Diabetes Care 28:2246-2248, 2005
© 2005 by the American Diabetes Association, Inc.
Pathophysiology/Complications
Brief Report |
Female Advantage in AMI Mortality Is Reversed in Patients With Type 2 Diabetes in the Skaraborg Project
Charlotte A. Larsson, MSCPH1,
Bo Gullberg, PHD1,
Juan Merlo, MD, PHD1,
Lennart Rastam, MD, PHD1 and
Ulf Lindblad, MD, PHD1,2
1 Department of Clinical Sciences, Lund University, Malmö, Community Medicine and Malmö University Hospital, Malmö, Sweden
2 Skaraborg Institute, Skövde, Sweden
Address correspondence and reprint requests to Charlotte A. Larsson, Community Medicine, Ing. 59, Malmö University Hospital, SE-205 02 Malmö, Sweden. E-mail: charlotte_a.larsson{at}med.lu.se
Abbreviations: AMI, acute myocardial infarction • CHD, coronary heart disease
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INTRODUCTION
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Two major risk factors for acute myocardial infarction (AMI) are hypertension and type 2 diabetes (1). Men are also recognized as having a higher incidence of AMI than women (1); however, in subjects with type 2 diabetes, the female advantage is known to disappear. In fact, a Finnish study recently presented a significant interaction between female sex and type 2 diabetes in the risk of coronary heart disease (CHD) (2). The current study was therefore designed to explore further the potential interaction between sex and type 2 diabetes in the risk of AMI in patients treated within primary care. Since previous studies in patients with type 2 diabetes have shown that hypertension has stronger macrovascular implications than type 2 diabetes itself, the analyses also include hypertension (3, 4).
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RESEARCH DESIGN AND METHODS
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In the Skaraborg county in southwestern Sweden, including the small community of Skara, patients with hypertension and/or diabetes have been treated at special outpatient clinics within primary care since the 1970s (the Skaraborg Hypertension and Diabetes Project) (5). From 1992 to 1993, all 1,149 patients with hypertension and/or diabetes who completed an annual check-up at the hypertension and diabetes clinic in Skara were consecutively surveyed for cardiovascular risk factors (5–10). From 1993 to 1994, a population survey using the same protocol as the patient survey was conducted with a randomized sample from the population census register, stratified by age and sex (11). Of 1,400 invited subjects  40 years of age, 1,109 (80%) completed the study visit. The ethics committee at Gothenburg University, Gothenburg, Sweden, approved both surveys.
After excluding 33 patients with type 1 diabetes, 1,116 patients of all ages remained from the patient survey. From the 1,109 subjects in the population survey, 824 remained after excluding 285 subjects with hypertension and/or diabetes. In both samples, all cases 85 years of age at baseline were excluded, leaving 1,085 subjects in the patient sample and 804 in the population sample. Those who reached 85 years of age during the follow-up period were then censored. The patient sample was divided into two categories according to diagnoses of hypertension and type 2 diabetes. All 804 remaining subjects in the population sample served as reference. Information on the end points, fatal AMI events, and all fatal events in this observational cohort study was ascertained according to a valid method (12, 13) by record linkage with national inpatient and mortality registers from baseline through 2002.
SPSS Base System for Macintosh 11.0 (SPSS, Chicago, IL) was used for data analyses. Mortality rates were age standardized in ten-year intervals using the whole Skara population 40 years old as standard. After controlling for proportionality, hazard ratios were examined, and confounders were accounted for by Cox proportional hazard model and expressed with 95% CIs. Two-way interaction terms were used to explore the association of sex, type 2 diabetes, and hypertension on AMI risk. All tests were two-sided and statistical significance assumed at P < 0.05.
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RESULTS
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While there were no obvious differences in risk factor levels between men and women at baseline, patients generally had more dyslipidemia and higher blood pressure and glucose than the reference population. The mean age for women was 67 years in patients and 59 years in the population, whereas corresponding means in men were 66 and 60 years. The majority of women were postmenopausal (92% of patients and 73% of the population were 50 years old).
After a mean follow-up of 8.1 years, there were 52 events of fatal AMI in men and 29 in women. Mortality rates were considerably lower in women (2/10,000 person-years) than in men (39/10,000) in subjects without type 2 diabetes, whereas they were higher in women (116/10,000) than in men (95/10,000) in patients with type 2 diabetes. The age-adjusted hazard ratios for patients with type 2 diabetes compared with the population were 5.0 (2.4–10.8) in women and 1.9 (1.1–3.2) in men. The only significant interaction was revealed between sex and type 2 diabetes showing, with a female disadvantage, a tripled risk of fatal AMI (Table 1). All results remained when also adjusting for smoking, total cholesterol, BMI, and leisure-time physical activity.
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CONCLUSIONS
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Whereas the overall incidence of AMI is lower in women, the female advantage is known to disappear in subjects with type 2 diabetes, and the risk is sometimes even considered to be higher in women than in men (14). This has, however, been argued to depend mainly on lack of adjustments for other risk factors such as age, smoking, and total cholesterol (15). Since those were adjusted for in the present study, they could not explain the higher female risk found here. Another study largely explains the higher relative risk of CHD mortality in women with type 2 diabetes with the more favorable survival rate in women without type 2 diabetes than in men without type 2 diabetes (16). Although this phenomenon can be seen in the current study too, the female disadvantage was seen with both absolute and relative measures, and a clearly significant interaction between sex and type 2 diabetes was found. Since the interaction is also supported by a recent Finnish study on the risk of CHD (2), other mechanisms must be working too, such as possible postmenopausal changes in sexual hormones or estrogen replacement therapy (17). Unfortunately, this was not accounted for in the present study. Moreover, although women with type 2 diabetes seem to consume more health care than men, there are indications that preventative and interventional measures are not applied to women to the same extent as men, which may have contributed to our results (18–20).
Besides the interaction between sex and type 2 diabetes, we also looked for a potential interaction between hypertension and sex and hypertension and type 2 diabetes but found none. Furthermore, we separated the patients with only type 2 diabetes from those with both type 2 diabetes and hypertension. Although power was insufficient to conclusively distinguish any effect of hypertension on the interaction between sex and type 2 diabetes, the association was stronger in patients with both conditions.
The interaction between sex and type 2 diabetes shows that the effect of type 2 diabetes on fatal AMI was significantly stronger in women than in men independent of other major cardiovascular risk factors. To improve the prognosis of female patients with type 2 diabetes, more research on sex-specific mechanisms is warranted, and special reference should be made to hypertension.
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Acknowledgments
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This study was supported by grants from the Swedish Medical Research Council, the Skaraborg Institute, Skaraborg Primary Care, the Health & Medical Care Committee of the Regional Executive Board of the Region Västra Götaland, the NEPI Foundation (The Swedish Network for Pharmacoepidemiology), Malmö University Hospital, Region Skåne, and the Faculty of Medicine, Lund University.
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Footnotes
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A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
Received for publication April 8, 2005.
Accepted for publication June 11, 2005.
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References
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INTRODUCTION
RESEARCH DESIGN AND METHODS