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Cardiovascular risk factors, change in risk factors over 7 years, and the risk of clinical diabetes mellitus type 2
Journal of Clinical Epidemiology 55 (2002) 647–653
Cardiovascular risk factors, change in risk factors over 7 years, and the risk of clinical diabetes mellitus type 2 The Tromsø study Bjarne K. Jacobsen*, Kaare H. Bønaa, Inger Njølstad Institute of Community Medicine, University of Tromsø, N-9037 Tromsø, Norway Received 28 June 2000; received in revised form 21 January 2002; accepted 7 February 2002
Abstract In a large longitudinal study, we examined the relationships between cardiovascular risk factors (blood lipids, blood pressure, smoking, and physical activity), and change in these risk factors over a 7-year period, and the risk of clinical diabetes mellitus type 2. There were 73 verified new cases of clinical diabetes mellitus type 2 (diagnosed between 1987 and 1995) and 9,982 controls who consistently denied diabetes in three health surveys in 1979/1980, 1986/1987, and 1994/1995. Baseline body mass index, serum triglycerides, high-density lipoprotein (HDL) cholesterol, blood pressure, and physical activity in leisure, as well as change in these risk factors, were significant predictors for clinical diabetes mellitus type 2. Thus, both the level of risk factors at baseline and change in risk factor level are of importance for the risk of clinical diabetes mellitus type 2. © 2002 Elsevier Science Inc. All rights reserved. Keywords: Body mass index; Blood lipids; Blood pressure; Cardiovascular risk; Smoking; Physical activity
1. Introduction The incidence and prevalence of diabetes mellitus type 2 are increasing in many populations [1]. The incidence of this disease is strongly influenced by changes in life style [2–4]. During World War II (1940–1945), the incidence of diabetes mellitus in subjects 60 years and above in Oslo, Norway, was reduced by approximately two-thirds, and increased to pre-war levels shortly after the war [2]. This is but one example that environmental factors like food habits, physical activity, and obesity are of importance in the etiology, although diabetes mellitus type 2 also has a genetic basis [5]. The increasing prevalence of the disease is of importance by itself because of some of the complications due to microangiopathy that may follow (mainly diabetic eye and kidney disease), but also because the disease is associated with macrovascular disease with a more than twofold increased risk of cardiovascular diseases [6–8]. The aim of the present study was to investigate relationships between both baseline levels of known risk factors for cardiovascular diseases and the changes in these risk factors
* Corresponding author. Tel.: 47-77-64-48-16; fax: 47-77-64-48-31. E-mail address: [email protected] (B.K. Jacobsen).
over a 7-year period, and the risk of developing clinical diabetes mellitus type 2. 2. Methods 2.1. Study population Eligible for this study were 10,070 men and women who attended three surveys in the Tromsø Study in 1979/1980, 1986/1987, and 1994/1995, and denied diabetes in the two first surveys. Women who were pregnant in one of the first two surveys were excluded. The 5,095 men were 20–54 years old, and the 4,975 women were 20–49 years old at baseline in 1979/1980. They represent 47% of the population who were invited to the survey in 1979/1980 and 96% of the persons who attended all three screenings. In a separate set of analyses, we restricted the population to a subgroup of 4,144 men and women (aged 42.1 years in 1979) with information about glycated hemoglobin (HbA1C) in 1994/1995. Glycated hemoglobin was measured in the 1994/1995 survey only, and only in a subgroup. 2.2. Screening procedures and risk factor determination All three screenings included a questionnaire concerning cardiovascular diseases and diabetes, treatment for hypertension, smoking habits, and usual level of leisure physical
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activity (low, moderate, regular training, or hard training). Low physical activity was defined as a sedate leisure time like reading and watching TV, or other activities that do not need physical activity; moderate physical activity was defined as physical activity like walking, bicycling, or other forms of physical activity for at least 4 hr per week. Subjects who took part in regular training with higher intensity (exercises to keep fit, heavy gardening, etc., for at least 4 hr per week) were categorized into the next category (regular training). The last category of subjects comprised subjects who took part in hard training or competitive sports, regularly and several times a week. In our analysis, persons who reported regular or hard training were merged into one group. There were several questions about smoking (e.g., current smoking, previous smoking, and duration of smoking and number of cigarettes smoked per day). Height and weight was measured at screening and the body mass index (BMI) was computed as weight/height2 (kg/m2). In the survey in 1979/1980, a mercury sphygmomanometer was used for blood pressure measurement. In the survey in 1986/1987, a Dinamap automatic blood pressure measurement device was used (Dinamap Vital Signs Monitor 1846, Critikon Inc., Tampa, FL). For systolic blood pressures between 100 to 180 mmHg, the readings differ little between the two methods (2 mmHg) [9]. A nonfasting blood sample was taken and analyzed for serum total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides by enzymatic colorimetric methods with commercial kits. High-density lipoprotein (HDL) cholesterol was measured after precipitation of lower density lipoproteins with heparin and manganese chloride. The analyses were performed at the University Teaching Hospital in Tromsø. Details about the methods are given elsewhere [10,11]. Risk factor level in 1979/1980 and changes in risk factors from the survey in 1979/1980 to 1986/1987 were the independent variables. The following variables were considered as possible predictors for diabetes in our analysis: Age, sex, smoking, serum glucose, body mass index and change in body mass index, systolic blood pressure and change in systolic blood pressure, serum lipids (total cholesterol, HDL cholesterol, and triglycerides), and change in serum lipids as well as physical activity and treatment for hypertension in the 1979/1980 and 1986/1987 screenings. 2.3. Case identification New cases of self-reported diabetes were individuals who denied diabetes in 1979/1980 and 1986/1987, but stated to have diabetes in 1994/1995. There were a total of 88 incident cases of self-reported diabetes, 56 men and 32 women. We (K.H.B.) searched the medical records in the only local hospital (including the out-patient clinics). A diagnosis of diabetes mellitus type 2 was confirmed in 73 sub-
jects of the 83 subjects with a present medical record. These 48 men and 25 women are the cases of clinical diabetes mellitus type 2 in our study. The year of diagnosis was from 1987 to 1995. A diagnosis of diabetes mellitus type 2 could not be confirmed in 15 subjects. They were excluded from the analysis. 2.4. Statistical analysis and ethical approval The age- and sex-adjusted differences in risk factor level between new cases of diabetes mellitus type 2 and clinical nondiabetics (controls) were assessed by analysis of covariance. Predictors for diabetes were analyzed with logistic regression in a multivariate model with new cases of clinical diabetes mellitus type 2 as cases, and the clinical nondiabetics as controls. The statistical analyses were performed using the SAS package [12]. A P-value 5% was considered statistically significant. The Tromsø Study has been approved by the Regional Committee for Medical Research Ethics.
