WITHDRAWN: Antihypertensive therapy for preventing cardiovascular complications in people with diabetes mellitus.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

Autonomic neuropathy is associated with increased cardiovascular risk factors: the EURODIAB IDDM Complications Study.

AIMS: To assess the prevalence of and risk factors for autonomic neuropathy in the EURODIAB IDDM Complications Study. METHODS: The study involved the examination of randomly selected Type I (insulin-dependent) diabetic patients from 31 centres in 16 European countries. Neuropathic symptoms and two tests of autonomic function (changes in heart rate and blood pressure from lying to standing) were assessed and data from 3007 patients were available for the present analysis. Autonomic neuropathy was defined as an abnormality of at least one of the tests. RESULTS: The prevalence of autonomic neuropathy was 36% with no sex differences. The frequency of one and two abnormal reflex tests was 30% and 6%, respectively. The R-R ratio was abnormal in 24% of patients while 18% had orthostatic hypotension defined as a fall in systolic blood pressure > 20 mmHg on standing. Significant correlations were observed between autonomic neuropathy and age (P < 0.01), duration of diabetes (P < 0.0001), HbA1c (P < 0.0001), diastolic blood pressure (P < 0.05), lower HDL-cholesterol (P < 0.01), the presence of retinopathy (P < 0.0001) and albuminuria (P < 0.0001). New associations have been identified from the study: the strong relationship of autonomic neuropathy to cigarette smoking (P < 0.01), total cholesterol/HDL-cholesterol ratio (P < 0.05) and fasting triglyceride (P < 0.0001). As a key finding, autonomic neuropathy was related to the presence of cardiovascular disease (P < 0.0001). All analyses were adjusted for age, duration of diabetes and HbA1c. However, data have been only partly confirmed by logistic regression analyses. Frequency of dizziness on standing up was 18%, while only 4% of patients had nocturnal diarrhoea and 5% had problems with bladder control. CONCLUSION: Cardiovascular reflex tests, even in the form of the two tests applied, rather than a questionnaire, seem to be appropriate for the diagnosis of autonomic neuropathy. The study has identified previously known and new potential risk factors for the development of autonomic neuropathy, which may be important for the development of risk reduction strategies. Our results may support the role of vascular factors in the pathogenesis of autonomic neuropathy.

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 for renal failure: the WHO Mulinational Study of Vascular Disease in Diabetes.

AIMS/HYPOTHESIS: We aimed to examine risk factors for, and differences in, renal failure in diabetic patients from 10 centres. METHODS: Risk factors for renal failure were examined in 3,558 diabetic patients who did not have renal disease at baseline in the WHO Multinational Study of Vascular Disease in Diabetes (WHO MSVDD). RESULTS: In 959 subjects with Type I (insulin-dependent) diabetes mellitus and 2,559 with Type II (non-insulin-dependent) diabetes mellitus, the average follow-up was 8.4 years (+/- 2.7). By the end of the follow-up period 53 patients in the Type I diabetic group and 134 patients in the Type II diabetic group had developed renal failure (incidence rate 6.3:1,000 person years). Increasing age and duration of diabetes were associated with renal failure in Type II and Type I diabetes. In Type II diabetes duration of diabetes was a more important risk factor than age. In both Type I and Type II diabetic retinopathy and proteinuria were strongly associated with renal failure. Systolic blood pressure was associated with renal failure in Type I but not in Type II diabetic patients. ECG abnormalities at baseline, self-reported smoking and cholesterol were not associated with renal failure. Triglycerides were measured in a subset of centres. Among those with Type II, but not Type I diabetes, triglycerides were associated with renal failure independently of systolic blood pressure, proteinuria or retinopathy. In Type II diabetes fasting plasma glucose was associated with renal failure independently of other risk factors. CONCLUSION/INTERPRETATION: We have confirmed the role of proteinuria and retinopathy as markers of renal failure and the importance of hyperglycaemia in renal failure in Type I and Type II diabetes. Plasma triglycerides seem to be an important predictor of renal failure in Type II diabetes. In Type I diabetes systolic blood pressure is an important predictor of renal failure.

