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OBJECTIVE: Rates of cardiovascular disease are highest in the elderly. Lipid-lowering statin therapy reduces the proportional risk as effectively in older patients as in younger individuals; however, limited data are available for elderly patients with type 2 diabetes. We conducted a post hoc analysis to compare the efficacy and safety of atorvastatin among 1,129 patients aged 65-75 years at randomization with 1,709 younger patients in the Collaborative Atorvastatin Diabetes Study (CARDS). RESEARCH DESIGN AND METHODS: CARDS was a randomized placebo-controlled trial of 10 mg/day atorvastatin for primary prevention of cardiovascular disease in patients aged 40-75 years with LDL cholesterol concentrations

For people with insulin-dependent diabetes mellitus (IDDM) renal disease represents a life-threatening and costly complication. The EURODIAB IDDM Complications Study, a cross-sectional, clinic-based study, was designed to determine the prevalence of renal complications and putative risk factors in stratified samples of European individuals with IDDM. The present study examined the relationship between dietary protein intake and urinary albumin excretion rate (AER). Food intake was assessed centrally by a standardized 3-day dietary record. Urinary AER was determined in a central laboratory from a timed 24-h urine collection. Complete data were available from 2696 persons with IDDM from 30 centres in 16 European countries. In individuals who reported protein consumption less than 20 % of total food energy intake, mean AER was below 20 μg/min. In those in whom protein intake constituted more than 20 %, mean AER increased, a trend particularly pronounced in individuals with hypertension and/or poor metabolic control. Trends reached statistical significance for intakes of total protein (% of energy, p = 0.01) and animal protein (% of energy, p = 0.02), while no association was seen for vegetable protein (p = 0.83). These findings support the current recommendation for people with diabetes not to exceed a protein intake of 20 % of total energy. Monitoring and adjustment of dietary protein appears particularly desirable for individuals with AER exceeding 20 μg/min (approximately 30 mg/24 h), especially when arterial pressure is raised and/or diabetic control is poor. [Diabetologia (1997) 40: 1219–1226]

Objectives: Repeatability of a dietary method is important in determining the quality of nutritional data. It should be assessed in the population of interest. This study evaluated the repeatability of nutritional data from standardized three-day dietary records, from the clinic-based, cross-sectional multi-centre EURODIAB IDDM Complications Study. Design and Subjects: 15% of the total EURODIAB cohort was randomly selected to test the repeatability of nutritional intake data. Two three-day records, completed three weeks apart, were available for 216 diabetic patients (7.5%) representative of the total cohort. All records were analysed centrally, for intakes of protein (animal and vegetable), fat (saturated fat and cholesterol), carbohydrate, fibre, alcohol and energy. Repeatability was measured comparing mean intakes, determining the proportion of patients classified into the same/opposite quartile by the two three-day records and assessing mean differences with standard deviations (s.d.d). Results: There were no significant differences in mean energy and nutrient intakes between the first and second records. Classification of individuals into the opposite quartile occurred only in 0–4% of patients and overall about 50% (range 44–74%) of the subjects were classified into the same quartiles of intakes. Only small mean differences were found for energy intake (−156 (1633) kJ; 95% confidence limits −375, 63 kJ) and nutrients with s.d.ds comparable to intra-individual variations in the general population. The differences in energy intake were randomly distributed over the range of intakes. Conclusions: The present study demonstrates that standardized three day dietary records show a high degree of repeatability within a short period of time in a sample of European IDDM patients. The good repeatability strengthens the conclusions drawn from the nutritional data in the EURODIAB IDDM Complications Study. Sponsorship: Nutrition Co-ordinating Centre research funds, Diabetes Research Institute at Heinrich-Heine University, Dusseldorf. The EURODIAB IDDM Complications Study was supported by the European Community.