3. Results Table 1 shows the mean value of some risk factors in new cases of diabetes mellitus type 2 and in clinical nondiabetics. The cases of diabetes were older, had significantly lower age- and sex-adjusted high-density lipoprotein cholesterol, higher nonfasting serum glucose and triglycerides, systolic blood pressure, and body mass index in 1979/1980 than clinical nondiabetics. Treatment for hypertension was a risk factor for diabetes (P .001). Marginally significant relationships were found for total serum cholesterol and level of physical activity. The difference in total serum cho-
Table 1 Baseline values (1979/1980) in subjects who developed diabetes mellitus type 2 between 1987 and 1995, and in subjects who consistently (in 1979/ 1980, 1986/1987, and 1994/1995) denied diabetes (clinical nondiabetics). New cases of diabetes
Clinical nondiabetics
P-value
a
73 9,982 Number of subjects Percent men 61 51 Age 41.4 (8.6) 35.5 (8.6) Serum glucose (mmol/L) 5.36 (0.95) 5.11 (0.80) Serum total cholesterol (mmol/L) 6.16 (1.21) 5.89 (1.22) Serum HDL cholesterol (mmol/L) 1.43 (0.58) 1.60 (0.46) Serum triglycerides (mmol/L) 1.95 (1.35) 1.36 (0.84) 26.6 (4.3) 23.5 (3.1) Body mass index (kg/m2) Systolic blood pressure (mmHg) 135 (17) 126 (14) 70 80 Physically active (%)b Treated for hypertension (%) 17 1 Current smoking (%) 48 47 Mean number of cigarettes smoked per day 7.1 (12.0) 5.7 (7.5)
.07 .001 .008 .04 .001 .001 .001 .001 .04 .001 .9 .1
Means (standard deviation) and percentages, adjusted for age and sex. a The number of clinical nondiabetic subjects vary somewhat due to missing values b Walking, bicycling, etc., for at least 4 hr a week or regular training.
B.K. Jacobsen et al. / Journal of Clinical Epidemiology 55 (2002) 647–653
lesterol was not statistically significant when adjusted for serum triglycerides (P .9). Current smoking was not associated with the risk of diabetes. This was also the case when adjusted for body mass index (P .3). The mean number of cigarettes currently smoked was 1.4 higher in cases of diabetes than in clinical nondiabetics (P .1). This reflected an increased risk of diabetes with heavy smoking (more than 20 cigarettes per day, P .05 when adjusted for body mass index in addition to age and sex). No dose–response relationship was observed however (P .5). Compared with clinical nondiabetics, new cases of diabetes mellitus type 2 experienced a significantly larger drop in age- and sex-adjusted high density lipoprotein cholesterol (P .01), and a larger increase in serum triglycerides and in body mass index in the period from 1979/1980 to 1986/ 1987 (both P-values .001). There was also a statistically significant (P .02) larger increase in the systolic blood pressure. Both ending and starting treatment for hypertension was associated with increased risk of diabetes. Change in serum total cholesterol was not statistically significantly associated with diabetes risk. There were indications (albeit not statistically significant) that change in leisure physical activity was associated with diabetes risk (Table 2). Table 3 gives the results from the multivariate analysis. A total of 72 cases of clinical diabetes mellitus type 2 and 9,792 clinical nondiabetics (controls) with complete data on considered risk factors were included. As total serum cholesterol (after adjustment for triglycerides) and smoking
Table 2 Change in risk factors from 1979/1980 to 1986/1987 in subjects who developed diabetes mellitus type 2 between 1987 and 1995 and in subjects who consistently (in 1979/1980, 1986/1987, and 1994/1995) denied diabetes (clinical nondiabetics). New cases diabetes a
Number of subjects Total serum cholesterol (mmol/L) HDL cholesterol (mmol/L) Triglycerides (mmol/L) Body mass index (kg/m2) Systolic blood pressure (mmHg) Started treatment for hypertension (%) Ended treatment for hypertension (%) Increased leisure physical activity (%) Reduced leisure physical activity (%)
73 0.22 (1.19) 0.19 (0.49) 0.74 (1.71) 1.41 (1.80)
Clinical nondiabetics
P-value
9,982 0.12 (0.83) 0.08 (0.36) 0.04 (0.86) 0.73 (1.59)
.3 .01 .001 .001
3 (16)
0 (12)
.02
7
2
.003
5
0.3
.001
10
17
.1
28
25
.5
Mean changes (standard deviation) for blood lipids and blood pressure and percentages that started or ended treatment for hypertension and changed level of physical activity, adjusted for age and sex. a The number of clinical nondiabetic subjects vary somewhat due to missing values. Change in high density lipoprotein (HDL) cholesterol was available for 72 cases of clinical diabetes mellitus type 2.
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Table 3 Risk factors for diabetes mellitus type 2, 1979/1980–1994/1995. Risk factor
Unit
Female sex Age group 5 years Nonfasting glucose 1 mmol/L Body mass index 3 kg/m2 Change in body mass index 1 kg/m2 Nonfasting serum triglycerides 1 mmol/L Change in serum triglycerides 1 mmol/L Serum HDL cholesterol 0.5 mmol/L Change in serum HDL cholesterol 0.5 mmol/L Systolic blood pressure 15 mmHg Change in systolic blood pressure 10 mmHg Treatment for hypertension Not treated Treated in either 1979/1980 or 1986/1987 Treated in both surveys P-value for linear trend Physical activity in leisure Unchanged low activity Reduced activity Unchanged moderate/high activity Increased activity P-value for linear trend
Odds ratio 95% CI P-value 1.3 1.3 1.3 1.6 1.2 1.4 1.5 0.5 0.5 1.5 1.3
0.8–2.4 .4 1.1–1.5 .005 1.0–1.7 .03 1.3–1.9 .001 1.0–1.3 .04 1.1–1.8 .006 1.2–1.8 .001 0.3–0.8 .002 0.3–0.8 .002 1.2–2.0 .002 1.1–1.6 .001
1.0 2.0 2.4
ref. 0.9–4.5 0.9–5.9
1.0 0.5 0.4 0.3
ref. 0.2–0.9 0.2–0.7 0.1–0.7
.08 .07 .03
.03 .003 .007 .002
Odds ratio (OR) and 95% confidence intervals (95% CI). All factors are mutually adjusted for the other factors.
