Incidence of prolonged QTc and severe hypoglycemia in type 1 diabetes: the EURODIAB Prospective Complications Study.

AIMS: To assess the independent role of severe hypoglycemia on 7-year cumulative incidence of prolonged QTc in a large cohort of patients with type 1 diabetes. METHODS: People with type 1 diabetes recruited by the EURODIAB Prospective Complications Study who had normal QTc were examined at baseline and after 7 years with standardized methods (n = 1415; mean age ± SD 32.1 ± 9.6 years; diabetes duration 14.2 ± 8.8 years). Hypoglycemic episodes were assessed by a questionnaire. QTc was calculated according to Bazett's formula. In logistic regression analysis, we examined the role of severe hypoglycemia (none, 1-2, or 3 and more episodes/year) on the cumulative incidence of prolonged QTc, independently of age, sex, HbA1c, blood pressure, BMI, physical activity, distal symmetrical and autonomic neuropathy. RESULTS: In total, 264/1415 (17%) patients had incident prolonged QTc. Compared to those with persistently normal QTc, a greater proportion of incident cases had 3 and more hypoglycemic episodes at baseline (16.3 vs 11.2%, p = 0.03) and after 7 years (15.2 vs 9.6%, p = 0.01). In logistic regression analysis, 3 or more episodes of severe hypoglycemia at baseline did not increase cumulative incidence of prolonged QTc (OR 1.34, 95% CI 0.88-2.03). By contrast, severe hypoglycemia at the follow-up examination was associated with higher incidence of QTc prolongation (OR 1.68, 1.09-2.58), which reverted to not significant after adjustment for diabetic neuropathy. CONCLUSIONS: Severe hypoglycemia was not associated with incidence QTc prolongation in type 1 diabetic patients from the EURODIAB PCS.

Association of diet and lifestyle with glycated haemoglobin in type 1 diabetes participants in the EURODIAB prospective complications study.

BACKGROUND/OBJECTIVES: Diet and lifestyle advice for type 1 diabetes (T1DM) patients is based on little evidence and putative effects on glycaemic control. Therefore, we investigated the longitudinal relation between dietary and lifestyle variables and HbA1c levels in patients with type 1 diabetes. SUBJECTS/METHODS: A 7-year prospective cohort analysis was performed in 1659 T1DM patients (52% males, mean age 32.5 years) participating in the EURODIAB Prospective Complications Study. Baseline dietary intake was assessed by 3- day records and physical activity, smoking status and alcohol intake by questionnaires. HbA1c during follow-up was centrally assessed by immunoassay. Analysis of variance (ANOVA) and restricted cubic spline regression analyses were performed to assess dose-response associations between diet and lifestyle variables and HbA1c levels, adjusted for age, sex, lifestyle and body composition measures, baseline HbA1c, medication use and severe hypoglycaemic attacks. RESULTS: Mean follow-up of our study population was 6.8 (s.d. 0.6) years. Mean HbA1c level was 8.25% (s.d. 1.85) (or 66.6 mmol/mol) at baseline and 8.27% (s.d. 1.44) at follow-up. Physical activity, smoking status and alcohol intake were not associated with HbA1c at follow-up in multivariable ANOVA models. Baseline intake below the median of vegetable protein (<29 g/day) and dietary fibre (<18 g/day) was associated with higher HbA1c levels. Restricted cubic splines showed nonlinear associations with HbA1c levels for vegetable protein (P (nonlinear)=0.008) and total dietary fibre (P (nonlinear)=0.0009). CONCLUSIONS: This study suggests that low intake of vegetable protein and dietary fibre are associated with worse glycaemic control in type 1 diabetes.

Unhealthy dietary patterns associated with inflammation and endothelial dysfunction in type 1 diabetes: the EURODIAB study.

