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There are few published trial data on the effectiveness of lipid lowering in diabetic patients with impaired renal function. CARDS was a randomised placebo-controlled trial of atorvastatin 10 mg daily versus placebo in 2838 type 2 diabetic patients with no prior cardiovascular disease. Estimated glomerular filtration rate (eGFR) was assessed at baseline in 2744 patients with renal data using the Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault equations. Cox proportional hazards models with adjustment for age and sex were used to establish whether baseline eGFR status (≥60 and <60 ml/min/1.73 m²) predicted risk of a major cardiovascular event (MCVE) and whether the efficacy of atorvastatin differed by baseline eGFR by testing for a treatment by eGFR interaction. At baseline, 967 patients (35%) had MDRD eGFR <60 mL/min/1.73 m². Compared to those with eGFR ≥60 mL/min/1.73 m², these patients were older, comprised more women and, adjusted for age and sex, did not have higher blood pressure, body mass index or lipid levels, but were more likely to be taking medications for hypertension and less likely to be smokers. During follow-up patients with eGFR <60 mL/min/1.73 m² were not at increased risk of MCVE (HR=0.99, p=0.96) or death (HR=1.25, p=0.28) compared to patients with eGFR ≥60 mL/min/1.73 m², although without adjustment their risk of death was higher (HR=1.50, p=0.04). These results were similar when the Cockcroft-Gault equation was used to estimate GFR. The treatment reduction in MCVE among all subjects with renal data at baseline was 41% (p<0.001). Among those with eGFR <60 mL/min/1.73 m², a similar treatment effect of atorvastatin was seen, with a 48% reduction in MCVE including a 42% reduction in acute coronary heart disease event, a 62% reduction in stroke and a 59% reduction in coronary revascularisation (p>0.25 for all tests of eGFR by treatment interaction). The absolute risk reduction in MCVE associated with atorvastatin over a median of 4 years was 3.8% in those with eGFR <60 mL/min/1.73 m² compared to 3.0% in those with eGFR ≥60 mL/min/1.73 m². These data show that atorvastatin 10 mg daily is equally efficacious in reducing coronary heart disease and stroke in diabetic patients with impaired renal function as in those with normal or near normal renal function. [ABSTRACT FROM AUTHOR]

Reports on a cross sectional study which uses coronary artery calcification to determine whether socioeconomic status affects the likelihood of coronary artery disease in participants between the ages of 30 and 40. Methodology including the random sampling of patients from two general practices; Classification of different social classes according to occupation and education; Indications that socioeconomic differences are recognizable in calcification levels.

A letter to the editor is presented in response to the article regarding the study of the Diabetic Retinopathy Candesartan Trials (DIRECT) Programe for the potentials of candesartan treatment in reducing retinopathy incidence in type 1 diabetic patients.

OBJECTIVE Diabetes-associated autoantibodies can be detected in adult-onset diabetes, even when initially non-insulin requiring, i.e., with latent autoimmune diabetes. We aimed to identify adult-onset autoimmune diabetes in patients with established "type 2 diabetes" participating in the Collaborative Atorvastatin Diabetes Study (CARDS) to characterize their phenotype and clinical outcome. RESEARCH DESIGN AND METHODS We prospectively studied 2,425 European patients with presumed type 2 diabetes (mean age 62 years, diabetes duration 7.9 years) for outcomes at 3.9 years after randomization to either atorvastatin or placebo. Subjects were screened for autoantibodies to GAD (GADA), insulinoma-associated antigen-2 (IA-2A), and zinc-transporter 8 (ZnT8A). RESULTS A total of 173 patients (7.1%) had GADA, of whom 11 (0.5%) and 5 (0.2%) were also positive for IA-2A and ZnT8A, respectively. At baseline, 44% of GADA-positive patients were not on insulin. Fewer autoantibody-positive than autoantibody-negative patients had metabolic syndrome (64 vs. 80%), and more were on insulin (56 vs. 17%) (P < 0.0001 for each) without lower HbA1c (69 mmol/mol [8.5%] vs. 62 mmol/mol [7.8%]). The frequency of microvascular and macrovascular events was similar in both cohorts, independent of atorvastatin. CONCLUSIONS Adult-onset autoimmune diabetes was prevalent, even in patients with established diabetes presumed to have type 2 diabetes. After 11.8 years' diabetes duration, nearly half the patients with autoimmune diabetes were not on insulin treatment and almost two-thirds had metabolic syndrome. The type of diabetes, whether autoimmune diabetes or type 2 diabetes, did not impact the risk of microvascular disease. [ABSTRACT FROM AUTHOR]

