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Aims/hypothesis: Whether hypoglycaemia increases the risk of other adverse outcomes in diabetes remains controversial, especially for hypoglycaemia episodes not requiring assistance from another person. An objective of the Hypoglycaemia REdefining SOLutions for better liVEs (Hypo-RESOLVE) project was to create and use a dataset of pooled clinical trials in people with type 1 or type 2 diabetes to examine the association of exposure to all hypoglycaemia episodes across the range of severity with incident event outcomes: death, CVD, neuropathy, kidney disease, retinal disorders and depression. We also examined the change in continuous outcomes that occurred following a hypoglycaemia episode: change in eGFR, HbA 1c , blood glucose, blood glucose variability and weight., Methods: Data from 84 trials with 39,373 participants were pooled. For event outcomes, time-updated Cox regression models adjusted for age, sex, diabetes duration and HbA 1c were fitted to assess association between: (1) outcome and cumulative exposure to hypoglycaemia episodes; and (2) outcomes where an acute effect might be expected (i.e. death, acute CVD, retinal disorders) and any hypoglycaemia exposure within the last 10 days. Exposures to any hypoglycaemia episode and to episodes of given severity (levels 1, 2 and 3) were examined. Further adjustment was then made for a wider set of potential confounders. The within-person change in continuous outcomes was also summarised (median of 40.4 weeks for type 1 diabetes and 26 weeks for type 2 diabetes). Analyses were conducted separately by type of diabetes., Results: The maximally adjusted association analysis for type 1 diabetes found that cumulative exposure to hypoglycaemia episodes of any level was associated with higher risks of neuropathy, kidney disease, retinal disorders and depression, with risk ratios ranging from 1.55 (p=0.002) to 2.81 (p=0.002). Associations of a similar direction were found when level 1 episodes were examined separately but were significant for depression only. For type 2 diabetes cumulative exposure to hypoglycaemia episodes of any level was associated with higher risks of death, acute CVD, kidney disease, retinal disorders and depression, with risk ratios ranging from 2.35 (p<0.0001) to 3.00 (p<0.0001). These associations remained significant when level 1 episodes were examined separately. There was evidence of an association between hypoglycaemia episodes of any kind in the previous 10 days and death, acute CVD and retinal disorders in both type 1 and type 2 diabetes, with rate ratios ranging from 1.32 (p=0.017) to 2.68 (p<0.0001). These associations varied in magnitude and significance when examined separately by hypoglycaemia level. Within the range of hypoglycaemia defined by levels 1, 2 and 3, we could not find any evidence of a threshold at which risk of these consequences suddenly became pronounced., Conclusions/interpretation: These data are consistent with hypoglycaemia being associated with an increased risk of adverse events across several body systems in diabetes. These associations are not confined to severe hypoglycaemia requiring assistance., (© 2024. The Author(s).)

