WITHDRAWN: Antihypertensive therapy for preventing cardiovascular complications in people with diabetes mellitus.

BACKGROUND: Hypertension and diabetes mellitus are closely associated diseases which are both strongly related to the risk of cardiovascular disease. OBJECTIVES: To assess the effect of intervention, both pharmacological and non-pharmacological, to reduce blood pressure in people with diabetes mellitus on all cause mortality, specific causes of death, including cardiovascular disease, stroke, ischaemic heart disease and renal disease, morbidity associated with macro- and microvascular complications of diabetes mellitus and also side effects of the interventions and their influence on quality of life and well being. SEARCH STRATEGY: The search strategy employed was to searching electronic databases such as Embase and Medline for all trials of anti-hypertensive treatment in diabetes mellitus. As well as searching specialist journals in the fields of cardiovascular disease, stroke, hypertension and renal diease. SELECTION CRITERIA: All trials were considered independently and then discussed by 2 reviewers to determine there eligibility for inclusion in the review. Their methodological quality was also assessed from details of the randomisation methods, blinding and whether the intention-to-treat method of analysis was used. Trials included in the review were all randomised controlled trials of the treatment for anti-hypertensive therapy for the specified endpoints which included subjects with diabetes mellitus. DATA COLLECTION AND ANALYSIS: Data was sought on the number of patients with diabetes with each outcome measure by allocated treatment group, either from previous publications or, if this was not possible, the raw data was obtained and analysed using the intention-to-treat method. If these data were not available the results from the 'Per Protocol' analysis were used. To compare the treatment effect of the intervention with that of placebo on all cause mortality and cardiovascular mortality and morbidity, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each trial and a meta analysis performed using Peto's ORs as the summary measure. MAIN RESULTS: The initial search yielded 760 references, from which 23 appropriate trials were identified (3 for primary prevention and 20 for secondary prevention), and 15 of these trials had data available for analysis. For the primary prevention trials the summary ORs (95% CIs) for all cause mortality and cardiovascular disease were 0.85 (0.62,1.17) and 0.64 (0.50,0.82) respectively. Of the seven trials for long-term secondary prevention (i.e. follow-up greater than one year), the summary OR (95% CI) for all cause mortality was 0.82 (0.69,0.99). Data on cardiovascular disease mortality and morbidity was only available for 2 of these trials and the summary OR (95% CI) was 0.82 (0.60,1.13). There were five trials for short term secondary prevention trials (i.e. follow-up of less than 1 year) with data available for analysis. The summary ORs (95% CIs) for all cause mortality and cardiovascular disease were 0.64 (0.50,0.83) and 0.68 (0.43,1.05) respectively. AUTHORS' CONCLUSIONS: Primary intervention trials indicated a treatment benefit for cardiovascular disease, but not for total mortality in people with diabetes. For both short- and long-term secondary prevention, the present meta-analysis indicated a benefit for total mortality in diabetic subjects. However lack of information on cardiovascular disease outcomes probably reduced the power of the meta-analysis to detect any corresponding benefit for this end-point. This, along with the fact that all published data of randomised control trials of anti-hypertensive therapy in diabetes for all cause mortality and cardiovascular disease outcomes are taken from the hypertension trials not specific to diabetes, underlines the need for further high quality trials examining the effects of blood pressure lowering interventions in people with diabetes.

Epidemiology of hypertension in diabetic patients and implications for treatment.

We review the epidemiology of hypertension in diabetic patients and discuss the implications for treatment. The relationship between coronary heart disease (CHD) mortality and blood pressure (BP) in the World Health Organization Multinational Study of Vascular Disease in Diabetics (WHO MSVDD) is evaluated. One thousand two hundred seventy-seven patients with insulin-dependent diabetes mellitus (IDDM) and 3463 patients with non-insulin-dependent diabetes mellitus (NIDDM), aged 35-55 yr at baseline, from 10 centers throughout the world were evaluated. CHD mortality after a follow-up of 6-7 yr was measured. Estimates of usual diastolic BP were made with data from the Framingham study. The relative risk (RR) of CHD death was plotted against usual diastolic BP for IDDM and NIDDM, and the shapes of the relationship were compared with a meta-analysis of nine prospective studies in nondiabetic populations. For the NIDDM group, the CHD RRs were significantly greater than 1.0 only for the uppermost diastolic BP category (RR 2.23, 95% confidence interval 1.14-4.40). For the IDDM group, the shape of the diastolic BP-CHD relationship was difficult to assess in view of the small number of events. In neither diabetic group was the evidence for a J-shaped relationship. Elevated BP is associated with increased cardiovascular/renal mortality in both types of diabetes. However, the efficacy of antihypertensive therapy in the prevention of these outcomes remains unclear. Prospective data from the WHO MSVDD do not provide clear evidence of benefit from treating diastolic BP less than 95-100 mmHg in NIDDM patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Mortality and morbidity associated with body weight in people with IDDM. The WHO Multinational Study of Vascular Disease in Diabetes.

