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European Heart Journal Advance Access published online on January 22, 2007
European Heart Journal, doi:10.1093/eurheartj/ehl458
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© The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Sex-related aspects on abnormal glucose regulation in patients with coronary artery disease

Annika Dotevall1,*, Annika Rosengren1, Malgorzata Bartnik2, Klas Malmberg2, John Öhrvik2, Maarten Simoons3, Lars Rydén2 on behalf of the Euro Heart Survey Investigators

1 Department of Medicine, Sahlgrenska University Hospital/Östra, S-416 85 Göteborg, Sweden
2 Department of Cardiology, Karolinska University Hospital, Solna, Stockholm, Sweden
3 Thoraxcenter, Department of Cardiology, Erasmus University Medical Center, Rotterdam, the Netherlands

Received 15 July 2006; revised 9 November 2006; accepted 14 December 2006.

* Corresponding author. Tel: +46 31 343 40 84; fax: +46 31 25 92 54. E-mail address: annika.dotevall{at}vgregion.se


   Abstract
Top
 Abstract
Introduction
 Methods
 Statistics
 Results
 Discussion
 Limitations
 Conclusion
 Acknowledgements
 References
 
Aim To investigate the prevalence of diabetes and impaired glucose regulation (IGR) in a large cohort of men and women with coronary artery disease (CAD), and to describe the effect of abnormal glucose regulation by sex on symptoms, clinical course, and diagnosis.

Methods and results A total of 4855 patients with CAD (median age 66 years; 29% women) were analysed within the framework of the Euro Heart Survey on Diabetes and the Heart. In all, 967 (28.1%) men and 528 (37.5%) women had diabetes. Of 3185 patients with unknown glucose regulation, 1835 (57.6%; 1400 men and 435 women) underwent an oral glucose tolerance test revealing that 17% of the men and 18% of the women had diabetes and 35 and 39% impaired glucose tolerance or impaired fasting glucose, respectively. Thus, only 19% of the women and 27% of the men had a normal glucose regulation. Women were more likely to have diabetes than men with an odds ratio (OR) of 1.32 (1.13–1.54). The corresponding OR for abnormal glucose regulation was 1.34 (1.11–1.62). Gender did not influence differences in clinical presentation between patients with diabetes or IGR and those with a normal glucose metabolism.

Conclusion Abnormal glucose regulation was more common in women than men with CAD. However, the influence of diabetes on presenting symptoms and clinical course was similar in men and women.

Key Words: Diabetes • Coronary artery disease • Euro Heart Survey on Diabetes and the Heart • Women • IGT


   Introduction
Top
 Abstract
 Introduction
Methods
 Statistics
 Results
 Discussion
 Limitations
 Conclusion
 Acknowledgements
 References
 
Diabetes and indeed already impaired glucose tolerance (IGT) are important risk factors for coronary artery disease (CAD).1–8 Whereas the absolute risk of CAD is higher in men than in women regardless of diabetes, the diabetes associated relative risk of CAD is considerably higher in women than men.1,5,7,9,10 This disease combination does also have a more serious prognosis in women.2–4,9,11 Comparing patients with and without diabetes and CAD, those with diabetes have a more unfavourable risk factor pattern, more in-hospital complications, and a more dismal short- and long-term prognosis.3,4 A common limitation of previous studies is a lack of separation by sex and that the diabetic state usually has been based on questionnaires or reviews of medical records. However, a considerable proportion of patients with myocardial infarction has unrecognized diabetes or impaired glucose regulation (IGR).12,13 It is not known if there is a sex-related difference in the prevalence of IGR, and if this condition impacts the clinical presentation differently in men and women.

In the Euro Heart Survey on diabetes and CAD,14 a large proportion of the patients without known diabetes underwent an oral glucose tolerance test (OGTT). This report explores the prevalence of perturbations in glucose regulation and their relation to risk factors, reasons for admission, clinical presentation, medication, and the final diagnosis, in a sex-related perspective.


   Methods
Top
 Abstract
 Introduction
 Methods
Statistics
 Results
 Discussion
 Limitations
 Conclusion
 Acknowledgements
 References
 
The Diabetes and Heart Survey is a multicentre, European prospective observational study involving 110 centres in 25 countries. The purpose and methods of the survey have been described in detail previously.14 Each centre was asked to recruit at least 20 patients during a limited time period, usually two to six weeks, between February 2003 and January 2004. The limitation in time was instituted to simplify consecutive patient recruitment. Patients aged 18–85 years were screened for a diagnosis of CAD when admitted to the hospital wards or visiting the outpatient clinics. A total of 5195 case records were submitted. Out of them, 340 were protocol violators, primarily screened for diabetes and not CAD, leaving 4855 as the present patient population. All patients were assessed, investigated, and treated at the discretion of their physicians in charge according to their usual institutional practice. Hospital admissions were labelled as acute or elective. Unscheduled admissions were defined as acute while elective patients were those included in connection to an outpatient visit or scheduled hospital admission (Table 1).


