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Aim: To investigate the effect of DAFNE and continuous subcutaneous insulin infusion in clinical practice. Methods: Within NHS Lothian, continuous subcutaneous insulin infusion started in 2004 and DAFNE education began in 2006. We extracted anonymized data from the national database for all those aged > 18 years with type 1 diabetes having a Dose Adjustment For Normal Eating course or continuous subcutaneous insulin infusion start date (n = 4617). Results: In total, 956 persons received DAFNE education, and 505 had received an insulin pump, 208 of whom had DAFNE education followed by insulin pump. Mean (SD) HbA1c before DAFNE education was 68 (15) mmol/mol (8.4% [1.4%]) and 66 (13) mmol/mol (8.2% [1.2%]) before continuous subcutaneous insulin infusion. In the year following DAFNE education, the mean fall in within‐person HbA1c was 3.8 mmol/mol (95% CI 4.0 to 3.4; 0.3% [0.4% to 0.3%]). Those with the poorest control (HbA1c ≥ 85 mmol/mol [9.9%]) experienced the largest decline (15.7 mmol/mol [1.4%]). Those in the lowest HbA1c band at initiation (< 53 mmol/mmol [7.0%]) experienced a rise. In the year following continuous subcutaneous insulin infusion initiation there was a mean fall in within‐person HbA1c of 6.6 mmol/mol (6.8 to 6.4; 0.6% [0.6% to 0.6%]). In those with the poorest control (HbA1c ≥ 85 mmol/mol [9.9%]), the mean fall in HbA1c was 22.2 mmol/mol (23 to 21; 2.0% [2.1% to 1.9%]). Continuous subcutaneous insulin infusion effectiveness was not different with or without DAFNE education. The effects of both interventions were sustained over 5 years. Conclusions: Both DAFNE education and insulin pump therapy had the greatest effect on HbA1c in those with higher baseline values. There was little difference to attained HbA1c when Dose Adjustment For Normal Eating education was introduced before insulin pump therapy. What's new?: Both DAFNE (Dose Adjustment For Normal Eating) education and continuous subcutaneous insulin infusion lower the levels of HbA1c in people with type 1 diabetes. The size and duration of effect are not well documented.HbA1c decreases with either intervention and the effect lasts at least 5 years. Those with high HbA1c to start with have a very large decrease in HbA1c. Continuous subcutaneous insulin infusion is effective in lowering HbA1c with or without previous DAFNE education.DAFNE education and continuous subcutaneous insulin infusion are good options for people with high HbA1c. DAFNE education should not be a prerequisite before continuous subcutaneous insulin infusion. [ABSTRACT FROM AUTHOR]

Summary: Background: Diabetic foot ulcers (DFUs) are a devastating complication of diabetes. Objectives: To identify genetic contributors to the development of DFUs in the presence of peripheral neuropathy in a Scottish cohort with diabetes using a genome‐wide association study. Methods: A genome‐wide association approach was applied. A case was defined as a person with diabetes (type 1 or type 2) who had ever had a foot ulcer (current or previous) in at least one foot, as well as a positive monofilament test result (i.e. evidence of peripheral neuropathy) recorded in their longitudinal e‐health records. A control was defined as an individual with diabetes (type 1 or type 2) who has never been recorded as having a foot ulcer in either foot but who had a positive monofilament test result recorded in either foot in their longitudinal e‐health records. Results: There were 699 DFU cases and 2695 controls in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) dataset. The single‐nucleotide polymorphism rs80028505 (Chr6p21·31) in MAPK14 reached genome‐wide significance with a lowest P‐value of 2·45 × 10−8. The narrow‐sense heritability of this phenotype is 0·06. Conclusions: We suggest that MAPK14 is associated with DFUs. [ABSTRACT FROM AUTHOR]

