1 Epidemiology and Disease Control Division, Ministry of Health, Singapore, Republic of Singapore.
2 Department of Endocrinology, Singapore General Hospital, Singapore, Republic of Singapore.
Received for publication January 21, 2003; accepted for publication April 17, 2003.
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ABSTRACT |
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Asia; cardiovascular diseases; diabetes mellitus; ethnic groups; mortality
Abbreviations: Abbreviations: CI, confidence interval; HR, hazard ratio; IFG, impaired fasting glucose; IGT, impaired glucose tolerance.
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INTRODUCTION |
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The incidence and prevalence of diabetes have been rising worldwide. However, the increase has been most pronounced in non-Europoid populations (9). China and India (each with a population of over one billion people) represent the two most populous nations in the world today. As such, Chinese and Asian Indians comprise the majority of people living in Southeast Asia. Another major ethnic group in Southeast Asia is Malays. Although the prevalence of diabetes in many Asian countries remains low, particularly in rural areas (in China, the overall prevalence of type 2 diabetes has been found to be less than 2.5 percent (10)), it is clear that Chinese, Malays, and Indians have a propensity to develop diabetes. There was a notable secular increase in the prevalence of diabetes among Indians in Mauritius between 1987 and 1998 (11). The prevalence of diabetes among Chinese, Malays, and Indians in Singapore doubled between 1984 and 1992 (12). Chinese in Taiwan and Mauritius also exhibit a high prevalence of diabetes (13).
Despite the high prevalence of diabetes in these ethnic groups, there is a paucity of data on mortality associated with diabetes in Asia. Of several studies that have assessed the risk of mortality associated with diabetes (48, 1418), only one (4) included significant numbers of Southeast Asians. Unfortunately, in that study, which included significant numbers of Indians and Micronesians living on the islands of Fiji, Nauru, and Mauritius, the results were adjusted for ethnic group and the mortality rates of persons with diabetes in the various ethnic groups were not compared.
The socioeconomic and public health impact of premature mortality and morbidity associated with diabetes on the workforce is a major concern. Therefore, it is important to estimate the impact of diabetes in Asian ethnic groups. The population of Singapore comprises three major ethnic groups: Chinese, Malays, and Indians. Thus, Singapore offers us a model in which to examine the effects of hyperglycemia on mortality in these three ethnic groups.
Apart from diabetes per se, there is particular concern about two groups of people with hyperglycemia. Undiagnosed or asymptomatic diabetes has been associated with the same mortality as or greater mortality than that of persons with known diabetes (19). In addition, persons with intermediate degrees of glucose intolerance also have increased risk of cardiovascular disease and mortality (20). The World Health Organization now recommends classification of the latter group as persons having impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) (21).
The aim of this study was to determine the risk of mortality associated with known diabetes, newly diagnosed diabetes, and IFG/IGT in Singapore, a country with a multiethnic Southeast Asian population. A secondary aim was to determine whether the risk associated with hyperglycemia differed between Chinese, Malays, and Asian Indians.
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MATERIALS AND METHODS |
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Demographic data and data on lifestyle factors were collected using an interviewer-administered questionnaire. Smoking status was defined as ever smoking or never smoking. Alcohol intake was assessed using a questionnaire based on the Behavioral Risk Factor Surveillance System questionnaire of the Centers for Disease Control and Prevention. For this analysis, an alcohol drinker was defined as someone who consumed alcohol at least once per month. Educational level was ascertained according to the following classification: no formal education, Primary School Leaving Examination (reflecting the completion of 6 years of formal education), and General Certificate of Education, ordinary level (reflecting the completion of 10 years of formal education).
Height and weight were measured for all participants, and body mass index (weight (kg)/height (m)2) was calculated. Blood pressure was measured at heart level using a standard mercury sphygmomanometer with the subject seated and the right arm supported by the table. A cuff of suitable size was applied 3 cm above the cubital fossa on the subjects exposed right upper arm. After the subject had rested adequately in a quiet room, two measurements were taken with a 30-second interval between measurements. If the systolic pressure between the two measurements differed by more than 25 mmHg or the diastolic pressure differed by more than 15 mmHg, a third measurement was taken. The mean of the two closest readings was then calculated. Hypertension was defined according to the criteria of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (22) as mean systolic pressure 140 mmHg or diastolic pressure
90 mmHg or both, or self-reported current use of antihypertensive medication.