(both before and after adjustment for body mass index) were not associated with risk of diabetes mellitus type 2 in the age- and sex-adjusted analysis, these two variables were not initially included in the multivariate model. Increasing age, nonfasting serum glucose, body mass index in 1979/1980 and gain in weight from 1979/1980 to 1986/1987 were all associated with increased risk of diabetes (P .04). Both serum triglycerides at baseline and change in triglycerides between the two surveys were significantly associated with diabetes (P .006). We also found a statistically significant inverse relationship with risk of diabetes mellitus type 2 for both baseline high-density lipoprotein and change in high density lipoprotein (HDL) cholesterol concentration and risk of diabetes mellitus type 2 (P .002). Baseline systolic blood pressure and change in blood pressure were both significantly associated with diabetes (P .002). A model with interaction terms for baseline values of body mass index, serum triglycerides, and HDL cholesterol and systolic blood pressure on one hand, and the changes in the same risk factors from 1979/1980 to 1986/1987 on the other hand (a total of four interaction terms), did not give a significantly (P .2) better fit than the model presented in Table 3. There were, however, indications of an interaction between triglycerides and change in triglycerides (P .002), but both in subjects with low (2.0 mmol/L) and high (2.0 mmol/L) triglycerides, change in triglycerides was a significant risk factor for diabetes (P .003). In persons with high triglycerides, however, HDL cholesterol was not a predictor for clinical diabetes.
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In our study, treatment for hypertension was associated with risk of getting diabetes, with an increasing odds ratio with increasing exposure to treatment for hypertension (P .03). Compared to men and women who reported consistent sedate lifestyle, subjects who reported unchanged moderate and high physical activity in leisure at both screenings in 1979/1980 and 1986/1987 had lower risk of contracting diabetes (P .003). Individuals who had reduced their activity between the two surveys also had lower diabetes risk than subjects who reported consistent low activity did (OR 0.5, P .03). The lowest risk was, however, found in subjects who had increased their level of physical activity (OR 0.3, P .007). Because of the indications of a direct association with heavy smoking in the age- and sex-adjusted analysis, heavy smoking (currently smoking 20 cigarettes per day) was also included in a separate multivariate model. We found a nonsignificant association between heavy smoking and the risk of diabetes mellitus type 2 (OR 1.9, P .2). The results with regard for the other variables included in the model did not change when adjustment for heavy smoking was undertaken. In a separate analysis, we considered as cases all 88 subjects who reported to be diabetics. A total of 85 of them had information about all considered covariates. The results were very similar to those presented in Table 3. Glycated hemoglobin (HbA1c) was measured in 1994/ 1995 only, and only in a subgroup. In an analysis comprising of 44 new cases of diabetes mellitus type 2 and 4,015 clinical nondiabetics with measured glycated hemoglobin and all considered covariates, we excluded 150 controls who denied diabetes but had glycated hemoglobin 6.0%. The results before and after exclusion were similar and confirmed the results from the analysis with 72 cases referred above. Subject with high glycated hemoglobin may, however, also be included in analysis as cases of diabetes. Thus, in a separate analysis, we accepted as cases of diabetes the 44 individuals who had identified themselves as such (and later confirmed by us) and 13 individuals who denied diabetes, but had HbA1c 7.0%. In the control group we have excluded individuals who denied diabetes, but had HbA1c in the range 6.1–6.9%. A total of 3,927 subjects were included with data about all covariates. Comparing the results from this analysis (with 57 cases of diabetes) with the same analysis conducted in the group of subjects with known HbA1c value and with the same definition of case and control as in the main analysis (including 44 cases of diabetes type 2 and 4015 clinical nondiabetics), gave a very similar picture of body mass index, nonfasting triglycerides, and hypertension directly, and HDL cholesterol and physical activity inversely associated with diabetes risk, thus confirming the results from the main analysis. Due to the limited number of cases, we do not present a gender or age-specific analysis in the tables. However, models including risk-factor-by-gender or risk-factor-by-age
group interactions terms did not give a significant better fit than a model without interaction terms (P .4). To get a relatively low number of covariates, we chose to include as many of the possible predictors for diabetes mellitus type 2 as continues variables. We have, however, also tried to include them as grouped (using a total of 35 dummy variables). The main results were very similar to those presented above, the only exception being that HDL cholesterol and baseline and change in HDL cholesterol (although both inversely related to diabetes risk) were not statistically significant. 4. Discussion The results from this study strongly indicate that some risk factors for cardiovascular diseases and change in these risk factors are of importance in the etiology of diabetes mellitus type 2. The main strength of this study is that, although it is analyzed as a case–control study, it has a prospective design. Furthermore, we analyze in a comprehensive manner the impact of change in risk factors for cardiovascular disease on the risk of diabetes mellitus type 2. The information about predictors of disease was collected before the diagnosis was known. This reduces the likelihood that the disease process itself influences the risk factor level, for example, that serum lipids are increased due to a latent prediabetic state. However, insulin resistance and impaired glucose tolerance is a part of the metabolic syndrome, which also includes dyslipidaemia, hypertension, and central obesity, and there may be several years from onset of diabetes mellitus type 2 to a diagnosis is made [13]. Several recent previous studies have shown that one measurement of body mass index, blood lipids, blood pressure, or indicator for physical activity predict diabetes mellitus type 2 in the following years [5,14–22]. Also, increase in weight has been linked to increased diabetes risk [23–26]. Our results confirm this, and show that also changes in other risk factors for cardiovascular diseases, particularly triglycerides, HDL cholesterol, and systolic blood pressure, modulate diabetes risk. The latter seems to be a new, although perhaps not surprising, finding. An important issue is the identification of cases and noncases. We base the identification of cases on self-reported diabetes following a confirmation of the diagnosis by review of the medical records by a physician. We, therefore, find it unlikely that any of our cases do not have clinical diabetes mellitus type 2. It is possible that the confirmed cases are the most severe cases as they have been treated in the only local hospital or out-patient clinic for internal medicine. The results were, however, essentially unchanged whether we base them on the 85 self-reported cases or the 72 confirmed cases with information about all considered covariates. However, there are, without doubt, in our study some subjects with unrecognized diabetes mellitus type 2 who we
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classify as clinical nondiabetics, as they consistently denied diabetes. In a Norwegian population-based prevalence survey, one out of five cases of diabetes in persons above the age of 40 was not previously known [27]. Most probably, this has not influenced our results markedly as the subgroup analysis of subjects with known glycated hemoglobin demonstrated that the inclusion of some individuals with possible subclinical diabetes did not influence the findings. This result was expected, as the inclusion of a proportionally small group of subjects with undiagnosed diabetes mellitus type 2 in the noncase group will have little impact on the mean values for noncases. Furthermore, the results from the main analysis were confirmed when we, in separate analysis, included in the cases group subjects who denied diabetes, but had high glycated hemoglobin (7.0%), and excluded from the control group subjects with glycated hemoglobin in the range 6.1– 6.9%. In our analysis of possible biases, we used elevated glycated hemoglobin as an indicator for possible diabetes. It would have been of interest to know the fasting blood glucose in subjects who denied diabetes, but had glycated hemoglobin 7.0%. Unfortunately, we do not have fasting blood glucose for any person. A further concern may be differential misclassification, as subjects with certain characteristics (e.g., obesity) are more likely to have diabetes diagnosed, contributing to a spurious relationship between, for example, obesity and diabetes type 2. Although it is in most observational epidemiologic studies difficult to exclude bias, the above-mentioned analysis suggest that this does not explain our findings. To be included in our analysis, the subjects must have attended three health screenings. Selective survival according to risk for diabetes could theoretically bias our results. However, a comparison of the group of 10,070 subjects included in our analysis with the 16,621 men and women who attended the screening in 1979/1980, revealed only very minor differences with regard to the baseline variables examined. The only difference of some magnitude was a mean 1.2 year higher age in the subjects included in our analysis. It may be that the body mass index is not the most relevant measure for the diabetogenic effect of obesity, that, for example, the waist circumference or waist-to-hip ratio would have been stronger associated with future diabetes risk [28,29]. The waist and hip circumferences were not measured in the 1979/1980 or 1986/1987 studies. In the subgroup of the 1994/1995 population that was comprehensively examined, however, waist and hip circumferences were recorded. The correlation coefficient between body mass index and waist-to-hip ratio was 0.6 and 0.4 in men and women, respectively. The corresponding correlation coefficients for the relationship between waist circumference and body mass index were 0.8 in both genders. Thus, the body mass index was stronger correlated to waist circumference than to waist-to-hip ratio. This is relevant, as it has been suggested that waist circumference is the better predictor for diabetes mellitus type 2 [29].