Background: Good glycaemic control in type 2 diabetes (T2DM) protects the microcirculation. Current guidelines suggest glycaemic targets be relaxed in advanced diabetes. We explored whether disease duration or pre-existing macrovascular complications attenuated the association between hyperglycaemia and microvascular function. Methods: 743 participants with T2DM (n = 222), cardiovascular disease (CVD = 183), both (n = 177) or neither (controls = 161) from two centres in the UK, underwent standard clinical measures and endothelial dependent (ACh) and independent (SNP) microvascular function assessment using laser Doppler imaging. Results: People with T2DM and CVD had attenuated ACh and SNP responses compared to controls. This was additive in those with both (ANOVA p < 0.001). In regression models, cardiovascular risk factors accounted for attenuated ACh and SNP responses in CVD, whereas HbA1c accounted for the effects of T2DM. HbA1c was associated with ACh and SNP response after adjustment for cardiovascular risk factors (adjusted standardised beta (β) -0.096, p = <0.008 and -0.135, p < 0.001, respectively). Pre-existing CVD did not modify this association (β -0.099; p = 0.006 and -0.138; p < 0.001, respectively). Duration of diabetes accounted for the association between HbA1c and ACh (β -0.043; p = 0.3), but not between HbA1c and SNP (β -0.105; p = 0.02). Conclusions: In those with T2DM and CVD, good glycaemic control is still associated with better microvascular function, whereas in those with prolonged disease this association is lost. This suggests duration of diabetes may be a better surrogate for "advanced disease" than concomitant CVD, although this requires prospective validation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims Patients with Type 2 diabetes have an elevated risk of stroke. The role of lipid levels and diabetes-specific factors in risk prediction of stroke is unclear, and estimates of efficacy of lipid-lowering therapy vary between trials. We examined predictors of stroke and the effect of atorvastatin on specific stroke subtypes in Type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS) [a trial of 2838 participants with mean low-density lipoprotein cholesterol < 4.14 mmol/l, no history of macrovascular disease and randomized to atorvastatin 10 mg daily or placebo]. Methods Median follow-up was 3.9 years. Cox regression models were used to estimate the effect of atorvastatin on stroke rate and risk of stroke associated with baseline risk factors. Risk factors that predicted stroke in univariate models were examined in a multivariable model. Results Independent risk factors predicting stroke were age [10-year increments; hazard ratio (HR) 2.3, P < 0.001], microalbuminuria (albumin : creatinine ratio > 2.5 mg/mmol; HR 2.0, P = 0.007) and glycaemic control (HbA1c > 10%; HR 2.7, P = 0.007). Women were at lower risk of stroke (HR 0.3, P = 0.004). Lipids did not predict stroke. Of 60 first strokes, 47 were non-haemorrhagic, 13 were indeterminate and none was definitely haemorrhagic. Atorvastatin treatment was associated with 50% reduction in non-haemorrhagic stroke (95% confidence interval 9%–72% P = 0.024), similar to the 48% reduction (11%–69%) for all strokes combined. Conclusions Diabetes-specific risk factors are important predictors of stroke in Type 2 diabetes. Despite the lack of association between baseline lipids and first stroke, there was a reduction of 50% of non-haemorrhagic strokes associated with atorvastatin treatment in the CARDS population. [ABSTRACT FROM AUTHOR]

Risk estimates for stroke in patients with diabetes vary. We sought to obtain reliable risk estimates for stroke and the association with diabetes, comorbidity and lifestyle in a large cohort of type 2 diabetic patients in the UK. Using the General Practice Research Database, we identified all patients who had type 2 diabetes and were aged 35 to 89 years on 1 January 1992. We also identified five comparison subjects without diabetes and of the same age and sex. Hazard ratios (HRs) for stroke between January 1992 and October 1999 were calculated, and the association with age, sex, body mass index, smoking, hypertension, atrial fibrillation and duration of diabetes was investigated. The absolute rate of stroke was 11.91 per 1,000 person-years (95% CI 11.41–12.43) in people with diabetes ( n = 41,799) and 5.55 per 1,000 person-years (95% CI 5.40–5.70) in the comparison group ( n = 202,733). The age-adjusted HR for stroke in type 2 diabetic compared with non-diabetic subjects was 2.19 (95% CI 2.09–2.32) overall, 2.08 (95% CI 1.94–2.24) in men and 2.32 (95% CI 2.16–2.49) in women. The increase in risk attributable to diabetes was highest among young women (HR 8.18; 95% CI 4.31–15.51) and decreased with age. No investigated comorbidity or lifestyle characteristic emerged as a major contributor to risk of stroke. This study provides risk estimates for stroke for an unselected population from UK general practice. Patients with type 2 diabetes were at an increased risk of stroke, which decreased with age and was higher in women. Additional risk factors for stroke in type 2 diabetic patients included duration of diabetes, smoking, obesity, atrial fibrillation and hypertension. [ABSTRACT FROM AUTHOR]

