Diabetes,glycaemic control and mortality risk in patients on haemodialysis: the Japan Dialysis Outcomes and Practice Pattern Study

Aims/hypothesis There are few data on the target level of glycaemic control among patients with diabetes on haemodialysis. We investigated the impact of glycaemic control on mortality risk among diabetic patients on haemodialysis. Subjects and methods Data were analysed from the Dialysis Outcomes Practice Pattern Study (DOPPS) for randomly selected patients on haemodialysis in Japan. The diagnosis of diabetes at baseline and information on clinical events during follow-up were abstracted from the medical records. A Cox proportional hazards model was used to evaluate the association between presence or absence of diabetes, glycaemic control (HbA_1c quintiles) and mortality risk. Results Data from 1,569 patients with and 3,342 patients without diabetes on haemodialysis were analysed. Among patients on haemodialysis, those with diabetes had a higher mortality risk than those without (multivariable hazard ratio 1.37, 95% CI 1.08–1.74). Compared with those in the bottom quintile of HbA_1c level, the multivariable-adjusted hazard ratio for mortality was not increased in the bottom second to fourth quintiles of HbA_1c (HbA_1c 5.0–5.5% to 6.2–7.2%), but was significantly increased to 2.36 (95% CI 1.02–5.47) in the fifth quintile (HbA_1c ≥ 7.3%). The effect of poor glycaemic control did not statistically correlate with baseline mortality risk (p = 0.27). Conclusions/interpretation Among dialysis patients, poorer glycaemic control in those with diabetes was associated with higher mortality risk. This suggests a strong effect of poor glycaemic control above an HbA_1c level of about 7.3% on mortality risk, and that this effect does not appear to be influenced by baseline comorbidity status.     

Addition of vildagliptin to insulin improves glycaemic control in type 2 diabetes

Aims/hypothesis Type 2 diabetes is difficult to manage in patients with a long history of disease requiring insulin therapy. Moreover, addition of most currently available oral antidiabetic agents increases the risk of hypoglycaemia. Vildagliptin is a dipeptidyl peptidase-IV inhibitor, which improves glycaemic control by increasing pancreatic beta cell responsiveness to glucose and suppressing inappropriate glucagon secretion. This study assessed the efficacy and tolerability of vildagliptin added to insulin therapy in patients with type 2 diabetes. Materials and methods This was a multicentre, 24-week, double-blind, randomised, placebo-controlled, parallel-group study in patients with type 2 diabetes that was inadequately controlled (HbA_1c = 7.5–11%) by insulin. Patients received vildagliptin (n = 144; 50 mg twice daily) or placebo (n = 152) while continuing insulin therapy. Results Baseline HbA_1c averaged 8.4 ± 0.1% in both groups. The adjusted mean change from baseline to endpoint (AMΔ) in HbA_1c was −0.5 ± 0.1% and −0.2 ± 0.1% in patients receiving vildagliptin or placebo, respectively, with a significant between-treatment difference (p = 0.01). In patients aged ≥65 years, the AMΔ HbA_1c was −0.7 ± 0.1% in the vildagliptin group vs −0.1 ± 0.1% in the placebo group (p < 0.001). The incidence of adverse events was similar in the vildagliptin (81.3%) and placebo (82.9%) groups. However, hypoglycaemic events were less common (p < 0.001) and less severe (p < 0.05) in patients receiving vildagliptin than in those receiving placebo. Conclusions/interpretation Vildagliptin decreases HbA_1c in patients whose type 2 diabetes is poorly controlled with high doses of insulin. Addition of vildagliptin to insulin therapy is also associated with reduced confirmed and severe hypoglycaemia. ClinicalTrials.gov ID no.: NCT 00099931. Electronic supplementary material The online version of this article (doi:) contains a complete list of investigators which is available to authorised users.     

A comparison of twice-daily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: a non-inferiority study