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

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.

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.

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.

Different risk factors of microangiopathy in patients with type I diabetes mellitus of short versus long duration. The EURODIAB IDDM Complications Study.

AIMS/HYPOTHESIS: To identify factors associated with early development of and late protection from microvascular complications in subjects with Type I (insulin-dependent) diabetes mellitus. METHODS: The frequency of microvascular complications and their relation to risk factors were studied in 300 Type I diabetic subjects with short duration of disease (< or = 5 years) compared with 1062 subjects with long duration (> or = 14 years). Microvascular disease was defined as the presence of either retinopathy (assessed from centrally-graded retinal photographs) or urinary albumin excretion rate of more than 20 micrograms/min. RESULTS: The prevalence of microvascular disease was 25% in the short duration group. In the long duration group 18% had no evidence of microvascular complications. In the short duration group factors associated with early development of complications were cigarette smoking and a family history of hypertension. Subjects free of microvascular complications in spite of long duration of diabetes had better glycaemic control, lower blood pressure, better lipid profile and lower von Willebrand factor levels. CONCLUSION/INTERPRETATION: At the early stages of Type I diabetes, cigarette smoking and genetic susceptibility to hypertension are important risk factors for microvascular complications. At a later stage, additional risk factors are poorer glycaemic control, higher blood pressure, and an unfavourable lipid profile possibly associated with endothelial dysfunction. Many of these factors are amenable to long-term intervention which should be started as soon as possible in the course of the disease.

Prevalence and management of hypertension in type 1 diabetes mellitus in Europe: the EURODIAB IDDM Complications Study.

AIM: To examine the prevalence of hypertension and the rates of hypertension awareness by investigating treatment and control among respondents to the EURODIAB IDDM Complications Study, and to explore the variation in hypertension management by age, sex and end-organ damage. METHODS: A cross-sectional study, examining 3250 randomly selected Type 1 diabetic patients from 31 diabetes clinics in 16 European countries between 1989 and 1990. Mean age was 32.7 years (SD= 10.0) and mean duration of diabetes mellitus (DM) was 14.7 years (SD=9.3). Subjects were asked about a history of high blood pressure (BP) and current prescribed medications were recorded by the subject's physician. Hypertension was defined as having a systolic BP > or = 140 mmHg or diastolic BP > or = 90 mmHg or current use of antihypertensives. Control was defined as a BP < 130/85 mmHg. RESULTS: Twenty-four per cent of subjects had hypertension, among whom fewer than one-half (48.5%) were aware of a previous diagnosis and a similar proportion (42.2%) were on treatment. Only 11.3% of those with hypertension were both treated and controlled. The majority (81%) of those receiving drug therapy for hypertension were on a single drug, most commonly an angiotensin-converting enzyme inhibitor (47%). CONCLUSION: These data show the extent of undermanagement of hypertension in Type 1 DM across Europe prior to the publication of the St. Vincent Declaration and provide a useful baseline against which future improvements in the management of hypertension can be monitored.

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.

Parental history of hypertension and parental history of diabetes and microvascular complications in insulin-dependent diabetes mellitus: the EURODIAB IDDM Complications Study.

Diabetic nephropathy clusters in families, suggesting an inherited predisposition. Parental history of hypertension and of Type 2 diabetes mellitus have been associated with nephropathy in offspring with Type 1 diabetes in some studies but not in others. The associations of parental history of hypertension and of diabetes with both albuminuria and proliferative retinopathy were studied in a large cross-sectional study of 3250 patients with Type 1 diabetes, from 16 European countries. Albuminuria was associated with hypertension in a parent (p < 0.01 in men, p < 0.05 in women), adjusted for age. Patients with a parental history of hypertension had a higher prevalence of hypertension (p < 0.001 in men, p < 0.01 in women) and a higher prevalence of parental diabetes (p < 0.001 in men, p < 0.001 in women). The association of albuminuria with parental hypertension was independent of parental diabetes in men but not women (OR = 1.28 in men p = 0.04, OR = 1.25 in women p = 0.09) and was not independent of hypertension in the patient him/herself in either sex. Albuminuria was associated with parental diabetes in women only (OR = 1.36, p = 0.04). This association was independent of both parental hypertension and hypertension in the patient herself. Proliferative retinopathy was not associated with parental hypertension or diabetes. The implications of these data are that both candidate genes for hypertension and Type 2 diabetes should be considered in the search for the genetic determinants of diabetic nephropathy.

