© 1996 American Heart Association, Inc.
Articles |
Coronary Artery Disease in IDDM
Gender Differences in Risk Factors but Not Risk
From the Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh (C.E.L., L.H.K., R.R.W., T.J.O.), and Children's Hospital of Pittsburgh, Department of Pediatrics, School of Medicine (D.E., D.J.B.), Pa.
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Abstract |
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Abstract Insulin-dependent diabetes mellitus (IDDM) increases the risk of developing coronary artery disease (CAD) compared with that seen in the general population, while the sex differential in rates of CAD is considerably reduced in IDDM populations. To further our understanding of these observations, the effects of gender on baseline risk factors for CAD incidence were examined. Participants in the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study were recruited from the Children's Hospital of Pittsburgh IDDM registry and had been diagnosed between 1950 and 1980. Subjects completed a series of questionnaires and were given a full clinical examination at baseline (1986 through 1988) and every subsequent 2 years. This report is based on the first 4 years of follow-up. Similar incidence rates of new CAD events were observed in men and women. In neither sex was glycemic control a predictor of later CAD. Sex-specific Cox proportional hazards models showed that for men, duration of IDDM, HDL cholesterol, fibrinogen, hypertension, and smoking were all significantly associated with the onset of CAD. Hypertension, fibrinogen, and smoking were all replaced by nephropathy when this latter variable was added to the model. For women, duration, hypertension, waist-hip ratio, physical activity, and depressive symptomatology were all significant independent predictors of CAD. Nephropathy status did not enter the model for women. While 4-year incidence of CAD in IDDM varies little by sex in this population, the predictive risk factors vary considerably. In particular, the effect of renal disease was stronger in men, while the cluster of physical activity, waist-to-hip ratio, and depressive symptomatology were more important in women. These results may help explain the relatively greater impact IDDM has on CAD risk for women and suggest new potential preventive approaches.
Key Words: fibrinogen • insulin-dependent diabetes mellitus • depression • nephropathy • coronary artery disease
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Introduction |
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Compared with the general population, people with IDDM have an increased risk of developing and dying from CAD.1 2 This increased risk may be even greater for women than for men, reducing the sex differential seen in the general population, in which women appear to be relatively protected from CAD, at least until menopausal age.3 Various explanations have been put forward as to why those with IDDM constitute such a high-risk group in terms of CAD. Mortality may be increased because of comorbid conditions, eg, renal disease,4 diabetic cardiomyopathy,5 or a later diagnosis of symptomatic disease.6 Alternatively, the severity and extent of atherosclerosis may be greater, which is sometimes, but not universally, reported.6 7 These observations have led to a search for risk factors that might explain the enhanced risk. Although lipid and lipoprotein disturbances are associated with CAD risk in both diabetic and nondiabetic populations, serum cholesterol levels may not be greatly elevated in IDDM subjects compared with their nondiabetic counterparts and may account for only a small proportion of excess CAD risk.8 Serum triglyceride levels have been found to be particularly increased in IDDM patients, especially in those with renal disease, and may make a stronger contribution to the risk of CAD.8 9 Further, recent possibilities include altered composition and glycation and oxidative modification of lipoproteins.10 Another facet may be a more frequent presence of multiple CAD risk factors in diabetes (eg, blood pressure, lipids, smoking, etc), for there is some evidence to suggest that those with diabetes, particularly women, may be more likely to have several risk factors at the same time.11 Psychosocial factors may be associated with CAD, although few studies have investigated the relationship between this disease and factors such as depression or stress in populations with IDDM.12 Although the prevalence of depression may be higher in those with diabetes,13 there has been little agreement on whether an association exists between psychological state and the development of diabetes complications.12 13 In a previous report,12 a relationship between depressive symptomatology and the prevalence of diabetes complications was noted. In particular, men and women with CVD (defined as MI, angina, or stroke) had higher depression scores compared with men and women without CVD. That report12 was based on cross-sectional data. The current cohort who were free of CVD at baseline have subsequently been followed for 4 years, allowing investigation of the association between baseline physiological and psychological status and the incidence of diabetes complications.
The aim of this report, therefore, was to identify risk factors for the development of CAD over 4 years in a sample of men and women with IDDM and to determine whether a similar constellation of risk factors predicted onset of CAD in the two sexes.