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 [0.55-1.37]; 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. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Circulating levels of soluble receptor for advanced glycation end products (sRAGE) likely comprise both a secreted isoform (esRAGE) and wild-type RAGE cleaved from the cell membrane. Both sRAGE , and esRAGE have been proposed as biomarkers of cardiovascular disease (CVD), but prospective data are limited. We examined the relationship of sRAGE mid esRAGE to incident coronary heart disease (CHD) and stroke in type 2 diabetic patients followed for 3.9 years in a trial of atorvastatin: the Collaborative Atorvastatin Diabetes Study (CARDS). RESEARCH DESIGN AND METHODS--We used a nested case-control design sampling all incident cases of CVD with available plasma and randomly selecting three control subjects, who were free of CVD throughout follow-up, per case. Analysis was by Cox regression with adjustment for treatment allocation and relevant covariates. RESULTS--sRAGE and esRAGE were strongly correlated (ρ = 0.88) and were both higher in those with lower BMI (P < 0.001), higher adiponectin (P < 0.001), lower estimated glomerular filtration rate (P = 0.009), and white ethnicity (P < 0.001). Both sRAGE mid esRAGE were associated with incident CHD events, independently of treatment allocation and the above factors; hazard ratio (HR) = 1.74 (95% CI 1.25-2.41; P = 0.002) for a doubling of the sRAGE level; HR = 1.45 ( 1.11-1.89; P = 0.006) for a doubling of the esRAGE level. There was no significant association with stroke; HR for sRAGE = 0.66 (0.38-1.14). Atorvastatin, 10 mg daily, did not alter sRAGE. CONCLUSIONS--Higher levels of sRAGE and esRAGE are associated with incident CHD but not stroke in type 2 diabetes. [ABSTRACT FROM AUTHOR]

Objective: Slow nerve conduction velocity and reduction in response amplitude are objective hallmarks of diabetic sensorimotor polyneuropathy. Because subjective or clinical indicators of neuropathy do not always match well with the presence of abnormal nerve physiology tests, we evaluated associations to nerve conduction in patients with type 1 diabetes.Research Design and Methods: Nerve conduction studies were performed in the distal sural and ulnar sensory nerves and the peroneal motor nerve in 456 individuals with type 1 diabetes who participated in the follow-up visit of the EURODIAB Prospective Complications Study (EPCS). We used multivariate regression models to describe associations to decreased nerve conduction measures.Results: In addition to an effect of duration of diabetes and A1C, which were both associated with low nerve conduction velocity and response amplitude, we found that the presence of nephropathy, retinopathy, or a clinical diagnosis of neuropathy was associated with low nerve conduction velocity and amplitude. In the case of nonproliferative retinopathy, the odds ratio (OR) for being in lowest tertile was 2.30 (95% CI 1.13-4.67) for nerve conduction velocity. A similar OR was found for each 2% difference in A1C (2.39 [1.68-3.41]).Conclusions: We show that the presence of other microvascular diabetes complications, together with diabetes duration and A1C, are associated with low nerve conduction velocity and amplitude response and that cardiovascular disease or risk factors do not seem to be associated with these measures. [ABSTRACT FROM AUTHOR]

A response by Solomon Tesfaye, Daniel R. Witte and John H. Fuller to several letters to the editor about their article "Vascular Risk Factors and Diabetic Neuropathy" in the January 27, 2005 issue is presented.