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High nonfasting blood glucose in 1979/1980 was a risk factor for diabetes 7–15 years later. As measurement of blood glucose was not included in the survey in 1986/1987, we are, unfortunately, not able to investigate the relationship between change in blood glucose and future diabetes risk. There is, however, no reason to expect other than a strong positive relationship. Serum triglycerides was positively related to diabetes risk. As the blood sample was nonfasting, it does not reflect the fasting triglyceride level, and if the relevant variable is fasting triglycerides, the relationships between serum triglycerides and diabetes risk is attenuated. On the other hand, although there is probably no differential identification of diabetic subjects with respect to the nonfasting triglyceride level, the misclassification may not be random with respect to diabetes risk as high nonfasting triglycerides may reflect a tendency to postprandial hypertriglyceridemia, which is likely to be higher in future diabetics. Our results with regard to baseline triglyceride levels are in accordance with some previous studies [14,15,21]. In accordance with our findings, low levels of high-density lipoprotein (HDL) cholesterol was a risk factor for diabetes in some studies [14,15,21]. Perry and coworkers [21] found that when adjusted for serum triglycerides, no significant relationship was found between HDL cholesterol and diabetes risk. However, high serum triglycerides and low HDL cholesterol probably reflect the same metabolic disturbances including hyperinsulinaemia [30]. The finding of a lack of association with HDL cholesterol in subjects with relatively high nonfasting serum triglycerides also underlines the need for some caution. Thus, it is premature to conclude which of the two variables to be the better predictor for diabetes risk. We found that high blood pressure was associated with increased risk of diabetes mellitus type 2. This is in accordance with most previous research [14,15,18,21], although the association with hypertension observed in some studies was not always statistically significant when multivariate adjusted [15,21]. Recently, Gress and coworkers showed in a large prospective study of 12,550 adults aged 45 to 64 that normotensive subjects had lower diabetes incidence than untreated hypertensives [18]. A relatively low proportion of the population included in our study reported treatment for hypertension, and we do not know which types of antihypertensive medication that were used; it is even possible that the treatment for hypertension was nonpharmacological only. Theoretically, our data could imply that antihypertensive agents are diabetogenic [14,18,31,32]. Another likely explanation is, however, that treatment for hypertension simply reflects a more severe hypertensive condition. As we do not have data about type of treatment, our data do not allow us to explore this topic further. A large recent study [18] indicate that use of thiazides does not influence diabetes risk, but that -blockers increase the risk with approximately 30%. There may also be differences between the different types of -block-
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ers with respect to possible hyperglycemic effects, as some of them also have -blocking effects [32]. Our results underline that high blood pressure is a risk factor for diabetes mellitus type 2, and should not be misconstrued to imply that hypertension should not be treated. This may be particularly true in a diabetic population, because tight blood pressure control reduces the risk of vascular complications in diabetics [33]. Our finding of an inverse relationship between physical activity and risk of clinical diabetes mellitus type 2 is in accordance with numerous previous studies [5,16,17,19–22]. We observed that not very much physical activity is needed for preventing diabetes. Eighty percent of those who had consistent moderate or high activity, indicated moderate physical activity. The latter was in our study defined as physical activity like walking, bicycling, or other forms of physical activity for at least 4 hr per week. A considerable proportion of the population (approximately 25%) reported reduced physical activity from 1979/ 1980 to 1986/1987. They still had a reduced risk of diabetes compared to subjects who had a consistent sedate leisure time. Thus, the subjects with reduced activity between 1979/1980 and 1986/1987 seem to profit from the higher physical activity in the past. Some studies have suggested that smoking may be a risk factor for diabetes mellitus type 2 [34,35], but there has also been negative findings [15,21]. We found some indications for an increased diabetes risk associated with heavy smoking (20 cigarettes per day). In the multivariate model, it was not statistically significant. In conclusion, our study demonstrates that some of the classical risk factors for coronary heart disease are also independent risk factors for clinical diabetes mellitus type 2. Furthermore, changes in these risk factors are of importance, thus increasing the likelihood that causal relationships are observed. Our results underline the need for nonpharmacologic control of lipids, blood pressure, and body weight through amendments of life style. Acknowledgments The research was supported by grants from University of Tromsø, Norway, the Norwegian Council on Cardiovascular Diseases, and the National Research Council. The screenings were conducted in cooperation with the National Health Screening Service, Oslo, Norway. References [1] Amos AF, McCarty DJ, Zimmet P. The rising global burden of diabetes and its complications: estimates and projections to the year 2010. Diabet Med 1997;14(Suppl 5):S1–85. [2] Westlund K. Incidence of diabetes mellitus in Oslo, Norway 1925 to 1954. Report No.11 of the Life Insurance Companies’ Institute for Medical Statistics at the Oslo City Hospitals. Br J Prev Soc Med 1966;20:105–16. [3] Collins VR, Dowse GK, Toelupe PM, Imo TT, Aloaina FL, Spark
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[30] Haffner SM. Cardiovascular risk factors and the prediabetic syndrome. Ann Med 1996;28:363–70. [31] Sowers JR, Bakris GL. Antihypertensive therapy and the risk of type 2 diabetes mellitus. N Engl J Med 2000;342:969–70. [32] Luna B, Feinglos MN. Drug-induced hyperglycemia. JAMA 2001; 286:1945–8. [33] UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317:703–13. [34] Rimm EB, Chan J, Stampfer MJ, Colditz GA, Willett WC. Prospective study of cigarette smoking, alcohol use, and the risk of diabetes in men. BMJ 1995;310:555–9. [35] Manson JE, Ajani UA, Liu S, Nathan DM, Hennekens CH. A prospective study of cigarette smoking and the incidence of diabetes mellitus among US male physicians. Am J Med 2000;109:538–42.