Aims/hypothesis The aim of this 52-week, open-label, non-inferiority trial was to compare the safety and efficacy of exenatide (an incretin mimetic) with that of biphasic insulin aspart. Materials and methods Patients on metformin and a sulfonylurea were randomised to exenatide (n = 253; 5 μg twice daily for 4 weeks, 10 μg thereafter) or biphasic insulin aspart (n = 248; twice-daily doses titrated for optimal glucose control), while continuing with metformin and sulfonylurea treatment. Results Glycaemic control achieved with exenatide was non-inferior to that achieved with biphasic insulin aspart (mean±SEM, HbA_1c change: exenatide −1.04 ± 0.07%, biphasic insulin aspart −0.89 ± 0.06%; difference −0.15 [95% CI −0.32 to 0.01]%). Exenatide-treated patients lost weight, while patients treated with biphasic insulin aspart gained weight [between-group difference −5.4 (95% CI −5.9 to −5.0) kg]. Both treatments reduced fasting serum glucose (exenatide −1.8 ± 0.2 mmol/l, p < 0.001; biphasic insulin aspart −1.7 ± 0.2 mmol/l, p < 0.001). Greater reductions in postprandial glucose excursions following morning (p < 0.001), midday (p = 0.002) and evening meals (p < 0.001) were observed with exenatide. The withdrawal rate was 21.3% (54/253) for exenatide and 10.1% (25/248) for biphasic insulin aspart. Nausea (33% incidence, 3.5% discontinuation) was the most common adverse event observed with exenatide. Conclusions/interpretation Exenatide treatment resulted in HbA_1c reduction similar to biphasic insulin aspart and provided better postprandial glycaemic control, making it a potential alternative for the treatment of type 2 diabetes. Treatment with biphasic insulin aspart was associated with weight gain and lower risk of adverse gastrointestinal events. Although the availability of glucose-lowering agents associated with weight reduction may be considered a therapeutic advance, the long-term implications of progressive weight reduction observed with exenatide have yet to be defined. Electronic supplementary material A list of the site investigators is available as electronic supplementary material in the online version of this article at and is accessible to authorised users.     

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus

Aims/hypothesis The aim of this study was to assess the efficacy and safety of sitagliptin (MK-0431) as monotherapy in patients with type 2 diabetes mellitus and inadequate glycaemic control (HbA_1c ≥7% and ≤10%) on exercise and diet.Methods A total of 521 patients aged 27–76 years with a mean baseline HbA_1c of 8.1% were randomised in a 1:2:2 ratio to treatment with placebo, sitagliptin 100 mg once daily, or sitagliptin 200 mg once daily, for 18 weeks. The efficacy analysis was based on an all-patients-treated population using an analysis of covariance, excluding data obtained after glycaemic rescue.Results After 18 weeks, HbA_1c was significantly reduced with sitagliptin 100 mg and 200 mg compared with placebo (placebo-subtracted HbA_1c reduction: −0.60% and −0.48%, respectively). Sitagliptin also significantly decreased fasting plasma glucose relative to placebo. Patients with higher baseline HbA_1c (≥9%) experienced greater placebo-subtracted HbA_1c reductions with sitagliptin (−1.20% for 100 mg and −1.04% for 200 mg) than those with HbA_1c <8% (−0.44% and −0.33%, respectively) or ≥8% to 8.9% (−0.61% and −0.39%, respectively). Homeostasis model assessment beta cell function index and fasting proinsulin:insulin ratio, markers of insulin secretion and beta cell function, were significantly improved with sitagliptin. The incidence of hypoglycaemia and gastrointestinal adverse experiences was not significantly different between sitagliptin and placebo. Sitagliptin had a neutral effect on body weight.Conclusions/interpretation Sitagliptin significantly improved glycaemic control and was well tolerated in patients with type 2 diabetes mellitus who had inadequate glycaemic control on exercise and diet. Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible to authorised users.For the Sitagliptin Study 023 Group see electronic supplementary material for list of study investigators.     

Effect of non-oil-seed pulses on glycaemic control: a systematic review and meta-analysis of randomised controlled experimental trials in people with and without diabetes

Aims/hypothesis  Dietary non-oil-seed pulses (chickpeas, beans, peas, lentils, etc.) are a good source of slowly digestible carbohydrate, fibre and vegetable protein and a valuable means of lowering the glycaemic-index (GI) of the diet. To assess the evidence that dietary pulses may benefit glycaemic control, we conducted a systematic review and meta-analysis of randomised controlled experimental trials investigating the effect of pulses, alone or as part of low-GI or high-fibre diets, on markers of glycaemic control in people with and without diabetes. Methods  We searched MEDLINE, EMBASE, CINAHL, and the Cochrane Library for relevant controlled trials of ≥7 days. Two independent reviewers (A. Esfahani and J. M. W. Wong) extracted information on study design, participants, treatments and outcomes. Data were pooled using the generic inverse variance method and expressed as standardised mean differences (SMD) with 95% CIs. Heterogeneity was assessed by χ ² and quantified by I ². Meta-regression models identified independent predictors of effects. Results  A total of 41 trials (39 reports) were included. Pulses alone (11 trials) lowered fasting blood glucose (FBG) (−0.82, 95% CI −1.36 to −0.27) and insulin (−0.49, 95% CI −0.93 to −0.04). Pulses in low-GI diets (19 trials) lowered glycosylated blood proteins (GP), measured as HbA_1c or fructosamine (−0.28, 95% CI −0.42 to −0.14). Finally, pulses in high-fibre diets (11 trials) lowered FBG (−0.32, 95% CI −0.49 to −0.15) and GP (−0.27, 95% CI −0.45 to −0.09). Inter-study heterogeneity was high and unexplained for most outcomes, with benefits modified or predicted by diabetes status, pulse type, dose, physical form, duration of follow-up, study quality, macronutrient profile of background diets, feeding control and design. Conclusions/interpretation  Pooled analyses demonstrated that pulses, alone or in low-GI or high-fibre diets, improve markers of longer term glycaemic control in humans, with the extent of the improvements subject to significant inter-study heterogeneity. There is a need for further large, well-designed trials. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorised users. A. Esfahani and J. M. W. Wong contributed equally to this study.     