Aims Under-reporting of diabetes on death certificates contributes to the unreliable estimates of mortality as a result of diabetes. The influence of obesity on mortality in Type 2 diabetes is not well documented. We aimed to study mortality from diabetes and the influence of obesity on mortality in Type 2 diabetes in a large cohort selected from the General Practice Research Database (GPRD). Methods A cohort of 44 230 patients aged 35–89 years in 1992 with Type 2 diabetes was identified. A comparison group matched by year of birth and sex with no record of diabetes at any time was identified (219 797). Hazards ratios (HRs) for all-cause mortality during the period January 1992 to October 1999 were calculated using the Cox Proportional Hazards Model. The effects of body mass index (BMI), smoking and duration of diabetes on all-cause mortality amongst people with diabetes was assessed ( n = 28 725). Results The HR for all-cause mortality in Type 2 diabetes compared with no diabetes was 1.93 (95% CI 1.89–1.97), in men 1.77 (1.72–1.83) and in women 2.13 (2.06–2.20). The HR decreased with increasing age. In the multivariate analysis in diabetes only, the HR for all-cause mortality amongst smokers was 1.50 (1.41–1.61). Using BMI 20–24 kg/m2 as the reference range, for those with a BMI 35–54 kg/m2 the HR was 1.43 (1.28–1.59) and for those with a BMI 15–19 kg/m2 the HR was 1.38 (1.18–1.61). Conclusions Patients with Type 2 diabetes have almost double the mortality rate compared with those without. The relative risk decreases with age. In people with Type 2 diabetes, obesity and smoking both contribute to the risk of all-cause mortality, supporting doctrines to stop smoking and lose weight. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

To describe baseline characteristics of patients in the Collaborative AtoRvastatin Diabetes Study (CARDS), a randomized, placebo-controlled trial of lipid lowering with atorvastatin 10 mg daily for the primary prevention of major cardiovascular events in patients with Type 2 diabetes. The main eligibility criteria were Type 2 diabetes, age 40–75 years, no previous history of coronary heart disease, stroke or other major cardiovascular events, a documented history of at least one of retinopathy, micro- or macroalbuminuria, hypertension or current smoking, LDL-cholesterol ≤ 4.14 mmol/l and triglycerides ≤ 6.78 mmol/l. Randomization of 2838 persons (909 women) into CARDS was completed in June 2001. At entry, mean age was 62 years, 12% were over 70 years old and median duration of diabetes was 6 years. Median fasting lipid levels were total cholesterol 5.4 mmol/l, LDL-cholesterol 3.1 mmol/l, HDL-cholesterol 1.4 mmol/l and triglyceride 1.7 mmol/l. There was a documented history of retinopathy in 30% of patients, micro/macroalbuminuria in 11% (additionally 17% had micro/macroalbuminuria based on two elevated pretreatment measurements of albumin–creatinine ratios), hypertension in 79% and 23% were current smokers. CARDS will contribute importantly to the evidence for the macrovascular and microvascular benefits of lipid lowering with atorvastatin in patients with Type 2 diabetes. The results are likely to have important implications for the management of patients. Diabet. Med. 21, 901–905 (2004) [ABSTRACT FROM AUTHOR]

Aims/hypothesis. Our aim was to examine the change in the management of hypertension in patients with Type I (insulin-dependent) diabetes mellitus in Europe, between 1989–1990 and 1997–1999. Methods. Seven-year changes in hypertension treatment and control (defined as blood pressure <130/85 mmHg) were examined in a large sample of Type I diabetic patients recruited from 26 centres involved in the EURODIAB Prospective Complications Study. Hypertension was defined as a systolic and/or diastolic blood pressure greater than 140 and/or 90 mmHg respectively, and/or use of blood pressure lowering drugs. Results. Of 1866 Type I diabetic patients, 412 had hypertension at baseline and 631 at follow-up. A greater proportion of hypertensive patients were treated at follow-up (69% vs 40%, p<0.0001), which persisted after adjustment for age or centre. Of those who were treated, a modest increase in the proportion of those controlled for hypertension was found (41% vs 32%, p=0.048), which disappeared after adjustment for age. Among hypertensive patients with albuminuria, the proportions treated also increased, from 35% to 76% (p<0.0001) in microalbuminuric and 64% to 95% (p<0.0001) in macroalbuminuric patients. Control of hypertension in albuminuric patients did not change significantly and was below 50%. The use of more than one anti-hypertensive drug increased over a 7-year period, from 19% to 33% (p<0.0001), and a marked increase was shown in the proportion of those taking an ACE inhibitor (from 57% to 82%, p<0.0001). Conclusion/interpretation. The management of hypertension in Type I diabetic patients across Europe has improved over a 7-year follow-up period. Optimal levels of blood pressure treatment and optimal levels of control have not yet been achieved. [ABSTRACT FROM AUTHOR]