Fasting venous blood was collected from each respondent after an overnight fast of 10 hours. Subjects who were not on oral hypoglycemic agents or insulin underwent a 75-g oral glucose tolerance test using the method recommended by the World Health Organization for field surveys (23). Glucose measurement was carried out on the same day by the glucose oxidase method using a Vitros 700 chemistry analyzer (Ortho-Clinical Diagnostics, Inc., Rochester, New York) (intrarun coefficient of variation, 1.2 percent; interrun coefficient of variation, 1.5 percent).
A total of 150 subjects had a history of diabetes (known diabetes). Of these, 121 were being treated with oral hypoglycemic agents or insulin. Eleven with venipuncture failure or refusal of blood testing were excluded. For this analysis, subjects were classified into three categories of glucose tolerancenormal glucose tolerance, IFG/IGT, and diabetesusing both fasting glucose and 2-hour postchallenge glucose. Diagnostic criteria were in line with those recommended by the World Health Organization (21). IFG was diagnosed if the fasting glucose level was greater than 6.0 mmol/liter and less than 7.0 mmol/liter and the 2-hour postchallenge glucose level was less than 7.8 mmol/liter. IGT was diagnosed if the fasting glucose level was less than 7.0 mmol/liter and the 2-hour postchallenge glucose level was greater than or equal to 7.8 mmol/liter and less than 11.1 mmol/liter. Diabetes was diagnosed if the fasting glucose level was greater than or equal to 7.0 mmol/liter or the 2-hour postchallenge glucose level was greater than or equal to 11.1 mmol/liter. Persons with diabetes were further classified into those with known diabetes and those with newly diagnosed diabetes based on self-reported history of the disease.
Mortality follow-up
The unique identification numbers, further confirmed by sex and date of birth, for the 3,568 members of the 1992 National Health Survey cohort were matched with mortality databases provided by the Registry of Births and Deaths. Seventy-six persons were excluded because their unique identification numbers were not long enough for matching and were probably recorded incorrectly at the time of interview. Thus, vital status was determined for 97.9 percent (3,492/3,568) of the subjects as of December 31, 2001. Mortality data with the cause of death coded by the International Classification of Diseases, Ninth Revision, and the date of death were obtained from the Registry of Births and Deaths. Cause of death was taken as the primary cause of death given on the death certificate. One death was excluded from the data analysis because the subject had died within the survey period. Therefore, 3,492 subjects were included in the final data analysis, and person-years of follow-up during the follow-up period (December 1, 1992December 31, 2001) were then calculated for each individual.
Statistical analysis
Hazard ratios and 95 percent confidence intervals for all causes of death, adjusted for potentially confounding factors or stratified by group, were calculated using Coxs proportional hazards regression. We checked the proportional hazards assumption by plotting the log of the negative log of the estimated survival functions against log time. Because of limitations in the sample size, disease-specific mortality risk could not be determined. Plots of survival curves stratified by group were generated by means of the Kaplan-Meier method. The log-rank test was used for comparing different groups with respect to their survival distributions. All survival analyses were performed with S-Plus 2000 software (Insightful Corporation, Seattle, Washington).
In a sensitivity analysis, the analyses were repeated after all persons who died within the first year of follow-up (n = 8) had been eliminated to remove the potentially confounding effects of undiagnosed morbidity at baseline. The results were very similar. Therefore, only the results including all participants are presented.
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RESULTS |
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DISCUSSION |
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Our study had some limitations, one of which is the small number of deaths that occurred during the follow-up period. This could have affected the reliability of the estimated mortality rates presented in table 2. However, we believe that the differences between groups are of sufficiently high statistical significance to suggest that the hazard ratios reflect true differences in risk between groups. The small number of deaths also precluded more detailed examination of the effects of diabetes on mortality in specific subgroups based on gender and/or age. Another limitation is that assessment of glucose tolerance and other risk factors was carried out at only one time point. It is possible that peoples status might have changed upon subsequent assessment; this may have resulted in regression dilution bias. However, we feel that even if such bias were present, the implication would be that the mortality associated with the risk factors would be greater, not less, than the mortality we reported. Therefore, such bias would not alter the conclusions drawn from this study.