Cardiovascular risk factors, change in risk factors over 7 years, and the risk of clinical diabetes mellitus type 2 The Tromsø study Bjarne K. Jacobsen*, Kaare H. Bønaa, Inger Njølstad Institute of Community Medicine, University of Tromsø, N-9037 Tromsø, Norway Received 28 June 2000; received in revised form 21 January 2002; accepted 7 February 2002
Abstract In a large longitudinal study, we examined the relationships between cardiovascular risk factors (blood lipids, blood pressure, smoking, and physical activity), and change in these risk factors over a 7-year period, and the risk of clinical diabetes mellitus type 2. There were 73 verified new cases of clinical diabetes mellitus type 2 (diagnosed between 1987 and 1995) and 9,982 controls who consistently denied diabetes in three health surveys in 1979/1980, 1986/1987, and 1994/1995. Baseline body mass index, serum triglycerides, high-density lipoprotein (HDL) cholesterol, blood pressure, and physical activity in leisure, as well as change in these risk factors, were significant predictors for clinical diabetes mellitus type 2. Thus, both the level of risk factors at baseline and change in risk factor level are of importance for the risk of clinical diabetes mellitus type 2. © 2002 Elsevier Science Inc. All rights reserved. Keywords: Body mass index; Blood lipids; Blood pressure; Cardiovascular risk; Smoking; Physical activity
1. Introduction The incidence and prevalence of diabetes mellitus type 2 are increasing in many populations [1]. The incidence of this disease is strongly influenced by changes in life style [2–4]. During World War II (1940–1945), the incidence of diabetes mellitus in subjects 60 years and above in Oslo, Norway, was reduced by approximately two-thirds, and increased to pre-war levels shortly after the war [2]. This is but one example that environmental factors like food habits, physical activity, and obesity are of importance in the etiology, although diabetes mellitus type 2 also has a genetic basis [5]. The increasing prevalence of the disease is of importance by itself because of some of the complications due to microangiopathy that may follow (mainly diabetic eye and kidney disease), but also because the disease is associated with macrovascular disease with a more than twofold increased risk of cardiovascular diseases [6–8]. The aim of the present study was to investigate relationships between both baseline levels of known risk factors for cardiovascular diseases and the changes in these risk factors
* Corresponding author. Tel.: 47-77-64-48-16; fax: 47-77-64-48-31. E-mail address: [email protected] (B.K. Jacobsen).
over a 7-year period, and the risk of developing clinical diabetes mellitus type 2. 2. Methods 2.1. Study population Eligible for this study were 10,070 men and women who attended three surveys in the Tromsø Study in 1979/1980, 1986/1987, and 1994/1995, and denied diabetes in the two first surveys. Women who were pregnant in one of the first two surveys were excluded. The 5,095 men were 20–54 years old, and the 4,975 women were 20–49 years old at baseline in 1979/1980. They represent 47% of the population who were invited to the survey in 1979/1980 and 96% of the persons who attended all three screenings. In a separate set of analyses, we restricted the population to a subgroup of 4,144 men and women (aged 42.1 years in 1979) with information about glycated hemoglobin (HbA1C) in 1994/1995. Glycated hemoglobin was measured in the 1994/1995 survey only, and only in a subgroup. 2.2. Screening procedures and risk factor determination All three screenings included a questionnaire concerning cardiovascular diseases and diabetes, treatment for hypertension, smoking habits, and usual level of leisure physical
0895-4356/02/$ – see front matter © 2002 Elsevier Science Inc. All rights reserved. PII: S0895-4356(02)00 4 0 4 - 3
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activity (low, moderate, regular training, or hard training). Low physical activity was defined as a sedate leisure time like reading and watching TV, or other activities that do not need physical activity; moderate physical activity was defined as physical activity like walking, bicycling, or other forms of physical activity for at least 4 hr per week. Subjects who took part in regular training with higher intensity (exercises to keep fit, heavy gardening, etc., for at least 4 hr per week) were categorized into the next category (regular training). The last category of subjects comprised subjects who took part in hard training or competitive sports, regularly and several times a week. In our analysis, persons who reported regular or hard training were merged into one group. There were several questions about smoking (e.g., current smoking, previous smoking, and duration of smoking and number of cigarettes smoked per day). Height and weight was measured at screening and the body mass index (BMI) was computed as weight/height2 (kg/m2). In the survey in 1979/1980, a mercury sphygmomanometer was used for blood pressure measurement. In the survey in 1986/1987, a Dinamap automatic blood pressure measurement device was used (Dinamap Vital Signs Monitor 1846, Critikon Inc., Tampa, FL). For systolic blood pressures between 100 to 180 mmHg, the readings differ little between the two methods (2 mmHg) [9]. A nonfasting blood sample was taken and analyzed for serum total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides by enzymatic colorimetric methods with commercial kits. High-density lipoprotein (HDL) cholesterol was measured after precipitation of lower density lipoproteins with heparin and manganese chloride. The analyses were performed at the University Teaching Hospital in Tromsø. Details about the methods are given elsewhere [10,11]. Risk factor level in 1979/1980 and changes in risk factors from the survey in 1979/1980 to 1986/1987 were the independent variables. The following variables were considered as possible predictors for diabetes in our analysis: Age, sex, smoking, serum glucose, body mass index and change in body mass index, systolic blood pressure and change in systolic blood pressure, serum lipids (total cholesterol, HDL cholesterol, and triglycerides), and change in serum lipids as well as physical activity and treatment for hypertension in the 1979/1980 and 1986/1987 screenings. 2.3. Case identification New cases of self-reported diabetes were individuals who denied diabetes in 1979/1980 and 1986/1987, but stated to have diabetes in 1994/1995. There were a total of 88 incident cases of self-reported diabetes, 56 men and 32 women. We (K.H.B.) searched the medical records in the only local hospital (including the out-patient clinics). A diagnosis of diabetes mellitus type 2 was confirmed in 73 sub-
jects of the 83 subjects with a present medical record. These 48 men and 25 women are the cases of clinical diabetes mellitus type 2 in our study. The year of diagnosis was from 1987 to 1995. A diagnosis of diabetes mellitus type 2 could not be confirmed in 15 subjects. They were excluded from the analysis. 2.4. Statistical analysis and ethical approval The age- and sex-adjusted differences in risk factor level between new cases of diabetes mellitus type 2 and clinical nondiabetics (controls) were assessed by analysis of covariance. Predictors for diabetes were analyzed with logistic regression in a multivariate model with new cases of clinical diabetes mellitus type 2 as cases, and the clinical nondiabetics as controls. The statistical analyses were performed using the SAS package [12]. A P-value 5% was considered statistically significant. The Tromsø Study has been approved by the Regional Committee for Medical Research Ethics.