Aims/hypothesis: The aim of this study was to compare the performance of the second-generation basal insulins, insulin degludec 100 U/ml (Deg-100) and insulin glargine 300 U/ml (Gla-300), in terms of change in HbA 1c , hospitalisation for hypoglycaemia and all-cause mortality among individuals with type 2 diabetes and concurrent chronic kidney disease., Methods: This register-based cohort study, based on the entire Danish diabetes population, included 6519 new users of Deg-100 and Gla-300 with type 2 diabetes and moderate to end-stage chronic kidney disease. HbA 1c trajectories, from initiation of either Deg-100 (2013) or Gla-300 (2015) to end of follow-up (2020), were modelled with mixed-effect models while rates of hospitalisation for hypoglycaemia and all-cause mortality were modelled in separate models using Poisson likelihood., Results: Of the 6519 (44% women) individuals included in the study, 3747 were exposed to Deg-100 and 2772 to Gla-300. Both mean (SD) type 2 diabetes duration (14.4 [6.6] years vs 15.2 [6.7] years) and median (IQR) chronic kidney disease duration (2.3 [1.3, 3.9] years vs 2.8 [1.6, 4.6] years) were significantly shorter in the Gla-300 group. The median (IQR) follow-up time was similar between groups: 1.0 (0.5-1.6) year for Gla-300 and 1.0 (0.3-1.5) year for Deg-100. In both groups mean HbA 1c levels were reduced by 13-14 mmol/mol (1.2-1.3%) from initiation to end of follow-up, with the largest reduction (of 8-9 mmol/mol [0.7-0.8%]) occurring during the first year. There was no significant difference in HbA 1c reduction between Deg-100 and Gla-300. Both the rate of hospitalisation for hypoglycaemia (rate ratio 1.02 [95% CI 0.70, 1.49], Deg-100 vs Gla-300) and the rate of all-cause mortality (rate ratio 0.98 [95% CI 0.84, 1.15], Deg-100 vs Gla-300) were similar between the groups., Conclusions/interpretation: We found no difference in HbA 1c reduction, hospitalisation for hypoglycaemia or all-cause mortality between Gla-300 and Deg-100 in a real-world population of new users with type 2 diabetes and moderate to end-stage chronic kidney disease. Therefore, we conclude that these two treatment options are equally effective and safe in this vulnerable population., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aims/hypothesis: The aim of this study was to assess whether the addition of intermittently scanned continuous glucose monitoring (isCGM) to standard care (self-monitoring of blood glucose [SMBG] alone) improves glycaemic control and pregnancy outcomes in women with type 1 diabetes and multiple daily injections., Methods: This was a multicentre observational cohort study of 300 pregnant women with type 1 diabetes in Spain, including 168 women using SMBG (standard care) and 132 women using isCGM in addition to standard care. In addition to HbA 1c , the time in range (TIR), time below range (TBR) and time above range (TAR) with regard to the pregnancy glucose target range (3.5-7.8 mmol/l) were also evaluated in women using isCGM. Logistic regression models were performed for adverse pregnancy outcomes adjusted for baseline maternal characteristics and centre., Results: The isCGM group had a lower median HbA 1c in the second trimester than the SMBG group (41.0 [IQR 35.5-46.4] vs 43.2 [IQR 37.7-47.5] mmol/mol, 5.9% [IQR 5.4-6.4%] vs 6.1% [IQR 5.6-6.5%]; p=0.034), with no differences between the groups in the other trimesters (SMBG vs isCGM: first trimester 47.5 [IQR 42.1-54.1] vs 45.9 [IQR 39.9-51.9] mmol/mol, 6.5% [IQR 6.0-7.1%] vs 6.4% [IQR 5.8-6.9%]; third trimester 43.2 [IQR 39.9-47.5] vs 43.2 [IQR 39.9-47.5] mmol/mol, 6.1% [IQR 5.8-6.5%] vs 6.1% [IQR 5.7-6.5%]). The whole cohort showed a slight increase in HbA 1c from the second to the third trimester, with a significantly higher rise in the isCGM group than in the SMBG group (median difference 2.2 vs 1.1 mmol/mol [0.2% vs 0.1%]; p=0.033). Regarding neonatal outcomes, newborns of women using isCGM were more likely to have neonatal hypoglycaemia than newborns of non-sensor users (27.4% vs 19.1%; OR adjusted 2.20 [95% CI 1.14, 4.30]), whereas there were no differences between the groups in large-for-gestational-age (LGA) infants (40.6% vs 45.1%; OR adjusted 0.73 [95% CI 0.42, 1.25]), Caesarean section (57.6% vs 48.8%; OR adjusted 1.33 [95% CI 0.78, 2.27]) or prematurity (27.3% vs 24.8%; OR adjusted 1.05 [95% CI 0.55, 1.99]) in the adjusted models. A sensitivity analysis in pregnancies without LGA infants or prematurity also showed that the use of isCGM was associated with a higher risk of neonatal hypoglycaemia (non-LGA: OR adjusted 2.63 [95% CI 1.01, 6.91]; non-prematurity: OR adjusted 2.52 [95% CI 1.12, 5.67]). For isCGM users, the risk of delivering an LGA infant was associated with TIR, TAR and TBR in the second trimester in the logistic regression analysis., Conclusions/interpretation: isCGM use provided an initial improvement in glycaemic control that was not sustained. Furthermore, offspring of isCGM users were more likely to have neonatal hypoglycaemia, with similar rates of macrosomia and prematurity to those of women receiving standard care., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aims/hypothesis: We aimed to investigate the nationwide trends in incidence and associated risk factors, with focus on blood glucose-lowering medication, for the first hypoglycaemic episode leading to hospitalisation in Denmark among people with type 1 and 2 diabetes mellitus., Methods: A cohort study of all people with diabetes from 1977 to 2018 experiencing hypoglycaemic episodes leading to hospitalisation in 1998-2018 was established. Data were extracted from the Danish National Patient Registry. Trends in incidence rates were investigated with Poisson regression models and linear regressions, and risk factors were investigated with Cox proportional hazards models., Results: A total of 66,438 hypoglycaemic episodes leading to hospitalisation in 1998-2018 was investigated among 641,402 people with type 1 (mean ± SD age 37 ± 22 years) and type 2 diabetes (mean ± SD age 61 ± 17 years). Between 2003 and 2018, the incidence rate fell by 66% for type 1 diabetes (incidence rate ratio [IRR] 0.34 [95% CI 0.31, 0.36], p < 0.0001) and 61% for type 2 diabetes (IRR 0.39 [95% CI 0.36, 0.42], p < 0.0001). With respect to hypoglycaemic episodes, insulin glargine (HR 1.20 [95% CI 1.05, 1.36], p = 0.0059), insulin detemir (HR 1.18 [95% CI 1.04, 1.32], p = 0.0077) and insulin degludec (HR 1.04 [95% CI 0.81,1.33], p = 0.7706) seemed safer than human insulin (long-acting insulin HR 1.38 [95% CI 1.25, 1.52], p < 0.0001; combination insulins HR 1.84 [95% CI 1.65, 2.05], p < 0.0001) and, especially, sodium-glucose cotransporter 2 inhibitors (HR 0.43 [95% CI 0.33, 0.56], p < 0.0001), glucagon-like peptide 1 receptor agonists (HR 0.51 [95% CI 0.44, 0.58], p < 0.0001) and dipeptidyl peptidase 4 inhibitors (HR 0.44 [95% CI 0.38, 0.49], p < 0.0001) seemed safer than sulfonylureas (HR 2.27 [95% CI 2.18, 2.37], p < 0.0001)., Conclusions/interpretation: Incidence rates of hypoglycaemic episodes leading to hospitalisation are declining in Denmark, and the advent of new treatment alternatives may play a significant role in this decline. From a safety perspective, these findings are important and should be considered by clinicians when assessing treatment options for patients., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Insulin therapy has been a life saver for people with type 1 diabetes and has been an essential tool in the therapy of people with type 2 diabetes, but the risk for hypoglycaemia has been a major hurdle to achieving good glycaemic control for most. Insulin analogues, the availability of novel technologies for the administration of insulin, like insulin pumps, and, in particular, tools to measure glucose levels, evolving from capillary measurements to continuous glucose monitoring, have revolutionised the way in which people living with diabetes use insulin. Novel insulin concepts, like once-weekly or oral insulin administration, will have to demonstrate safety on the side of hypoglycaemia before they will be able to move into the clinic.

Aims/hypothesis: More than 25% of older adults (age ≥75 years) have diabetes and may be at risk of adverse events related to treatment. The aim of this study was to assess the prevalence of intensive glycaemic control in this group, potential overtreatment among older adults and the impact of overtreatment on the risk of serious events., Methods: We conducted a retrospective, population-based cohort study of community-dwelling older adults in Ontario using administrative data. Participants were ≥75 years of age with diagnosed diabetes treated with at least one anti-hyperglycaemic agent between 2014 and 2015. Individuals were categorised as having intensive or conservative glycaemic control (HbA 1c <53 mmol/mol [<7%] or 54-69 mmol/mol [7.1-8.5%], respectively), and as undergoing treatment with high-risk (i.e. insulin, sulfonylureas) or low-risk (other) agents. We measured the composite risk of emergency department visits, hospitalisations, or death within 30 days of reaching intensive glycaemic control with high-risk agents., Results: Among 108,620 older adults with diagnosed diabetes in Ontario, the mean (± SD) age was 80.6 (±4.5) years, 49.7% were female, and mean (± SD) diabetes duration was 13.7 (±6.3) years. Overall, 61% of individuals were treated to intensive glycaemic control and 21.6% were treated to intensive control using high-risk agents. Using inverse probability treatment weighting with propensity scores, intensive control with high-risk agents was associated with nearly 50% increased risk of the composite outcome compared with conservative glycaemic control with low-risk agents (RR 1.49, 95% CI 1.08, 2.05)., Conclusions/interpretation: Our findings underscore the need to re-evaluate glycaemic targets in older adults and to reconsider the use of anti-hyperglycaemic medications that may lead to hypoglycaemia, especially in setting of intensive glycaemic control.

Hypoglycaemia (blood glucose concentration below the normal range) has been recognised as a complication of insulin treatment from the very first days of the discovery of insulin, and remains a major concern for people with diabetes, their families and healthcare professionals today. Acute hypoglycaemia stimulates a stress response that acts to restore circulating glucose, but plasma glucose concentrations can still fall too low to sustain normal brain function and cardiac rhythm. There are long-term consequences of recurrent hypoglycaemia, which are still not fully understood. This paper reviews our current understanding of the acute and cumulative consequences of hypoglycaemia in insulin-treated diabetes.