Summary Background Retinopathy commonly occurs in people with type 1 diabetes. Strict glycaemic control can decrease development and progression of retinopathy only partially. Blood pressure is also a risk factor for microvascular complications. Antihypertensive therapy, especially with inhibitors of angiotensin-converting enzyme (ACE), can slow progression of nephropathy, but the effects on retinopathy have not been established. We investigated the effect of lisinopril on retinopathy in type 1 diabetes. Methods As part of a 2-year randomised double-blind placebo-controlled trial, we took retinal photographs at baseline and follow-up (24 months) in patients aged 20–59 in 15 European centres. Patients were not hypertensive, and were normoalbuminuric (85%) or microalbuminuric. Retinopathy was classified from photographs on a five-level scale (none to proliferative). Findings The proportion of patients with retinopathy at baseline was 65% (117) in the placebo group and 59% (103) in the lisinopril group (p=0·2). Patients on lisinopril had significantly lower HbA 1c at baseline than those on placebo (6·9% vs 7·3 p=0·05). Retinopathy progressed by at least one level in 21 (13·2%) of 159 patients on lisinopril and 39 (23·4%) of 166 patients on placebo (odds ratio 0·50 [95% Cl 0·28–0·89], p=0·02). This 50% reduction was the same when adjusted for centre and glycaemic control (0·55 [0·30–1·03], p=0·06). Lisinopril also decreased progression by two or more grades (0·27 [0·07–1·00], p=0·05), and progression to proliferative retinopathy (0·18 [0·04–0·82], p=0·03). Progression was not associated with albuminuric status at baseline. Treatment reduced retinopathy incidence (0·69 [0·30–1·59], p=0·4). Interpretation Lisinopril may decrease retinopathy progression in non-hypertensive patients who have type 1 diabetes with little or no nephropathy. These findings need to be confirmed before changes to clinical practice can be advocated.

Summary Background Renal disease in people with insulin-dependent diabetes (IDDM) continues to pose a major health threat. Inhibitors of angiotensin-converting enzyme (ACE) slow the decline of renal function in advanced renal disease, but their effects at earlier stages are unclear, and the degree of albuminuria at which treatment should start is not known. Methods We carried out a randomised, double-blind, placebo-controlled trial of the ACE inhibitor lisinopril in 530 men and women with IDDM aged 20–59 years with normoalbuminuria or microalbuminuria. Patients were recruited from 18 European centres, and were not on medication for hypertension. Resting blood pressure at entry was at least 75 and no more than 90 mm hg diastolic, and no more than 155 mm hg systolic. Urinary albumin excretion rate (AER) was centrally assessed by means of two overnight urine collections at baseline, 6, 12, 18, and 24 months. Findings There were no differences in baseline characteristics by treatment group; mean AER was 8.0 μg/min in both groups; and prevalence of microalbuminuria was 13% and 17% in the placebo and lisinopril groups, respectively. On intention-to-treat analysis at 2 years, AER was 2.2 μg/min lower in the lisinopril than in the placebo group, a percentage difference of 18.8% (95% CI 2·0–32·7, p=0·03), adjusted for baseline AER and centre, absolute difference 2.2 μg/min. In people with normoalbuminuria, the treatment difference was 1·0 μg/min (12·7% [−2·9 to 26·0], p=0·1). In those with microalbuminuria, however, the treatment difference was 34.2 μg/min (49·7% [−14·5 to 77·9], p=0·1; for interaction, p=0·04). For patients who completed 24 months on the trial, the final treatment difference in AER was 38·5 μg/min in those with microalbuminuria at baseline (p=0·001), and 0·23 μg/min in those with normoalbuminuria at baseline (p=0·6). There was no treatment difference in hypoglycaemic events or in metabolic control as assessed by glycated haemoglobin. Interpretation Lisinopril slows the progression of renal disease in normotensive IDDM patients with little or no albuminuria, though greatest effect was in those with microalbuminuria (AER ≥20 μg/min). Our results show that lisinopril does not increase the risk of hypoglycaemic events in IDDM.

OBJECTIVE To determine the extent that mortality in IDDM and NIDDM patients is inexcess of that of the general population and examine its relation to hypertension and proteinuriain diabetic patients. RESEARCH DESIGN AND METHODS A stratified random sample of 4,714 diabetic patients aged 35–55 years participating in the World Health Organization MultinationalStudy of Vascular Disease in Diabetes has been followed up from 1975 to 1987. Excess mortality,compared with the background population, was assessed in terms of standardized mortalityratios (SMRs) for each of the 10 international cohorts. The relationship between excess mortalityand proteinuria/hypertension was examined by diabetes type and sex. RESULTS SMRs were in general higher in patients with IDDM (ranging from 188 to 686 formen and from 336 to 790 for women) than with NIDDM (from 138 to 370 for men and from 126to 435 for women). For both diabetes types and in both sexes, SMRs decreased with increasingage and increased with increasing diabetes duration. Patients with both hypertension and proteinuria experienced a strikingly high mortality risk: 11-fold for men with IDDM and 18-fold forwomen with IDDM and 5-fold for men with NIDDM and 8-fold for women with NIDDM. Evenin the absence of proteinuria and hypertension, SMRs were significantly increased in both IDDM(284 men and 360 women) and NIDDM (192 men and 236 women) patients. CONCLUSIONS Considerable international differences were found not only in mortalityrates for the two types of diabetes but also in the extent of excess mortality among centers. IDDM patients had a high excess mortality in comparison with the general population. The significantexcess mortality was demonstrated even in patients without proteinuria and without hypertension for both sexes and diabetes types.