Abstract Background There are few data on the role of lipid lowering in the primary prevention of coronary heart disease (CHD) in diabetic patients. This paper describes the design of a collaborative clinical trial between Diabetes UK, the NHS Research and Development Directorate and Pfizer UK, that addresses this question. Methods The Collaborative AtoRvastatin Diabetes Study (CARDS) is a multicentre, randomized, placebo-controlled, double-blind clinical trial of primary prevention of cardiovascular disease in patients with Type 2 diabetes. The primary objective is to investigate whether treatment with the hydroxymethylglutaryl coenzyme A reductase inhibitor, atorvastatin, reduces the incidence of major cardiovascular events. At entry patients have at least one other risk factor for CHD in addition to diabetes, namely current smoking, hypertension, retinopathy, or micro- or macroalbuminuria. At randomization patients have been selected for a serum low-density lipoprotein (LDL) cholesterol concentration ≤ 4.14 mmol/l (160 mg/dl) and triglycerides ≤ 6.78 mmol/l (600 mg/dl). Randomization was completed in June 2001. Patients will be followed until 304 primary endpoints have accrued (expected date early 2005). The trial includes 2838 men and women aged 40–75 years. This report describes the design and administration of the study and reviews the evidence to date of the effectiveness of lipid-lowering therapy in Type 2 diabetes. Conclusions The case for lipid-lowering therapy for the primary prevention of CHD in diabetes has not been demonstrated. CARDS will provide essential information on the extent of any benefits and adverse effects of lipid-lowering therapy in diabetic patients without prior CHD. Diabet. Med. 19, 201–211 (2002). [ABSTRACT FROM AUTHOR]

Aims/hypothesis: We aimed to examine risk factors for, and differences in, renal failure in diabetic patients from 10 centres. Methods: Risk factors for renal failure were examined in 3558 diabetic patients who did not have renal disease at baseline in the WHO Multinational Study of Vascular Disease in Diabetes (WHO MSVDD). Results: In 959 subjects with Type I (insulin-dependent) diabetes mellitus and 2559 with Type II (non-insulin-dependent) diabetes mellitus, the average follow-up was 8.4 years ( ± 2.7). By the end of the follow-up period 53 patients in the Type I diabetic group and 134 patients in the Type II diabetic group had developed renal failure (incidence rate 6.3:1000 person years). Increasing age and duration of diabetes were associated with renal failure in Type II and Type I diabetes. In Type II diabetes duration of diabetes was a more important risk factor than age. In both Type I and Type II diabetic retinopathy and proteinuria were strongly associated with renal failure. Systolic blood pressure was associated with renal failure in Type I but not in Type II diabetic patients. ECG abnormalities at baseline, self-reported smoking and cholesterol were not associated with renal failure. Triglycerides were measured in a subset of centres. Among those with Type II, but not Type I diabetes, triglycerides were associated with renal failure independently of systolic blood pressure, proteinuria or retinopathy. In Type II diabetes fasting plasma glucose was associated with renal failure independently of other risk factors. Conclusion/interpretation: We have confirmed the role of proteinuria and retinopathy as markers of renal failure and the importance of hyperglycaemia in renal failure in Type I and Type II diabetes. Plasma triglycerides seem to be an important predictor of renal failure in Type II diabetes. In Type I diabetes systolic blood pressure is an important predictor of renal failure. [Diabetologia (2001) 44 [Suppl 2]: S 46–S 53] [ABSTRACT FROM AUTHOR]