HbA1c measured in stored erythrocytes and mortality rate among middle-aged and older women

Aims/hypothesis Diabetes is known to increase mortality rate, but the degree to which mild hyperglycaemia may be associated with the risk of death is uncertain. We examined the association between HbA_1c measured in stored erythrocytes and mortality rate in women with and without diabetes. Methods We conducted a cohort study of 27,210 women ≥ 45 years old with no history of cardiovascular disease or cancer who participated in the Women’s Health Study, a randomised trial of vitamin E and aspirin. Results Over a median of 10 years of follow-up, 706 women died. Proportional hazards models adjusted for age, smoking, hypertension, blood lipids, exercise, postmenopausal hormone use, multivitamin use and C-reactive protein were used to estimate the relative risk of mortality. Among women without a diagnosis of diabetes and HbA_1c <5.60%, those in the top quintile (HbA_1c 5.19–5.59%) had a relative risk of mortality of 1.28 (95% CI 0.98–1.69, p value for linear trend = 0.14) compared with those with HbA_1c 2.27–4.79%. Women with HbA_1c 5.60–5.99% and no diagnosis of diabetes had a 54% increased risk of mortality (95% CI 1–136%) compared with those with HbA_1c 2.27–4.79%. HbA_1c was significantly associated with mortality across the range 4.50–7.00% (p value for linear trend = 0.02); a test of deviation from linearity was not statistically significant (p = 0.67). Diabetic women had more than twice the mortality risk of non-diabetic women. Conclusions/interpretation This study provides further evidence that chronic mild hyperglycaemia, even in the absence of diagnosed diabetes, is associated with increased risk of mortality. ClinicalTrials.gov ID no.: NCT00000479     

Similar progression of diabetic retinopathy with insulin glargine and neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes: a long-term, randomised, open-label study

Aims/hypothesis  This long-term study was designed to further characterise the retinal safety profile of insulin glargine and human neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes mellitus. Methods  An open-label, 5 year, randomised (1:1), multicentre, stratified, parallel-group study conducted in the USA and Canada enrolled individuals with type 2 diabetes and either no or non-proliferative retinopathy (less than severe; Early Treatment Diabetic Retinopathy Study [ETDRS] level less than 53 in both eyes) who were treated with oral hypoglycaemic agents (OHAs) alone, insulin alone or OHAs with insulin for ≥3 months prior to study entry and a baseline HbA_1c level of 6.0–12.0%. Patients were randomised by the investigator according to the centralised interactive voice response system to receive twice-daily NPH insulin (n = 509) or once-daily basal insulin glargine (n = 515). The investigator was not blinded to the treatment group to which each participant had been assigned. The main objective of this study was to compare the progression of diabetic retinopathy between treatment groups by analysing the percentage of patients with three or more step progression in the ETDRS retinopathy patient-level severity scale after treatment with either basal insulin. Masked, centralised grading of seven-field stereoscopic fundus photographs was used. Results  Similarly sustained glycaemic control was observed in both the insulin glargine and NPH insulin treatment groups. Despite a slightly greater severity of diabetic retinopathy for the insulin glargine group at baseline, three or more step progression in ETDRS score from baseline to end-of-study was similar between treatment groups (14.2% [53/374] of insulin glargine-treated patients vs 15.7% [57/363] of NPH-treated patients); the difference in the incidence of progression was −1.98% (95% CI −7.02, 3.06%). Other measures of retinopathy—the development of proliferative diabetic retinopathy and progression to clinically significant macular oedema—occurred to a similar degree in both treatment groups. No other safety issues, such as unexpected adverse events for either insulin emerged during the 5 year study. However, NPH insulin treatment was associated with a higher incidence of severe hypoglycaemia compared with insulin glargine. Conclusions/interpretation  This study shows no evidence of a greater risk of the development or progression of diabetic retinopathy with insulin glargine vs NPH insulin treatment in patients with type 2 diabetes mellitus. Trial registration  ClinicalTrials.gov NCT00174824 Funding  This study was sponsored by sanofi-aventis. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