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Methods |
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Study participants were recruited from the Children's Hospital of Pittsburgh registry of IDDM, which has been shown to be representative of a community-based population.14 All were diagnosed or seen within 1 year of diagnosis at this hospital between 1950 and 1980. Individuals were required to have been less than 17 years old at IDDM onset and to be on insulin therapy at discharge.15 The recruitment and response rates for the EDC study population have been previously described in detail.16 17 Sixty-seven percent of the 977 eligible (alive, locally resident subjects who previously participated in a follow-up survey with a 95% response rate) attended the baseline examination. Those who participated differed from those who did not in that they were more likely to have attended college and were marginally more likely to have seen their physician in the last year.16 17 At baseline examination (1986 through 1988) and subsequent biennial exams, participants were examined for the presence of diabetes complications and potential risk factors. Before attending the clinic, information was collected by questionnaire concerning demographic characteristics, medical history, depressive symptomatology (BDI),18 and Kriska's physical activity questionnaire.19 Sitting blood pressures were measured using a random zero sphygmomanometer, according to the Hypertension Detection and Follow-up Program protocol.20 The mean of the second and third blood pressures was determined and used in the analyses, and a 12-lead electrocardiogram was obtained. Fasting blood samples were taken for measurement of lipids, lipoproteins, GHb, and fibrinogen. For the first 18 months of the study, GHb (stable levels of total hemoglobin A1) was determined with saline-incubated blood samples and microcolumn cation-exchange chromatography (Isolab). Thereafter, GHb was measured using automated high-performance liquid chromatography (Diamat, Bio-Rad). The two methods were shown to be almost identical (r=.95), with an absolute difference of 0.158 (% HbA1). The normal range for GHb was 4.9% to 7.3%.
Three timed urine samples (24-hour, overnight, and 4-hour clinic) were collected to calculate AER, which determined microalbuminuria (defined as an AER of 20 to 200 µg/min) in at least two of the samples, while overt nephropathy was defined as renal failure (dialysis and/or post–kidney transplant) or AER>200 µg/min; albuminuria was determined immunonephelometrically.21 DSP was determined according to the Diabetes Control and Complications Trial clinical exam protocol.22 Stereoscopic fundus photographs (fields 1, 2, and 4) read by the Fundus Photography Reading Center, University of Wisconsin (Madison), were used to determine retinopathy, which was classified according to the modified Airlie House System.23 All subjects were invited to return for a full clinical examination every 2 years after their baseline exam. Copies of hospital records and death certificates were sought for subjects who died. Any participants electing not to attend the first and second follow-ups were asked to complete survey forms.
Definition of CAD
CAD was defined as the presence of angina (diagnosed by the EDC
examining physician), a history of MI (confirmed by
electrocardiogram or by review of medical records,
using standard criteria24 ), or death due to CAD (from the
death certificate) during the follow-up period.
Statistical Analysis
Statistical analyses were performed using the
statistical package for the social sciences (SPSSX) and BMDP for
multivariate analysis. Differences between
males and females at baseline (Table 1
) and those
without onset of CAD (Tables 2 and 3)
were examined using Student's t test and
2 analysis. Serum
triglycerides were log transformed before analysis,
as they were not normally distributed. The crude incidence of CAD was
calculated as the ratio of observed new cases of CAD to the total
number at risk for this complication during the follow-up period.
Both overall and sex-specific multivariate
analyses were performed using Kaplan-Meier
product-limit estimates of the survival function and Cox
proportional hazards modeling,25 entering those
variables found to be statistically significant (P<.05)
at the univariate level of analysis but avoiding
use of highly intercorrelated variables (ie, >.7; systolic
blood pressure, diastolic blood pressure, age, and
duration) in the same model. Standardized RRs were calculated with a
base of 1 SD for each variable. Models were compared by their
log-likelihood values. First, multivariate models
were run for the total study population, making available all those
variables found to be statistically significant at the
univariate level (ie, P<.05) and including an
examination of sexxrisk factor–interaction terms. Using the same
criteria for inclusion of variables, analyses were then
performed for each sex. Other established risk factors that did not
already fit these inclusion criteria were then made available to the
sex-specific models. A further step was to examine whether any risk
factors found to be significant in the opposite sex could make any
difference to the best models for males and females. Finally, to
examine the role of renal status in CAD risk,
nephropathy was added to the best model for each sex.