Aims/hypothesis: Gestational diabetes mellitus (GDM) is generally defined based on glycaemia during an OGTT, but aetiologically includes women with defects in insulin secretion, insulin sensitivity or a combination of both. In this observational study, we aimed to determine if underlying pathophysiological defects evaluated as continuous variables predict the risk of important obstetric and neonatal outcomes better than the previously used dichotomised or categorical approaches., Methods: Using data from blinded OGTTs at mean gestational week 28 from five Hyperglycemia and Adverse Pregnancy Outcome study centres, we estimated insulin secretion (Stumvoll first phase) and sensitivity (Matsuda index) and their product (oral disposition index [DI]) in 6337 untreated women (1090 [17.2%] with GDM as defined by the International Association of Diabetes and Pregnancy Study Groups). Rather than dichotomising these variables (i.e. GDM yes/no) or subtyping by insulin impairment, we related insulin secretion and sensitivity as continuous variables, along with other maternal characteristics, to obstetric and neonatal outcomes using multiple regression and receiver operating characteristic curve analysis., Results: Stratifying by GDM subtype offered superior prediction to GDM yes/no only for neonatal hyperinsulinaemia and pregnancy-related hypertension. Including the DI and the Matsuda score significantly increased the area under the receiver operating characteristic curve (AUROC) and improved prediction for multiple outcomes (large for gestational age [AUROC 0.632], neonatal adiposity [AUROC 0.630], pregnancy-related hypertension [AUROC 0.669] and neonatal hyperinsulinaemia [AUROC 0.688]). Neonatal hypoglycaemia was poorly predicted by all models. Combining the DI and the Matsuda score with maternal characteristics substantially improved the predictive power of the model for large for gestational age, neonatal adiposity and pregnancy-related hypertension., Conclusion/interpretation: Continuous measurement of insulin secretion and insulin sensitivity combined with basic clinical variables appeared to be superior to GDM (yes/no) or subtyping by insulin secretion and/or sensitivity impairment in predicting obstetric and neonatal outcomes in a multi-ethnic cohort. Graphical abstract.

Aims/hypothesis: Several pathophysiological mechanisms would suggest a causal link between hypoglycaemia and cardiovascular death; conversely, current knowledge would not support a causal relationship with other causes of death. To clarify the nature and the magnitude of the association between hypoglycaemia and death, we investigated the 5 year mortality risks for cardiovascular disease, cancer and other causes in individuals with type 2 diabetes admitted to hospital for a severe hypoglycaemic episode., Methods: We defined in the UK Clinical Practice Research Datalink database a prevalent cohort of adults with type 2 diabetes diagnosed between 1 January 1998 and 1 January 2011 (index date), with available linkage to the Office for National Statistics (ONS) and the Hospital Episode Statistics (HES). A hospital admission reporting hypoglycaemia as the underlying cause was identified before the index date in the HES; date and underlying cause of death were obtained from the ONS. We quantified the 5 year risk of cause-specific death in people with and without admission to hospital for severe hypoglycaemia, adjusting for potential confounders and accounting for competing risk., Results: Of the 74,610 subjects included in the cohort, 388 (0.5%) were admitted at least once for a severe hypoglycaemic episode; subjects admitted were older, with higher HbA 1c and a greater prevalence of multimorbidity. During a median follow-up of 7.1 years, 236 (60.8%) and 18,539 (25.0%) deaths occurred in subjects with and without a previous severe hypoglycaemia, respectively. Non-cardiovascular causes accounted for 71% of all deaths in both subjects with and without hypoglycaemia. In a 60-year-old person with severe hypoglycaemia, the 5 year absolute risk of death, adjusted for age, sex, ethnicity, systolic blood pressure, total cholesterol, HbA 1c , BMI, eGFR, smoking status, alcohol consumption and deprivation (Townsend score), was 6.6%, 1.1% and 13.1% for cardiovascular, cancer and other causes, respectively, while the 5 year absolute risk difference compared with a subject without severe hypoglycaemia was 4.7% (95% CI 1.0, 8.3) for cardiovascular, -1.4% (-4.1, 1.4) for cancer and 11.1% (6.1, 16.1) for other causes of death. Results were consistent in models further adjusted for medications and comorbidities (myocardial infarction, stroke, peripheral artery disease, heart failure, atrial fibrillation, cancer), with sulfonylurea and insulin associated with increased mortality rates (from cause-specific hazard ratio of 1.06 [95% CI 0.99, 1.14] for cancer death with use of sulfonylurea to 1.42 [1.29, 1.56] for cardiovascular death with use of insulin). Results were robust to missing data., Conclusions/interpretation: The results of this study indicate severe hypoglycaemia as a marker of, rather than causally linked to, an increased risk of long-term mortality. Regardless of the nature of the association, a severe hypoglycaemic episode represents a strong negative prognostic factor in patients with type 2 diabetes. Graphical abstract.

Aims/hypothesis: A head-to-head randomised trial was conducted to evaluate hypoglycaemia safety with insulin degludec 200 U/ml (degludec U200) and insulin glargine 300 U/ml (glargine U300) in individuals with type 2 diabetes treated with basal insulin., Methods: This randomised (1:1), open-label, treat-to-target, multinational trial included individuals with type 2 diabetes, aged ≥18 years with HbA 1c ≤80 mmol/mol (9.5%) and BMI ≤45 kg/m 2 . Participants were previously treated with basal insulin with or without oral glucose-lowering drugs (excluding insulin secretagogues) and had to fulfil at least one predefined criterion for hypoglycaemia risk. Both degludec U200 and glargine U300 were similarly titrated to a fasting blood glucose target of 4.0-5.0 mmol/l. Endpoints were assessed during a 36 week maintenance period and a total treatment period up to 88 weeks. There were three hypoglycaemia endpoints: (1) overall symptomatic hypoglycaemia (either severe, an event requiring third-party assistance, or confirmed by blood glucose [<3.1 mmol/l] with symptoms); (2) nocturnal symptomatic hypoglycaemia (severe or confirmed by blood glucose with symptoms, between 00:01 and 05:59 h); and (3) severe hypoglycaemia. The primary endpoint was the number of overall symptomatic hypoglycaemic events in the maintenance period. Secondary hypoglycaemia endpoints included the number of nocturnal symptomatic events and number of severe hypoglycaemic events during the maintenance period., Results: Of the 1609 randomised participants, 733 of 805 (91.1%) in the degludec U200 arm and 734 of 804 (91.3%) in the glargine U300 arm completed the trial (87.3% and 87.8% completed on treatment, respectively). Baseline characteristics were comparable between the two treatment arms. For the primary endpoint, the rate of overall symptomatic hypoglycaemia was not significantly lower with degludec U200 vs glargine U300 (rate ratio [RR] 0.88 [95% CI 0.73, 1.06]). As there was no significant difference between treatments for the primary endpoint, the confirmatory testing procedure for superiority was stopped. The pre-specified confirmatory secondary hypoglycaemia endpoints were analysed using pre-specified statistical models but were now considered exploratory. These endpoints showed a lower rate of nocturnal symptomatic hypoglycaemia (RR 0.63 [95% CI 0.48, 0.84]) and severe hypoglycaemia (RR 0.20 [95% CI 0.07, 0.57]) with degludec U200 vs glargine U300., Conclusions/interpretation: There was no significant difference in the rate of overall symptomatic hypoglycaemia with degludec U200 vs glargine U300 in the maintenance period. The rates of nocturnal symptomatic and severe hypoglycaemia were nominally significantly lower with degludec U200 during the maintenance period compared with glargine U300., Trial Registration: ClinicalTrials.gov NCT03078478 FUNDING: This trial was funded by Novo Nordisk (Bagsvaerd, Denmark).