Self‐monitoring in Type 2 diabetes: a randomized trial of reimbursement policy

Aim Self‐monitoring of blood glucose is often considered a cornerstone of self‐care for patients with diabetes. We assessed whether provision of free testing strips would improve glycaemic control in non‐insulin‐treated Type 2 diabetic patients. Methods Adults with Type 2 diabetes, excluding those with private insurance or using insulin, were recruited through community pharmacies and randomized to receive free testing strips for 6 months or not; all patients received similar baseline education and a glucose meter. Primary outcome was change in HbA_1c over 6 months. Results We randomized 262 patients (131 intervention and 131 control subjects). Mean age was 68.4 years (sd 10.9), 48% were male, mean duration of diabetes was 8.2 years (sd 7.2), 97% used oral glucose‐lowering agents and mean baseline HbA_1c was 7.4% (sd 1.2). After 6 months, we observed no difference in HbA_1c between intervention and control patients, after adjusting for baseline HbA_1c[adjusted difference 0.03, 95% confidence interval (CI) ?0.16, 0.22; P = 0.78]. A per protocol analysis of study completers (152/262; 60%) yielded similar results. Intervention patients reported testing 0.64 days per week more often than control subjects (95% CI 0.18, 1.10; P = 0.007), although testing was not associated with better glycaemic control (Pearson r = ?0.10, P = 0.12). Conclusions Reducing financial barriers by providing free testing strips did not improve glycaemic control in patients with Type 2 diabetes not using insulin. Our results question the value of policies that reduce financial barriers to testing supplies in this population.     

Variants in KCNQ1 are associated with susceptibility to type 2 diabetes in the population of mainland China

Aims/hypothesis  Two recent genome-wide association studies have identified several novel type 2 diabetes susceptibility variants in intron 15 of the KCNQ1 gene. We aimed to evaluate the effects of the variants in KCNQ1 on type 2 diabetes and metabolic traits in the population of mainland China. Methods  Three candidate single nucleotide polymorphisms were genotyped in 1,912 individuals with type 2 diabetes and 2,041 normal controls using the ligase detection reaction method. Results  We confirmed the association of KCNQ1 with type 2 diabetes in the population of mainland China. Allele frequency ORs of the three single nucleotide polymorphisms (SNPs) were: rs2237892 (OR 1.19, 95% CI 1.08–1.31, p = 3.0 × 10⁻⁴); rs2237895 (OR 1.20, 95% CI 1.09–1.32, p = 1.9 × 10⁻⁴); and rs2237897 (OR 1.24, 95% CI 1.13–1.36, p = 3.9 × 10⁻⁵). We also found a significant difference in the distribution of the global haplotypes between the type 2 diabetes group and the normal control group (p = 2.6 × 10⁻⁵). In addition, in the control group SNP rs2237892 was marginally associated with increasing fasting plasma glucose and SNPs rs2237892 and rs2237897 were associated with HbA_1c. Furthermore, for all three variants, homozygous carriers of the diabetes-associated allele had significantly decreased BMI and waist circumferences. Conclusions/interpretation  Our investigation confirmed the effects of KCNQ1 variants on type 2 diabetes risk in the Chinese population. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorised users. Y. Liu and D. Z. Zhou contributed equally to this study.     

GAD65 vaccination: 5?years of follow-up in a randomised dose-escalating study in adult-onset autoimmune diabetes

Aims/hypothesis  The aim of this study was to ascertain whether treatment of GAD65 autoantibody (GADA)-positive diabetic patients with alum-formulated recombinant GAD65 (GAD-alum) is safe and does not compromise beta cell function. Methods  This Phase 2, placebo-controlled, dose-escalation clinical trial, which was randomized through a central office, was performed in 47 GADA-positive type 2 diabetic patients, who received subcutaneous injections of GAD-alum (4 [n = 9], 20 [n = 8], 100 [n = 9] or 500 [n = 8] μg) or placebo (n = 13) at weeks 1 and 4 of the trial. Participants and caregivers were blinded to group assignments. The primary outcome was safety as assessed by neurological tests, medications and beta cell function evaluated over 5 years, representing the end of the trial. Results  No severe study-related adverse events occurred during the 5 year follow-up. None of the dose groups was associated with an increased risk of starting insulin treatment compared with the placebo group. The use of oral hypoglycaemic agents did not differ between the dose groups. After 5 years, fasting C-peptide levels declined in the placebo group (−0.24; 95% CI −0.41 to −0.07 log₁₀ nmol/l; p = 0.01) and the 500 μg dose group (−0.37; 95% CI −0.57 to −0.17 log₁₀ nmol/l; p = 0.003), but not in the 4 μg (−0.10; 95% CI −0.28 to 0.07 log₁₀ nmol/l; p = 0.20), 20 μg (0.04; 95% CI −0.12 to 0.19 log₁₀ nmol/l; p = 0.58) and 100 μg (0.00; 95% CI −0.20 to −0.20 log₁₀ nmol/l; p = 0.98) dose groups. Conclusions/interpretation  The primary outcome of safety was achieved, since no severe study-related adverse events occurred. Trial registration  Because the study was initiated before 1 July 2005, the protocol was not registered in a registry. Funding  This trial was funded by the National Institutes of Health (grant numbers DK26190 and DK53004), the Swedish Research Council (grant number 72X-14064) and Diamyd Therapeutics (Stockholm, Sweden). Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