3. Results Table 1 shows the mean value of some risk factors in new cases of diabetes mellitus type 2 and in clinical nondiabetics. The cases of diabetes were older, had significantly lower age- and sex-adjusted high-density lipoprotein cholesterol, higher nonfasting serum glucose and triglycerides, systolic blood pressure, and body mass index in 1979/1980 than clinical nondiabetics. Treatment for hypertension was a risk factor for diabetes (P .001). Marginally significant relationships were found for total serum cholesterol and level of physical activity. The difference in total serum cho-
Table 1 Baseline values (1979/1980) in subjects who developed diabetes mellitus type 2 between 1987 and 1995, and in subjects who consistently (in 1979/ 1980, 1986/1987, and 1994/1995) denied diabetes (clinical nondiabetics). New cases of diabetes
Clinical nondiabetics
P-value
a
73 9,982 Number of subjects Percent men 61 51 Age 41.4 (8.6) 35.5 (8.6) Serum glucose (mmol/L) 5.36 (0.95) 5.11 (0.80) Serum total cholesterol (mmol/L) 6.16 (1.21) 5.89 (1.22) Serum HDL cholesterol (mmol/L) 1.43 (0.58) 1.60 (0.46) Serum triglycerides (mmol/L) 1.95 (1.35) 1.36 (0.84) 26.6 (4.3) 23.5 (3.1) Body mass index (kg/m2) Systolic blood pressure (mmHg) 135 (17) 126 (14) 70 80 Physically active (%)b Treated for hypertension (%) 17 1 Current smoking (%) 48 47 Mean number of cigarettes smoked per day 7.1 (12.0) 5.7 (7.5)
.07 .001 .008 .04 .001 .001 .001 .001 .04 .001 .9 .1
Means (standard deviation) and percentages, adjusted for age and sex. a The number of clinical nondiabetic subjects vary somewhat due to missing values b Walking, bicycling, etc., for at least 4 hr a week or regular training.
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lesterol was not statistically significant when adjusted for serum triglycerides (P .9). Current smoking was not associated with the risk of diabetes. This was also the case when adjusted for body mass index (P .3). The mean number of cigarettes currently smoked was 1.4 higher in cases of diabetes than in clinical nondiabetics (P .1). This reflected an increased risk of diabetes with heavy smoking (more than 20 cigarettes per day, P .05 when adjusted for body mass index in addition to age and sex). No dose–response relationship was observed however (P .5). Compared with clinical nondiabetics, new cases of diabetes mellitus type 2 experienced a significantly larger drop in age- and sex-adjusted high density lipoprotein cholesterol (P .01), and a larger increase in serum triglycerides and in body mass index in the period from 1979/1980 to 1986/ 1987 (both P-values .001). There was also a statistically significant (P .02) larger increase in the systolic blood pressure. Both ending and starting treatment for hypertension was associated with increased risk of diabetes. Change in serum total cholesterol was not statistically significantly associated with diabetes risk. There were indications (albeit not statistically significant) that change in leisure physical activity was associated with diabetes risk (Table 2). Table 3 gives the results from the multivariate analysis. A total of 72 cases of clinical diabetes mellitus type 2 and 9,792 clinical nondiabetics (controls) with complete data on considered risk factors were included. As total serum cholesterol (after adjustment for triglycerides) and smoking
Table 2 Change in risk factors from 1979/1980 to 1986/1987 in subjects who developed diabetes mellitus type 2 between 1987 and 1995 and in subjects who consistently (in 1979/1980, 1986/1987, and 1994/1995) denied diabetes (clinical nondiabetics). New cases diabetes a
Number of subjects Total serum cholesterol (mmol/L) HDL cholesterol (mmol/L) Triglycerides (mmol/L) Body mass index (kg/m2) Systolic blood pressure (mmHg) Started treatment for hypertension (%) Ended treatment for hypertension (%) Increased leisure physical activity (%) Reduced leisure physical activity (%)
73 0.22 (1.19) 0.19 (0.49) 0.74 (1.71) 1.41 (1.80)
Clinical nondiabetics
P-value
9,982 0.12 (0.83) 0.08 (0.36) 0.04 (0.86) 0.73 (1.59)
.3 .01 .001 .001
3 (16)
0 (12)
.02
7
2
.003
5
0.3
.001
10
17
.1
28
25
.5
Mean changes (standard deviation) for blood lipids and blood pressure and percentages that started or ended treatment for hypertension and changed level of physical activity, adjusted for age and sex. a The number of clinical nondiabetic subjects vary somewhat due to missing values. Change in high density lipoprotein (HDL) cholesterol was available for 72 cases of clinical diabetes mellitus type 2.
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Table 3 Risk factors for diabetes mellitus type 2, 1979/1980–1994/1995. Risk factor
Unit
Female sex Age group 5 years Nonfasting glucose 1 mmol/L Body mass index 3 kg/m2 Change in body mass index 1 kg/m2 Nonfasting serum triglycerides 1 mmol/L Change in serum triglycerides 1 mmol/L Serum HDL cholesterol 0.5 mmol/L Change in serum HDL cholesterol 0.5 mmol/L Systolic blood pressure 15 mmHg Change in systolic blood pressure 10 mmHg Treatment for hypertension Not treated Treated in either 1979/1980 or 1986/1987 Treated in both surveys P-value for linear trend Physical activity in leisure Unchanged low activity Reduced activity Unchanged moderate/high activity Increased activity P-value for linear trend
Odds ratio 95% CI P-value 1.3 1.3 1.3 1.6 1.2 1.4 1.5 0.5 0.5 1.5 1.3
0.8–2.4 .4 1.1–1.5 .005 1.0–1.7 .03 1.3–1.9 .001 1.0–1.3 .04 1.1–1.8 .006 1.2–1.8 .001 0.3–0.8 .002 0.3–0.8 .002 1.2–2.0 .002 1.1–1.6 .001
1.0 2.0 2.4
ref. 0.9–4.5 0.9–5.9
1.0 0.5 0.4 0.3
ref. 0.2–0.9 0.2–0.7 0.1–0.7
.08 .07 .03
.03 .003 .007 .002
Odds ratio (OR) and 95% confidence intervals (95% CI). All factors are mutually adjusted for the other factors.