BACKGROUND AND AIMS: A healthy diet has been inversely associated with endothelial dysfunction (ED) and low-grade inflammation (LGI). We investigated the association between nutrient consumption and biomarkers of ED and LGI in type 1 diabetes. METHODS AND RESULTS: We investigated 491 individuals. Nutrient consumption and lifestyle risk factors were measured in 1989 and 1997. Biomarkers of ED (von Willebrand factor, soluble vascular cell adhesion molecule-1 and soluble endothelial selectin) and LGI (C-reactive protein, interleukin 6 and tumour necrosis factor α) were measured in 1997 and averaged into Z-scores. The nutrient residual method was used to adjust individual nutrient intake for energy intake. Data were analysed with generalised estimation equations. We report increments/decrements in nutrient consumption, averaged over time, per +1 standard deviation (SD) of 1997 ED or LGI Z-scores, after adjustment for sex, age, duration of diabetes, investigation centre, body mass index, energy intake, smoking behaviour, alcohol consumption, and each of the other nutrients. One SD elevation in ED Z-score was associated with a diet lower in fibre [ß(95%CI);-0.09(-0.18;-0.004)], polyunsaturated fat [-0.18(-0.31;-0.05)] and vegetable protein [-0.10(-0.20;-0.001)]. For the LGI Z-score results showed associations with fibre [-0.09(-0.17;-0.01)], polyunsaturated fat [-0.14(-0.24;-0.03)] and cholesterol [0.10(0.01; 0.18)]. CONCLUSION: In type 1 diabetes, consumption of less fibre, polyunsaturated fat and vegetable protein, and more cholesterol over the study period was associated with more ED and LGI. Following dietary guidelines in type 1 diabetes may reduce cardiovascular disease risk by favourably affecting ED and LGI.

Association of physical activity with all-cause mortality and incident and prevalent cardiovascular disease among patients with type 1 diabetes: the EURODIAB Prospective Complications Study.

AIMS/HYPOTHESIS: The aim of this study was to examine the association of physical activity (PA) with all-cause mortality and incident and prevalent cardiovascular disease (CVD) among patients with type 1 diabetes. METHODS: The EURODIAB Prospective Complications Study is a cohort including 3,250 male and female patients with type 1 diabetes (mean age 32.7 ± 10.2 years) from 16 European countries, of whom 1,880 participated in follow-up examinations. In analysis 1 (longitudinal), the association of baseline PA (based on the reported number of hours per week spent in mild, moderate and vigorous PA) with all-cause mortality and incident CVD was examined by performing survival analysis. In analysis 2 (cross-sectional), we focused on the association between PA at follow-up (data on sports, walking distance and regular bicycling) and prevalent CVD by performing logistic regression analysis. Adjustments were made for age, sex, BMI, smoking, consumption of alcohol, consumption of certain nutrients and diabetic complications. RESULTS: Analysis 1 (longitudinal): participation in moderate or vigorous PA once a week or more was borderline inversely associated with all-cause mortality (men and women combined) (HR 0.66, 95% CI 0.42, 1.03) and incident CVD (women only) (HR 0.66, 95% CI 0.40, 1.08). No association was found in men. Analysis 2 (cross-sectional): total PA (indexed by sports, walking, bicycling) and distance walked were inversely associated with prevalent CVD (OR(totalPA) 0.66, 95% CI 0.45, 0.97; and OR(walking) 0.61, 95% CI 0.42, 0.89). CONCLUSIONS/INTERPRETATION: PA showed a borderline inverse association with both all-cause mortality (both sexes) and incident CVD (women only) in patients with type 1 diabetes. Since this is an under-researched clinical population, future longitudinal studies with objective PA measurements are needed to expand on these results.

Dietary saturated fat and fibre and risk of cardiovascular disease and all-cause mortality among type 1 diabetic patients: the EURODIAB Prospective Complications Study.