OBJECTIVE-Frequent episodes of severe hypoglycemia may increase the risk of cardiovascular disease (CVD) in people with diabetes. Our aim was to study the relationship between severe hypoglycemic episodes and CVD incidence in subjects with type 1 diabetes, and further, to assess if markers of inflammation/endothelial injury were enhanced in individuals who experienced hypoglycemic episodes. RESEARCH DESIGN AND METHODS-The prospective study included 2,181 type 1 diabetic patients from the EURODIAB Prospective Complications Study. At baseline, frequency of self-reported severe hypoglycemia, defined as episodes serious enough to require the help of another person, was assessed based on responses to a patient questionnaire. Both fatal/nonfatal CVD was assessed 7.3 years after baseline examination. At the follow-up visit, data on both severe and nonsevere hypoglycemic episodes in the previous year were collected through a questionnaire and markers of inflammation/stress response/endothelial injury measured by enzyme-linked immunosorbent assays in the 531 subjects of the nested case-control study, including 363 case subjects with one or more complications of diabetes and 168 control subjects with no evidence of any complication. RESULTS-During the follow-up period, 176 patients had incident CVD. Logistic regression analysis showed that severe hypoglycemia at the baseline examination was not associated with incidence of CVD (adjusted odds ratios [95% CI]: one to two episodes, 0.87 [0.55-1.3]; three or more episodes, 1.09 [0.68-1.75]). Furthermore, follow-up serum levels of markers of endothelial damage/inflammation were not cross-sectionally associated with the frequency of hypoglycemic episodes. CONCLUSIONS-Taken together our data do not support the hypothesis that in type 1 diabetes, severe hypoglycemia increases the risk of CVD. Diabetes Care 35:1598-1604,2012

2011 Jun;54(6):1298-303. Epub 2011 Jan 12. AIMS/HYPOTHESIS: The teratogenic consequences of angiotensin-converting enzyme inhibitors angiotensin receptor blockers (ARBs) during the second and third trimesters of pregnancy are well described. However, the consequences of exposure during the first trimester are unclear, especially in diabetes. We report the experience from DIRECT (DIabetic REtinopathy and Candesartan Trials), three placebo-controlled studies designed to examine the effects of an ARB, candesartan, on diabetic retinopathy. METHODS: Over 4 years or longer, 178 normotensive women with type 1 diabetes (86 randomised to candesartan, 32 mg once daily, and 92 assigned to placebo) became pregnant (total of 208 pregnancies). RESULTS: More than half of patients were exposed to candesartan or placebo prior to or in early pregnancy, but all discontinued it at an estimated 8 weeks from the last menstrual period. Full-term pregnancies (51 vs 50), premature deliveries (21 vs 27), spontaneous miscarriages (12 vs 15), elective terminations (15 vs 14) and other outcomes (1 vs 2) were similar in the candesartan and placebo groups. There were two stillbirths and two 'sick babies' in the candesartan group, and one stillbirth, eight 'sick babies' and one cardiac malformation in the placebo group. CONCLUSIONS/INTERPRETATION: The risk for fetal consequences of ARBs in type 1 diabetes may not be high if exposure is clearly limited to the first trimester. Long-term studies in fertile women can be conducted with ARBs during pregnancy, provided investigators diligently stop their administration upon planning or detection of pregnancy. TRIAL REGISTRATION: ClinicalTrials.gov DIRECT-Prevent 1 NCT00252733; DIRECT-Protect 1 NCT00252720; DIRECT-Protect 2 NCT00252694. FUNDING: The study was funded jointly by AstraZeneca and Takeda.