(both before and after adjustment for body mass index) were not associated with risk of diabetes mellitus type 2 in the age- and sex-adjusted analysis, these two variables were not initially included in the multivariate model. Increasing age, nonfasting serum glucose, body mass index in 1979/1980 and gain in weight from 1979/1980 to 1986/1987 were all associated with increased risk of diabetes (P .04). Both serum triglycerides at baseline and change in triglycerides between the two surveys were significantly associated with diabetes (P .006). We also found a statistically significant inverse relationship with risk of diabetes mellitus type 2 for both baseline high-density lipoprotein and change in high density lipoprotein (HDL) cholesterol concentration and risk of diabetes mellitus type 2 (P .002). Baseline systolic blood pressure and change in blood pressure were both significantly associated with diabetes (P .002). A model with interaction terms for baseline values of body mass index, serum triglycerides, and HDL cholesterol and systolic blood pressure on one hand, and the changes in the same risk factors from 1979/1980 to 1986/1987 on the other hand (a total of four interaction terms), did not give a significantly (P .2) better fit than the model presented in Table 3. There were, however, indications of an interaction between triglycerides and change in triglycerides (P .002), but both in subjects with low (2.0 mmol/L) and high (2.0 mmol/L) triglycerides, change in triglycerides was a significant risk factor for diabetes (P .003). In persons with high triglycerides, however, HDL cholesterol was not a predictor for clinical diabetes.
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In our study, treatment for hypertension was associated with risk of getting diabetes, with an increasing odds ratio with increasing exposure to treatment for hypertension (P .03). Compared to men and women who reported consistent sedate lifestyle, subjects who reported unchanged moderate and high physical activity in leisure at both screenings in 1979/1980 and 1986/1987 had lower risk of contracting diabetes (P .003). Individuals who had reduced their activity between the two surveys also had lower diabetes risk than subjects who reported consistent low activity did (OR 0.5, P .03). The lowest risk was, however, found in subjects who had increased their level of physical activity (OR 0.3, P .007). Because of the indications of a direct association with heavy smoking in the age- and sex-adjusted analysis, heavy smoking (currently smoking 20 cigarettes per day) was also included in a separate multivariate model. We found a nonsignificant association between heavy smoking and the risk of diabetes mellitus type 2 (OR 1.9, P .2). The results with regard for the other variables included in the model did not change when adjustment for heavy smoking was undertaken. In a separate analysis, we considered as cases all 88 subjects who reported to be diabetics. A total of 85 of them had information about all considered covariates. The results were very similar to those presented in Table 3. Glycated hemoglobin (HbA1c) was measured in 1994/ 1995 only, and only in a subgroup. In an analysis comprising of 44 new cases of diabetes mellitus type 2 and 4,015 clinical nondiabetics with measured glycated hemoglobin and all considered covariates, we excluded 150 controls who denied diabetes but had glycated hemoglobin 6.0%. The results before and after exclusion were similar and confirmed the results from the analysis with 72 cases referred above. Subject with high glycated hemoglobin may, however, also be included in analysis as cases of diabetes. Thus, in a separate analysis, we accepted as cases of diabetes the 44 individuals who had identified themselves as such (and later confirmed by us) and 13 individuals who denied diabetes, but had HbA1c 7.0%. In the control group we have excluded individuals who denied diabetes, but had HbA1c in the range 6.1–6.9%. A total of 3,927 subjects were included with data about all covariates. Comparing the results from this analysis (with 57 cases of diabetes) with the same analysis conducted in the group of subjects with known HbA1c value and with the same definition of case and control as in the main analysis (including 44 cases of diabetes type 2 and 4015 clinical nondiabetics), gave a very similar picture of body mass index, nonfasting triglycerides, and hypertension directly, and HDL cholesterol and physical activity inversely associated with diabetes risk, thus confirming the results from the main analysis. Due to the limited number of cases, we do not present a gender or age-specific analysis in the tables. However, models including risk-factor-by-gender or risk-factor-by-age
group interactions terms did not give a significant better fit than a model without interaction terms (P .4). To get a relatively low number of covariates, we chose to include as many of the possible predictors for diabetes mellitus type 2 as continues variables. We have, however, also tried to include them as grouped (using a total of 35 dummy variables). The main results were very similar to those presented above, the only exception being that HDL cholesterol and baseline and change in HDL cholesterol (although both inversely related to diabetes risk) were not statistically significant. 4. Discussion The results from this study strongly indicate that some risk factors for cardiovascular diseases and change in these risk factors are of importance in the etiology of diabetes mellitus type 2. The main strength of this study is that, although it is analyzed as a case–control study, it has a prospective design. Furthermore, we analyze in a comprehensive manner the impact of change in risk factors for cardiovascular disease on the risk of diabetes mellitus type 2. The information about predictors of disease was collected before the diagnosis was known. This reduces the likelihood that the disease process itself influences the risk factor level, for example, that serum lipids are increased due to a latent prediabetic state. However, insulin resistance and impaired glucose tolerance is a part of the metabolic syndrome, which also includes dyslipidaemia, hypertension, and central obesity, and there may be several years from onset of diabetes mellitus type 2 to a diagnosis is made [13]. Several recent previous studies have shown that one measurement of body mass index, blood lipids, blood pressure, or indicator for physical activity predict diabetes mellitus type 2 in the following years [5,14–22]. Also, increase in weight has been linked to increased diabetes risk [23–26]. Our results confirm this, and show that also changes in other risk factors for cardiovascular diseases, particularly triglycerides, HDL cholesterol, and systolic blood pressure, modulate diabetes risk. The latter seems to be a new, although perhaps not surprising, finding. An important issue is the identification of cases and noncases. We base the identification of cases on self-reported diabetes following a confirmation of the diagnosis by review of the medical records by a physician. We, therefore, find it unlikely that any of our cases do not have clinical diabetes mellitus type 2. It is possible that the confirmed cases are the most severe cases as they have been treated in the only local hospital or out-patient clinic for internal medicine. The results were, however, essentially unchanged whether we base them on the 85 self-reported cases or the 72 confirmed cases with information about all considered covariates. However, there are, without doubt, in our study some subjects with unrecognized diabetes mellitus type 2 who we
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classify as clinical nondiabetics, as they consistently denied diabetes. In a Norwegian population-based prevalence survey, one out of five cases of diabetes in persons above the age of 40 was not previously known [27]. Most probably, this has not influenced our results markedly as the subgroup analysis of subjects with known glycated hemoglobin demonstrated that the inclusion of some individuals with possible subclinical diabetes did not influence the findings. This result was expected, as the inclusion of a proportionally small group of subjects with undiagnosed diabetes mellitus type 2 in the noncase group will have little impact on the mean values for noncases. Furthermore, the results from the main analysis were confirmed when we, in separate analysis, included in the cases group subjects who denied diabetes, but had high glycated hemoglobin (7.0%), and excluded from the control group subjects with glycated hemoglobin in the range 6.1– 6.9%. In our analysis of possible biases, we used elevated glycated hemoglobin as an indicator for possible diabetes. It would have been of interest to know the fasting blood glucose in subjects who denied diabetes, but had glycated hemoglobin 7.0%. Unfortunately, we do not have fasting blood glucose for any person. A further concern may be differential misclassification, as subjects with certain characteristics (e.g., obesity) are more likely to have diabetes diagnosed, contributing to a spurious relationship between, for example, obesity and diabetes type 2. Although it is in most observational epidemiologic studies difficult to exclude bias, the above-mentioned analysis suggest that this does not explain our findings. To be included in our analysis, the subjects must have attended three health screenings. Selective survival according to risk for diabetes could theoretically bias our results. However, a comparison of the group of 10,070 subjects included in our analysis with the 16,621 men and women who attended the screening in 1979/1980, revealed only very minor differences with regard to the baseline variables examined. The only difference of some magnitude was a mean 1.2 year higher age in the subjects included in our analysis. It may be that the body mass index is not the most relevant measure for the diabetogenic effect of obesity, that, for example, the waist circumference or waist-to-hip ratio would have been stronger associated with future diabetes risk [28,29]. The waist and hip circumferences were not measured in the 1979/1980 or 1986/1987 studies. In the subgroup of the 1994/1995 population that was comprehensively examined, however, waist and hip circumferences were recorded. The correlation coefficient between body mass index and waist-to-hip ratio was 0.6 and 0.4 in men and women, respectively. The corresponding correlation coefficients for the relationship between waist circumference and body mass index were 0.8 in both genders. Thus, the body mass index was stronger correlated to waist circumference than to waist-to-hip ratio. This is relevant, as it has been suggested that waist circumference is the better predictor for diabetes mellitus type 2 [29].