AIMS/HYPOTHESIS: Low adherence to recommendations for dietary saturated fatty acid (SFA) and fibre intake in patients with type 1 diabetes mellitus may heighten their increased risk of cardiovascular disease (CVD) and mortality. We examined the relationship of SFA and total, soluble and insoluble fibre with incident CVD and all-cause mortality in type 1 diabetic patients. METHODS: A prospective cohort analysis was performed in 2,108 European type 1 diabetic patients aged 15-60 years who were free of CVD at baseline and enrolled in the EURODIAB Prospective Complications Study (51% male). Diet was assessed from a standardised 3 day dietary record. HR were calculated using Cox proportional hazards models. RESULTS: During a mean follow-up of 7.3 years, 148 incident cases of fatal and non-fatal CVD and 46 all-cause deaths were documented. No statistically significant association was found between SFA and CVD and all-cause mortality. Total dietary fibre, per 5 g/day, was associated with lower all-cause mortality risk (HR 0.72; 95% CI 0.55, 0.95). This association was stronger for soluble fibre (per 5 g/day, HR 0.34; 95% CI 0.14, 0.80) compared with insoluble fibre (per 5 g/day; HR 0.66; 95% CI 0.45, 0.97). Similar results were found for the association with CVD. CONCLUSIONS/INTERPRETATION: This study suggests that reported dietary SFA is not significantly associated with CVD and all-cause mortality in type 1 diabetic patients. On the contrary, higher dietary fibre consumption, especially soluble fibre, within the range commonly consumed by type 1 diabetic patients, may contribute to the prevention of CVD and all-cause mortality in type 1 diabetic patients.

Exposure to candesartan during the first trimester of pregnancy in type 1 diabetes: experience from the placebo-controlled DIabetic REtinopathy Candesartan Trials.

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.

Helping students become the medical teachers of the future--the Doctors as Teachers and Educators (DATE) Programme of Barts and the London School of Medicine and Dentistry, London.

CONTEXT: In the United Kingdom (UK), learning about teaching is an integral part of the General Medical Council's recommendations for the undergraduate medical curriculum. Yet often, implementing this aspect of learning presents a challenge to curriculum organisers in terms of content, timing and student interest. PROGRAMME OBJECTIVES AND STRUCTURE: The Doctors as Teachers and Educators (DATE) programme was set up at Barts and the London School of Medicine and Dentistry specifically to meet the requirements for development in teaching. Although largely practical, the two-day programme offers an introduction to educational theory and the teaching requirements for junior doctors in training. The methods used are lectures and group work within plenary sessions, followed by small group micro-teaching sessions. The DATE programme has now been undertaken by over 900 graduates. EVALUATION METHODS: We evaluated the Date programme by means of end-of-course questionnaires completed by two cohorts of students during the 2007/8 academic year and through the use of Nominal Group Technique in 2008/9. In line with the goals of the evaluation, the data on students' views were analysed to elicit self-reported learning and develop the programme. RESULTS: Response rates of the two cohorts to the surveys were high (80% and 98%). Nearly 100% of the students reported through the survey that they had gained confidence in teaching. In the nominal groups, students indicated that they had gained insight into educational principles like student-centredness and gained an appreciation for the nature of educational evidence and scholarship. They challenged the curriculum organisers to achieve an appropriate balance between theory and practice. CONCLUSIONS: A programme about teaching at the undergraduate medical level can be well-received by students; the DATE model could be transferred to other international contexts.

Progression to microalbuminuria in type 1 diabetes: development and validation of a prediction rule.

