Risk factors for microvascular and macrovascular complications in men and women with type 2 diabetes

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1 ORIGINAL PAPER Risk factors for microvascular and macrovascular complications in men and women with type 2 diabetes Per Erik Wändell Family Medicine Stockholm, Karolinska Institutet, Huddinge, Sweden. Received March Accepted October Scand J Prim Health Care 1999;17: ISSN Key words: cardiovascular disease, cross-sectional survey, non-in- sulin-dependent diabetes mellitus, primary health care, risk factors, Sweden. Objecti e To evaluate the importance of risk factors for microvascular and macrovascular complications, separated by sex, in type 2 diabetes. Design Cross-sectional surveys of diabetic patients registered with primary health services in Setting Three community health centres in Stockholm County. Subjects 407 subjects with type 2 diabetes in For 78 of these, data were also registered in Main outcome measures Odds ratio (OR) by logistic regression for risk factors predicting microvascular and macrovascular complications, for age and duration in years. Results For microvascular complications, the most important factors were in men the duration of diabetes (OR 1.13, p 0.001) and Both microvascular and macrovascular complications are well-known among diabetic patients (1,2). The relationship between microvascular complications in diabetes, i.e. retinopathy, nephropathy and neuropathy, and the level of metabolic control measured as HbA1c is firmly established, especially in type 1 diabetes (3). As regards macrovascular complications, the risk factors include high blood pressure, high serum total and LDL cholesterol, low serum HDL cholesterol and raised serum triglycerides, poor glucose control, smoking, high body-mass index (BMI) and fat distribution (4). However, there is some controversy regarding macrovascular complications, especially in type 2 diabetes, in relation to metabolic control. Some studies have shown a relationship between a high level of HbA1c and macrovascular comorbidity (5,6), while others have not (7). Meigs et al. (8) found that age, duration and hypertension in diabetic patients were associated with cardiovascular disease, while the HbA1c value was not. In the United Kingdom Prospective Diabetes Study (UKPDS) (9) intensive blood glucose control decreased the risk of microvascular complications but not macrovascular complications. In a recently published study, Yamamoto et al. in women the duration of diabetes (OR 1.08, p 0.001) and age (OR 1.04, p 0.05). For macrovascular complications, the most important factors were in men, age (OR 1.09, p 0.001) and hypertension (OR 4.85, p 0.001) and in women, age (OR 1.08, p 0.001) and duration of diabetes (OR 1.08, p 0.01). Conclusions Hypertension is more important among men and the duration of diabetes among women as risk factor for macrovascular complications in type 2 diabetes. Per Erik Wändell, MD, Family Medicine Stockholm, No um, SE Huddinge, Sweden. (10) found differences in the development of microangiopathy and macroangiopathy in type 2 diabetes, early onset and maternal inheritance being more important for the former and hyperlipidaemia, obesity and hypertension for the latter. In the UKPDS (11), a tight control of hypertension was found to reduce the risk of microvascular disease, as well as the risk of stroke and all diabetes-related death. With regard to sexual differences, these have been mostly described in connection with macrovascular complications. There is an increased risk of coronary heart disease in type 2 diabetes, twofold for men and fourfold for women (12). Diabetes increases the death rate from ischaemic heart disease in the USA by 9 10 times for women but by only 2 3 times for men (13). Thus, type 2 diabetes reduces the sexual difference in the overall relative risk (the ratio of men to women) of mortality from coronary heart disease (CHD) from 2.29 to 1.46 (14). The aim of this study was to assess the importance of risk factors, separated by sex, of microvascular and macrovascular complications in patients with type 2 diabetes.