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  		Table 1 Glucose regulation in men and women participating in the Euro Heart Survey on diabetes and CAD

 
Previously known diabetes, impaired fasting glucose (IFG) and IGT, were defined based on the WHO classification.15 IGR refers to the presence of either IFG or IGT. Fasting plasma glucose was measured in the morning of the day following admission or on the day for outpatient visits. The protocol recommended a 75 g OGTT according to the WHO recommendations15 in all patients without previously known diabetes to be performed within two months following the index consultation. Glucose concentrations were measured locally and are expressed as venous plasma glucose (mmol/L).14

The study protocol had been approved by local Ethics committees and all patients gave their informed consent.


   Statistics
Top
 Abstract
 Introduction
 Methods
 Statistics
Results
 Discussion
 Limitations
 Conclusion
 Acknowledgements
 References
 
Descriptive statistics included counts and percentages for categorical variables and median and quartiles for continuous variables. Crude and age adjusted odds ratios (ORs) and corresponding 95% confidence intervals (CI) were calculated by logistic regression. The purpose of the study was to explore differences between men and women with and without glucose perturbations. Thus, formal statistical tests were put to a minimum and no means were taken to control the overall Type I error rate for baseline differences. All data analyses were performed using SAS statistical software (release 9.1, SAS Institute, Cary, NC, USA).


   Results
Top
 Abstract
 Introduction
 Methods
 Statistics
 Results
Discussion
 Limitations
 Conclusion
 Acknowledgements
 References
 
The present analysis comprises 4855 patients [men = 3446 (71%) and women = 1409 (29%); Figure 1]. The reason for admission was acute manifestations of CAD in 1440 (42%) of the men and 612 (43%) of the women, while the remaining patients were elective. Since the purpose of the present paper was to study the effect of sex and glucometabolic state on clinical presentation, reasons for admission, medication, and final diagnosis in patients with CAD, acute and elective patients were analysed together if not stated otherwise.


Figure 4581
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  		Figure 1 Flow diagram of the patient population.

 
As described in Figure 1, 967 (28%) men and 528 (38%) women had previously diagnosed diabetes. Another 83 men and 23 women had a random p-glucose ≥11.1 mmol/L or fasting p-glucose ≥7.0 mmol/L at inclusion and were classified as having diabetes. An OGTT was performed in 1400 (59%) men and 435 (52%) women without known glucometabolic disturbance. The test revealed a high proportion of previously undiagnosed diabetes, 17 and 18%, and IGR, 35 and 39%, in men and women, respectively (Figure 1). An abnormal glucose regulation was more common among women than men in both acute and elective patients (Table 1). Among the classified patients, only 19% of the women and 27% of the men presented with normal glucose regulation. Women were at higher risk for glucose perturbations than men. Combining IGR and diabetes, the age adjusted OR was 1.34 (95% CI: 1.11–1.62) and considering diabetes only 1.32 (95% CI: 1.13–1.54).

Table 2 presents medical history by sex and glucometabolic state. Comparing men and women with and without diabetes, the former were more likely to be non-smokers and to report previous hypertension, myocardial infarction, cerebrovascular disease, heart failure, and peripheral artery disease. Women and men with diabetes had more frequently been treated with CABG, but less often with PCI, than patients without diabetes. Hyperlipidemia, hypertension, and angina pectoris were reported more frequently among diabetic than non-diabetic women, a difference that was less apparent in men.


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  		Table 2 Medical history in men and women with and without glucometabolic perturbations participating in Euro Heart Survey on diabetes

 
Men and women with diabetes and IGR were older than non-diabetic subjects (Table 3). Waist circumference, body mass index (BMI), systolic blood pressure, and heart rate at enrolment in men and women with and without diabetes and IGR are shown in Table 3. Pharmacological treatment at enrolment is presented in Table 4. Irrespective of diabetes, a similar proportion of men and women were on aspirin at the time for enrolment. Statins had been prescribed slightly more often in diabetic than non-diabetic patients without any major sex difference while the use of ß-blockers was more frequent in diabetic men and less frequent in diabetic women compared with their non-diabetic counterparts. Subjects with diabetes were more likely to be treated with ACE-inhibitors, AT II-blockers, and diuretics, with no major differences between men and women. Among patients with diabetes, more women than men were on insulin, whereas treatment with oral hypoglycaemic agents was similar in men and women.