AIMS/HYPOTHESIS: Microalbuminuria is common in type 1 diabetes and is associated with an increased risk of renal and cardiovascular disease. We aimed to develop and validate a clinical prediction rule that estimates the absolute risk of microalbuminuria. METHODS: Data from the European Diabetes Prospective Complications Study (n = 1115) were used to develop the prediction rule (development set). Multivariable logistic regression analysis was used to assess the association between potential predictors and progression to microalbuminuria within 7 years. The performance of the prediction rule was assessed with calibration and discrimination (concordance statistic [c-statistic]) measures. The rule was validated in three other diabetes studies (Pittsburgh Epidemiology of Diabetes Complications [EDC] study, Finnish Diabetic Nephropathy [FinnDiane] study and Coronary Artery Calcification in Type 1 Diabetes [CACTI] study). RESULTS: Of patients in the development set, 13% were microalbuminuric after 7 years. Glycosylated haemoglobin, AER, WHR, BMI and ever smoking were found to be the most important predictors. A high-risk group (n = 87 [8%]) was identified with a risk of progression to microalbuminuria of 32%. Predictions showed reasonable discriminative ability, with c-statistic of 0.71. The rule showed good calibration and discrimination in EDC, FinnDiane and CACTI (c-statistic 0.71, 0.79 and 0.79, respectively). CONCLUSIONS/INTERPRETATION: We developed and validated a clinical prediction rule that uses relatively easily obtainable patient characteristics to predict microalbuminuria in patients with type 1 diabetes. This rule can help clinicians to decide on more frequent check-ups for patients at high risk of microalbuminuria in order to prevent long-term chronic complications.

ANTI-HSP60 and ANTI-HSP70 antibody levels and micro/ macrovascular complications in type 1 diabetes: the EURODIAB Study.

OBJECTIVES: The heat shock proteins 60 and 70 (HSP60, HSP70) play an important role in cytoprotection. Under stress conditions they are released into the circulation and elicit an immune response. Anti-HSP60 and anti-HSP70 antibody levels have been associated with cardiovascular disease. Type 1 diabetes is associated with a greatly increased risk of micro- and macrovascular complications. Therefore, we investigated whether anti-HSP60 and anti-HSP70 antibody levels were associated with micro- and macrovascular complications in type 1 diabetic patients. DESIGN: A cross-sectional nested case-control study from the EURODIAB Study of 531 type 1 diabetic patients was performed. SUBJECTS: Cases (n = 363) were defined as those with one or more complications of diabetes; control subjects (n = 168) were all those with no evidence of any complication. We measured anti-HSP60 and anti-HSP70 antibody levels and investigated their cross-sectional associations with diabetic complications. RESULTS: Anti-HSP70 antibody levels were significantly greater in control than in case subjects, whereas anti-HSP60 antibody levels were similar in the two groups. In logistic regression analysis, anti-HSP70 levels in the upper quartiles were associated with a 47% reduced odds ratio of micro/macrovascular complications, independently of conventional risk factors, markers of inflammation and endothelial dysfunction [odds ratio (OR) = 0.53, 95% confidence intervals (CI): 0.28-1.02]. CONCLUSIONS: In this large cohort of type 1 diabetic subjects, we found an independent and inverse association between serum anti-HSP70 antibody levels and diabetic micro/macrovascular complications. This suggests that anti-HSP70 antibody levels may be a novel marker of protection from chronic diabetic complications.

Levels of soluble receptor for AGE are cross-sectionally associated with cardiovascular disease in type 1 diabetes, and this association is partially mediated by endothelial and renal dysfunction and by low-grade inflammation: the EURODIAB Prospective Complications Study.

AIMS/HYPOTHESIS: Plasma soluble receptor for AGE (sRAGE) may reflect the activity of the AGE-RAGE axis, which has been proposed as a potential mechanism linking hyperglycaemia to vascular complications in diabetes. We have therefore investigated: (1) whether sRAGE is associated with greater prevalence of cardiovascular disease (CVD) and microvascular complications in type 1 diabetic individuals; and (2) the extent to which any such associations are explained by markers of endothelial and renal dysfunction and inflammation. METHODS: The study included 477 individuals (234 women; mean age 42 +/- 10 [SD] years) from the EURODIAB Prospective Complications Study. We used linear regression analyses to investigate the differences in sRAGE levels between individuals with and without vascular complications. All analyses were adjusted for age, sex, HbA(1c), duration of diabetes and other risk factors. RESULTS: Individuals with CVD (n = 116) had higher levels of sRAGE than those without CVD or any microvascular complications (n = 178): beta = 0.15 (95% CI 0.04-0.27). Further adjustments for markers of endothelial (beta = 0.13 [0.02-0.24]) and renal dysfunction (beta = 0.10 [-0.01, 0.20]) and inflammation (beta = 0.12 [0.01-0.23]) attenuated these differences; altogether these variables explained about 50% of the association between sRAGE and prevalent CVD. sRAGE levels tended to be higher in the presence and across the levels of severity of albuminuria (p for trend = 0.087) and retinopathy (p for trend = 0.057); adjustments for endothelial and renal dysfunction and inflammation also attenuated these differences. CONCLUSIONS/INTERPRETATION: sRAGE is associated with greater prevalence of CVD in type 1 diabetic individuals, and these associations may be partly explained by endothelial and renal dysfunction and low-grade inflammation.