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Results |
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Table 1
shows the demographic characteristics of the study
participants by sex. Of the 658 examined at baseline, 24 were excluded
because of known (21) or undetermined (3) CAD status. Mean age and
duration of diabetes were similar for males and females, while serum
triglyceride and LDL cholesterol levels were
somewhat higher in males compared with females (P=.06 and
P=.05, respectively). As in the general population, women
had significantly higher HDL concentrations compared with men. Men at
baseline had a significantly greater mean weekly alcohol intake and
blood pressure compared with women without CAD (P<.001).
Socioeconomic status, as measured by education level and household
income, did not differ significantly between the sexes. Smoking
histories were also similar; fibrinogen levels, however, were
significantly lower in men compared with women at baseline. Men
reported more physical activity.
Table 4 reports the 4-year incidence of CAD by sex and
shows that there is little difference in the types of CAD events each
sex experienced during this study's first 4 years of follow-up. As
this table also demonstrates, the crude annual incidence rate
dramatically increased for subjects aged 30+ years, suggesting a
powerful effect for age on risk of CAD.
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A comparison between the women who developed CAD during follow-up
and those who did not is reported in Table 2. Follow-up information
was available on 93% of women who entered the study. As expected, both
the mean age and mean duration of diabetes were significantly greater
in those who developed CAD (P<.001), but GHb did not
differ. Although there was no difference (after adjusting for IDDM
duration) in HDL cholesterol levels, women with CAD had
somewhat higher mean LDL cholesterol (P<.1) and
triglyceride (P<.1) levels. Mean
systolic (P<.001) and diastolic
(P<.05) blood pressure levels were significantly greater in
women who subsequently developed CAD compared with those who did not.
There were no differences in fibrinogen. Although women with CAD had a
significantly higher mean WHR compared with women without CAD onset
(P<.01), body mass index (kg/m2) did not
differ. Marital status, education level, household income, and drinking
history were similar in these two groups of women (data not shown);
however, women who developed CAD were somewhat more likely to have had
a positive history of smoking (P=.07). BDI scores were
significantly higher in women who developed CAD compared with those who
did not (P<.01). This was also true when depression was
examined categorically, ie, 67% of those developing CAD had BDI scores
of 10 or more (mild depression), and 33% had scores of 16 or more
(clinical depression) compared with 26% (P<.001) and 12%
(P<.05), respectively, for those not developing CAD.
Physical activity levels, as measured by the number of flights of
stairs climbed per day, were lower in women who developed CAD
(P<.05). Women who developed CAD were approximately twice
as likely to have had overt nephropathy or DSP and three
times as likely to have had proliferative retinopathy
than those women who did not develop CAD.
The baseline comparison between males who developed CAD during
follow-up and males who did not is reported in Table 3. Information
was available on 94% of men who entered this study. As for women, age
and duration were again significantly greater (P<.001) in
those who developed CAD, but GHb was not different. Males who developed
CAD were somewhat more likely to have a positive history of smoking
(P=.06) and in contrast to the women had significantly lower
HDL cholesterol levels compared with men who remained free
of this complication (P<.01). Like women, there were no
significant differences in LDL cholesterol, serum
triglyceride, or body mass index levels after adjustment
for duration. Fibrinogen levels, WHR, and blood pressure levels were
all significantly greater in men who subsequently developed CAD
compared with men who did not (all P<.01). There were no
differences in either education or household income between men with
and without onset of CAD, although men who developed CAD were more
likely to be married than single (57% versus 43%; P<.05).
In contrast to the women in the study, men who developed CAD during
follow-up did not differ in terms of their depression status, and
neither number of alcoholic drinks per week nor degree of physical
activity differed by subsequent CAD status. Compared with women, men
who developed CAD were even more likely (nearly fourfold increase) to
have had overt nephropathy at baseline, while DSP and
proliferative retinopathy were twice as common in those
who developed CAD.
To determine the independent risk factors for CAD,
multivariate analyses were carried out,
initially for the total population, ie, men and women together, as
described in the statistical methods section. These results, as shown
in Table 5, demonstrated that duration of diabetes,
hypertension, and high WHR were all significant independent risk
factors for CAD. Furthermore, significant sexxflights of stairs per
day– and sexxdepression–interaction terms were observed.