The role of intensive glycaemic control in preventing microvascular disease in diabetes is well established. Iatrogenic hypoglycaemia is, however, a major barrier to effective treatment. Hypoglycaemia is associated with a significant level of morbidity and, despite pharmacological and technological therapeutic advances, reported rates of severe hypoglycaemia in clinical practice have not fallen over the last 20 years. This suggests that human factors are of major relevance and that ensuring the effective self-management of diabetes is an important strategy for the reduction of hypoglycaemic risk. Most of the evidence for the impact of this strategy on hypoglycaemia risk is confined to adults with type 1 diabetes although, in this review, we also cite studies that have specifically addressed this in type 2 diabetes. There are relatively few adequately powered RCTs that have rigorously evaluated the effectiveness of structured education and training programmes on hypoglycaemia; however, the available data suggest a subsequent reduction in severe hypoglycaemia rates of around 50%, a rate reduction that is comparable with that observed following technological interventions. Furthermore, longitudinal observational cohorts support these data, showing similar reductions in rates of hypoglycaemia following structured education. Those who continue to experience recurrent hypoglycaemia and impaired awareness of hypoglycaemia despite education and training in diabetes self-management may benefit from technological interventions and/or interventions that specifically address psychological factors that contribute to hypoglycaemia risk; however, there is urgent need for further research in this area. In the meantime, structured education for effective self-management of diabetes should be part of routine therapy for all those with type 1 diabetes.

Aims/hypothesis: The aim of this research was to explore the relationship between incident epilepsy and type 1 diabetes in British participants., Methods: Using The Health Improvement Network database, we conducted a retrospective, open-cohort study. Patients who were newly diagnosed with type 1 diabetes mellitus at the age of ≤40 years were identified and followed-up from 1 January 1990 to 15 September 2015. These patients, identified as not suffering from epilepsy at the time of diagnosis, were randomly matched with up to four individuals without type 1 diabetes mellitus, based on age, sex and participating general practice. A Cox regression analysis was subsequently performed using Townsend deprivation index, cerebral palsy, head injury and learning disabilities as model covariates., Results: The study population consisted of a total of 24,610 individuals (4922 with type 1 diabetes and 19,688 controls). These individuals were followed up for a mean of 5.4 years (approximately 132,000 person-years of follow up). Patients with type 1 diabetes were significantly more likely to be diagnosed with epilepsy during the observation period compared with controls (crude HR [95% CI]: 3.02 [1.95, 4.69]). The incidence rate was estimated to be 132 and 44 per 100,000 person-years in patients and controls, respectively. This finding persisted after adjusting for model covariates (adjusted HR [95% CI]: 3.01 [1.93, 4.68]) and was also robust to sensitivity analysis, excluding adult-onset type 1 diabetes mellitus., Conclusions/interpretation: Patients with type 1 diabetes are at approximately three-times greater risk of developing epilepsy compared with matched controls without type 1 diabetes. This should be considered when investigating seizure-related disorders in patients with type 1 diabetes mellitus.

Aims/hypothesis: Type 1 diabetes mellitus is a major public health problem of increasing global concern, with potential neurological complications. A possible association exists between type 1 diabetes and subsequent epilepsy. This study evaluated the relationship between type 1 diabetes and epilepsy in Taiwan., Methods: Claims data from the Taiwan National Health Insurance Research Database were used to conduct retrospective cohort analyses. The study cohort contained 2568 patients with type 1 diabetes, each of whom was frequency-matched by sex, urbanisation of residence area and index year with ten patients without type 1 diabetes. Cox proportional hazard regression analysis was conducted to estimate the effects of type 1 diabetes on epilepsy risk., Results: In patients with type 1 diabetes, the risk of developing epilepsy was significantly higher than that in patients without type 1 diabetes (p < 0.0001 for logrank test). After adjustment for potential confounders, the type 1 diabetes cohort was 2.84 times as likely to develop epilepsy than the control cohort was (HR 2.84 [95% CI 2.11, 3.83])., Conclusions/interpretation: Patients with type 1 diabetes are at an increased risk of developing epilepsy. Metabolic abnormalities of type 1 diabetes, such as hyperglycaemia and hypoglycaemia, may have a damaging effect on the central nervous system and be associated with significant long-term neurological sequelae. The causative factors between type 1 diabetes and the increased risk of epilepsy require further investigation.

Aims/hypothesis: In patients with type 2 diabetes mellitus, the effects of HbA1c variability on macrovascular events remain uncertain. The present investigation evaluates the association of HbA1c variability with non-fatal cardiovascular events, emergency admissions and episodes of severe hypoglycaemia in a cohort of patients newly started on insulin therapy., Methods: HbA1c variability was defined as the rate of change in values between observations. The medical records of 406,356 patients enrolled in a disease management programme for type 2 diabetes mellitus were analysed to identify a cohort of 13,777 patients with observed transition to insulin therapy. The cohort was observed for a period of at least 5 years. Cox regression models were applied to quantify the association of HbA1c variability with the events of interest., Results: The models reveal a significant non-linear association between HbA1c variability and the risk of experiencing myocardial infarction, stroke and hypoglycaemia. The lowest risk is seen with a variability of approximately 0.5% (5.5 mmol/mol) per quarter. Using Cox models to predict survival curves for the cohort with hypothetical HbA1c variability of 0.5% (5.5 mmol/mol) and 1.5% (16.4 mmol/mol) per quarter, the proportion experiencing myocardial infarction within 2 years increases significantly from 1% to 10%. The proportion experiencing stroke increases from 1% to 29%, hypoglycaemia from 2% to 24% and the risk of emergency admission from 2% to 21%., Conclusions/interpretation: In patients newly started on insulin therapy, rapid and higher HbA1c variability is associated with an increased risk of myocardial infarction, stroke, severe hypoglycaemia and emergency admission.