OBJECTIVE -- Diabetic large-nerve fiber dysfunction, as measured by vibration perception threshold (VPT), predicts foot ulceration, amputation, and mortality. Thus, determination of modifiable risk factors is of great clinical importance. RESEARCH DESIGN AND METHODS -- We assessed 1,407 patients with type 1 diabetes and a normal VPT participating in the EURODIAB Prospective Complications Study, at baseline mean ± SD age of 32.7 ± 10.2 years with diabetes duration of 14.7 ± 9.3 years and follow-up of 7.3 ± 0.6 years. VPT was measured using biothesiometry on the right big toe and medial malleolus. An abnormal result was defined as >2 SD from the predicted mean for the patient's age. RESULTS -- An abnormal VPT was associated with an increased incidence of gangrene, amputation, foot ulceration, leg bypass or angioplasty, and mortality (P ≤ 0.02). The incidence of abnormal VPT was 24% over the 7.3-year follow-up. Duration of diabetes and A1C significantly influenced the incidence of abnormal VPT (P < 0.0001). After correction for these, established risk factors for cardiovascular disease (CVD), including male sex (P = 0.0004), hypertension (P < 0.0001), total cholesterol (P = 0.002), LDL cholesterol (P = 0.01), smoking (P < 0.0001), weight (P < 0.0001), and diabetes complications (retinopathy [P = 0.0001], nephropathy [P = 0.01], and autonomic neuropathy [P = 0.001]), were all found to be significant risk factors. A previous history of CVD doubled the incidence of abnormal VPT. CONCLUSIONS -- This prospective study indicates that cardiovascular risk factors predict development of large-fiber dysfunction, which may account for the high mortality rate in patients with an abnormal VPT, and emphasizes the importance of early determination of VPT to detect subclinical neuropathy and to address cardiovascular risk factors. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: Heat shock protein 27 (HSP27) is a member of the small heat shock protein family of proteins. HSP27 expression is enhanced in target tissues of diabetic microvascular complications, and changes in circulating serum HSP27 levels (sHSP27) have been reported in patients with macrovascular disease. We investigated whether sHSP27 levels were associated with micro- and macrovascular complications in type 1 diabetic patients.Research Design and Methods: A cross-sectional, nested, case-control study from the EURODIAB Prospective Complications Study of 531 type 1 diabetic patients was performed. Case subjects (n = 363) were defined as those with one or more complications of diabetes; control subjects (n = 168) were defined as those with no evidence of any complication. We measured sHSP27 levels and investigated their associations with diabetes complications.Results: Mean sHSP27 levels were significantly higher in case subjects with distal symmetrical polyneuropathy (DSP) than in control subjects, even after adjustment for age and albumin excretion rate (AER) (785.9 vs. 574.7 pg/ml, P = 0.03). In logistic regression analysis, sHSP27 levels in the upper quartile were associated with a twofold increased odds ratio (OR) of DSP, independently of conventional risk factors, markers of inflammation, and AER (OR 2.41 [95% CI 1.11-5.24]).Conclusions: In this large cohort of type 1 diabetic subjects, we found an independent association between sHSP27 and DSP. This suggests that sHSP27 levels may be a novel marker for diabetic neuropathy. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- Corrected QT (QTc) prolongation is predictive of cardiovascular mortality in both the general and diabetic populations. As part of the EURODIAB Prospective Complication Study, we have assessed the 7-year incidence and risk factors of prolonged QTc in people with type 1 diabetes. RESEARCH DESIGN AND METHODS -- A total of 1,415 type 1 diabetic subjects, who had normal QTc at baseline, were reanalyzed after the 7-year follow-up period. QTc >0.44s was considered abnormally prolonged. RESULTS -- Cumulative incidence of prolonged QTc was 18.7%, which is twofold higher in women than in men (24.5 vs. 13.9%, P < 0.0001). At the baseline examination, incident cases were older and less physically active than nonincident cases, had higher mean values of systolic blood pressure and HDL cholesterol, and had higher frequencies of hypertension, coronary heart disease, and distal symmetrical polyneuropathy. In multivariate logistic regression analyses, female sex and higher values of A1C and systolic blood pressure were associated with the risk of prolonged QTc, whereas physical activity and BMI within the range of 21.5-23.2 kg/m² were protective factors. In women, association with modifiable factors, particularly BMI, was stronger than in men. CONCLUSIONS-- In type 1 diabetic subjects from the EURODIAB cohort, female sex, A1C, and systolic blood pressure are predictive of prolonged QTc, whereas physical activity and BMI within the range of 21.5-23.2 kg/m² play a protective role. These findings are clinically relevant, as they may help to identify subjects at higher risk for prolonged QTc, as well as provide potential targets for risk-lowering strategies. [ABSTRACT FROM AUTHOR]

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 ≤4.14 mmol/l followed for a median of 3.9 years. The primary end point was time to first occurrence of acute coronary heart disease events, coronary revascularizations, or stroke. RESULTS -- Atorvastatin treatment resulted in a 38% reduction in relative risk ([95% CI -58 to -8], P = 0.017) of first major cardiovascular events in older patients and a 37% reduction ([-57 to -7], P = 0.019) in younger patients. Corresponding absolute risk reductions were 3.9 and 2.7%, respectively (difference 1.2% [95% CI -2.8 to 5.3], P = 0.546); numbers needed to treat for 4 years to avoid one event were 21 and 33, respectively. All-cause mortality was reduced nonsignificantly by 22% ([-49 to 18], P = 0.245) and 37% ([-64 to 9], P = 0.98), respectively. The overall safety profile of atorvastatin was similar between age-groups. CONCLUSIONS -- Absolute and relative benefits of statin therapy in older patients with type 2 diabetes are substantial, and all patients warrant treatment unless specifically contraindicated. [ABSTRACT FROM AUTHOR]