OBJECTIVE: The purpose of this study was to examine risk factors for mortality in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: Baseline risk factors were measured in the EURODIAB Prospective Cohort Study with 2, 787 type 1 diabetic patients (51% men and 49% women) recruited from 16 European countries. Mortality data were collected during a 7-year follow-up. RESULTS: There was an annual mortality rate of 5 per 1, 000 person-years in patients with type 1 diabetes (mean age at baseline 33 years, range 15-61 years) ; of the total 2, 787 subjects, 102 died. The final multivariable model contained age at baseline (standardized hazard ratio 1.78 [95% CI 1.44-2.20]), A1C (1.18 [0.95-1.46]), waist-to-hip ratio (WHR) (1.32 [1.14-1.52]), pulse pressure (1.33 [1.13-1.58]), and non-HDL cholesterol (1.33 [1.12-1.60]) as risk factors for all-cause mortality. Macroalbuminuria (2.39 [1.19-4.78]) and peripheral (1.88 [1.06-3.35]) and autonomic neuropathy (2.40 [1.32-4.36]) were the most important risk markers for mortality. Similar risk factors were found for all-cause, non-cardiovascular disease (CVD), unknown-cause, and CVD mortality. CONCLUSIONS: Important risk factors for the increased total and non-CVD mortality in type 1 diabetic patients are age, WHR, pulse pressure, and non-HDL cholesterol. Microvascular complications from macroalbuminuria and peripheral and autonomic neuropathy are strong risk markers for future mortality exceeding the effect of the traditional risk factors.

Aims/hypothesis Type 1 diabetes is associated with an increased risk of vascular complications. This increased risk could be explained by sialic acid and/or fibrinogen. It is also not clear what explains the abolition of sex-related differences affecting risk of CHD in the presence of type 1 diabetes. Therefore, we examined whether fibrinogen and sialic acid are related to incident micro- and macrovascular complications in patients with type 1 diabetes. Methods A subset (n = 2329) of the EURODIAB Prospective Complications Study was analysed. Sialic acid and fibrinogen concentrations were measured at baseline. The main outcomes after 7 years were development of albuminuria, retinopathy, neuropathy and CHD. Results Univariable and multivariable models using Cox proportional survival analyses showed that an SD unit increase in sialic acid and fibrinogen levels was significantly associated with CHD in men only. Adjusted standardised hazard ratios (sHRs) were 1.50 (95% CI 1.05–2.15) and 1.40 (95% CI 1.06–1.86) for sialic acid and fibrinogen, respectively. Initial associations between (1) sialic acid and incident retinopathy [standardised odds ratio (sOR) men 1.68, 95% CI 1.10–2.57], (2) fibrinogen and retinopathy (sOR women 1.37, 95% CI 1.06–1.78) and (3) sialic acid and neuropathy (sOR men 1.37, 95% CI 1.06–1.77) were shown, but became non-significant in multivariable models. Conclusions/interpretation Sialic acid and fibrinogen are strong predictors of CHD in men with type 1 diabetes, beyond the effect of established risk factors. The associations found with microvascular complications were not independent of other risk factors. Electronic supplementary material The online version of this article (doi:10.1007/s00125-007-0905-8) contains supplementary material and details of all EURODIAB Prospective Complications Study investigators and staff, and is available to authorised users.

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 these 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.

The EURODIAB IDDM Complications Study, a cross-sectional, clinic-based study, was designed to measure the prevalence of diabetic complications in stratified samples of European insulin-dependent diabetic (IDDM) patients. As diet may be related to diabetic complications, nutritional intake was analysed in the study population. The aims of this first nutritional paper are to describe the nutrient intake in 2868 IDDM patients from 30 centres in 16 countries throughout Europe, to investigate the degree of regional differences in nutrient intake and to compare current intakes with recommended levels. Nutritional intake from 1458 male and 1410 female IDDM patients was assessed by a validated 3-day record (two weekdays, Sunday) and centrally analysed. Mean energy intake for all patients was 2390 +/- 707 kcal/day. Mean protein intake was 1.5 +/- 0.5 g/kg body weight. Carbohydrate intake was 43% and fibre intake 18 g/day. Alcohol intake for the total cohort was 2% of energy. Total fat contributed 38% of energy, with 14% from saturated fat. The Italian centres reported lower total and saturated fat intakes compared with other centres. Recommendations from the Diabetes and Nutrition Study Group of the EASD for total fat, saturated fatty acids and carbohydrate were only achieved by 14%, 14% and 15% of patients, respectively. The data of the present study clearly indicate current problems in the nutritional intake of European IDDM patients. These findings contribute to the definition of future targets in the nutritional management of IDDM patients, to be achieved as part of the initiatives taken by the St. Vincent Declaration action programme.