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.

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.

Fibrinogen and von Willebrand factor in IDDM: relationships to lipid vascular risk factors, blood pressure, glycaemic control and urinary albumin excretion rate: the EURODIAB IDDM Complications Study.

The interrelationships between fibrinogen, von Willebrand factor, a marker of vascular endothelial cell damage, and serum lipids were explored in well-characterised subjects with insulin-dependent diabetes mellitus. The 2091 subjects were enrolled into a cross-sectional, clinic-based study of complications, from 16 European countries: the EURODIAB IDDM Complications study. The anticipated significant relationships between both plasma fibrinogen and plasma von Willebrand factor concentrations and age and glycaemic control, and between fibrinogen and body mass index, were noted. Fibrinogen, adjusted for age and glycated haemoglobin concentration, was also related to smoking habits and was higher in the quartiles with highest systolic and diastolic blood pressures. There was a clustering of vascular risk factors, with a positive relationship between plasma fibrinogen and serum triglyceride concentrations in both genders and between fibrinogen and total cholesterol in males. An inverse relationship between fibrinogen and high density lipoprotein cholesterol was also apparent in males. A prominent feature was a positive relationship between both fibrinogen and von Willebrand factor and albumin excretion rate (p < 0.001 and p < 0.003 respectively) in those with retinopathy but not in those without this complication. In view of previous observations on blood pressure and albuminuria in these subjects the findings are consistent with the hypothesis that microalbuminuria and increased plasma von Willebrand factor are due to endothelial cell perturbation in response to mildly raised blood pressure in subjects with retinopathy. Fibrinogen may also contribute to microvascular disease and its relationships to lipid vascular risk factors suggest a possible pathogenic role in arterial disease in diabetes.

Prevalence of diabetic peripheral neuropathy and its relation to glycaemic control and potential risk factors: the EURODIAB IDDM Complications Study.

The EURODIAB IDDM Complications Study involved the examination of 3250 randomly selected insulin-dependent diabetic patients, from 31 centres in 16 European countries. Part of the examination included an assessment of neurological function including neuropathic symptoms and physical signs, vibration perception threshold, tests of autonomic function and the prevalence of impotence. The prevalence of diabetic neuropathy across Europe was 28% with no significant geographical differences. Significant correlations were observed between the presence of diabetic peripheral neuropathy with age (p < 0.05), duration of diabetes (p < 0.001), quality of metabolic control (p < 0.001), height (p < 0.01), the presence of background or proliferative diabetic retinopathy (p < 0.01), cigarette smoking (p < 0.001), high-density lipoprotein cholesterol (p < 0.001) and the presence of cardiovascular disease (p < 0.05), thus confirming previous associations. New associations have been identified from this study - namely with elevated diastolic blood pressure (p < 0.05), the presence of severe ketoacidosis (p < 0.001), an increase in the levels of fasting triglyceride (p < 0.001), and the presence of microalbuminuria (p < 0.01). All the data were adjusted for age, duration of diabetes and HbA1c. Although alcohol intake correlated with absence of leg reflexes and autonomic dysfunction, there was no overall association of alcohol consumption and neuropathy. The reported problems of impotence were extremely variable between centres, suggesting many cultural and attitudinal differences in the collection of such information in different European countries. In conclusion, this study has identified previously known and new potential risk factors for the development of diabetic peripheral neuropathy.

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.

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.

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.

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.