OBJECTIVE: Strict glycemic control in people with insulin-dependent diabetes mellitus (IDDM) reduces the risk of microvascular complications, but improvements in control are also associated with weight gain. Fears about the mortality risks of obesity may limit the acceptability of tight control. Therefore, we examined morbidity and mortality risks associated with body weight in people with IDDM. RESEARCH DESIGN AND METHODS: This was a cohort study of 644 men and 576 women with IDDM from nine centers worldwide. Baseline examinations were performed in 1975-1977, and mortality follow-up continued until 1988. RESULTS: Body weight was positively associated with blood pressure and, in men, with cholesterol. Fasting blood glucose was higher in the most obese groups in women only. There were 204 deaths among the men and 148 among the women. There was a reverse J-shaped relationship between body weight and all-cause mortality, with the highest mortality rates occurring in the leanest body mass index (BMI) category. The age-, duration-, and center-adjusted mortality rate ratio (95% confidence interval) comparing BMI category < 20 kg/m2 with BMI category > or = 22 and < 24 kg/m2 was 2.64 (1.59-4.38) in men and 1.54 (0.77-3.06) in women. Additional adjustment for smoking, blood pressure, glucose, cholesterol, and proteinuria did not qualitatively alter these findings. CONCLUSIONS: We conclude that except in very lean people with IDDM, body weight is not significantly associated with mortality. Thus, efforts to improve glycemic control should not be restricted by concerns about the effects of weight gain on mortality.

Cardiovascular disease and its risk factors in IDDM in Europe. EURODIAB IDDM Complications Study Group.

OBJECTIVE: To study the prevalence of cardiovascular disease (CVD), its risk factors, and their associations in IDDM patients in different European countries. RESEARCH DESIGN AND METHODS: The prevalence of CVD (a past history or electrocardiogram abnormalities) and its risk factors were examined in a cross-sectional study in 3,250 IDDM patients from 16 European countries (EURODIAB IDDM Complications Study). The patients were examined in 31 centers and were stratified between centers for age, sex, and duration of diabetes. The mean +/- SD duration of diabetes was 14.7 +/- 9.3 years. RESULTS: The prevalence of CVD was 9% in men and 10% in women. The prevalence increased with age (from 6% in patients 15-29 years old to 25% in patients 45-59 years old) and with duration of diabetes. The between-center variation for the whole population was from 3 to 19%. In both sexes, fasting triglyceride concentration was higher and HDL cholesterol lower in those patients with CVD than in those without. In men, duration of diabetes was longer, waist-to-hip ratio greater, and hypertension more common in patients with CVD. In women, a greater BMI was associated with increased prevalence of CVD. There was no association between insulin dose, HbA1c level, age-adjusted rate of albumin excretion, or smoking status and CVD. Waist-to-hip ratio, particularly in men, was positively associated with age, age-adjusted HbA1c, prevalence of smoking, daily insulin dose, albumin excretion rate, and fasting triglyceride concentrations. CONCLUSIONS: The overall prevalence of CVD in these IDDM patients was approximately 10%, increasing with age and duration of diabetes and with a sixfold variation between different European centers. CVD prevalence was most strongly associated with elevated triglyceride and decreased HDL cholesterol concentrations. CVD was also associated with albuminuria, but when adjusted by age, this association vanished. Increasing waist-to-hip ratio was associated with a number of adverse characteristics, particularly in IDDM men, reflecting the metabolic syndrome previously described in other populations.

Cardiovascular disease in insulin dependent diabetes mellitus: similar rates but different risk factors in the US compared with Europe.