Changes in glycaemic control and risk of coronary artery disease in type 1 diabetes mellitus: findings from the Pittsburgh Epidemiology of Diabetes Complications Study (EDC)

Aims/hypothesis To complete a comparative analysis of studies that have examined the relationship between glycaemia and cardiovascular disease (CVD)/coronary artery disease (CAD) and perform a prospective analysis of the effect of change in glycosylated Hb level on CAD risk in the Pittsburgh Epidemiology of Diabetes Complications Study (EDC) of childhood-onset type 1 diabetes mellitus (n = 469) over 16 years of two yearly follow-up. Methods Measured values for HbA₁ and HbA_1c from the EDC were converted to the DCCT-standard HbA_1c for change analyses and the change in HbA_1c was calculated (final HbA_1c minus baseline HbA_1c). CAD was defined as EDC-diagnosed angina, myocardial infarction, ischaemia, revascularisation or fatal CAD after medical record review. Results The comparative analysis suggested that glycaemia may have a stronger effect on CAD in patients without, than in those with, albuminuria. In EDC, the change in HbA_1c differed significantly between CAD cases (+0.62 ± 1.8%) and non-cases (−0.09 ± 1.9%) and was an independent predictor of CAD. Conclusions/interpretation Discrepant study results regarding the relationship of glycaemia with CVD/CAD may, in part, be related to the prevalence of renal disease. Measures of HbA_1c change over time show a stronger association with CAD than baseline values.     

Coffee consumption and risk of cardiovascular events and all-cause mortality among women with type 2 diabetes

Aims/hypothesis  Coffee has been linked to both beneficial and harmful health effects, but data on its relationship with cardiovascular disease and mortality in patients with type 2 diabetes are sparse. Methods  This was a prospective cohort study including 7,170 women with diagnosed type 2 diabetes but free of cardiovascular disease or cancer at baseline. Coffee consumption was assessed in 1980 and then every 2–4 years using validated questionnaires. A total of 658 incident cardiovascular events (434 coronary heart disease and 224 stroke) and 734 deaths from all causes were documented between 1980 and 2004. Results  After adjustment for age, smoking and other cardiovascular risk factors, the relative risks were 0.76 (95% CI 0.50–1.14) for cardiovascular diseases (p trend = 0.09) and 0.80 (95% CI 0.55–1.14) for all-cause mortality (p trend = 0.05) for the consumption of ≥4 cups/day of caffeinated coffee compared with non-drinkers. Similarly, multivariable RRs were 0.96 (95% CI 0.66–1.38) for cardiovascular diseases (p trend = 0.84) and 0.76 (95% CI 0.54–1.07) for all-cause mortality (p trend = 0.08) for the consumption of ≥2 cups/day of decaffeinated coffee compared with non-drinkers. Higher decaffeinated coffee consumption was associated with lower concentrations of HbA_1c (6.2% for ≥2 cups/day versus 6.7% for <1 cup/month; p trend = 0.02). Conclusions  These data provide evidence that habitual coffee consumption is not associated with increased risk of cardiovascular diseases or premature mortality among diabetic women. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

Relationship between glyco-oxidation, antioxidant status and microalbuminuria in type 2 diabetic patients

Aims/hypothesis  This study examined the relationship, if any, between glucose-induced oxidative stress, antioxidant status and microalbuminuria in patients with type 2 diabetes. Methods  The study involved 99 consecutive type 2 diabetic patients (57 men, 42 women). Patients with persistent microalbuminuria were identified and the following variables evaluated: fasting plasma glucose, HbA_1c, malonyldialdehyde (MDA), pentosidine, AGE, the total radical-trapping antioxidant parameter (TRAP), vitamin E, creatinine, estimated GFR and lipid profile. Results  Patients were divided into two groups, i.e. 37 individuals without microalbuminuria (AER <20 μg/min) and 62 with microalbuminuria (AER ≥20 μg/min). The following variables were significantly higher in patients with microalbuminuria than in those without microalbuminuria (mean ± SD): fasting plasma glucose 9.41 ± 2.88 vs 8.19 ± 1.93 mmol/l, p < 0.05; HbA_1c 7.97 ± 1.51 vs 7.39 ± 1.03%, p < 0.05; MDA 1.18 ± 0.35 vs 1.02 ± 0.29 μmol/l, p < 0.05; pentosidine 98.5 ± 24.6 vs 82.9 ± 20.9 pmol/ml, p < 0.005; and AGE 13.2 ± 4.8 vs 10.6 ± 3.8 μg/mg protein, p < 0.01. However, vitamin E and TRAP did not differ between the two groups. Serum creatinine values and estimated GFR were similar in the two groups. Only in patients with microalbuminuria were significant linear correlations seen between AER and both oxidation (HbA_1c r = 0.33, p < 0.01; MDA r = 0.59, p < 0.001; pentosidine r = 0.48, p < 0.001; and AGE r = 0.44, p < 0.001) and antioxidation variables (vitamin E r = −0.55, p < 0.001; TRAP r = −0.49, p < 0.001). Considering all variables together, multiple regression revealed a correlation between microalbuminuria and vitamin E, TRAP, HbA_1c and MDA, but not pentosidine or AGE. Conclusions/interpretation  Our data suggest that microalbuminuria in type 2 diabetic patients might be promoted by an insufficient counter-regulation of the antioxidant system in the event of increased glyco-oxidation/glycation.     