Alcohol consumption and risk of microvascular complications in type 1 diabetes patients: the EURODIAB Prospective Complications Study.

AIMS/HYPOTHESIS: The aim of this study was to investigate the association between alcohol consumption and risk of microvascular complications (retinopathy, neuropathy, nephropathy) in type 1 diabetes mellitus patients in the EURODIAB Prospective Complications Study. METHODS: The EURODIAB Prospective Complications Study is a follow-up study including 3,250 type 1 diabetes mellitus patients from 16 different European countries. We investigated the cross-sectional association between moderate alcohol consumption and risk of retinopathy, neuropathy and nephropathy among 1,857 of these patients. RESULTS: We documented 304 cases of proliferative retinopathy, 660 cases of neuropathy and 157 cases of nephropathy (macroalbuminuria). Alcohol consumption was associated with risk of proliferative retinopathy, neuropathy and macroalbuminuria in a U-shaped fashion. Moderate consumers (30-70 g alcohol per week) had a lower risk of microvascular complications with odds ratios of 0.60 (95% CI 0.37-0.99) for proliferative retinopathy, 0.61 (0.41-0.91) for neuropathy and 0.36 (0.18-0.71) for macroalbuminuria in multivariate-adjusted models. These results were similar when excluding patients who had been advised to drink less alcohol because of their health. The relation was most pronounced for alcohol consumption from wine. Drinking frequency was significantly, inversely associated with risk of neuropathy, but a similar trend was visible for proliferative retinopathy and macroalbuminuria. Alcohol consumption was not associated with occurrence of ketoacidosis or hypoglycaemic attacks. CONCLUSIONS/INTERPRETATION: Consistent with its effects on macrovascular complications, moderate alcohol consumption is associated with a lower risk of all microvascular complications among type 1 diabetes patients.

Antibodies to periodontal pathogens and coronary artery calcification in type 1 diabetic and nondiabetic subjects.

BACKGROUND AND OBJECTIVE: The aim of this study was to examine whether serum immunoglobulin G (IgG) levels to Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans are higher in type 1 diabetic patients than in controls and are associated with coronary artery calcification, a measure of atherosclerosis. MATERIAL AND METHODS: One-hundred and ninety nine type 1 diabetic patients (mean age 38 +/- 4 years) and 201 age- and gender-matched nondiabetic subjects had coronary artery calcification, as measured by electron beam computed tomography. Serum IgG levels to P. gingivalis W50 and to A. actinomycetemcomitans HK1651 whole cells were measured by enzyme-linked immunosorbent assay. RESULTS: A similar proportion of diabetic patients (29%) and controls (31%, p = 0.7) had elevated serum IgG to periodontal bacteria, defined as being above the median antibody level for both microorganisms. Elevated antibody levels were associated with higher systolic blood pressure (p = 0.02) and an increased odds of coronary artery calcification in all subjects combined (odds ratio = 1.7, p = 0.047) and in diabetic subjects examined separately (odds ratio = 2.01, p = 0.027). Association of serum IgG levels with coronary artery calcification was independent of social class, lipids and antibody levels to other microorganisms, but not systolic blood pressure (odds ratio = 1.4, p = 0.1 on adjustment for blood pressure). There was no association between serum IgG level and vascular endothelial function. CONCLUSION: Elevated levels of serum IgG to P. gingivalis and A. actinomycetemcomitans are associated with coronary artery atherosclerosis. This may reflect a direct role for periodontal infection or a role for the host response to infection in coronary atherosclerosis, particularly in patients with type 1 diabetes.