Aims/hypothesis: Type 1 diabetes complicated by hypoglycaemia is prevalent in socioeconomically deprived populations. Islet transplantation is of proven efficacy in type 1 diabetes complicated by hypoglycaemia, but it is not known if nationally funded programmes reach the socioeconomically deprived. Our aim was to determine: (1) socioeconomic indices in participants referred to our nationally funded programme; and (2) if metabolic outcomes in our transplant recipients were improved., Methods: Participants referred (n = 106) and receiving transplants (n = 18; 32 infusions) were examined with respect to socioeconomic status (deprivation category score) and their ability to work and drive. In participants followed for ≥12 months after transplantation, metabolic and anthropometric measurements (n = 14) were recorded pre- and post-transplant (assessed ~1, ~3, ~6 and ~12 months with mixed-meal tolerance tests and 6 day continuous glucose monitoring assessments). Donor data was also examined., Results: There was a greater prevalence of socioeconomic deprivation in referred and transplant recipients than the general population (p < 0.05). Of the transplant recipients, 73% were socioeconomically deprived, 88% did not hold a driver's license and 94% had reduced ability to work (all p < 0.01 vs referred participants). Donors were predominantly obese and included circulatory death donors. At 12 months, 93% of participants who had received transplants had graft function, diminished frequency of hypoglycaemia (10 [4-11] vs 0 [0-2] hypoglycaemic episodes/week), improved awareness of hypoglycaemia (Gold score 7 [5-7] vs 1 [1-2]) and glycaemic control (HbA1c: 7.9% [7.2-8.5%]; 63 [55-69] mmol/mol vs 7.2% [6.8-7.5%]; 55 [51-58] mmol/mol), diminished glycaemic lability and decreased central adiposity (all p < 0.05)., Conclusions/interpretation: A nationally funded islet transplant programme reaches the socioeconomically deprived and outcomes are significantly improved in this group.

Aims/hypothesis: The aim of this study was to compare glycaemic control and maternal-fetal outcomes in women with type 1 diabetes managed on insulin pumps compared with multiple daily injections of insulin (MDI)., Methods: In a retrospective study, glycaemic control and outcomes of 387 consecutive pregnancies in women with type 1 diabetes who attended specialised clinics at three centres 2006-2010 were assessed., Results: Women using insulin pumps (129/387) were older and had a longer duration of diabetes, more retinopathy, smoked less in pregnancy, and had more preconception care (p < 0.01 for each). Among 113 pregnancies >20 weeks' gestation in women on insulin pumps and 218 in women on MDI, there was a significant difference in HbA1c in the first trimester (mean HbA1c 6.90 ± 0.71% (52 ± 7.8 mmol/mol) vs 7.60 ± 1.38% (60 ± 15.1 mmol/mol), p < 0.001), which persisted until the third trimester (mean HbA1c 6.49 ± 0.52% (47 ± 5.7 mmol/mol) vs 6.81 ± 0.85% (51 ± 9.3 mmol/mol), p = 0.002). Rates of diabetic ketoacidosis were similar in women on insulin pumps vs MDI (1.8% vs 3.0%, p = 0.72). Despite lower HbA1c, women on insulin pumps did not have an increased incidence of severe hypoglycaemia (8.0% vs 7.6%, p = 0.90) or more weight gain (16.3 ± 8.7 vs 15.2 ± 6.2 kg, p = 0.18). More large-for-gestational-age infants in the pump group (55.0% vs 39.2%, p = 0.007) may have resulted from confounding by parity., Conclusions/interpretation: In this large multicentre study, women using insulin pumps in pregnancy had lower HbA1c without increased risk of severe hypoglycaemia or diabetic ketoacidosis but no improvement in other pregnancy outcomes. This information can help inform care providers and patients about the glycaemic effectiveness and safety of insulin pumps in pregnancy.

Aims/hypothesis: Severe hypoglycaemia is a major barrier to optimising glycaemic control. Recent changes in therapy, however, may have altered the epidemiology of severe hypoglycaemia and its associated risk factors. The aim of this study was to examine the incidence rates and risk factors associated with severe hypoglycaemia in a contemporary cohort of children and adolescents with type 1 diabetes., Methods: Subjects were identified from a population-based register containing data on >99% of patients (<16 years of age) who were being treated for type 1 diabetes in Western Australia. Patients attend the clinic approximately every 3 months, where data pertaining to diabetes management, demographics and complications including hypoglycaemia are prospectively recorded. A severe hypoglycaemic event was defined as an episode of coma or convulsion associated with hypoglycaemia. Risk factors assessed included age, duration of diabetes, glycaemic control, sex, insulin therapy, socioeconomic status and calendar year., Results: Clinical visit data from 1,770 patients, providing 8,214 patient-years of data between 2000 and 2011 were analysed. During follow-up, 841 episodes of severe hypoglycaemia were observed. No difference in risk of severe hypoglycaemia was observed between age groups. Good glycaemic control (HbA1c <7% [53 mmol/mol]) compared with the cohort average (HbA1c 8-9% [64-75 mmol/mol]) was not associated with an increased risk of severe hypoglycaemia. When compared with patients on injection regimens, subjects aged 12-18 years on pump therapy were at reduced risk of severe hypoglycaemia (incidence risk ratio 0.6; 95% CI 0.4, 0.9)., Conclusions/interpretation: In this population-based sample of children and adolescents with type 1 diabetes, contemporary therapy is associated with a changed pattern and incidence of severe hypoglycaemia.

Continuous subcutaneous glucose monitoring (CGM) is a developing technology in the treatment of diabetes mellitus. The first randomised controlled trials on its efficacy have been performed. In several studies, CGM lowered HbA1c in adult patients with suboptimally controlled type 1 diabetes mellitus, when selecting compliant patients who tolerate the device. However, as a preventive tool for hypoglycaemia, CGM has not fulfilled the great expectations. Increasing reimbursement of CGM is expected in the near future, awaiting studies on cost-effectiveness.