Reducing glycaemic variability in type 1 diabetes self-management with a continuous glucose monitoring system based on wired enzyme technology

Aims/hypothesis  This study was designed to investigate the use and impact of a continuous glucose monitoring system (the FreeStyle Navigator) under home-use conditions in the self-management of type 1 diabetes. Methods  A 20 day masked phase, when real-time data and alarms were not available, was compared with a subsequent 40 day unmasked phase for a number of specified measures of glycaemic variability. HbA_1c (measured by DCA 2000) and a hypoglycaemia fear survey were recorded at the start and end of the study. Results  The study included 48 patients with type 1 diabetes (mean age 35.7 ± 10.9, range 18–61 years; diabetes duration 17.0 ± 9.5 years). Two patients did not complete the study for personal reasons. Comparing masked (all 20 days) and unmasked (last 20 days) phases, the following reductions were seen: time outside euglycaemia from 11.0 to 9.5 h/day (p = 0.002); glucose SD from 3.5 to 3.2 mmol/l (p < 0.001); hyperglycaemic time (>10.0 mmol/l) from 10.3 to 8.9 h/day (p = 0.0035); mean amplitude of glycaemic excursions (peak to nadir) down by 10% (p < 0.001); high blood glucose index down by 18% (p = 0.0014); and glycaemic risk assessment diabetes equation score down by 12% (p = 0.0013). Hypoglycaemic time (<3.9 mmol/l) decreased from 0.70 to 0.64 h/day without statistical significance (p > 0.05). Mean HbA_1c fell from 7.6 ± 1.1% at baseline to 7.1 ± 1.1% (p < 0.001). In the hypoglycaemia fear survey, the patients tended to take less snacks at night-time after wearing the sensor. Conclusions/interpretation  Home use of a continuous glucose monitoring system has a positive effect on the self-management of diabetes. Thus, continuous glucose monitoring may be a useful tool to decrease glycaemic variability.     

A randomised, 52-week,treat-to-target trial comparing insulin detemir with insulin glargine when administered as add-on to glucose-lowering drugs in insulin-naive people with type 2 diabetes

Aims/hypothesis This 52-week multinational, randomised, open-label, parallel-group, non-inferiority trial compared clinical outcomes following supplementation of oral glucose-lowering drugs with basal insulin analogues detemir and glargine in type 2 diabetic patients. Methods Insulin-naive adults (n = 582, HbA_1c 7.5–10.0%, BMI ≤ 40.0 kg/m²) were randomised 1:1 to receive insulin detemir or glargine once daily (evening) actively titrated to target fasting plasma glucose (FPG) ≤ 6.0 mmol/l. An additional morning insulin detemir dose was permitted if pre-dinner plasma glucose (PG) was >7.0 mmol/l after achieving FPG < 7.0 mmol/l. Due to labelling restrictions, no second glargine dose was allowed. Results Baseline HbA_1c decreased from 8.6 to 7.2 and 7.1% (NS) with detemir and glargine, respectively. FPG improved from 10.8 to 7.1 and 7.0 mmol/l (NS), respectively. With detemir, 45% of participants completed the study on once daily dosing and 55% on twice daily dosing, with no difference in HbA_1c. Overall, 52% of participants achieved HbA_1c ≤ 7.0%: 33% (detemir) and 35% (glargine) without hypoglycaemia. Within-participant variability for self-monitored FPG and pre-dinner PG did not differ by insulin treatment, nor did the relative risk of overall or nocturnal hypoglycaemia. Modest reductions in weight gain were seen with detemir vs glargine in completers (3.0 vs 3.9 kg, p = 0.01) and in the intention-to-treat population (2.7 vs 3.5 kg, p = 0.03), primarily related to completers on once-daily detemir. Mean daily detemir dose was higher (0.78 U/kg [0.52 with once daily dosing, 1.00 U/kg with twice daily dosing]) than glargine (0.44 IU/kg). Injection site reactions were more frequent with detemir (4.5 vs 1.4%). Conclusions/interpretation Supplementation of oral agents with detemir or glargine achieves clinically important improvements in glycaemic control with low risk of hypoglycaemia. Non-inferiority was demonstrated for detemir using higher insulin doses (mainly patients on twice daily dosing); weight gain was somewhat reduced with once daily insulin detemir. ClinicalTrials.gov ID no.: NCT00283751. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