Relationship between plasma sialic acid and fibrinogen concentration and incident micro- and macrovascular complications in type 1 diabetes. The EURODIAB Prospective Complications Study (PCS).

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.

Cost-effectiveness of primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes: results from the Collaborative Atorvastatin Diabetes Study (CARDS).

AIMS/HYPOTHESIS: We estimated the cost-effectiveness of atorvastatin treatment in the primary prevention of cardiovascular disease in patients with type 2 diabetes using data from the Collaborative Atorvastatin Diabetes Study (CARDS). SUBJECTS AND METHODS: A total of 2,838 patients, who were aged 40 to 75 years and had type 2 diabetes without a documented history of cardiovascular disease and without elevated LDL-cholesterol, were recruited from 32 centres in the UK and Ireland and randomly allocated to atorvastatin 10 mg daily (n = 1,428) or placebo (n = 1,410). These subjects were followed-up for a median period of 3.9 years. Direct treatment costs and effectiveness were analysed to provide estimates of cost per endpoint-free year over the trial period for alternative definitions of endpoint, and of cost per life-year gained and cost per quality-adjusted life-year (QALY) gained over a patient's lifetime. RESULTS: Over the trial period, the incremental cost-effectiveness ratio (ICER) was estimated to be 7,608 pounds per year free of any CARDS primary endpoint; the ICER was calculated to be 4,896 pounds per year free of any cardiovascular endpoint and 4,120 pounds per year free of any study endpoint. Over lifetime, the incremental cost per life-year gained was 5,107 pounds and the cost per QALY was 6,471 pounds (costs and benefits both discounted at 3.5%). CONCLUSIONS/INTERPRETATION: Primary prevention of cardiovascular disease with atorvastatin is a cost-effective intervention in patients with type 2 diabetes, with the ICER for this intervention falling within the current acceptance threshold ( 20,000 pounds per QALY) specified by the National Institute for Health and Clinical Excellence (NICE).

Weight gain is associated with improved glycaemic control but with adverse changes in plasma lipids and blood pressure isn Type 1 diabetes.

AIMS: To assess the effects of weight gain on metabolic control, plasma lipids and blood pressure in patients with Type 1 diabetes. METHODS: Patients in the EURODIAB Prospective Complications Study (n = 3250) were examined at baseline and 1800 (55%) were re-examined a mean of 7.3 years later. Patients had Type 1 diabetes, defined as a diagnosis made before age 36 years and with a need for continuous insulin therapy within a year of diagnosis. Patients were aged 15-60 years at baseline and were stratified for age, sex and duration of diabetes. RESULTS: The change in HbA(1c) from baseline to follow-up examination was significantly more favourable in those who gained 5 kg or more during follow-up ('marked weight gain') than in patients who gained less or no weight or lost weight ('less or no weight gain'). In those with marked weight gain, there was a significantly greater rise in plasma triglycerides and total cholesterol and significantly less favourable changes in low-density lipoprotein and high-density lipoprotein cholesterol compared with those with less or no weight gain, with or without adjustment for HbA(1c). Systolic and diastolic blood pressure also rose significantly more in the group with marked weight gain. CONCLUSION: Weight gain in patients with Type 1 diabetes has adverse effects on plasma lipids and blood pressure, despite a small improvement in glycaemic control.

All-cause mortality rates in patients with type 1 diabetes mellitus compared with a non-diabetic population from the UK general practice research database, 1992-1999.