Aims/hypothesis: The relationship between cognitive function, cardiovascular disease and premature death is not well established in patients with type 2 diabetes. We assessed the effects of cognitive function in 11,140 patients with type 2 diabetes who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Furthermore, we tested whether level of cognitive function altered the beneficial effects of the BP-lowering and glycaemic-control regimens in the trial., Methods: Cognitive function was assessed using the Mini Mental State Examination at baseline, and defined by scores 28-30 ('normal', n = 8,689), 24-27 ('mild dysfunction', n = 2,231) and <24 ('severe dysfunction', n = 212). Risks of major cardiovascular events, death and hypoglycaemia and interactions with treatment were assessed using Cox proportional hazards analysis., Results: Relative to normal function, both mild and severe cognitive dysfunction significantly increased the multiple-adjusted risks of major cardiovascular events (HR 1.27, 95% CI 1.11-1.46 and 1.42, 95% CI 1.01-1.99; both p < 0.05), cardiovascular death (1.41, 95% CI 1.16-1.71 and 1.56, 95% CI 0.99-2.46; both p

Aims/hypothesis: The aim was to investigate the relationship between severe hypoglycaemia and cognitive impairment in older patients with diabetes., Methods: A sample of 302 diabetic patients aged >/=70 years was assessed for dementia or cognitive impairment without dementia in 2001-2002 and a subsample of non-demented patients (n = 205) was followed to assess cognitive decline. A history of severe hypoglycaemia was determined from self-reports, physician assessments and records of health service use for hypoglycaemia (HSH). Prospective HSH was determined up to 2006. Data analysis, including multiple logistic and Cox regression models, was used to determine whether: (1) there were cross-sectional associations between hypoglycaemia and cognitive status, (2) historical hypoglycaemia predicted cognitive decline, and (3) baseline cognitive status predicted subsequent HSH., Results: There were significant cross-sectional associations between both cognitive impairment and dementia and hypoglycaemia. Independent risk factors for future HSH included dementia (hazard ratio 3.00, 95% CI 1.06-8.48) and inability to self-manage medications (hazard ratio 4.17, 95% CI 1.43-12.13). However, there were no significant associations between historical hypoglycaemia, incident HSH and cognitive decline., Conclusions/interpretation: Dementia is an important risk factor for hypoglycaemia requiring health service utilisation. We found no evidence that hypoglycaemia contributes to cognitive impairment in older patients with diabetes.

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.

Aims/hypothesis: The aim of this analysis was to quantify the relationship between the frequency of hypoglycaemia and various glucose cut-off points for the definition of hypoglycaemia, within a range of HbA(1c) strata., Methods: Data from two trials examining insulin glargine dose titration in 12,837 type 2 diabetic participants starting insulin therapy were combined. Curves for hypoglycaemia frequency plotted against endpoint HbA(1c) level were constructed, using a range of glucose cut-off points for hypoglycaemia., Results: During the 12-week study period, 3,912 patients recorded 21,592 hypoglycaemic episodes, comprising 242 severe, 8,871 symptomatic and 12,479 asymptomatic events, corresponding to hypoglycaemia event rates of 0.10, 3.8 and 5.3 events per patient year. Increasing the hypoglycaemia cut-off point from, for instance, <3.1 to <3.9 mmol/l more than doubled the percentage of affected patients, e.g. from 17.7 to 43.3% at HbA(1c) 7.0-7.2%. At higher hypoglycaemia cut-off points the proportion of patients having only asymptomatic hypoglycaemia increased, e.g. from 30.7% at <3.1 mmol/l to 61.7% of patients at a cut-off point of <3.9 mmol/l. In sensitivity analysis, 121 of 1,756 patients with at least one self-monitored blood glucose value <3.1 mmol/l experienced severe hypoglycaemia, compared with 149 of 3,912 patients with a self-monitored blood glucose level of <3.9 mmol/l. Thus, to identify 28 more patients with severe hypoglycaemia, the number of patients experiencing only non-severe hypoglycaemia more than doubled., Conclusions/interpretation: The glucose cut-off point defining hypoglycaemia greatly affects the reported frequency of hypoglycaemia. When hypoglycaemia is to be defined by a predetermined glucose level, to have clinical relevance the cut-off should be set at a lower level than the threshold of 3.9 mmol/l proposed by the American Diabetes Association.

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 (AMDelta) 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 AMDelta 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.

Aims/hypothesis: We explored the epidemiology of hypoglycaemia in individuals with insulin-treated diabetes by testing the hypothesis that diabetes type and duration of insulin treatment influence the risk of hypoglycaemia., Materials and Methods: This was an observational study over 9-12 months in six UK secondary care diabetes centres. Altogether 383 patients were involved. Patients were divided into the following three treatment groups for type 2 diabetes: (1) sulfonylureas, (2) insulin for <2 years and (3) insulin for >5 years, and into two treatment groups for type 1 diabetes, namely <5 years disease duration and >15 years disease duration. Self-reported (mild and severe) and biochemical episodes (interstitial glucose <2.2 mmol/l using continuous glucose monitoring) were recorded., Results: Mild hypoglycaemia in type 2 diabetic patients on insulin for <2 years was less frequent than in type 1 patients with <5 years disease duration (mean rate: 4 vs 36 episodes per subject-year, p < 0.001). In type 2 diabetic patients treated with sulfonylureas or insulin for <2 years, no differences were observed in the proportion experiencing severe hypoglycaemia (7 vs 7%, difference 0 [95% CI: -7 to 9%]), mild symptomatic (39 vs 51%, difference 12 [-3 to 25%]) or interstitial glucose <2.2 mol/l (22 vs 20%, difference 2 [-13 to 10%]). Severe hypoglycaemia rates were comparable in patients with type 2 diabetes on sulfonylureas or insulin < 2 years (0.1 and 0.2 episodes per subject-year) and far less frequent than in type 1 diabetes (<5 years group, 1.1; >15 years group, 3.2.episodes per subject-year)., Conclusions/interpretation: During early insulin use in type 2 diabetes, the frequency of hypoglycaemia is generally equivalent to that observed in patients treated with sulfonylureas and considerably lower than during the first 5 years of treatment in type 1 diabetes.

Aims/hypothesis: The aim of this study was to investigate the association of glucose levels and variability of glucose, assessed by continuous glucose monitoring, with mood in type 1 diabetic patients., Materials and Methods: Thirty-six type 1 diabetic patients (77.8% male, age: 31.1 +/- 10.0 years; disease duration: 14.7 +/- 7.1 years, BMI: 26.7 +/- 5.1 kg/m2, HbA1c 8.4 +/-1.8%, 27.8% with continuous subcutaneous insulin infusion [CSII] therapy) used a continuous glucose monitoring system for 48.8 h. During this time the patients rated their current mood states 14.6 times on average, using the University of Wales Institute of Science and Technology Mood Adjective Checklist and hand-held computers., Results: Sensor performance was satisfactory, with a mean absolute difference from reference laboratory glucose measurement of 13.7%. Current glucose values were significantly associated with ratings of 'tension' (z = 2.40), 'hedonic tone' (z = -2.63) and 'energetic arousal' (z = -2.09). 'Anger' (z = 1.64) was not significantly associated with glucose values. The glucose AUC during the 60 min prior to the mood rating showed similar associations. The two parameters of glucose variability-coefficient of variation and absolute glucose change during the 60 min prior to the mood ratings-did not show any significant association with the mood ratings. The magnitude of association was significantly higher for glucose level than for glucose variability in the scales 'tension' and 'hedonic tone'., Conclusions/interpretation: High glucose values had a negative impact on mood; positive mood ratings decreased, whereas negative mood ratings increased. The association between mood and glucose variability seemed to be less important than that between glucose level and mood.

