NFMI, and cardiovascular mortality
due to diabetes were higher among women than men, but differences were modest
and not statistically significant. The summary OR for CHD mortality from the
8 prospective cohort studies was 2.3 for men with diabetes and 2.9 for women
with diabetes. Differences in ORs can be misleading because CHD mortality
rates are higher in men than women of the same age.80
Although the odds for CHD mortality were slightly higher for women than for
men with diabetes, the number of excess deaths attributable to diabetes was
higher among men than women at all ages except those older than 85 years.
A previous meta-analysis14 included 25
prospective, population-based studies that provided crude data to examine
sex differences in relative risk of CHD mortality and MI associated with type
2 diabetes mellitus. The risk of fatal CHD was increased for diabetic women,
suggesting women's natural protection from CHD is reduced in the presence
of diabetes. However, many of the large cohort studies included in this meta-analysis
did not control for the main established risk factors for coronary disease.
A more recent meta-analysis15 that included
10 studies found that women with diabetes were at significantly higher risk
of CHD mortality compared with men (2.58 vs 1.85, P
= .04). This meta-analysis included studies that adjusted only for age, reported
combined end points for CHD mortality and NFMI, and followed up subjects with
prior CHD. In a subgroup analysis excluding studies of patients with existing
CHD, there was no significant difference between summary ORs for diabetic
men and women for CHD mortality (1.9 in men vs 2.4 in women, P = .18). These results are consistent with our findings.
The difference in relative risk for CHD mortality between men and women
was progressively attenuated with adjustment for age and other major cardiovascular
risk factors. Possible explanations for this phenomenon may be that diabetic
women compared with nondiabetic women may have a more severe degree of risk
factor abnormalities than diabetic men compared with nondiabetic men81 or the unfavorable cardiac risk factors may have
a bigger impact on women than men. Other explanations could be that risk factors
in women are managed less aggressively than in men82-83
or that women are more likely to have more than one risk factor.81
Adjustment for other cardiovascular risk factors that were not included in
most of the studies in our analysis (high-density lipoprotein cholesterol,
triglyceride levels, exercise, body mass index) or more specific adjustment
using continuous measures of risk rather than risk categories might eliminate
the remaining disparity between men and women. These data suggest that most
of the observed difference in risk between men and women for CHD mortality
from diabetes is mediated by traditional cardiac risk factors that are modifiable.
Four large, widely quoted prospective cohort studies5, 9, 12, 79
did not meet criteria for inclusion in our meta-analysis. These 4 studies
had conflicting results; 1 showed a higher diabetes-associated relative risk
for CHD mortality in men compared with women,79
1 showed an increased relative risk among women,5
and the 2 remaining studies found no difference between the sexes.9, 12 It is unlikely that the addition of
the results of these 4 studies would have changed our summary estimates significantly.
It is now recommended that cardiovascular risk factors be treated as
aggressively in diabetic patients without a history of CHD as in nondiabetic
patients with a prior MI.84-85
Based on the present meta-analysis, diabetes independently increases the risk
of fatal CHD in both men and women without preexisting CHD by 2- to 3-fold.
Since dyslipidemia and hypertension often cluster with type 2 diabetes mellitus
and there is an additive effect for each of these risk factors,49
diabetic patients are at high risk of CHD death and should be treated more
aggressively than persons at low risk. The larger effect of adjusting for
major risk factors in women vs men suggests that women with diabetes might
benefit more from blood pressure and cholesterol-lowering treatment than diabetic
men.
As with any meta-analysis, we are limited to the variables measured
and end points reported in each study. We insisted that the outcomes be adjusted
for major risk factors to study the association between diabetes and CHD,
but these variables were defined differently in the studies. For example,
some studies used categorical levels of elevated systolic blood pressure as
evidence of hypertension, whereas others included the use of an antihypertensive
medication as evidence. Likewise, there were differences in definition of
outcomes among studies. Most studies used predefined electrocardiographic
criteria to determine MI, but some used history of revascularization by coronary
artery bypass surgery or angioplasty or patient history of MI for this outcome.
Some studies differentiated patients with impaired glucose tolerance from
those with frank diabetes, whereas others included the impaired glucose tolerance
group with nondiabetic subjects. Most studies did not completely distinguish
participants with type 1 diabetes mellitus from those with type 2. However,
most of these errors of misclassification would be expected to occur similarly
for men and women and should not explain the lack of sex difference in relative
risk. Because most patients with type 2 diabetes mellitus have their conditions
diagnosed years after disease onset, length of follow-up in cohort studies
was used as a rough proxy for duration of diabetes. We found no significant
sex difference for any outcome among the adjusted prospective studies with
14 or more years of follow-up. Lastly, we were unable to analyze results based
on race/ethnicity for most of the outcomes owing to lack of studies meeting
our inclusion criteria in nonwhite populations.
The advantage of the present meta-analysis is that it is restricted
to the findings of studies controlled for age, hypertension, hypercholesterolemia,
and smoking. The most accurate adjusted summary OR for CHD mortality due to
diabetes for all race/ethnic groups combined is 2.3 for men and 2.9 for women.
The difference in risk between the men and women is modest and not statistically
significant. Most reports of a greatly elevated relative risk in women with
diabetes did not control for major CHD risk factors. The present meta-analysis
offers further evidence that much of the previously reported excess risk of
coronary outcomes in diabetic women is mediated by well-established modifiable
cardiac risk factors. Future prospective studies should present sex-specific
fatal and nonfatal cardiovascular disease end points before and after adjustment
for risk factors. Analyzing the effect of specific risk factors separately
and in combination will help to clarify their role in the cardiovascular protection
observed in women without diabetes. In addition, much remains to be learned
about cardiovascular outcomes among ethnic minority groups with diabetes.
AUTHOR INFORMATION
Accepted for publication November 19, 2001.
This study was supported in part by a grant from the Department of Health
and Human Services (Dr Kanaya) (Faculty Development in General Internal Medicine
1D08PE50109-01).
We thank the following authors, assistants, and statisticians for their
help in providing us with additional data from their studies: Leo Niskanen,
MD, Wilfred Fujimoto, MD, Jane Shofer, MS, Edward J. Boyko, MD, MPH, Donna
L. Leonetti, PhD, Marion Rewers, MD, Susan Shetterly, MS, Richard Hamman,
MD, DrPH, William deGrauw, MD, Hans Bor, BS, Robert Lindeman, MD, C. Lillian
Yau, MS, Maurice Sievers, MD, Robert Nelson, MD, PhD, Desmond Williams, MD,
and Christine Hoehner, MPH. We are indebted to Lily Chaput, MD, for data abstraction
and review and Eric Vittinghoff, PhD, for statistical expertise.
Corresponding author and reprints: Alka M. Kanaya, MD, 1701 Divisadero
St, Suite 554, San Francisco, CA 94143-1732 (e-mail: alkak{at}itsa.ucsf.edu).
From the Department of Medicine, Division of General Internal Medicine
(Drs Kanaya and Grady), and the Department of Epidemiology and Biostatistics
(Dr Grady), University of California, San Francisco; and the Department of
Family and Preventive Medicine, University of California, San Diego (Dr Barrett-Connor).
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