AIMS/HYPOTHESIS: We compiled up to date estimates of the absolute and relative risk of all-cause mortality in patients with type 1 diabetes in the UK. MATERIALS AND METHODS: We selected patients with type 1 diabetes (n=7,713), and for each of these diabetic subjects five age- and sex-matched control subjects without diabetes (n=38,518) from the General Practice Research Database (GPRD). Baseline was 1 January 1992; subjects were followed until 1999. The GPRD is a large primary-care database containing morbidity and mortality data of a large sample representative of the UK population. Deaths occurring in the follow-up period were identified. RESULTS: The study comprised 208,178 person-years of follow-up. The prevalence of type 1 diabetes was 2.15/1,000 subjects in 1992 (mean age 33 years, SD 15). Annual mortality rates were 8.0 per 1,000 person-years (95% CI 7.2-8.9) in type 1 diabetic subjects compared with 2.4 per 1,000 person-years (95% CI 2.2-2.6) in those without diabetes (hazard ratio [HR]=3.7, 95% CI 3.2-4.3). The increased mortality rates in patients with type 1 diabetes were apparent across all age-bands. The HR was higher in women (HR=4.5, 95% CI 3.5-5.6 compared with non-diabetic women) than men (HR=3.3, 95% CI 2.7-4.0), such that the sex difference (p<0.0001) in mortality in the non-diabetic population was abolished (p=0.3) in the type 1 diabetic patients. The predominant cause of death in patients with type 1 diabetes was cardiovascular disease. CONCLUSIONS/INTERPRETATION: Despite advances in care, UK mortality rates in the past decade continue to be much greater in patients with type 1 diabetes than in those without diabetes.

Rapid emergence of effect of atorvastatin on cardiovascular outcomes in the Collaborative Atorvastatin Diabetes Study (CARDS).

AIMS/HYPOTHESIS: The aim of this study was to determine the pattern of the effect of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin on cardiovascular events in patients with type 2 diabetes and no prior history of cardiovascular disease (CVD). MATERIALS AND METHODS: A post hoc analysis of data from the Collaborative Atorvastatin Diabetes Study (CARDS), a randomised, placebo-controlled trial of 2,838 patients with type 2 diabetes, was performed. Patients received atorvastatin (10 mg daily) or placebo and were evaluated for cardiovascular and other outcomes over a median follow-up period of 3.9 years. Cox proportional hazards modelling was carried out, and the hazard ratios calculated for various times after randomisation to treatment were investigated. RESULTS: A reduction in the primary endpoint of major CVD events was apparent and statistically significant as soon as 18 months after treatment initiation. The effect of atorvastatin on CHD events was apparent by 6 months, and at 1 year was similar to the 37% relative risk reduction observed at trial closure. CONCLUSIONS/INTERPRETATION: Atorvastatin alters the pathogenesis of CVD rapidly, such that the effect on cardiovascular events is apparent within months of initiation of therapy.

Is pregnancy a risk factor for microvascular complications? The EURODIAB Prospective Complications Study.

AIMS: To examine the long-term influence of pregnancy on the development and progression of microvascular complications in Type 1 diabetes. METHODS: In the EURODIAB Prospective Complications Study (PCS), 793 women potentially child bearing at baseline completed the follow-up (7.3 years) and 163 (21%) gave birth during the follow-up period. We compared risk factors [mean levels of age, duration of diabetes, HbA(1c), systolic blood pressure (SBP) and proportion giving birth] between those that did or did not develop microvascular complications during the follow-up period. RESULTS: For the 425 childless women at baseline, 102 gave birth during follow-up. HbA(1c) was a significant risk factor for progression to microalbuminuria but age, duration of diabetes, systolic blood pressure or giving birth were not. Duration of diabetes and high HbA(1c) were significant risk factors for progression to proliferative retinopathy, whereas giving birth was not. Similar results were obtained for progression to any form of retinopathy. Giving birth was not significantly related to the incidence of neuropathy. Similar results were obtained for women with children at baseline giving birth during follow-up (n = 61/368). CONCLUSIONS: In this European study, having a first or another pregnancy did not seem to be a risk factor for long-term progression of any microvascular complication. This is in accordance with the findings of the Diabetes Control and Complications Trial (DCCT).