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  		Table 3 Basal clinical characteristics in men and women participating in EHS on diabetes

 

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  		Table 4 Pharmacological treatment at enrolment in men and women participating in the Euro Heart Survey on diabetes

 
As outlined in Table 5, the reasons for acute admissions were somewhat different in patients with diabetes, IGR, and normal glucose metabolism. Differences between patients with diabetes and those with normal glucose regulation were usually more apparent than differences between patients with IGR and normal glucose metabolism, respectively. Irrespective of sex, severe chest pain was less often reported by patients with diabetes than those with normal glucose regulation. Diabetic subjects did, however, more often present with dyspnoea and signs of heart failure (Figures 2 and 3). IGR-patients of both sexes reported more chest pain and less dyspnoea or heart failure than those with diabetes, and were in this respect more like patients with normal glucose metabolism. Irrespective of sex, non-ST-elevation infarctions were somewhat more prevalent in patients with diabetes and IGR than in glucometabolically normal patients, while ST-elevation infarctions and unstable angina pectoris were less common in subjects with diabetes. In this respect IGR patients were more similar to those with normal glucose metabolism (Table 5, Figure 3). The final discharge diagnosis in acutely admitted patients is shown in Table 5. Regardless of sex, there were no statistically significant differences between patients with diabetes, IGR, and normal glucose regulation apart from heart failure that was more common in patients with diabetes (men: OR 3.6, 95% CI: 2.4–5.3; women: OR 3.3, 95% CI: 1.8–6.1).


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  		Table 5 Reasons for admission, clinical status at enrolment, and final diagnosis in men and women admitted acutely and participating in EHS on diabetes

 

Figure 4582
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  		Figure 2 Symptoms at acute admission. OR(95% CI) for men (—) and women (............) with diabetes (men = 589; women = 324) compared with normal subjects (men = 296; women = 80).

 

Figure 4583
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  		Figure 3 Clinical status at acute admission. OR(95% CI) for men (—) and women (............) with diabetes (men = 589; women = 324) compared with normal subjects (men = 296; women = 80).

 
One-year mortality was low and did not differ between men (4.5%) and women (4.7%). Due to few events, it was not meaningful to analyse each subgroup by glucose regulation and sex separately.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Statistics
 Results
 Discussion
Limitations
 Conclusion
 Acknowledgements
 References
 
The main finding of this survey is that a majority of patients with CAD have abnormal glucose metabolism and that women are significantly more likely to have diabetes or IGT than men. Among the classified participants only 19% of the women, compared with 27% of the men, had a normal glucose regulation. As expected, cardiovascular risk factors were more prevalent in patients with than those without diabetes. In this respect, sex-related differences were minor. Likewise, differences in clinical presentation between patients with diabetes or IGR were similar to those with normal glucose metabolism in both sexes.

In contrast to the general population, in which the prevalence of diabetes is 2–6%,16,17 15–25% of patients with myocardial infarction18,19 and acute coronary syndromes4,6,20 have known diabetes. Diabetes is more common among men than women in the general population,16 but the prevalence of diabetes is higher among women than men with CAD.6,20 In the present study, the proportion of already known diabetes at enrolment, 28 and 38% in men and women respectively, was higher than in previous reports.4,18,19 A higher awareness among the investigators, resulting in more thorough questions on previously diagnosed diabetes and medication might be a partial explanation.

In the Euro Heart Survey on Acute Coronary Syndromes 1, it was recently reported that diabetic women were more likely to present with ST-elevation, develop Q-wave myocardial infarction, and to have a less favourable prognosis, than women without diabetes, and that this difference was smaller and not significant in men.20 This is in contrast to the present report, where there were no major differences in the influence of diabetes on clinical presentation and symptoms between men and women. Different study populations, and a larger number of subjects with diabetes in the previous study, might explain the divergent results.