2 Micro ascular and macro ascular complications in patients with type 2 diabetes 117 Table I. Disease characteristics of 407 patients with type 2 diabetes from Stockholm County in 1995, divided by sex. Values within parentheses are SDs if not otherwise stated. When figures are based on fewer than the total number of patients, the actual number is given. Only significant p-values are given. Men Women n=198 n=209 p-value Age (year) 66.1 (11.2) 70.1 (11.3) Duration (year) 8.3 (6.4) (n=192) 10.0 (7.0) (n=202) Treatment regimen Diet only 47 (23.7%) 40 (19.1%) Tablets only 106 (53.5%) 114 (54.5%) Tablets+insulin 14 (7.1%) 19 (9.1%) Insulin 31 (15.7%) 36 (17.2%) fb-glucose (mmol/l) 8.6 (3.1) (n=185) 8.7 (2.8) (n=195) HbA1c (%-units) 7.5 (1.9) (n=135) 7.5 (1.8) (n=145) Cholesterol (mmol/l) 5.9 (1.2) (n=86) 6.2 (1.2) (n=89) LDL-cholesterol (mmol/l) 3.7 (1.1) (n=44) 3.6 (1.0) (n=31) HDL-cholesterol (mmol/l) 1.0 (0.3) (n=54) 1.3 (0.4) (n=42) LDL/HDL ratio 3.6 (1.4) (n=44) 2.9 (1.0) (n=31) Triglycerides (mmol/l) 2.6 (1.5) (n=91) 2.7 (1.8) (n=89) Blood pressure (n=186) (n=194) Systolic (mmhg) (20.5) (19.5) Diastolic (mmhg) 81.7 (9.1) 81.6 (9.9) BMI 29.1 (4.9) (n=82) 29.5 (6.6) (n=79) Hypertension Diabetic complications 86/185 (46.5%) 125/201 (62.2%) Retinopathy 48/134 (35.8%) 39/123 (31.7%) Nephropathy 33/151 (21.9%) 23/153 (15.0%) Neuropathy 57/94 (60.6%) 49/106 (46.2%) Diabetic ulcer 14/196 (7.1%) 13/209 (6.2%) Atheromatous complications Heart disease 75/195 (38.5%) 76/209 (36.4%) Cerebrovascular disease 27/194 (13.9%) 39/209 (18.7%) Peripheral artery disease 22/195 (11.3%) 13/209 (6.2%) Smoking habits (n=104) (n=107) Non-smokers 58 (50.9%) 76 (71.0%) Ex-smokers 27 (23.7%) 12 (11.2%) Smokers 29 (25.4%) 19 (17.8%) STUDY POPULATION AND METHODS Subjects The population in Stockholm County varies by geographic district as regards demographic and socioeconomic factors. Three community health centres (CHCs) were chosen as reflecting these differences (15). In 1995 the electronic medical records of 407 patients with type 2 diabetes 198 men and 209 women were studied. For 78 patients 30 men and 48 women data from 1992 were also obtainable. Medical data Data on the disease were extracted from the medical records kept by the CHCs. We noted general data and data of general interest for this particular study: the type of diabetes, treatment, duration, metabolic levels (HbA1c, and fasting blood glucose), hypertension (with actual value of blood pressure), diabetic and atheromatous complications. The patients classified as suffering from type 2 diabetes, according to the data in the medical records, were included. The upper reference level for HbA1c was 5.0% for two of the CHCs and 5.2% for the remaining one. Diabetic complications were registered regarding retinopathy, nephropathy, neuropathy and previous or present diabetic foot ulcers, and atheromatous complications regarding cardiac disease, cerebrovascular disorders, including transient ischaemic attacks, and peripheral artery disease. Non-vascular comorbidity was also noted. Statistics Calculations of statistical significance were performed using Pearson s correlation test for correlation between laboratory values, and Spearman s rank-correlation test for all other correlations. Analysis by

3 118 P. E. Wändell Table II. Univariate logistic regression regarding microvascular and macrovascular complications in 1995 for men with type 2 diabetes (n=198) with significant p-values shown (borderline values, i.e. values between 0.05 and 0.10, are given within parentheses). Age Duration Hypertension Ever smoked BMI Fasting blood Cholesterol LDL HDL LDL/HDL Triglycerides glucose (0.068) All diabetic complications Retinopathy Nephropathy Neuropathy Diabetic foot ulcer (0.077) (0.055) (0.054) All atheromatous complications (0.051) Coronary heart disease (0.081) Cerebrovascular disease (0.083) 1 (0.059) (0.084) (0.052) Peripheral artery disease (0.082) (0.091) 1 Negative correlation. logistic regression was performed as regards microvascular and macrovascular complications in relation to relevant risk factors, with odds ratio (OR) and 95% confidence interval (CI) given. RESULTS The diabetic sample in 1995 The characteristics of the diabetes sample divided by sex are given in Table I. Men were younger, had a shorter diabetes duration, had lower HDL-cholesterol with a higher LDL/HDL ratio, had hypertension less often and neuropathy more often, and were more often smokers or ex-smokers than women. Risk factors for microvascular and macrovascular complications were tested by univariate logistic regression one by one for men and women, with the results shown in Tables II and III. The significant risk factors were then used in a model by multivariate logistic regression, with the results given in Tables IV and V. On looking at the subgroup of women in whom BMI was known (n= 46), this was the most important factor in predicting neuropathy (OR 1.11, 95% CI , p=0.045). The diabetic sample followed between 1992 and 1995 As regards correlation over time between 1992 and 1995, the correlation coefficients were for fasting blood glucose 0.44 (p 0.001), for HbA1c 0.52 (p 0.01), for total cholesterol 0.79 (p 0.001), and for triglycerides 0.53 (p 0.05). Logistic regression was also performed regarding these patients for microvascular and macrovascular complications in relation to metabolic level 1992 (n= 78). The blood glucose value in 1992 predicted overall diabetic complications in 1995 with OR 1.32 (95% CI , p=0.004), i.e. when the blood glucose value increased by one mmol/l the risk of any diabetic complication increased by 32%. On looking at the deterioration in diabetic complications, blood glucose value was also a significant factor, with OR 1.20 (95% CI , p=0.021). DISCUSSION The validity of this study is limited by the incomplete data in the medical records, with the effects of BMI, blood lipids and smoking habits possible to be evaluated only in subgroups. Thus, one important issue is whether the patients supplied with data are representative of the whole diabetic sample. As regards the level of recorded data, no differences were found between men and women. There were differences regarding this between the CHCs with more metabolic data, i.e. HbA1c and blood lipids, being