Abstract: Objective: There are no large studies in Type 1 diabetic patients that have examined the relation between soluble adhesion molecules and micro- and macrovascular outcomes, although the risks of such complications are high. Therefore, the main objective is to examine the relationship between soluble (s) vascular cell adhesion molecule-1 (sVCAM-1) and sE-selectin and retinopathy, albuminuria, and cardiovascular disease (CVD) in Type 1 diabetic patients. Methods: Cross-sectional data on 540 Type 1 diabetic patients, with a mean age of 40 years and diabetes duration of 22 years, from the EURODIAB Prospective Complications Study (PCS) were analysed. Retinopathy was assessed by centrally graded retinal photographs. Albumin excretion rate (AER) was used to define micro- and macroalbuminuria. CVD was defined as having physician diagnosed myocardial infarction (MI), stroke, coronary artery bypass graft (CABG) or angina, or Minnesota coded ischaemic electrocardiograms (ECGs). Results: Unadjusted, there was a positive relationship between sVCAM-1 and sE-selectin with nonproliferative and proliferative retinopathy, micro- and macroalbuminuria, and CVD. After adjustment for age, sex, duration of diabetes, systolic blood pressure (BP), LDL-cholesterol, fasting triglycerides (TGs), smoking, body mass index (BMI), and glycated haemoglobin, as well as other complications, the strongest significant associations were shown between sVCAM-1 and macroalbuminuria, with an odds ratio of 1.83 (1.33–2.53) for every 100 ng/ml increase in sVCAM-1. Conclusions: In this large sample of Type 1 diabetic patients, it was shown that sVCAM-1 and sE-selectin have positive associations with retinopathy, albuminuria, and CVD. This suggests that adhesion molecules are important in the pathogenesis of vascular complications in Type 1 diabetes. [Copyright &y& Elsevier]

Presents a study assessing the persistence of the inverse socioeconomic mortality gradient observed in the general population on diabetic people. Discussion on the Whitehall cohort study and the London cohort of the World Health Organization (WHO) multinational study of vascular disease in diabetes; Subjects of the study; Comparison of the result of the study with the Finnish study. INSET: Key messages.

Aims/hypothesis: While the risk factors for diabetic peripheral neuropathy (DPN) are now well recognised, the risk factors for painful DPN remain unknown. We performed analysis of the EURODIAB Prospective Complications Study data to elucidate the incidence and risk factors of painful DPN., Methods: The EURODIAB Prospective Complications Study recruited 3250 participants with type 1 diabetes who were followed up for 7.3±0.6 (mean ± SD) years. To evaluate DPN, a standardised protocol was used, including clinical assessment, quantitative sensory testing and autonomic function tests. Painful DPN (defined as painful neuropathic symptoms in the legs in participants with confirmed DPN) was assessed at baseline and follow-up., Results: At baseline, 234 (25.2%) out of 927 participants with DPN had painful DPN. At follow-up, incident DPN developed in 276 (23.5%) of 1172 participants. Of these, 41 (14.9%) had incident painful DPN. Most of the participants who developed incident painful DPN were female (73% vs 48% painless DPN p=0.003) and this remained significant after adjustment for duration of diabetes and HbA 1c (OR 2.69 [95% CI 1.41, 6.23], p=0.004). The proportion of participants with macro- or microalbuminuria was lower in those with painful DPN compared with painless DPN (15% vs 34%, p=0.02), and this association remained after adjusting for HbA 1c , diabetes duration and sex (p=0.03)., Conclusions/interpretation: In this first prospective study to investigate the risk factors for painful DPN, we definitively demonstrate that female sex is a risk factor for painful DPN. Additionally, there is less evidence of diabetic nephropathy in incident painful, compared with painless, DPN. Thus, painful DPN is not driven by cardiometabolic factors traditionally associated with microvascular disease. Sex differences may therefore play an important role in the pathophysiology of neuropathic pain in diabetes. Future studies need to look at psychosocial, genetic and other factors in the development of painful DPN., (© 2023. The Author(s).)