Nephropathy status did not enter this model when it was
made available. Given these significant sexxrisk
factor–interaction terms and to further examine possible sex
differences in risk factors for CAD, multivariate
analyses were then carried out for men and women separately.
The results of this analysis are shown in Table 6. First, for males, when all variables found to be
statistically significant (P<.05) at the
univariate level were made available to the
multivariate model, hypertension, duration of diabetes,
HDL cholesterol, and fibrinogen were all found to be
significant independent risk factors for CAD (log
likelihood=-84.1). When smoking was made available to the model
(not significant univariately at the P<.05
level but an established risk factor for CAD), a better model was
observed on the basis of a significantly improved log likelihood
(-82.2). Thus, the best model for males (see Table 6) showed that
hypertension, duration, HDL cholesterol, fibrinogen, and
smoking were all significant independent risk factors for CAD in men.
Following the same procedure for women, duration of diabetes, high WHR,
hypertension, flights of stairs per day, and depression all entered the
model, giving a log likelihood of -46.8 (see Table 6). When other
established CAD risk factors were made available to the model (ie,
smoking, triglycerides, and HDL cholesterol),
the model did not change, and none of these variables entered the
model. These analyses were repeated after the removal of
outliers in the data on flights of stairs per day, but no significant
difference in the findings was observed. A further step in the
analyses was to examine whether those risk factors important in
the opposite sex could make a difference to the best models for men and
women. This procedure entailed making flights of stairs per day and
depression available to the model for men and fibrinogen available to
the model for women. None of these variables entered the models,
showing that depression and flights of stairs per day were risk factors
exclusively for women and fibrinogen was important only in men.
Finally, nephropathy status was made available to the best
models shown in Table 6. As shown in this table,
nephropathy did not enter the model for women. Conversely,
nephropathy did enter the model for the men, although the
log likelihood was not significantly improved. However, when
nephropathy entered the model, hypertension, fibrinogen,
and smoking did not remain in the model.
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Discussion |
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This study provides a uniquely comprehensive assessment of the role of potential CVD risk factors in predicting the incidence of CAD in a representative IDDM population. Particularly novel findings are the observations concerning depressive symptomatology in women and the much stronger influence of renal disease in men. Thus, though men and women with IDDM have similar rates of CAD, there are apparent differences in the role of these "new" risk factors and of more established risk factors (eg, lipoproteins, blood pressure, and smoking). In particular, men who developed CAD had significantly lower baseline HDL cholesterol and higher triglyceride concentrations, while women who developed CAD showed relatively little difference in these lipid concentrations. LDL cholesterol, though significantly higher in both men and women who developed CAD, did not contribute independently in the multivariate analyses. However, in neither sex were differences in GHb, a marker of glycemic control, significant. It should be noted that inevitably some otherwise eligible subjects had died before the EDC study started. In fact, 37 subjects had previously died from CVD causes (based on death certificate data). These data also support previous studies suggesting a loss of the sex differential for CAD risk in IDDM patients.8 26 27 28
Though our prospective study has, therefore, confirmed the importance of hypertension and (partially) lipid levels (eg, HDL cholesterol) as risk factors for CAD, the mean values for HDL cholesterol and blood pressure were well within the normal range. Thus, although a similar association between lipids/blood pressure and CAD may be seen in both IDDM and general population samples, excessive elevations of these factors are unlikely to account for the increased risk of CAD in IDDM. Furthermore, these observations suggest that risk factor target levels should be set substantially lower for those with IDDM.
In contrast to NIDDM,11 we do not have evidence to suggest that women with IDDM are more likely to have multiple risk factors than men. Our findings, however, do indicate that despite some similarities (eg, hypertension), the risk factor profiles for CAD may vary according to sex. The multivariate predictors of CAD for males (lower HDL cholesterol levels and smoking) contrast with the significant independent predictors for women (lower levels of physical activity, greater WHR, and greater depressive symptomatology). A further sex difference was the contribution of nephropathy. As overt renal disease was present in 90% of men developing CAD but only 47% of women, it clearly does not explain the relatively greater impact of IDDM on CAD risk in women. Nephropathy does not enter the Cox model in women, while in contrast, for men, smoking, fibrinogen, and hypertension were all removed in favor of nephropathy in the multivariate model (although the model was not significantly improved). Thus, the link between nephropathy and CAD, which has been observed previously,28 29 may be mostly a male characteristic and largely mediated by hypertension,30 31 32 33 34 35 36 which rises considerably in overt renal disease.