4 Micro ascular and macro ascular complications in patients with type 2 diabetes 119 Table III. Univariate logistic regression regarding microvascular and macrovascular complications in 1995 for women with type 2 diabetes (n=209) with significant p-values shown (borderline values, i.e. values between 0.05 and 0.10, are given within parentheses). Age Duration Ever smoked BMI Triglycerides All diabetic complications (0.068) Retinopathy Nephropathy Neuropathy Diabetic foot ulcer All atheromatous complications (0.089) 1 Coronary heart disease Cerebrovascular disease (0.056) Peripheral artery disease Negative correlation. recorded at the CHC with the youngest population (15). However, no differences were found between the CHCs in the numbers of patients on an acceptable or an unacceptable metabolic level. Besides, results from the entire diabetic sample regarding metabolic level, and microvascular and atheromatous complications were similar to those found in other studies from different parts of Sweden (15,16). Another remark is that hypertension among men was by far more important for macrovascular complications than blood cholesterol values and smoking habits, even in the subgroups where those could be evaluated. Thus, the high rate of missing data regarding some of the risk factors could not have been expected to affect the results as a whole, but of course limited the number of subjects in which these were evaluated. The predictive value of a current fb-glucose or HbA1c is limited by the relatively low correlation over time between fb-glucose and HbA1c. In contrast to this, the cholesterol showed a considerably higher correlation between the two occasions. The rate of hypertension was higher among diabetic women than men in this study, in contrast to a study from the south of Sweden by Hjelm et al. (17), but in accordance with a study from Finland by Kuusisto et al. (5). However, in the study by Hjelm et al., the diabetic patients were aged years, with a mean age of around 50 years, while in the study by Kuusisto et al. the mean age of the Table IV. Potential risk factors for microvascular and macrovascular complications in men with type 2 diabetes (n=198). Multivariate analysis, using logistic regression. Duration and age by 1 year. Coefficient ( ) SE ( ) OR (95% CI) p-value Diabetic complications: Duration ( ) Retinopathy: Duration ( ) Hypertension ( ) Nephropathy: Hypertension ( ) Foot ulcer: Duration ( ) Atheromatosis: Age ( ) Hypertension ( ) Heart disease: Age ( ) Hypertension ( ) Cerebrovascular disease: Age ( ) Hypertension ( ) Peripheral artery disease: Age ( ) 0.022

5 120 P. E. Wändell Table V. Potential risk factors for microvascular and macrovascular complications in women with type 2 diabetes (n=209). Multivariate analysis, using logistic regression. Duration and age by 1 year. Coefficient ( ) SE ( ) OR (95% CI) p-value Diabetic complications: Duration ( ) Age ( ) Retinopathy: Duration ( ) Neuropathy: Duration ( ) Foot ulcer: Duration ( ) Atheromatosis: Age ( ) Duration ( ) Heart disease: Age ( ) Duration ( ) Cerebrovascular disease: Age ( ) Duration ( ) Peripheral artery disease: Ever smoked ( ) diabetic patients was on a similar level to that in the present study. The findings regarding diabetic complications, with the duration as the most important factor, especially for retinopathy, are to be expected. In men, correlation is also noted with hypertension for retinopathy and nephropathy. The UKPDS also showed that tight control of hypertension reduced microvascular complications by 37% (11). As regards macrovascular complications, diabetes seems to be more important for women than for men, according to the studies mentioned earlier (12 14). This was also confirmed by the Scottish heart-health study (18), in which sex differences were found regarding coronary heart disease and in which total cholesterol and blood pressure being more important for men, and triglycerides and diabetes for women. The findings in this study confirm the importance of hypertension in men, and diabetes in itself for women, for the atheromatous complications. Type 2 diabetes is still sometimes called the diabetes of age among laymen, thereby implying a less serious disease, and diabetes in the elderly may also be understated by doctors. But as the disease contributes to the increased rate of atheromatous disorders in the elderly, it cannot be disregarded at any age. As regards the correlation between metabolic control and later complications, the chances of detecting this were small, owing to the small size of the diabetic sample that could be followed over 3 years. A correlation was found between the fb-glucose values in 1992 and the overall diabetic complications in The correlation of metabolic values over time in this study was low, as already mentioned. Earlier, Singh et al. (19) found a high variability of HbA1c in IDDM patients. In type 2 diabetes metabolic control is found to deteriorate over time (20), but in this study there was no significant sign of this. However, in an earlier paper, we found a more active anti-diabetic treatment in 1995, compared with 1992 (21). It seems that these two tendencies cancel each other out with regards to the mean values. The general conclusion is that predictive factors for both microvascular and macrovascular complications differ between diabetic men and women. Hypertension was of great importance among men in macrovascular complications, and also in retinopathy and nephropathy, but was of small importance among women. On the other hand, diabetes duration was of great importance among women in macrovascular complications. ACKNOWLEDGEMENTS Thanks are due to Jan Eggert and Henry Säfström, GPs at the community health centres.

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