BACKGROUND: Cardiovascular disease (CVD) in insulin dependent diabetes mellitus (IDDM) has been linked to renal disease. However, little is known concerning international variation in the correlations with hyperglycaemia and standard CVD risk factors. METHODS: A cross-sectional comparison was made of prevalence rates and risk factor associations in two large studies of IDDM subjects: the Pittsburgh Epidemiology of Diabetes Complications Study (EDC) and the EURODIAB IDDM Complications Study from 31 centres in Europe. Subgroups of each were chosen to be comparable by age and duration of diabetes. The EDC population comprises 286 men (mean duration 20.1 years) and 281 women (mean duration 19.9 years); EURODIAB 608 men (mean duration 18.1 years) and 607 women (mean duration 18.9 years). The mean age of both populations was 28 years. Cardiovascular disease was defined by a past medical history of myocardial infarction, angina, and/or the Minnesota ECG codes (1.1-1.3, 4.1-4.3, 5.1-5.3, 7.1). RESULTS: Overall prevalence of CVD was similar in the two populations (i.e. men 8.6% versus 8.0%, women 7.4% versus 8.5%, EURODIAB versus EDC respectively), although EDC women had a higher prevalence of angina (3.9% versus 0.5%, P < 0.001). Multivariate modelling suggests that glycaemic control (HbA1c) is not related to CVD in men. Age and high density lipoprotein cholesterol predict CVD in EURODIAB, while triglycerides and hypertension predict CVD in EDC. For women in both populations, age and hypertension (or renal disease) are independent predictors. HbA1c is also an independent predictor-inversely in EURODIAB women (P < 0.008) and positively in EDC women (P = 0.03). Renal disease was more strongly linked to CVD in EDC than in EURODIAB. CONCLUSIONS: Despite a similar prevalence of CVD, risk factor associations appear to differ in the two study populations. Glycaemic control (HbA1c) does not show a consistent or strong relationship to CVD.

Prevalence of hypertension among diabetic patients and its relation to vascular risk. Diabetes Hypertension Study Group.

In order to determine the factors related to the occurrence of hypertension in diabetic patients, blood pressure distributions were determined, using standardised methods, in a sample of 5,842 patients attending ten diabetic clinics in the London area. After allowing for the influence of age and obesity, BPs tended to be higher in patients with non-insulin-dependent diabetes compared with those with insulin-dependent diabetes, and were in general higher in males compared with females. Average BPs were lower in South Indian patients when contrasted with Caucasians and Afro-Caribbeans. The frequency of WHO-defined hypertension was highest in the non-insulin-dependent patients older than 55 years, being 43% for males and 52% for females. A substantial proportion of subjects already taking anti-hypertensive treatment had BPs above 160/95 mmHg. Centile distributions of BP in this population have been used to assess the implications of treatment strategies in diabetic patients.

Antihypertensive therapy for preventing cardiovascular complications in people with diabetes mellitus.