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 ∼ 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.

OBJECTIVE - To study the relationship of nonproliferative and proliferative retinopathy with all-cause mortality and cardiovascular disease (CVD) incidence in type 1 diabetic patients and, additionally, the role of cardiovascular risk factors in these associations. RESEARCH DESIGN AND METHODS - This prospective study included 2,237 type 1 diabetic patients from 31 centers in 16 European countries at baseline, aged 15-60 years, who were examined for retinopathy by taking two-field 45 degrees fundus photographs, which were centrally graded. Mortality and cardiovascular morbidity follow-up was assessed 6-8 years after baseline examination according to a standardized protocol. RESULTS - After 7.9 years of follow-up, 64 patients had died and 128 patients had incident CVD. The age- and sex-adjusted hazard ratios (HRs) of all-cause mortality were 1.45 (95% CI 0.71-2.96) and 4.16 (1.96 - 8.84) in patients with nonproliferative and proliferative retinopathy at baseline, respectively. Adjustments for cardiovascular risk factors completely obliterated the association with nonproliferative retinopathy, whereas the association with proliferative retinopathy remained twofold increased, although nonsignificant. The age- and sex-adjusted HRs of incident CVD were 1.73 (1.15-2.60) and 2.05 (1.22-3.45) in patients with nonproliferative and proliferative retinopathy, respectively. After adjustments for cardiovascular risk factors, both associations were attenuated and lost statistical significance. CONCLUSIONS - This study shows that type 1 diabetic patients with nonproliferative or proliferative retinopathy have an increased risk for all-cause mortality and incident CVD. The presence of cardiovascular risk factors explained the associations to a large extent, except for the associations with proliferative retinopathy, which suggests that other shared mechanisms may be involved.

Several studies have shown an association between blood pressure and nephropathy, but few have been large enough to examine whether, or how, this relation is influenced by retinopathy. We have therefore examined the independent relations of blood pressure to urinary albumin excretion and retinopathy in a cross-sectional observational study of over 3000 insulin-dependent diabetic patients (the EURODIAB IDDM Complications Study). The relation of blood pressure to urinary albumin excretion differed strikingly between patients with (46%) and without (54%) retinopathy. In those with retinopathy, mean urinary albumin excretion rate was normal (20 micrograms/min) below median diastolic pressure (75 mmHg) and increased steeply (p0.001) with blood pressure above this level. However, in patients without retinopathy, mean albumin excretion rate was normal across the range of diastolic pressure. This finding could not be explained by differences in glycaemic control or duration of diabetes between patients with and without retinopathy. These data identify a subgroup of patients whose high risk of nephropathy may reflect abnormal renal vulnerability to mildly raised blood pressure. Retinopathy is a close correlate of this vulnerability. Detection of even mild retinopathy, together with raised blood pressure, may be important in assessing nephropathy risk.

OBJECTIVE To examine the relationship between smoking and both glycemic control and microvascular complications in patients with insulin-dependent diabetes mellitus (IDDM). RESEARCH DESIGN AND METHODS This was a prevalence survey of 3,250 men and women aged 15–60 years with IDDM from 31 diabetes centers in 16 European countries. Participants completed a questionnaire, had retinal photographs taken, and performed a 24-h urine collection. HbA1c, frequency of hypoglycemic and ketoacidotic episodes, urinary albumin excretion rates, and retinopathy were compared by smoking category. RESULTS The prevalence of smoking was 35% in men and 29% in women. Current smokers had poorer glycemic control and, among men, were more likely to have had a ketoacidotic episode than were those who never smoked. Ex-smokers had equivalent glycemic control and marginally more hypoglycemic episodes did than those who never smoked. Current smokers had a higher prevalence of microalbuminuria and total retinopathy than did those who never smoked. Ex-smokers had a higher prevalence of macroalbuminuria and proliferative retinopathy than did those who never smoked, but both had a similar prevalence of microalbuminuria. Adjustment for either current or long-term glycemic control could not fully account for these differences. CONCLUSIONS Smoking is associated with poorer glycemic control and an increased prevalence of microvascular complications compared with not smoking. Ex-smokers can achieve glycemic control equivalent to and have a prevalence of early complications similar to that of those who never smoked. We suggest that poorer glycemic control can account for some of the increased risk of complications in smokers, and that quitting smoking would be effective in reducing the incidence of complications. Urgent action is required to reduce the high smoking rates in people with IDDM.