Aims: The aim of this prospective study was to examine CVD risk reduction in type 1 diabetes (1) for people with favourable cardiovascular health metrics and (2) by clustering of these metrics., Methods: Data from 2313 participants from the EURODIAB Prospective Complications Study were analysed. All had type 1 diabetes (51% men, mean ± SD age 32 ± 9 years). Seven cardiovascular health metrics were studied-smoking, BMI, physical activity, a diet score, total cholesterol/HDL-cholesterol ratio, combined systolic and diastolic BP and HbA 1c -divided into favourable/less favourable categories. Cox proportional hazards models were used to calculate HRs (95% CIs) of incident CVD for each metric. Clusters were made by scoring each individual by the number of favourable metrics., Results: A total of 163 people developed incident CVD during a mean ± SD follow-up of 7.2 ± 1.3 years. Participants with more favourable HbA 1c levels of <57 mmol/mol (<7.4%) had a 37% significantly lower CVD risk than those with a less favourable HbA 1c (HR [95% CI] 0.63 [0.44, 0.91]), and participants with a more favourable BP (systolic BP <112 mmHg and diastolic BP <70 mmHg) had a 44% significantly lower CVD risk than participants in the less favourable BP group (HR [95% CI] 0.56 [0.34, 0.92]). There was a dose-response relation with a lower HR observed with greater clustering of more favourable metrics: people with four or more favourable metrics had an HR of 0.37 (95% CI 0.18, 0.76), adjusted for sex and age at diabetes diagnosis, compared with those with no favourable metrics., Conclusions/interpretation: Low HbA 1c and low BP were protective cardiovascular health metrics in our study of people with type 1 diabetes. Targeting all cardiovascular health metrics could be more effective in preventing CVD than targeting single metrics., (© 2022. The Author(s).)

Aims: Increasing evidence suggests a potential role of circulating miRNAs as clinical biomarkers, and loss of miRNA-126 has been proposed as a predictor of type 2 diabetes onset. However, a systematic analysis of circulating miRNAs in type 1 diabetic patients with micro-/macrovascular complications has not yet been performed., Methods: A cross-sectional nested case-control study from the EURODIAB Prospective Complications Study of 455 type 1 diabetic patients was performed. Case subjects (n = 312) were defined as those with one or more complications of diabetes; control subjects (n = 143) were those with no evidence of any complication. A differential miRNA expression profiling was performed in pooled serum samples from cases and controls. Furthermore, miR-126 levels were quantified by qPCR in all individual samples and associations with diabetic complications investigated., Results: Twenty-five miRNAs differed in pooled samples from cases and controls. miR-126 levels were significantly lower in case than in control subjects, even after adjustment for age and sex. In logistic regression analyses, miR-126 was negatively associated with all complications (OR = 0.85, 95 % CI 0.75-0.96) as well as with each micro-/macrovascular complication examined separately. This was likely dependent of diabetes as associations were no longer significant after adjustment for both hyperglycemia and diabetes duration. However, a significant 25 % risk reduction, independent of age, sex, A1C, and diabetes duration, was still observed for proliferative retinopathy (OR = 0.75, 95 % CI 0.59-0.95)., Conclusions: In this large cohort of type 1 diabetic subjects, we found that miR-126 levels are associated with vascular complications of diabetes, particularly with proliferative retinopathy.

Aims/hypothesis: In an individual-level analysis we examined the effect of atorvastatin on glycaemia progression in type 2 diabetes and whether glycaemia effects reduce the prevention of cardiovascular disease (CVD) with atorvastatin., Methods: The study population comprised 2,739 people taking part in the Collaborative Atorvastatin Diabetes Study (CARDS) who were randomised to receive atorvastatin 10 mg or placebo and who had post-randomisation HbA1c data. This secondary analysis used Cox regression to estimate the effect of atorvastatin on glycaemia progression, defined as an increase in HbA1c of ≥ 0.5% (5.5 mmol/mol) or intensification of diabetes therapy. Mixed models were used to estimate the effect of atorvastatin on HbA1c as a continuous endpoint., Results: Glycaemia progression occurred in 73.6% of participants allocated placebo and 78.1% of those allocated atorvastatin (HR 1.18 [95% CI 1.08, 1.29], p < 0.001) by the end of follow-up. The HR was 1.22 (95% CI 1.19, 1.35) in men and 1.11 (95% CI 0.95, 1.29) in women (p = 0.098 for the sex interaction). A similar effect was seen in on-treatment analyses: HR 1.20 (95% CI 1.07, 1.35), p = 0.001. The net mean treatment effect on HbA1c was 0.14% (95% CI 0.08, 0.21) (1.5 mmol/mol). The effect did not increase through time. Diabetes treatment intensification alone did not differ with statin allocation. Neither baseline nor 1-year-attained HbA1c predicted subsequent CVD, and the atorvastatin effect on CVD did not vary by HbA1c change (interaction p value 0.229)., Conclusions/interpretation: The effect of atorvastatin 10 mg on glycaemia progression among those with diabetes is statistically significant but very small, is not significantly different between sexes, does not increase with duration of statin and does not have an impact on the magnitude of CVD risk reduction with atorvastatin.