OBJECTIVES: To assess the effect of intervention, both pharmacological and non-parmacological, to reduce blood pressure in people with diabetes mellitus on all cause mortality, specific causes of death, including cardiovascular disease, stroke, ischaemic heart disease and renal disease, morbidity associated with macro- and microvascular complications of diabetes mellitus and also side effects of the interventions and their influence on quality of life and well being. SEARCH STRATEGY: The search strategy employed was to searching electronic databases such as EMBASE and MEDLINE for all trials of anti-hypertensive treatment in diabetes mellitus. As well as searching specialist journals in the fields of cardiovascular disease, stroke, hypertension and renal diease. SELECTION CRITERIA: All trials were considered independently and then discussed by 2 reviewers to determine there eligibility for inclusion in the review. Their methodological quality was also assessed from details of the randomisation methods, blinding and whether the intention-to-treat method of analysis was used. Trials included in the review were all randomised contolled trials of the treatment for anti-hypertensive therapy for the specified endpoints which included subjects with diabetes mellitus. DATA COLLECTION AND ANALYSIS: Data was sought on the number of patients with diabetes with each outcome measure by allocated treatment group, either from previous publications or, if this was not possible, the raw data was obtained and analysed using the intention-to-treat method. If these data were not available the results from the 'Per Protocol' analysis were used. To compare the treatment effect of the intervention with that of placebo on all cause mortality and cardiaovascular mortality and morbidity, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each trial and a meta analysis performed using Peto's ORs as the summary measure. MAIN RESULTS: The initial search yielded 760 references, from which 23 appropriate trials were identified (3 for primary prevention and 20 for secondary prevention), and 15 of these trials had data available for analysis. For the primary prevention trials the summary ORs (95% CIs) for all cause mortality and CVD were 0.85 (0.62,1.17) and 0.64 (0.50,0.82) respectively. Of the seven trials for long-term secondary prevention (i.e. follow-up greater than one year), the summary OR (95% CI) for all cause mortality was 0.82 (0.69,0.99). Data on CVD mortality and morbidity was only available for 2 of these trials and the summary OR (95% CI) was 0.82 (0.60,1.13). There were five trials for short term secondary prevention trials (i.e. follow-up of less than 1 year) with data available for analysis. The summary ORs (95% CIs) for all cause mortality and CVD were 0.64 (0.50,0.83) and 0.68 (0.43,1.05) respectively. REVIEWER'S CONCLUSIONS: Primary intervention trials indicated a treatment benefit for CVD, but not for total mortality in people with diabetes. For both short- and long-term secondary prevention, the present meta-analysis indicated a benefit for total mortality in diabetic subjects. However lack of information on CVD outcomes probably reduced the power of the meta-analysis to detect any corresponding benefit for this end-point. This, along with the fact that all published data of randomised control trials of anti-hypertensive therapy in diabetes for all cause mortailty and CVD outcomes are taken from the hypertension trials not specific to diabetes, underlines the need for further high quality trials examining the effects of blood pressure lowering interventions in people with diabetes.

Blood pressure response to standing in the diagnosis of autonomic neuropathy: the EURODIAB IDDM Complications Study.

Autonomic neuropathy is associated with poor prognosis. Cardiovascular reflexes are essential for the diagnosis of autonomic nerve dysfunction. Blood pressure response to standing is the most simple test for the evaluation of sympathetic integrity, however it is still discussed which diagnostic criteria of abnormal response should be considered as optimal. The EURODIAB IDDM Complications Study involved the examination of randomly selected Type 1 diabetic patients from 31 centres in 16 European counties. Data from 3007 patients were available for the present evaluation. Two tests of autonomic function (response of heart rate /R-R ratio/ and blood pressure from lying to standing) just as the frequency of feeling faint on standing up were assessed. R-R ratio was abnormal in 24% of patients. According to different diagnostic criteria of abnormal BP response to standing (>30 mmHg, >20 mmHg, and >10 mmHg fall in systolic BP), the frequency of abnormal results was 5.9%, 18% and 32%, respectively (p < 0.001). The frequency of feeling faint on standing was 18%, thus, it was identical with the prevalence of abnormal blood pressure response to standing when >20 mmHg fall in systolic blood pressure was considered as abnormal. Feeling faint on standing correlated significantly with both autonomic test results (p < 0.001). A fall >20 mmHg in systolic blood pressure after standing up seems to be the most reliable criterion for the assessment of orthostatic hypotension in the diagnosis of autonomic neuropathy in patients with Type 1 diabetes mellitus.

Validity of routinely collected hospital admissions data on diabetes.

Data from the clinical records of patients known to have diabetes and admitted to hospital in North West London, Cambridge or Newcastle were compared with data on the same admissions taken from the system responsible for recording information on all acute hospital admissions (Hospital Activity Analysis). In 89 out of 751 admissions (12%), either the sex, date of birth or marital status of the patient was incorrectly recorded. The diagnosis of diabetes was omitted in 32 (10%) of 315 admissions in which diabetes or a complication of diabetes was regarded as the principal cause of admission and in 12 (23%) out of 53 in which the principal cause was closely related to diabetes. These included cases in which the diagnosis had not been stated (by the clinician) on the discharge summary (the source document for Hospital Activity Analysis) as well as instances in which the coding clerk had failed to record the diagnosis. The validity of information collected on hospital admissions is dependent on the presentation of data by the clinician to the coding clerk. There may be a lack of awareness of the importance of the clinical discharge summary as a source document for such systems.

Education and employment for young people with diabetes.