A further sex difference reported in the current study is the
significant association between the development of CAD and prior
depressive symptomatology (as measured by the BDI) found in women but
not in men. This partly confirms earlier cross-sectional work,
which demonstrated that both men and women with CVD (MI, angina, and
stroke) had higher depression scores, although this value reached
statistical significance only in men.12 The association
between prior depressive symptomatology and CAD, although an
independent one, was not particularly strong, as can be seen in Table 5
(P=.1). However, a model that did not contain WHR showed a
stronger effect for depression (P=.028). As we have
previously observed a significant correlation between WHR and
depression in women,37 the current
multivariate findings suggest that WHR and depression
may be linked in the prediction of CAD.
Whereas with cross-sectional data it is not possible to distinguish cause and effect, our present findings raise the possibility of a causal role for prior depressive symptomatology in women but not men. Although there may be some confounding of certain somatic symptoms of depression with those of diabetes (eg, weight loss, fatigue, sleep disturbances), it has been shown in samples of people with diabetes that the BDI remains a useful tool for distinguishing depressed from nondepressed patients, particularly through the cognitive symptoms of depression.13
Until recently, few longitudinal studies of CAD in the general population have included women subjects38 39 ; however, there is now evidence to show a role for depressive symptoms as a predictor for CAD in women as well as men.38 40 41 42 We have previously reported an association between depression and the later onset of CAD in an analysis that did not distinguish between the sexes,43 which we are now able to confirm in women only. Often overlooked, depression may be an important variable to investigate, particularly because people with diabetes (both NIDDM and IDDM) are more likely to be depressed than those without the disease.13 Furthermore, it has been frequently shown that women report greater depressive symptomatology than men,44 an observation we can confirm because the women in our study had significantly higher Beck scores than their male counterparts.
The pathological mechanisms leading from feelings of depression to CAD are not entirely understood, and there may be both direct and indirect pathways.45 46 47 For example, feelings of depression may lead to particular coronary events directly or indirectly via poorer health behaviors such as increased smoking, alcohol intake, and decreased physical activity.40 48 49 Behavior changes such as these might then lead to a poorer cardiovascular risk profile, for example, higher cholesterol or blood pressure levels. It is interesting to note that high WHR reduces the contribution of depressive symptoms in the Cox model (as well as the contribution of physical activity), raising the possibility of a close association between depression, activity, and WHR. A common factor underlying these associations is likely to be insulin resistance, as Bjorntop has proposed.50 The sex-specific nature of these associations is supported to a great extent in the multivariate analysis for women and men combined. In this pooled analysis, a stronger effect of depression and physical activity was shown for women versus men.
These results may not fully explain the overall increase in CAD risk in IDDM. In addition to the influence of renal disease28 29 51 and associated risk factor changes (eg, hypertension), other potential explanations include altered lipoprotein composition10 and/or its glycation52 and oxidation.53 Interestingly, in a small case control study, we have recently demonstrated that plasma concentrations of thiobarbituric acid–reactive substances (a measure of lipid peroxidation) are increased in female but not male IDDM subjects.54
In conclusion, this study has shown similar rates of CAD in men and women with IDDM, despite sex differences in the predictive power of the established CAD risk factors. HDL cholesterol and smoking appear somewhat more important in men, while women who developed CAD had significantly higher depression scores and climbed fewer stairs daily compared with women who did not develop this complication, differences not observed in the men. The renal link with CAD appears stronger for men and is likely to be closely related to hypertension. These findings warrant further investigation and may have important implications for future preventive measures.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by National Institutes of Health grant DK 34818. We would like to thank Robb Wilson for data management, the staff of the EDC study, and most importantly the participants of this study for their continued support.
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Footnotes |
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Reprint requests to Dr Trevor J. Orchard, 5th Floor, Rangos Research Center, 3460 Fifth Ave, Pittsburgh, PA 15213.
Received August 28, 1995; accepted January 25, 1996.
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