A heavier risk factor burden and a stronger effect of risk factors in diabetic women than men might, at least partly, influence the effect of diabetes on cardiovascular risk in women.7 In the present study, important risk factors such as hypertension, hyperlipidaemia, and anxiety/depression, as expression for psychosocial factors, were more apparent among female patients. In the DECODE-study, an OGTT was performed in 17579 men and women without previously known diabetes. Newly diagnosed diabetes was related to a higher relative risk of death from all causes, especially cardiovascular disease, in women than men.10 Moreover, in subjects who smoked, were overweight, hypertensive, or had hyperlipidaemia, the effect of diabetes on the relative risk of cardiovascular mortality was higher in women than men, indicating that diabetes has a stronger synergistic effect on cardiovascular risk factors in women.10

Previous studies have reported on different management of diabetic and non-diabetic patients with cardiovascular disease.19,21,22 A more serious outcome for women after myocardial infarction might reflect not only different co-morbidities, but it may also relate to management. A satisfying finding of the present study was that there were no major sex-related differences in pharmacological treatment at enrolment. The lower proportion of ß-blocker treatment in diabetic compared with non-diabetic women may be explained by the higher prevalence of heart failure in the former group. Current recommendations do, however, underscore the favourable effect of ß-blocker treatment in patients with impaired left ventricular function.

Specific treatment options to be used in patients with early detected glucose abnormalities remain to be firmly established. However, in subjects with IGT, life-style changes reduce or retard the development of diabetes.23,24 If abnormal glucose tolerance is undetected, life style changes might be more difficult to encourage.


   Limitations
Top
 Abstract
 Introduction
 Methods
 Statistics
 Results
 Discussion
 Limitations
Conclusion
 Acknowledgements
 References
 
An important question is whether the patients in the present study are representative for a general population of patients with CAD. Surveys have a more limited possibility than clinical trials to monitor the inclusion process ensuring enrolment of consecutive patients. In contrast surveys recruit patients as seen in all day clinical practices free from exclusion criteria commonly applied in clinical trials. It has to be acknowledged that the patients of the present study may not be truly consecutive, but the size of the current survey, comprising almost 5000 individuals with a wide spectrum of CAD, makes it reasonable to assume that the findings represent a true picture of the clinical situation.

A major reason why only 59% of the men and 52% of the women with unknown glucose regulation performed an OGTT is that some domestic Ethics Committees did not approve such testing. A voluntary, and not reimbursed, participation and lack of local routines for OGTT in the cardiology settings might also have contributed. Patients without an OGTT were somewhat older, more often females, and had higher waist circumference and HbA1c values. If anything this would have resulted in an increased likelihood for glucometabolic perturbations, making an underestimation of the problem more likely than an exaggeration.


   Conclusion
Top
 Abstract
 Introduction
 Methods
 Statistics
 Results
 Discussion
 Limitations
 Conclusion
Acknowledgements
 References
 
In conclusion, glucometabolic abnormalities are very common in patients with CAD, especially in women. However, the influence of diabetes on presenting symptoms and clinical course was in the present study similar in men and women. The outcome of the present investigation underlines the importance of looking for glucometabolic disturbances particularly in women with CAD, and to study whether strict control of newly detected abnormal glucose regulation may improve subsequent prognosis.


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Statistics
 Results
 Discussion
 Limitations
 Conclusion
 Acknowledgements
References
 
This analysis was performed as part of the Women at Heart project of the European Society of Cardiology. The Swedish participation was supported by the Swedish Heart and Lung Foundation. The Göteborg Medical Society supported the preparation of the manuscript. For a detailed description of the organization of the survey and participating centres please see ref.14

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Methods
 Statistics
 Results
 Discussion
 Limitations
 Conclusion
 Acknowledgements
 References
 

  1. Barrett-Connor EL, Cohn BA, Wingard DL, Edelstein SL. (1991) Why is diabetes mellitus a stronger risk factor for fatal ischaemic heart disease in women than in men? The Rancho Bernardo Study. JAMA 265:627–631.[Abstract/Free Full Text]
  2. Miettinen H, Lehto S, Salomaa V, Mahonen M, Niemela M, Haffner SM, Pyorala K, Tuomilehto J. (1998) For the FINMONICA Myocardial Infarction Register Study Group. Impact of diabetes on mortality after the first myocardial infarction. Diabetes Care 21:69–75.[Abstract]
  3. Huxley R, Barzi F, Woodward M. (2006) Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta analysis of 37 prospective cohort studies. BMJ 332:73–78.[Abstract/Free Full Text]
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  5. Almdal T, Scharling H, Jensen JS, Vestergaard H. (2004) The independent effect of type 2 diabetes mellitus on ischaemic heart disease, stroke, and death: a population-based study of 13,000 men and women with 20 years of follow-up. Arch Intern Med 164:1422–1426.[Abstract/Free Full Text]
  6. Franklin K, Goldberg RJ, Spencer F, Klein W, Budaj A, Brieger D, Marre M, Steg PG, Gowda N, Gore JM. GRACE Investigators. (2004) Implications of diabetes in patients with acute coronary syndromes. The Global Registry of Acute Coronary Events. Arch Intern Med 164:1457–1463.[Abstract/Free Full Text]
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