Educational achievements and employment experiences were examined using a postal questionnaire in a random sample of diabetic clinic attenders and non-diabetic control subjects aged 16-21 years, selected from 13 different centres in Great Britain. A response rate of 63% and 42% for diabetic and control subjects, respectively, was obtained. The diabetic group experienced a significantly greater number of health difficulties and problems at school (compared with their control group (21% vs 11%, p = 0.01) and there was a significant difference in perceived useful careers advice obtained at school for the two groups (5% vs 59%, p < 0.0001, diabetic and control groups, respectively). There was no difference in the number of General Certificates of Secondary Education (GCSEs) and Advanced (A) level qualifications obtained between the two groups. Of the young people who had left school, diabetic adolescents were significantly more likely to report having lost their jobs than their non-diabetic counterparts (19% vs 6%, p = 0.002). The diabetic group were also more likely to report that they were unable to do the job they wanted compared with the non-diabetic group (28% vs 16%, p = 0.005) and were more likely to report shift work problems (41% vs 12%, p = 0.04). With the increasing rate of unemployment it is important that youngsters with diabetes obtain specific diabetes-orientated vocational guidance in order to plan their careers and provision should be made for this in educational establishments.

International variations in cardiovascular mortality associated with diabetes mellitus: the WHO Multinational Study of Vascular Disease in Diabetes.

The WHO Multinational Study of Vascular Disease in Diabetes was launched in 1975-77 to investigate international variations in the occurrence of different manifestations of vascular disease in subjects with insulin-dependent and non-insulin-dependent diabetes. A morbidity and mortality follow-up extending until January 1, 1988 was carried out in 10 centres, including five European centres (London, Switzerland, Berlin, Warsaw and Zagreb), two East Asian centres (Hong Kong and Tokyo), two Native American centres (Arizona and Oklahoma) and one Caribbean centre (Havana). Of a total of 4714 diabetic subjects (2310 men and 2404 women) aged between 35 and 55 years at baseline who were successfully followed up, 1266 were classified as having insulin-dependent diabetes and 3448 as having non-insulin-dependent diabetes. There was a large variation between the centres in ischaemic heart disease and cerebrovascular disease mortality rates for both insulin-dependent and non-insulin-dependent diabetic subjects, presumably reflecting in part differences between the background populations in mortality rates from these cardiovascular causes. The lowest ischaemic heart disease mortality rates for diabetic subjects were observed in Hong Kong and Tokyo centres, representing industrialized countries which have continued to have low ischaemic heart disease mortality rates. The importance of raised blood pressure and proteinuria as potentially modifiable cardiovascular risk factors in diabetic subjects was confirmed in this study.

Social deprivation and mortality in adults with diabetes mellitus.

To investigate the relationship between measures of social deprivation and mortality in adults with diabetes, data from 2104 randomly selected adults (> 16 years of age) with Type 1 and Type 2 diabetes mellitus from 8 hospital out-patient departments were analysed. A total of 38% of subjects had Type 1 (diagnosed before the age of 36 years and treated with insulin), 55% were male and 85% Caucasian. During a follow-up period (mean (SD) of 8.4 (0.9) years), 293 (14%) of the subjects died, the most commonly recorded cause of death being cardiovascular disease. Duration adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated separately for Type 1 and Type 2 subjects. The mortality rates for men were higher than for women (Type 1: OR 1.27, CI 0.61-2.62; Type 2: OR 1.79, CI 1.27-2.52); were higher for those of lower vs higher social class (Type 1: OR 1.34, CI 0.61-2.96; Type 2: OR 2.0, CI 1.41-2.85); and were higher for those who left school before 16 years of age compared to those who left school at or after 16 years of age (Type 1: OR 3.98, CI 1.96-8.06; Type 2: OR 2.86, CI 1.93-4.25). Subjects who were unemployed had a higher mortality rate than those employed at the time of the study (Type 1: OR 3.10, CI 1.67-5.79; Type 2: OR 2.88, CI 2.12-3.91) and those living in council housing had a greater mortality than those who were living in other types of housing (Type 1: OR 2.57, CI 1.35-4.91, Type 2: OR 2.76, CI 2.05-3.73). Also for both Type 1 and Type 2 subjects mortality was significantly higher in those subjects who had a least one diabetic complication at baseline and reported one or more hospital admissions in the previous year and in Type 2 subjects with poor glycaemic control. After adjusting for duration of diabetes, hospital admissions, and the presence of diabetic complications, being unemployed, male, in poor glycaemic control (Type 2 only), and less educated were significant risk factors for mortality (p<0.001). These results suggest that there are important indicators of social deprivation which predict mortality over and above diabetic health status itself. Locally targeted action will be required if these inequalities in health experienced by people with diabetes are to be reduced.