Clinical effectiveness of a brief educational intervention in Type 1 diabetes: results from the BITES (Brief Intervention in Type 1 diabetes,Education for Self‐efficacy) trial

Aims Intensive 5‐day educational interventions for people with Type 1 diabetes have shown improved outcomes in a number of European studies. The aim was to assess the effectiveness of a brief (2.5 days) psycho‐educational intervention. Methods Our randomized trial in a secondary‐care setting had 54 and 60 participants allocated to intervention and control groups, respectively. Primary outcomes were HbA_1c and severe hypoglycaemia. Secondary outcomes were blood pressure, weight, height, lipids and psychometric profile. Results HbA_1c showed no statistically significant change at 3 months [difference = 0.01, 95% confidence interval (CI) –0.23, 0.26, P = 0.92], 6 months (difference = –0.06, 95% CI –0.32, 0.20, P = 0.67) and 12 months (difference = 0.01, 95% CI –0.30, 0.32, P = 0.94). Incidence of severe hypoglycaemia (per patient per year) in the intervention group (0.41) and control group (0.48) was not statistically different. Treatment satisfaction improved at 3 months (difference = 9.4, 95% CI 5.2, 13.6, P = 0.0005), 6 months (difference = 10.4, 95% CI 6.0, 14.8, P = 0.0005) and 12 months (difference = 7.1, 95% CI 2.1, 12.1, P = 0.006). The ‘Managing psychological aspects’ and ‘Setting and achieving goals’ dimensions of the Diabetes Empowerment Scale also showed significant improvement at 3, 6 and 12 months. Diabetes Knowledge Test, Illness Perception Questionnaire, Hypoglycaemia Fear Scale and Short Form 36 showed no significant change. Conclusions This brief intervention had no significant impact on HbA_1c or severe hypoglycaemia, but improved diabetes treatment satisfaction and patient empowerment. Current Controlled Trials ISRCTN75807800.     

Additive effects of glycaemia and blood pressure exposure on risk of complications in type 2 diabetes: a prospective observational study (UKPDS 75)

Aims/hypothesis The relative importance of glucose and blood pressure control in type 2 diabetes remains uncertain. We assessed interactive effects of glycaemia and systolic blood pressure (SBP) exposure on the risk of diabetic complications over time.Subjects, materials and methods HbA_1c and SBP, measured annually for a median of 10.4 years in 4,320 newly diagnosed type 2 diabetic patients from the UK Prospective Diabetes Study (UKPDS), were categorised as updated mean values <6.0, 6.0–6.9, 7.0–7.9 or ≥8.0%, and <130, 130–139, 140–149 or ≥150 mmHg, respectively. Clinical outcomes were UKPDS predefined composite endpoints.Results The incidence of the ‘any diabetes-related endpoint’ in the lowest (HbA_1c <6.0%, SBP <130 mmHg) and highest (HbA_1c ≥8%, SBP ≥150 mmHg) category combinations was 15 and 82 per 1,000 person-years, respectively, and 24 and 120 per 1,000 person-years in a Poisson model adjusted to white Caucasian male sex, age 50 to 54 years and diabetes duration of 7.5 to 12.5 years. Updated mean HbA_1c and SBP effects were additive in an adjusted proportional hazards model with risk reductions of 21% per 1% HbA_1c decrement and 11% per 10 mmHg SBP decrement. Endpoint rates obtained in the 887 patients randomised in both the glycaemia and hypertension intervention trial arms were consistent with the observational data. Those allocated to both intensive glucose and tight blood pressure control policies had fewer events than those allocated to either policy alone or to neither (p for trend 0.024).Conclusions/interpretation Risk of complications in type 2 diabetes is associated independently and additively with hyperglycaemia and hypertension. Intensive treatment of both these risk factors is required to minimise the incidence of complications.     