In line with previous studies, our data showed that both diabetes and the intermediate stage of hyperglycemia (IFG/IGT) are associated with increased mortality (tables 2 and 3 and figure 1) among Chinese, Malays, and Indians. We also found (see table 2) that most of the excess mortality associated with known/newly diagnosed diabetes was related to cardiovascular disease (mortality ratio = 8.76; 95 percent CI: 4.94, 15.52). This is not surprising given that other studies of mortality in persons with diabetes have shown that cardiovascular disease is a major cause of death (18). Even among persons with no clinical evidence of cardiovascular disease antemortem, autopsy studies have revealed extensive coronary atherosclerosis in the majority of persons with diabetes (27).
The excess mortality associated with diabetes could be due to the presence of other cardiovascular disease risk factors. We previously reported that subjects with diabetes in this study population were older and more obese than those with normal glucose tolerance (28). In addition, blood pressure and serum triglyceride concentrations were higher among those with diabetes, whereas serum high density lipoprotein cholesterol concentrations were lower. Subjects with IFG/IGT had levels of cardiovascular disease risk factors that were intermediate between those of persons with normal glucose tolerance and persons with diabetes (29). However, after adjustment for these other risk factors in the multivariate model, glucose tolerance remained a significant predictor of mortality (table 4), which suggests that additional features may be present that might underlie the excess mortality associated with these conditions.
Singapore has undergone rapid economic development over the past 30 years. This socioeconomic growth has been accompanied by a change in disease patterns, such that today, the major causes of death in Singapore are noncommunicable diseases like cancer and cardiovascular disease. All three of the ethnic groups in this study live in close proximity and have experienced urbanization at the same time. Furthermore, the population is relatively homogenous in terms of socioeconomic class (table 1) and access to health care. However, the three ethnic groups have not been equally affected by urbanization in terms of diabetes prevalence. Indians have the highest prevalence of diabetes and the greatest risk of cardiovascular disease, followed by Malays and Chinese. This is seen in both men and women (12). We have previously suggested that the greater prevalence of diabetes among Indians may contribute to the increased risk of cardiovascular disease in this ethnic group (12). However, a subsequent prospective study showed that ethnicity remained a significant predictor of cardiovascular disease even after adjustment for diabetes and other cardiovascular disease risk factors (30). Our current study provides an added dimension to those findings. In addition to a higher prevalence of diabetes, Malays and Indians with diabetes have mortality rates that are almost double those of Chinese (table 2). An Indian with diabetes had a greater than threefold increased risk of mortality compared with a Chinese with diabetes.
Several hypotheses could explain these findings. Firstly, Indians and Malays may have more prolonged exposure to diabetes, resulting in increased risk of mortality. Cho et al. (31) showed recently that duration of diabetes significantly alters the risk of cardiovascular disease among diabetics with and without preexisting cardiovascular disease. At baseline in this study, the mean age at diagnosis among subjects with known diabetes was 47.3 years in Chinese, 45.7 years in Malays, and 45.8 years in Indians. Among persons with diabetes newly diagnosed during the baseline examination, the mean age was 48.7 years in Chinese, 47.3 years in Malays, and 44.2 years in Indians. None of these differences reached statistical significance. We believe that this lack of statistical significance may result from an inability to accurately determine the onset of diabetes due to a prolonged asymptomatic phase. Furthermore, we found that the ethnic group with the highest prevalence of diabetes had the lowest prevalence of IFG/IGT and vice versa (table 1). Given that IFG and IGT are thought to be intermediate stages in the development of diabetes arising from the same pathologic processes, it is possible that the high prevalence of IFG/IGT among Chinese is a consequence of slower progression to diabetes in this ethnic group. In contrast, Indians have the highest prevalence of diabetes and the lowest prevalence of IFG/IGT, raising the possibility that in this ethnic group, more of those at risk had converted to diabetes before they were studied. To prove this hypothesis, we would require a much longer period of follow-up with assessment of diabetes status at multiple time points.