Risk factors for cardiovascular mortality and morbidity: the WHO Mutinational Study of Vascular Disease in Diabetes.

AIMS/HYPOTHESIS: We aimed to examine the associations between classic cardiovascular risk factors and diabetes specific factors and the incidence of fatal and non-fatal end-points in a large cohort of diabetic patients. METHODS: A cohort of 4,743 diabetic patients participating in the WHO Multinational Study of Vascular Disease in Diabetes (WHO MSVDD) has been followed up for about 12 years and the incidence of fatal and non-fatal cardiovascular disease outcomes assessed. RESULTS: The importance of blood pressure, serum cholesterol and proteinuria as predictors for cardiovascular disease mortality, fatal and non-fatal myocardial infarction and stroke is confirmed for patients with Type I (insulin-dependent) and Type II (non-insulin-dependent diabetes mellitus. Serum triglyceride was associated with cardiovascular disease death in Type II diabetes and in women with Type I diabetes and with MI incidence in Type II diabetes and stroke in Type II diabetic women. Fasting plasma glucose was associated with cardiovascular disease death, incidence of myocardial infarction and stroke in Type II diabetes only. In Type II diabetes, multivariate analysis confirmed that fasting plasma glucose was related to cardiovascular disease mortality independent of other risk factors. The independent relation of triglyceride to cardiovascular disease death was statistically significant only for Type II diabetic men. The presence of retinopathy was related to cardiovascular disease death and incidence of myocardial infarction in both types of diabetes and to stroke in Type II diabetes. CONCLUSION/INTERPRETATION: This large cohort study shows that the assessment of cardiovascular disease risk in diabetes must include 'diabetes-related' variables such as glycaemic control, proteinuria and retinopathy, as well as the classic risk factors, blood pressure, smoking and dyslipidaemia. [Diabetologia

Incidence of macrovascular disease in diabetes mellitus: the London cohort of the WHO Multinational Study of Vascular Disease in Diabetics.

We report on the incidence of new macrovascular disease among the 497 members of the London Cohort of the WHO Multinational Study of Vascular Disease in Diabetics (aged 35-54 years at recruitment) over a mean 8.33 year follow-up period. Overall at the end of the follow-up period the prevalence of macrovascular disease in the cohort was 45%; 43% of the subjects showed evidence of ischaemic heart disease, 4.5% of cerebrovascular disease and 4.2% of peripheral vascular disease. The incidence rates for new disease in those subjects who were free at baseline expressed per 1000 patient years of follow-up were: ischaemic ECG abnormality 23.6 (patients with insulin-dependent diabetes 19.8, patients with non-insulin-dependent diabetes 28.1), myocardial infarction 17.6 (patients with insulin-dependent diabetes 16.5, patients with non-insulin-dependent diabetes 18.8), all ichaemic heart disease 31.7 (patients with insulin-dependent diabetes 30.3, patients with non-insulin-dependent diabetes 33.4), cerebrovascular disease 5.9 and peripheral vascular disease 5.2. Incidence rates were generally similar among men and women except for myocardial infarction in patients with non-insulin-dependent diabetes where men had a significantly higher incidence rate. Macrovascular disease is a major problem in patients with diabetes and in this age group is mainly manifested as ischaemic heart disease.

Risk factors for macrovascular disease in diabetes mellitus: the London follow-up to the WHO Multinational Study of Vascular Disease in Diabetics.