Plasma homocysteine and microvascular and macrovascular complications in type 1 diabetes: a cross-sectional nested case-control study.

OBJECTIVES: To examine the independent relationship between plasma total homocysteine (tHcy) and microvascular and macrovascular complications. DESIGN: We performed a cross-sectional nested case-control study from the EURODIAB Prospective Complications Study. SETTING: A hospital-based multicentre study at 24 centres in 13 European countries. SUBJECTS: A total of 533 type 1 diabetic patients, diagnosed at <36 years of age. Cases (n=359) were defined as those with one or more complications of diabetes and control subjects (n=174) were all those with no evidence of any complication. Main outcome measures. Retinopathy, albumin excretion rate (AER), glomerular filtration rate (GFR) estimated by Cockcroft-Gault formula, hypertension and cardiovascular disease (CVD) were assessed. RESULTS: In unadjusted models, tHcy (per 5 micromol L(-1)) was significantly associated with nonproliferative retinopathy (OR=1.45, 95% CI: 1.10-1.91), proliferative retinopathy (OR=1.74, 95% CI: 1.34-2.27), macroalbuminuria (OR=1.90, 95% CI: 1.49-2.42), hypertension (OR=2.23, 95% CI: 1.69-2.93) and CVD (OR=1.59, 95% CI: 1.18-2.14). In multivariate models, tHcy was significantly related to macroalbuminuria (OR=1.66, 95% CI: 1.24-2.24) and hypertension (OR=1.57, 95% CI: 1.19-2.07), independent of age, sex, diabetes duration, GFR, microvascular and macrovascular complications and cardiovascular risk factors. There was a significant relationship between tHcy and decreased GFR, independent of established risk factors. The relationship between tHcy and retinopathy was not independent of albuminuria or GFR. The initial positive relationship with CVD was explained by cardiovascular risk factors. CONCLUSION: In this large study of European type 1 diabetic subjects, increased concentrations of tHcy were independently related to macroalbuminuria, renal function and hypertension, which suggests that tHcy might play an important role in the pathogenesis of vascular complications in type 1 diabetes.

Markers of inflammation are cross-sectionally associated with microvascular complications and cardiovascular disease in type 1 diabetes--the EURODIAB Prospective Complications Study.

AIMS/HYPOTHESIS: The pathogenesis of vascular complications in type 1 diabetes is poorly understood, but may involve chronic, low-grade inflammation. We investigated the association of markers of inflammation with vascular complications in type 1 diabetes. METHODS: A cross-sectional nested case-control study of the follow-up data of the EURODIAB Prospective Complications Study. This study included 543 individuals (278 men) with type 1 diabetes diagnosed at <36 years of age. Cases (n=348) had complications of diabetes, controls (n=195) had no complications. RESULTS: C-reactive protein, interleukin-6 and tumour necrosis factor-alpha levels, which were combined in an inflammatory marker Z-score, were associated with albuminuria, retinopathy and cardiovascular disease. Calculated means (95% confidence intervals) of the marker Z-score were -0.15 (-0.22 to -0.07), 0.10 (-0.05 to 0.25), and 0.28 (0.15 to 0.41), p for trend <0.0001, in individuals with normo-, micro- and macroalbuminuria; -0.23 (-0.33 to -0.13), 0.14 (0.02 to 0.25) and 0.20 (0.07 to 0.32), p for trend <0.0001, in individuals with no, non-proliferative and proliferative retinopathy; and -0.28 (-0.39 to -0.18) and 0.06 (-0.08 to 0.20), p<0.001, in individuals without and with cardiovascular disease. Per 1 SD increase of the inflammatory marker Z-score, GFR decreased by -4.6 (-6.6 to -2.6) ml per min per 1.73 m(2) (p<0.001). CONCLUSIONS/INTERPRETATION: We have shown that markers of inflammation are strongly and independently associated with microvascular complications and cardiovascular disease in type 1 diabetes. These data suggest that strategies to decrease inflammatory activity may help to prevent the development of vascular complications in type 1 diabetes.