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High nonfasting blood glucose in 1979/1980 was a risk factor for diabetes 7–15 years later. As measurement of blood glucose was not included in the survey in 1986/1987, we are, unfortunately, not able to investigate the relationship between change in blood glucose and future diabetes risk. There is, however, no reason to expect other than a strong positive relationship. Serum triglycerides was positively related to diabetes risk. As the blood sample was nonfasting, it does not reflect the fasting triglyceride level, and if the relevant variable is fasting triglycerides, the relationships between serum triglycerides and diabetes risk is attenuated. On the other hand, although there is probably no differential identification of diabetic subjects with respect to the nonfasting triglyceride level, the misclassification may not be random with respect to diabetes risk as high nonfasting triglycerides may reflect a tendency to postprandial hypertriglyceridemia, which is likely to be higher in future diabetics. Our results with regard to baseline triglyceride levels are in accordance with some previous studies [14,15,21]. In accordance with our findings, low levels of high-density lipoprotein (HDL) cholesterol was a risk factor for diabetes in some studies [14,15,21]. Perry and coworkers [21] found that when adjusted for serum triglycerides, no significant relationship was found between HDL cholesterol and diabetes risk. However, high serum triglycerides and low HDL cholesterol probably reflect the same metabolic disturbances including hyperinsulinaemia [30]. The finding of a lack of association with HDL cholesterol in subjects with relatively high nonfasting serum triglycerides also underlines the need for some caution. Thus, it is premature to conclude which of the two variables to be the better predictor for diabetes risk. We found that high blood pressure was associated with increased risk of diabetes mellitus type 2. This is in accordance with most previous research [14,15,18,21], although the association with hypertension observed in some studies was not always statistically significant when multivariate adjusted [15,21]. Recently, Gress and coworkers showed in a large prospective study of 12,550 adults aged 45 to 64 that normotensive subjects had lower diabetes incidence than untreated hypertensives [18]. A relatively low proportion of the population included in our study reported treatment for hypertension, and we do not know which types of antihypertensive medication that were used; it is even possible that the treatment for hypertension was nonpharmacological only. Theoretically, our data could imply that antihypertensive agents are diabetogenic [14,18,31,32]. Another likely explanation is, however, that treatment for hypertension simply reflects a more severe hypertensive condition. As we do not have data about type of treatment, our data do not allow us to explore this topic further. A large recent study [18] indicate that use of thiazides does not influence diabetes risk, but that -blockers increase the risk with approximately 30%. There may also be differences between the different types of -block-
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ers with respect to possible hyperglycemic effects, as some of them also have -blocking effects [32]. Our results underline that high blood pressure is a risk factor for diabetes mellitus type 2, and should not be misconstrued to imply that hypertension should not be treated. This may be particularly true in a diabetic population, because tight blood pressure control reduces the risk of vascular complications in diabetics [33]. Our finding of an inverse relationship between physical activity and risk of clinical diabetes mellitus type 2 is in accordance with numerous previous studies [5,16,17,19–22]. We observed that not very much physical activity is needed for preventing diabetes. Eighty percent of those who had consistent moderate or high activity, indicated moderate physical activity. The latter was in our study defined as physical activity like walking, bicycling, or other forms of physical activity for at least 4 hr per week. A considerable proportion of the population (approximately 25%) reported reduced physical activity from 1979/ 1980 to 1986/1987. They still had a reduced risk of diabetes compared to subjects who had a consistent sedate leisure time. Thus, the subjects with reduced activity between 1979/1980 and 1986/1987 seem to profit from the higher physical activity in the past. Some studies have suggested that smoking may be a risk factor for diabetes mellitus type 2 [34,35], but there has also been negative findings [15,21]. We found some indications for an increased diabetes risk associated with heavy smoking (20 cigarettes per day). In the multivariate model, it was not statistically significant. In conclusion, our study demonstrates that some of the classical risk factors for coronary heart disease are also independent risk factors for clinical diabetes mellitus type 2. Furthermore, changes in these risk factors are of importance, thus increasing the likelihood that causal relationships are observed. Our results underline the need for nonpharmacologic control of lipids, blood pressure, and body weight through amendments of life style. Acknowledgments The research was supported by grants from University of Tromsø, Norway, the Norwegian Council on Cardiovascular Diseases, and the National Research Council. The screenings were conducted in cooperation with the National Health Screening Service, Oslo, Norway. References [1] Amos AF, McCarty DJ, Zimmet P. The rising global burden of diabetes and its complications: estimates and projections to the year 2010. Diabet Med 1997;14(Suppl 5):S1–85. [2] Westlund K. Incidence of diabetes mellitus in Oslo, Norway 1925 to 1954. Report No.11 of the Life Insurance Companies’ Institute for Medical Statistics at the Oslo City Hospitals. Br J Prev Soc Med 1966;20:105–16. [3] Collins VR, Dowse GK, Toelupe PM, Imo TT, Aloaina FL, Spark
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