We have examined the relationship between baseline variables and the incidence of new macrovascular complications amongst the 497 members of the London cohort of the WHO Multinational Study of Vascular Disease in Diabetics over a mean 8.33-year follow-up. In univariate logistic regression analysis the incidence of new ischaemic electrocardiographic abnormality was significantly associated with systolic and diastolic blood pressure, diabetes duration and hypertension in patients with insulin-dependent diabetes, and with smoking in patients with non-insulin-dependent diabetes. New myocardial infarction was associated with systolic blood pressure, plasma cholesterol, proteinuria and smoking in patient with non-insulin-dependent diabetes; there were no significant associations among patients with insulin-dependent diabetes. All new ischaemic heart disease was associated with hypertension in patients with insulin-dependent diabetes, and plasma cholesterol and smoking in patients with non-insulin-dependent diabetes. New cerebrovascular disease was associated with systolic and diastolic blood pressure, ECG abnormality and hypertension. New peripheral vascular disease was associated with smoking. Multivariate analysis showed the following significant associations 1) in patients with insulin-dependent diabetes: ECG abnormality; hypertension, myocardial infarction; smoking, ischaemic heart disease; hypertension, diabetes duration and smoking, 2) in patients with non-insulin-dependent diabetes: ECG abnormality; smoking, myocardial infarction; serum cholesterol, proteinuria and smoking ischaemic heart disease; smoking. For new cerebrovascular disease, proteinuria and ECG abnormality were significant predictors in multivariate analysis. Patients with diabetes share many of the established risk factors for nondiabetic subjects, in addition proteinuria may be of significance in the prediction of macrovascular disease in diabetes.

Proteinuria and mortality in diabetes: the WHO Multinational Study of Vascular Disease in Diabetes.

The relation between proteinuria and mortality was investigated in 1188 patients with Type 1 diabetes and 3234 patients with Type 2 diabetes, aged 35-55 at baseline and followed up for a mean of 9.4 +/- 3.1 years in the WHO Multinational Study of Vascular Disease in Diabetes. Baseline prevalence of light or heavy proteinuria was the same (25%) in both types of diabetes after adjustment for differences in diabetes duration. Compared with patients with no proteinuria, all cause mortality ratios were 1.5 (95% confidence interval 1.1-2.0) and 2.9 (2.2-3.8) for Type 1 patients with light and heavy proteinuria, respectively, and 1.5 (1.2-1.8) and 2.8 (2.3-3.4) for Type 2 patients, after adjustment for age, duration of diabetes, blood pressure, cholesterol, and smoking. Proteinuria was associated with significantly increased mortality from renal failure, cardiovascular disease, and all other causes of death. In both types of diabetes, the association was strongest for renal deaths, and of similar magnitude for cardiovascular and all other causes of death. In conclusion, proteinuria is a common, important, and rather non-specific risk factor for increased morbidity and mortality in diabetes. The relation of proteinuria to mortality is similar for both types of diabetes. The benefits and risks of proteinuria reduction should be examined in large randomized trials with clinical endpoints.

The relation between QTc interval prolongation and diabetic complications. The EURODIAB IDDM Complication Study Group.

The prevalence of QT interval prolongation is higher in people with diabetes and its complications. Sudden death has been reported as a common cause of death in insulin-dependent diabetic patients affected by autonomic neuropathy. It has been postulated that QT prolongation predisposes to cardiac arrhythmias and sudden death. In this analysis the prevalence of QT interval prolongation and its relation with diabetic complications were evaluated in the EURODIAB IDDM Complications Study (3250 insulin-dependent diabetic patients attending 31 centres in 16 European countries). Five consecutive RR and QT intervals were measured with a ruler on the V5 lead of the resting ECG tracing and the QT interval corrected for the previous cardiac cycle length was calculated according to the Bazett's formula. The prevalence of an abnormally prolonged corrected QT was 16% in the whole population, 11% in males and 21 % in females (p < 0.001). The mean corrected QT was 0.412 s in males and 0.422 s in females (p < 0.001). Corrected QT duration was independently associated with age, HbA1c and blood pressure. Corrected QT was also correlated with ischaemic heart disease and nephropathy but this relation appeared to be stronger in males than in females. Male patients with neuropathy or impaired heart rate variability or both showed a higher mean adjusted corrected QT compared with male patients without this complication. The relation between corrected QT prolongation and autonomic neuropathy was not observed among females. In conclusion we have shown that corrected QT in insulin-dependent diabetic female patients is longer than in male patients, even in the absence of diabetic complications known to increase the risk of corrected QT prolongation.

The relationship between stress and the development of diabetic complications.