Aims/hypothesis: We investigated whether atorvastatin 10 mg daily lowered C-reactive protein (CRP) and whether the effects of atorvastatin on cardiovascular disease (CVD) varied by achieved levels of CRP and LDL-cholesterol., Methods: CRP levels were measured at baseline and 1 year after randomisation to atorvastatin in 2,322 patients with type 2 diabetes (40-75 years, 69% males) in a secondary analysis of the Collaborative Atorvastatin Diabetes Study, a randomised placebo-controlled trial. We used Cox regression models to test the effects on subsequent CVD events (n = 147) of CRP and LDL-cholesterol lowering at 1 year., Results: After 1 year, the atorvastatin arm showed a net CRP lowering of 32% (95% CI -40%, -22%) compared with placebo. The CRP response was highly variable, with 45% of those on atorvastatin having no decrease in CRP (median [interquartile range, IQR] per cent change -9.8% [-57%, 115%]). The LDL-cholesterol response was less variable, with a median (IQR) within-person per cent change of -41% (-51%, -31%). Baseline CRP did not predict CVD over 3.8 years of follow-up (HRper SD log 0.89 [95% CI 0.75, 1.06]), whereas baseline LDL-cholesterol predicted CVD (HRper SD 1.21 [95% CI 1.02, 1.44]), as did on-treatment LDL-cholesterol. There was no significant difference in the reduction in CVD by atorvastatin, with above median (HR 0.57) or below median (HR 0.52) change in CRP or change in LDL-cholesterol (HR 0.61 vs 0.50)., Conclusions/interpretation: CRP was not a strong predictor of CVD. Statin efficacy did not vary with achieved CRP despite considerable variability in CRP response. The use of CRP as an indicator of efficacy of statin therapy on CVD risk in patients with type 2 diabetes is not supported by these data. Trial registration NCT00327418.

Aims/hypothesis: High dietary salt intake has been associated with elevated BP and may also have a deleterious effect on microvascular complications. We studied the cross-sectional associations between dietary salt intake (estimated from 24 h urinary sodium excretion) and urinary potassium excretion on the one hand, and the prevalence of microvascular complications on the other, in individuals with type 1 diabetes., Methods: We measured sodium and potassium concentrations in two 24 h urine samples in 1,212 individuals with type 1 diabetes (40 ± 10 years old, 51% men) who participated in the EURODIAB Prospective Complications Study. We used multiple logistic regression analyses to investigate associations between dietary salt intake and microvascular complications adjusted for age and sex, and additionally for BMI, smoking, urinary potassium excretion, antihypertensive medication and physical activity, and total energy, protein, alcohol, saturated fat and fibre intake., Results: After full adjustment, 1 g/day higher dietary salt intake was positively associated with the presence of microalbuminuria (OR 1.06 [95% CI 1.01, 1.10]), but not macroalbuminuria (OR 0.99 [95% CI 0.94, 1.05]), non-proliferative retinopathy (OR 1.00 (95% CI 0.96, 1.04]) or proliferative retinopathy (OR 1.02 (95% CI 0.95, 1.08]). After excluding individuals with cardiovascular disease and/or antihypertensive medication (n = 418), we found a non-significant association with microalbuminuria (OR 1.04 [95% CI 0.99, 1.10]) and macroalbuminuria (OR 1.05 [95% CI 0.96, 1.16]). The association between dietary salt intake and microalbuminuria was stronger in individuals with a BMI above 25 kg/m(2) (OR 1.11 [95% CI 1.04, 1.18]) than in those with BMI below 25 kg/m(2) (OR 1.03 [95% CI 0.97, 1.09]). No significant associations were found between urinary potassium excretion and microvascular complications., Conclusions/interpretation: In individuals with type 1 diabetes, higher dietary salt intake, as determined by 24 h urinary sodium excretion, may be positively associated with microalbuminuria, particularly in overweight individuals.

Aims/hypothesis: Type 1 diabetes is associated with a higher risk of major vascular complications and death. A reliable method that predicted these outcomes early in the disease process would help in risk classification. We therefore developed such a prognostic model and quantified its performance in independent cohorts., Methods: Data were analysed from 1,973 participants with type 1 diabetes followed for 7 years in the EURODIAB Prospective Complications Study. Strong prognostic factors for major outcomes were combined in a Weibull regression model. The performance of the model was tested in three different prospective cohorts: the Pittsburgh Epidemiology of Diabetes Complications study (EDC, n = 554), the Finnish Diabetic Nephropathy study (FinnDiane, n = 2,999) and the Coronary Artery Calcification in Type 1 Diabetes study (CACTI, n = 580). Major outcomes included major CHD, stroke, end-stage renal failure, amputations, blindness and all-cause death., Results: A total of 95 EURODIAB patients with type 1 diabetes developed major outcomes during follow-up. Prognostic factors were age, HbA1c, WHR, albumin/creatinine ratio and HDL-cholesterol level. The discriminative ability of the model was adequate, with a concordance statistic (C-statistic) of 0.74. Discrimination was similar or even better in the independent cohorts, the C-statistics being: EDC, 0.79; FinnDiane, 0.82; and CACTI, 0.73., Conclusions/interpretation: Our prognostic model, which uses easily accessible clinical features can discriminate between type 1 diabetes patients who have a good or a poor prognosis. Such a prognostic model may be helpful in clinical practice and for risk stratification in clinical trials.