Aims/hypothesis: Genetic factors may account for familial clustering related to diabetes complications. Studies have shown a significant relationship between the presence of the deletion (D) allele of the gene encoding ACE and risk of severe hypoglycaemia. This large prospective cohort study assesses this relationship in a large sample of children and adolescents with type 1 diabetes., Subjects and Methods: We studied 585 children and adolescents (mean age 11.9 +/- 4 years, 48.4% males). The frequency of severe hypoglycaemia (an event leading to loss of consciousness or seizure) was prospectively assessed over the 13-year period 1992-2004. Patients were seen with their parents every 3 months and data recorded at each visit. The ACE gene was detected using PCR., Results: In our cohort of 585 children, 186 (31.8%) had at least one episode of severe hypoglycaemia, and of these 28.0% had the II genotype, 48.9% had the ID genotype and 23.1% had the DD genotype. This was in agreement with the Hardy-Weinberg proportion. A total of 477 severe hypoglycaemic episodes was recorded with a total of 3,404 person-years of follow-up, giving a total incidence of 14 per 100 patient-years. No significant increase in risk for DD genotype (incidence rate ratio = 0.97, 95% CI 0.61-1.55) relative to II genotype was observed., Conclusions/interpretation: This large prospective study concludes that the presence of the D allele of the ACE gene does not predict a significantly higher risk of severe hypoglycaemia in type 1 diabetic children and adolescents.

Aims/hypothesis: Gestational diabetes mellitus (GDM) is a risk factor for perinatal complications. In several countries, the criteria for the diagnosis of GDM have been in flux, the American Diabetes Association (ADA) thresholds recommended in 2000 being lower than those of the National Diabetes Data Group (NDDG) that have been in use since 1979. We sought to determine the extent to which infants of women meeting only the ADA criteria for GDM are at increased risk of neonatal complications., Materials and Methods: In a multiethnic cohort of 45,245 women who did not meet the NDDG criteria and were not treated for GDM, we conducted nested case-control studies of three complications of GDM that occurred in their infants: macrosomia (birthweight >4,500 g, n = 494); hypoglycaemia (plasma glucose <2.2 mmo/l, n = 488); and hyperbilirubinaemia (serum bilirubin > or =342 micromol/l (20 mg/dl), n = 578). We compared prenatal glucose levels of the mothers of these infants and mothers of 884 control infants., Results: Women with GDM by ADA criteria only (two or more glucose values exceeding the threshold) had an increased risk of having an infant with macrosomia (odds ratio OR = 3.40, 95% CI = 1.55-7.43), hypoglycaemia (OR = 2.61, 95% CI = 0.99-6.92) or hyperbilirubinaemia (OR = 2.22, 95% CI = 0.98-5.04). Glucose levels 1 h after the 100-g glucose challenge that exceeded the ADA threshold were particularly strongly associated with each complication., Conclusions/interpretation: These results lend support to the ADA recommendations and highlight the importance of the 1-h glucose measurement in a diagnostic test for GDM.

Aims/hypothesis: Pregnancies of women with type 1 diabetes mellitus are associated with maternal and perinatal complications. These complication rates remain elevated despite achievement of the treatment goals described in the widely used guidelines of the American Diabetes Association (i.e. HbA(1)c level 7.0%. Self-monitored glucose levels and those measured with CGMS were compared between patients with four or five, six to nine and ten or more SMBG determinations daily., Results: In patients with HbA(1)c levels 6.0%. In women with HbA(1)c levels 6.0-7.0% and >7.0%, these levels did not differ. The detection rate of hyper- and hypoglycaemic episodes was significantly higher in patients with ten or more SMBG determinations daily than in patients with fewer than ten., Conclusions/interpretation: Treatment of diabetes in pregnant women should be aimed at achieving HbA(1)c levels within the normal range, i.e.

Aims/hypothesis: The aim of this study was to evaluate the implementation of a course teaching flexible, intensive insulin therapy on glycaemic control and severe hypoglycaemia in routine care., Methods: This is a continuous quality-assurance project involving hospital diabetes centres. Every third year each centre re-examines 50 consecutive patients (evaluation sample) 1 year after participation in the course. Ninety-six diabetes centres in Germany participated and 9,583 patients with type 1 diabetes (190 evaluation samples) were re-examined between 1992 and 2004. The intervention was a 5-day inpatient course for groups of up to ten patients with a fixed curriculum of education and training for dietary flexibility and insulin adjustment. The main outcome measures were HbA1c and severe hypoglycaemia., Results: Mean baseline HbA1c was 8.1%, and had decreased to 7.3% at follow-up; incidence of severe hypoglycaemia was 0.37 events per patient per year prior to intervention and 0.14 after intervention. In mixed-effects models adjusted for effects of centres, age and diabetes duration, the mean difference was -0.7% (95% CI -0.9 to -0.6%, p<0.0001) for HbA1c and -0.21 events per patient per year (95% CI -0.32 to -0.11, p=0.0001) for severe hypoglycaemia, with similar results for evaluation samples, with a maximum of 10% of patients lost to follow-up. Before intervention, the incidence of severe hypoglycaemia was three-fold higher in the lowest quartile than in the highest quartile of HbA1c, whereas the risk was comparable across the range of HbA1c values after intervention., Conclusions/interpretation: Implemented as part of a continuous quality-assurance programme the self-management programme is effective and safe in routine care. Improvement of glycaemic control can be achieved without increasing the risk of severe hypoglycaemia.

Aims/hypothesis: This study was conducted to evaluate the long-term outcome of a structured outpatient diabetes teaching and treatment programme (DTTP) for intensified insulin therapy in patients with Type 1 diabetes, which aims to improve metabolic control without increasing the risk of severe hypoglycaemia., Methods: All 123 diabetic outpatients (age 41+/-14 years; 64 women; BMI 23.5+/-3.1; diabetes duration 17+/-11 years; HbA1c 7.9+/-1.6%; 32 patients with a history of severe hypoglycaemia; 18 with overt nephropathy; 22 with proliferative retinopathy) who participated in the DTTP between June 1989 and June 1990 were invited for follow-up visits after 3, 6 and 12 years., Results: Out of the 123 patients, 11 died during the follow-up period, two were lost for follow-up, and one was not willing to participate in re-evaluation after 12 years. Mean HbA1c levels decreased from 7.9+/-1.6% to 7.1+/-1.2% (p<0.01) after 3 years, and were 7.8+/-1.5% (NS) and 7.8+/-1.2% (NS) after 6 and 12 years respectively. Frequency of hypoglycaemia decreased from 0.49 episodes per patient per year to 0.14 after 3 years (p<0.01), 0.19 after 6 years (p<0.01) and 0.16 after 12 years (p<0.01). Of the participants, 41% were able to lower HbA1c levels without episodes of severe hypoglycaemia and to maintain this improvement at all follow-up visits over the 12-year period. At follow-up, intensified insulin therapy was carried out by 94% of the patients., Conclusions/interpretation: A sustained reduction of the incidence of severe hypoglycaemia was observed in patients with Type 1 diabetes after participation in a structured outpatient DTTP over a 12-year period.