Secondly, we hypothesize that Indians and Malays have more prolonged exposure to other cardiovascular disease risk factors that are usually associated with diabetes. In Singapore, Malays and Indians are more obese than Chinese and have greater insulin resistance and lower high density lipoprotein cholesterol concentrations than Chinese (12, 32). These are all components of the metabolic syndrome and are risk factors for cardiovascular disease. Although we previously reported that diabetes abolishes the ethnic differences in these metabolic parameters (28), the fact that these metabolic differences are present among Malays and Indians even in those with normal glucose tolerance suggests that they could well precede the development of diabetes in Malays and Indians. As with the duration of diabetes, more prolonged exposure to these risk factors could contribute to the greater mortality associated with diabetes in these ethnic groups.
Finally, we also considered the possibility that these ethnic groups possess other risk factors for cardiovascular disease not examined in this study. For example, Indians in Singapore have been found to exhibit higher serum concentrations of lipoprotein(a) (33), which could add to the risk of cardiovascular disease in this ethnic group.
Perhaps of greater concern than the mortality risk among persons with known diabetes is the increased mortality associated with undiagnosed diabetes and the intermediate state of IFG/IGT. Unlike the Paris Prospective Study and the Whitehall Study (19), undiagnosed diabetes in our population appears to be associated with lower mortality rates than does known diabetes. Among those with diabetes, subjects with newly diagnosed diabetes and known diabetes were similar in terms of blood pressure and lipid profiles. However, subjects with newly diagnosed diabetes were younger than persons with known diabetes (28). It is possible that the lower age in the former group accounts for the lower mortality in this group in comparison with persons with known diabetes.
While we focus on the dramatic increase in mortality associated with diabetes, we must also bear in mind the small but significant increase in mortality associated with IFG/IGTa finding that confirms data from previous studies (1, 14, 24), including a recent meta-analysis (20). Despite the small increase in mortality among persons with IFG/IGT as compared with diabetics, overall 16.2 percent of the population had IFG/IGT after the results were weighted back to the 1990 population (data not shown). IFG/IGT is twice as common as diabetes. As a consequence, the absolute number of deaths attributable to IFG/IGT approached that for diabetes. This has resulted in identification of this subgroup for intensive control of other cardiovascular disease risk factors, including the aggressive management of hyperlipidemia. Note also that the majority of persons classified as having IFG/IGT were classified as such on the basis of 2-hour postchallenge glucose level and not fasting glucose level (data were reported previously (29, 34)). In the light of these findings, it seems likely that 2-hour postchallenge glucose will continue to play a role in the identification of persons at high risk of developing complications, especially among those with a fasting glucose level less than 7.0 mmol/liter. Modification of the current screening strategies, which currently recommend limiting the use of an oral glucose tolerance test to persons with a fasting glucose level greater than 6.0 mmol/liter and less than 7.0 mmol/liter (34), may be required to optimize the detection of persons with IGT. This is important, because lifestyle modification (35) and pharmacologic intervention (35, 36) have been shown to successfully retard the progression of these intermediate states of hyperglycemia to diabetes and to reduce cardiovascular disease (37) in these subjects.
In conclusion, we have shown that IFG/IGT and diabetes are associated with significant risk of mortality in Chinese, Malays, and Asian Indians. Even in a developed country such as Singapore, the proportion of persons with undiagnosed diabetes exceeds that of persons with known diabetes. Diabetes has been identified as a coronary artery disease risk equivalent (38). It has also been shown that aggressive management of risk factors such as dyslipidemia is cost-effective (39, 40) and reduces not only cardiovascular disease (37) but also mortality (41) in these persons. On the basis of these data, we recommend a comprehensive screening program to detect these high-risk persons, followed by aggressive management after diagnosis in order to reduce mortality and morbidity from this disease. Such a program may be particularly important in other Southeast Asian countries where populations are similarly at risk of diabetes but remote locations make access to health care problematic.
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ACKNOWLEDGMENTS |
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NOTES |
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REFERENCES |
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