Context: Glycemic targets and the benefit of intensive glucose control are currently under debate because intensive glycemic control has been suggested to have negative effects on mortality risk in type 2 diabetes patients., Objective: We examined the association between glycated hemoglobin (HbA1c) and all-cause mortality in patients with type 1 diabetes mellitus., Design, Setting, and Patients: A clinic-based prospective cohort study was performed in 2764 European patients with type 1 diabetes aged 15-60 years enrolled in the EURODIAB Prospective Complications Study., Outcome Measure: Possible nonlinearity of the association between HbA1c and all-cause mortality was examined using multivariable restricted cubic spline regression using three (at HbA1c 5.6%, 8.1%, and 11.8%) and five knots (additionally at HbA1c 7.1% and 9.5%). Mortality data were collected approximately 7 years after baseline examination., Results: HbA1c was related to all-cause mortality in a nonlinear manner after adjustment for age and sex. All-cause mortality risk was increased at both low (5.6%) and high (11.8%) HbA1c compared with the reference (median HbA1c: 8.1%) following a U-shaped association [P overall effect = .008 and .04, P nonlinearity = .03 and .11 (three and five knots, respectively)]., Conclusions: Results from our study in type 1 diabetes patients suggest that target HbA1c below a certain threshold may not be appropriate in this population. We recognize that these low HbA1c levels may be related to anemia, renal insufficiency, infection, or other factors not available in our database. If our data are confirmed, the potential mechanisms underlying this increased mortality risk among those with low HbA1c will need further study.

Background/objectives: Individuals with type 1 diabetes have a high risk of developing cardiovascular diseases, and it has been reported that they consume a high atherogenic diet. We examined how nutrient intake and adherence to current European nutritional recommendations evolved in a large cohort of European individuals with type 1 diabetes over a period of 7 years., Subjects/methods: We analysed data from the EURODIAB Prospective Complications Study, a European multicentre prospective cohort study. Standardized 3-day dietary records were employed in individuals with type 1 diabetes. One thousand one hundred and two patients (553 men, 549 women, baseline age 33 ± 10 years, duration 15 ± 9 years) had complete nutritional data available at baseline and after 7 years. We calculated mean differences in reported nutrients over time and adjusted these for age, gender, HbA1c and BMI with ANOVA models., Results: Compared to baseline, there were minor changes in nutrients. Reported protein (-0.35% energy (en), fat (-1.07% en), saturated fat (-0.25% en) and cholesterol (-7.42 mg/1000 kcal) intakes were lower, whereas carbohydrate (+1.23% en) and fibre (+0.46 g/1000 kcal) intakes were higher at the 7-year follow-up. European recommendations for adequate nutrient intakes were followed in individuals with type 1 diabetes for protein (76% at baseline and 78% at follow-up), moderately for fat (34, 40%), carbohydrate (34, 41%) and cholesterol (39, 47%), but poorly for fibre (1.4, 2.4%) and saturated fat (11, 13%)., Conclusion: European individuals with type 1 diabetes consume a high atherogenic diet as few patients met recommendations for dietary fibre and saturated fat. This study showed minor changes in dietary nutrients and energy intakes over a period of 7 years. Nutrition education needs particular focus on strategies to increase dietary fibre and reduce saturated fat to exploit their potential benefit.