Aims/hypothesis. To examine whether the HDL-cholesterol:apoA-I + apoA-II ratio and the ℇ2 allele are related to albuminuria at baseline and whether they are risk factors for progression of albuminuria in a cohort study of patients with Type I (insulin-dependent) diabetes mellitus.¶Methods. At baseline, the study cohort comprised 617 patients, aged 15–60 years, from seven European diabetic centres of the EURODIAB study. Albumin excretion rate, measured in a central laboratory, was categorised as normoalbuminuria at 20 μg/min or less, microalbuminuria between 20 and 200 μg/min or macroalbuminuria at 200 μg/min or over. Of the 250 patients who were normoalbuminuric at baseline and had follow-up albuminuria measurements, 34 patients were defined as early progressors.¶Results. At baseline, the mean HDL-cholesterol:apoA-I + apoA-II ratio was lower in macroalbuminuric patients (0.79, 95 % CI:0.74–0.83) compared with normoalbuminuric (0.88, 95 % CI:0.87–0.90) patients (p = 0.0002, adjusted for age and sex). At follow-up, 34 patients who progressed from normoalbuminuria to microalbuminuria or macroalbuminuria also had a slightly lower baseline ratio (0.85, 95 % CI:0.80–0.89) than those 216 who remained normoalbuminuric (0.89, 95 % CI:0.87–0.92) (adjusted p = 0.08). Neither of these relations were independent of LDL-cholesterol or fasting triglyceride. There was no association of the ℇ2 allele with albuminuria either at baseline (OR = 1.4, 95 % CI:0.7–2.8) or with progression of albuminuria (OR = 0.4, 95 % CI:0.1–3.5).¶Conclusion/interpretation. There is an inverse relation of HDL-cholesterol:apoA-I + apoA-II ratio with albuminuria at baseline. This lower ratio in microalbuminuric or macroalbuminuric patients could contribute to the increased risk of cardiovascular disease associated with nephropathy. There is weak evidence that HDL-composition is a risk factor for progression of albuminuria and no association of the ℇ2 allele with diabetic nephropathy. [Diabetologia 2000 43: 1353–1359] [ABSTRACT FROM AUTHOR]

Vascular complications are major causes of morbidity and mortality in patients with diabetes mellitus. The mechanisms underlying the development of microvascular and macrovascular angiopathy in Type I (insulin-dependent) diabetes mellitus are complex and incompletely understood. The discovery of endothelium-derived nitric oxide has greatly improved our understanding of vascular biology. Nitric oxide has an important role in the regulation of vascular tone and impaired nitric oxide activity could be implicated in the development of diabetic vasculopathy. Vascular studies of endothelial function in Type I diabetes have produced conflicting results. The role of nitric oxide in diabetic vasculopathy is still not clear. [Diabetologia (2000) 43: 137–147] [ABSTRACT FROM AUTHOR]

SummaryAims To examine the scope for cardiovascular disease risk factor intervention among diabetic patients in England was examined using data from the Health Surveys for England 1991–94. This evaluation included calculating the proportion who require lipid lowering therapy according to the Standing Medical Advisory Committee (SMAC) guidelines. Methods The Health Survey for England is an annual, nationwide household-based in which anthropomorphic data, blood pressure, lipids and details of cardiovascular risk factors are collected from households after random stratification for geographical and socio-economic factors within a population sample of 39 639 adults, 970 (2.3%) diabetic subjects were identified. Results Overall, 51% of those with diabetes had hypertension (systolic blood pressure ≥ 160 mmHg or a diastolic BP ≥ 95 mmHg or being on antihypertensive therapy), 27% were obese (body mass index ≥ 30 kg/m2) and 19% were current smokers. One-third of those with hypertension were untreated and less than one-half of those on treatment had their hypertension controlled to below 160/95 mmHg. More than one-quarter had poor glycaemic control (glycated Hb > 11% or an HbA1c > 7.5%). Of those aged < 70 years, 29% required lipid lowering therapy according to the SMAC guidelines and almost all (94%) of these were not on treatment. An analysis showed that, because the SMAC guidelines do not require high density lipoprotein (HDL) cholesterol to be measured, their use is likely to result in substantial underestimation of the need for lipid lowering, particularly in diabetic women. Conclusion In England, among those with diabetes there is considerable unmet need for cardiovascular risk factor intervention, particularly for hypertension and raised cholesterol. With this baseline established, future improvements can be monitored. Diabet. Med. 16, 35–40 (1999). [ABSTRACT FROM AUTHOR]