Using the Life Events and Difficulties Schedule of Brown and Harris, the relationship between preceding stress and the onset of diabetic complications and premature death was investigated prospectively in a random sample of 130 patients with diabetes, aged 35-59 years. The presence of stress, assessed as severe life-events and severe long-term difficulties, was not significantly associated with premature death or the onset of macrovascular disease over the relatively short period of follow-up (4 years). Those who commenced anti-hypertensive therapy during the follow-up period were significantly more likely to have experienced five or more severe life-events during the previous 5 years (40 vs 6%, p less than 0.01), and also to have experienced one or more severe long-term difficulties during the same time period (60 vs 28%, p less than 0.05). A multiple Cox regression analysis showed that the effects of stress were independent of other factors such as baseline blood pressure, type of diabetes, sex, and ethnic group.

Mortality and causes of death in the WHO Multinational Study of Vascular Disease in Diabetes.

AIMS/HYPOTHESIS: We aimed to examine the mortality rates, excess mortality and causes of death in diabetic patients from ten centres throughout the world. METHODS: A mortality follow-up of 4713 WHO Multinational Study of Vascular Disease in Diabetes (WHO MSVDD) participants from ten centres was carried out, causes of death were ascertained and age-adjusted mortality rates were calculated by centre, sex and type of diabetes. Excess mortality, compared with the background population, was assessed in terms of standardised mortality ratios (SMRs) for each of the 10 cohorts. RESULTS: Cardiovascular disease was the most common underlying cause of death, accounting for 44 % of deaths in Type I (insulin-dependent) diabetes mellitus and 52 % of deaths in Type II (non-insulin-dependent) diabetes mellitus. Renal disease accounted for 21% of deaths in Type I diabetes and 11% in Type II diabetes. For Type I diabetes, all-cause mortality rates were highest in Berlin men and Warsaw women, and lowest in London men and Zagreb women. For Type II diabetes, rates were highest in Warsaw men and Oklahoma women and lowest in Tokyo men and women. Age adjusted mortality rates and SMRs were generally higher in patients with Type I diabetes compared with those with Type II diabetes. Men and women in the Tokyo cohort had a very low excess mortality when compared with the background population. CONCLUSION/INTERPRETATION: This study confirms the importance of cardiovascular disease as the major cause of death in people with both types of diabetes. The low excess mortality in the Japanese cohort could have implications for the possible reduction of the burden of mortality associated with diabetes in other parts of the world.

Risk factors, ethnic differences and mortality associated with lower-extremity gangrene and amputation in diabetes. The WHO Multinational Study of Vascular Disease in Diabetes.

AIMS/HYPOTHESIS: We aimed to examine geographic differences, risk factors and mortality associated with amputation. METHODS: Data from 10 of the original 14 centres of the WHO Multinational Study of Vascular Disease in Diabetes were used. This included 3443 men and women aged 35 to 55 years at baseline. RESULTS: Incidences of amputation, adjusted for sex and duration in Type I (insulin-dependent) diabetes mellitus, were 31.0, 8.2, 3.5 and 1.0 per 1,000 person years in the American Indian, Cuban, European and East Asian centres respectively. In Type II (non-insulin-dependent) diabetes mellitus, incidences of amputation were 9.7, 2.0, 2.5 and 0.7 per 1000 person years in the American Indian, Cuban, European and East Asian centres respectively. Key risk factors for amputation included glucose, triglyceride, and retinopathy, and were similar for American Indians and Europeans. The age, duration and sex adjusted relative risk for amputation in American Indians compared with Europeans was 11.48 (95% CI 3.56, 36.98) in Type I diabetes and 3.86 (95 % CI 2.36, 6.32) in Type II diabetes. Adjusting for heart disease, retinopathy, proteinuria, glucose, blood pressure and triglyceride attenuated these relative risks to 10.83 (95 % CI 3.20, 36.65) and 3.15 (1.91, 5.20) in Type I and Type II diabetes respectively. Amputation doubled mortality rates in all groups. CONCLUSION/INTERPRETATION: Vascular complications and their risk factors are themselves risk factors for amputation in both Type I and Type II diabetes and are common to several geographical regions worldwide. However, reasons for differences between geographical regions and the degree to which different health care systems could be responsible is not clear.