Glycaemic control is associated with pre-eclampsia but not with pregnancy-induced hypertension in women with Type I diabetes mellitus

Aims/hypothesis. To investigate the association between glycaemic control and hypertensive pregnancy complications. Methods. From 1988 to 1997, we followed up 683 consecutive non-selected pregnancies in women with Type I (insulin-dependent) diabetes mellitus. Glycaemic control was assessed by assay of HbA_{1 c}. Pre-eclampsia was defined as diastolic blood pressure of 90 mmHg or more at the end of pregnancy after an increase of 15 mmHg or more, combined with proteinuria of 0.3 g or more for 24 h. Pregnancy-induced hypertension was defined similarly but without proteinuria. The same criteria were applied to a control group of 854 non-selected non-diabetic women. Results. Pre-eclampsia developed in 12.8 % of the women with diabetes (excluding those with nephropathy before pregnancy) and in 2.7 % of the control women (odds ratio 5.2; 95 % CI 3.3–8.4). In multiple logistic regression, glycaemic control, nulliparity, retinopathy and duration of diabetes emerged as statistically significant independent predictors of pre-eclampsia. The adjusted odds ratios for pre-eclampsia were 1.6 (95 % CI 1.3–2.0) for each 1 % increment in the HbA_{1 c} value at 4–14 (median 7) weeks of gestation and 0.6 (0.5–0.8) for each 1 % decrement achieved during the first half of pregnancy. Changes in glycaemic control during the second half of pregnancy did not significantly alter the risk of pre-eclampsia. Unlike pre-eclampsia, the risk of pregnancy-induced hypertension was not associated with glycaemic control. Conclusion/interpretation. In women with Type I diabetes, poor glycaemic control is associated with an increased risk of pre-eclampsia but not with a risk of pregnancy-induced hypertension. [Diabetologia (2000) 43: 1534–1539] Received: 23 June 2000 and in revised form: 9 August 2000     

HbA<Subscript>1c</Subscript> as a risk factor for heart failure in persons with diabetes: the Atherosclerosis Risk in Communities (ARIC) study

Aims/hypothesis  Heart failure (HF) incidence in diabetes in both the presence and absence of CHD is rising. Prospective population-based studies can help describe the relationship between HbA_1c, a measure of glycaemia control, and HF risk. Methods  We studied the incidence of HF hospitalisation or death among 1,827 participants in the Atherosclerosis Risk in Communities (ARIC) study with diabetes and no evidence of HF at baseline. Cox proportional hazard models included age, sex, race, education, health insurance status, alcohol consumption, BMI and WHR, and major CHD risk factors (BP level and medications, LDL- and HDL-cholesterol levels, and smoking). Results  In this population of persons with diabetes, crude HF incidence rates per 1,000 person-years were lower in the absence of CHD (incidence rate 15.5 for CHD-negative vs 56.4 for CHD-positive, p<0.001). The adjusted HR of HF for each 1% higher HbA_1c was 1.17 (95% CI 1.11–1.25) for the non-CHD group and 1.20 (95% CI 1.04–1.40) for the CHD group. When the analysis was limited to HF cases which occurred in the absence of prevalent or incident CHD (during follow-up) the adjusted HR remained 1.20 (95% CI 1.11–1.29). Conclusions/interpretations  These data suggest HbA_1c is an independent risk factor for incident HF in persons with diabetes with and without CHD. Long-term clinical trials of tight glycaemic control should quantify the impact of different treatment regimens on HF risk reduction.     

The effect of the availability of inhaled insulin on glycaemic control in patients with Type 2 diabetes failing on oral therapy: the evaluation of Exubera® as a therapeutic option on insulin initiation and improvement in glycaemic control in clinical practice (EXPERIENCE) trial

Aim To examine the impact of inhaled human insulin (Exubera®, EXU) on patient or physician willingness to adopt insulin after oral glucose‐lowering agent failure. Methods During a randomized controlled trial in primary, secondary and tertiary care in Europe and North America, 739 patients using ≥ 2 oral glucose‐lowering agents with glycated haemoglobin (HbA_1c) ≥ 8.0% were assigned to two treatment groups: Group 1 (standard care with the option of EXU) or Group 2 (standard care only). Standard care included adjusting oral therapy (optimizing current regimen or adding/omitting agents) and/or initiating subcutaneous (s.c.) insulin. The primary endpoint was difference in HbA_1c between randomized groups at 26 weeks. Secondary outcomes included differences in the rate of uptake of insulin therapy, proportion achieving satisfactory glycaemic control, treatment satisfaction and safety outcomes. Results At baseline, insulin was initiated by more [odds ratio 6.0; 95% confidence interval (CI) 4.2 to 8.8; P < 0.0001] patients in Group 1 (86.2%; 76.7% EXU plus 9.5% s.c.) than Group 2 (50.7%; s.c. insulin only). At 26 weeks, mean (sd ) changes in HbA_1c from baseline were –2.0% (1.2%) and –1.7% (1.3%) in Groups 1 and 2, respectively, a difference of –0.2% (95% CI: –0.1% to –0.4%; P = 0.004). In Group 1, 45% of patients achieved an HbA_1c≤ 7.0% by 26 weeks compared with 39% in Group 2 (P = 0.02). Conclusion The availability of EXU may increase initiation of insulin, thereby contributing to improved overall glycaemic control in patients with Type 2 diabetes inadequately controlled on two or more oral glucose‐lowering agents.