Objective: Circulating levels of NH(2)-terminal probrain natriuretic peptide (NT-proBNP), a marker of acute heart failure, are associated with increased risk of cardiovascular disease (CVD) in the general population. However, there is little information on the potential role of NT-proBNP as a biomarker of vascular complications in type 1 diabetic patients. We investigated whether serum NT-proBNP levels were associated with micro- and macrovascular disease in type 1 diabetic subjects., Research Design and Methods: A cross-sectional nested case-control study from the EURODIAB Prospective Complications Study of 507 type 1 diabetic patients was performed. Case subjects (n = 345) were defined as those with one or more complications of diabetes; control subjects (n = 162) were those with no evidence of any complication. We measured NT-proBNP levels by a two-site sandwich electrochemiluminescence immunoassay and investigated their associations with complications., Results: Mean NT-proBNP levels were significantly higher in case than in control subjects. In logistic regression analyses, NT-proBNP values >26.46 pg/mL were independently associated with a 2.56-fold increased risk of all complications. Odds ratios of CVD (3.95 [95% CI 1.26-12.35]), nephropathy (4.38 [1.30-14.76]), and distal symmetrical polyneuropathy (4.32 [1.41-13.23]) were significantly increased in patients with NT-proBNP values in the highest quartile (>84.71 pg/mL), independently of renal function and known risk factors. These associations were no longer significant after inclusion of TNF-α into the model., Conclusions: In this large cohort of type 1 diabetic subjects, we found an association between NT-proBNP and diabetic micro- and macrovascular complications. Our results suggest that the inflammatory cytokine TNF-α may be involved in this association.

Background: We examined whether atorvastatin affects diabetic kidney disease and whether the effect of atorvastatin on cardiovascular disease (CVD) varies by kidney status in patients with diabetes., Study Design: The Collaborative Atorvastatin Diabetes Study (CARDS) randomized placebo-controlled trial., Setting & Participants: Patients with type 2 diabetes and no prior CVD (n = 2,838)., Intervention: Random allocation to atorvastatin, 10 mg/d, or placebo, with a median follow-up of 3.9 years., Outcomes: Estimated glomerular filtration rate (eGFR), albuminuria, CVD., Measurements: Baseline and follow-up GFRs were estimated by using the Modification of Diet in Renal Disease Study equation. Urinary albumin-creatinine ratio was measured on spot urine samples., Results: At baseline, 34% of patients had an eGFR of 30 to 60 mL/min/1.73 m(2). Atorvastatin treatment was associated with a modest improvement in annual change in eGFR (net, 0.18 mL/min/1.73 m(2)/y; 95% confidence interval [CI], 0.04 to 0.32; P = 0.01) that was most apparent in those with albuminuria (net improvement, 0.38 mL/min/1.73 m(2)/y; P = 0.03). At baseline, 21.5% of patients had albuminuria and an additional 6.8% developed albuminuria during follow-up. Atorvastatin did not influence the incidence of albuminuria (hazard ratio, 1.49; 95% CI, 0.73 to 3.04; P = 0.3) or regression to normoalbuminuria (hazard ratio, 1.19; 95% CI, 0.57 to 2.49; P = 0.6). In 970 patients with a moderately decreased eGFR of 30 to 60 mL/min/1.73 m(2), there was a 42% reduction in major CVD events with treatment, including a 61% reduction in stroke. This treatment effect was similar to the 37% (95% CI, 17 to 52; P < 0.001) reduction in CVD observed in the study overall (P = 0.4 for the eGFR-treatment interaction)., Limitations: Low incidence rates of albuminuria and transition to more severe kidney status limit power to detect treatment effects., Conclusions: A modest beneficial effect of atorvastatin on eGFR, particularly in those with albuminuria, was observed. Atorvastatin did not influence albuminuria incidence. Atorvastatin was effective at decreasing CVD in those with and without a moderately decreased eGFR and achieved a high absolute benefit.

To evaluate whether beta-catenin signaling has a role in the regulation of angiogenesis in colon cancer, a series of angiogenesis-related gene promoters was analyzed for beta-catenin/TCF binding sites. Strikingly, the gene promoter of human vascular endothelial growth factor (VEGF, or VEGF-A) contains seven consensus binding sites for beta-catenin/TCF. Analysis of laser capture microdissected human colon cancer tissue indicated a direct correlation between up-regulation of VEGF-A expression and adenomatous polyposis coli (APC) mutational status (activation of beta-catenin signaling) in primary tumors. In metastases, this correlation was not observed. Analysis by immunohistochemistry of intestinal polyps in mice heterozygous for the multiple intestinal neoplasia gene (Min/+) at 5 months revealed an increase and redistribution of VEGF-A in proximity to those cells expressing nuclear beta-catenin with a corresponding increase in vessel density. Transfection of normal colon epithelial cells with activated beta-catenin up-regulated levels of VEGF-A mRNA and protein by 250-300%. When colon cancer cells with elevated beta-catenin levels were treated with beta-catenin antisense oligodeoxynucleotides, VEGF-A expression was reduced by more than 50%. Taken together, our observations indicate a close link between beta-catenin signaling and the regulation of VEGF-A expression in colon cancer.