Aims/hypothesis: The aim of the trial was to compare the efficacy and tolerability of two types of basal-bolus therapy, using either the soluble long-acting basal insulin analogue, insulin detemir, in combination with the rapid-acting analogue, insulin aspart, or NPH insulin in combination with mealtime regular human insulin., Methods: In this 18-week, 1:1 randomised, open-labelled, parallel trial, 595 patients with Type 1 diabetes mellitus received insulin detemir or NPH insulin in the morning and at bedtime in combination with mealtime insulin aspart or regular human insulin respectively., Results: Glycaemic control with insulin detemir/insulin aspart was improved in comparison with NPH insulin/regular human insulin (HbA1c: 7.88% vs 8.11%; mean difference: -0.22% point [95% CI: -0.34 to -0.10]; p<0.001). Self-measured 8-point plasma glucose profiles differed between the groups (p<0.001), with lower postprandial plasma glucose levels in the insulin detemir/insulin aspart group. Within-person day-to-day variation in plasma glucose was lower with insulin detemir/insulin aspart than with NPH insulin/regular human insulin (SD: 2.88 vs 3.12 mmol/l; p<0.001). Risk of overall and nocturnal hypoglycaemia (23.00-06.00 hours) was, respectively, 21% (p=0.036) and 55% (p<0.001) lower in the insulin detemir/insulin aspart group than in the NPH insulin/regular human insulin group. Body weight (adjusted for baseline and change in HbA1c) was 1 kg lower with insulin detemir/insulin aspart than with NPH insulin/regular human insulin (p<0.001)., Conclusions/interpretation: Basal-bolus therapy using insulin detemir/insulin aspart offers a better balance of control and tolerability than with NPH insulin/regular human insulin. The low variability and more physiological action profiles generated with these insulin analogues resulted in improved glycaemic control with lower risk of hypoglycaemia and no concomitant body weight increase.

Aims/hypothesis: The study was done to assess how well fasting and 2-h plasma glucose (FPG, 2-h PG) after a 75-g OGTT predict cardiovascular disease (CVD) and all-cause mortality in Asian subjects., Methods: People ( n=6817) of Japanese and Asian Indian origin from five prospective studies in five countries were monitored for 5 to 10 years. Hazard ratios for death from all causes and CVD were estimated using Cox proportional hazard models, adjusting for FPG, 2-h PG and established risk factors., Results: Multivariate Cox regression analysis showed that an increase in FPG from 7.0 to 8.0 mmol/l (increase of 0.76 SD) increased relative risk (95% CI) by 1.14 (1.05-1.25) for all-cause and 1.24 (1.10-1.39) for CVD mortality. An increase in 2-h PG from 9.0 to 11.9 mmol/l (0.76 SD) increased relative risks by 1.29 (1.18-1.41) and 1.35 (1.19-1.54). Inclusion of 2-h PG in the FPG model improved the predictive value ( p<0.001), whereas FPG did not influence the predictive value of 2-h PG ( p>10). In a model containing FPG and 2-h PG, hazards ratios for 2-h PG in subjects with IGT or diabetes were 1.35 (1.03-1.77) or 3.03 (2.18-4.21) for all-cause and 1.27 (0.86-1.88) or 3.39 (2.14-5.37) for CVD mortality, compared with normal subjects. The respective hazards ratio for FPG in subjects with IFG or diabetes were 0.94 (0.68-1.31) or 0.88 (0.59-1.32) for all-cause and 1.05 (0.67-1.65) or 0.88 (0.51-1.51) for CVD mortality, compared with normal subjects., Conclusions/interpretation: For prediction of premature death, 2-h PG was superior to FPG in several Asian populations.

Aims/hypothesis: To investigate the incidence of foetal macrosomia (i.e. birth weight >90th percentile) in a non-selected nationwide cohort of women with Type I (insulin-dependent) diabetes mellitus in The Netherlands and to identify risk indicators predictive for macrosomia., Methods: We conducted a prospective nationwide cohort based survey regarding the outcome of Type I diabetic pregnancy in The Netherlands. Data of 289 women who gave birth to a live singleton infant without major congenital malformations at more than or equal to 28 weeks of gestation are shown., Results: The incidence of foetal macrosomia was very high (48.8%), with 26.6% of infants weighing more than 97.7th percentile. Glycaemic control during pregnancy was good (i.e. mean HbA(1c)

Aims/hypothesis: The aim of the work was to evaluate the vestibular organ condition in children and young adults suffering from Type I (insulin-dependent) diabetes mellitus., Methods: The group examined consisted of 95 children and young adults aged from 6 to 28 years with Type I diabetes diagnosed. The diabetic group was divided into subgroups according to duration of the disease, compensation of the disease, and presence and character of hypoglycaemic incidents, and presence of diabetic complications. The control group consisted of 44 healthy children and young adults aged 6 to 28 years. After collecting detailed medical history in each case an electronystagmographic test was performed using the computed two-canal electronystagmographer., Results: Within the diabetic group 6 patients complained about vertigo and balance disorders. Spontaneous nystagmus occurred in 10 cases, positional one in 21 cases. Impaired optokinesis occurred in 36 cases and impaired eye tracking test in 33 cases. In caloric tests there was partial canal paresis in 4 cases and directional preponderance in 7 cases., Conclusion/interpretation: Metabolic disturbances present in Type I diabetes cause disturbances in different parts of vestibular organ but mostly in its central part. Comparing disturbances in the vestibular organ with clinical and biochemical parameters characterising diabetes, the range of vestibular organ impairment in diabetes mellitus type 1 seems to depend mainly on the presence and character of hypoglycaemic incidents and the duration of the disease and to some extent on the compensation of diabetes.

The objective of this study was to identify possible risk factors of severe hypoglycaemia (SH) in a prospective population based study of adult Type I (insulin-dependent) diabetic patients. A representative sample of 684 patients (41% women, mean +/- SD age 36 +/- 11, diabetes duration 18 +/- 11 years), living in the district of Northrhine (9.5 million inhabitants), Germany, were examined in their homes using a mobile ambulance. A comprehensive baseline assessment of possible predictors of SH included sociodemographic and disease related variables, hypoglycaemia awareness, diabetes management, and attitudes and behavioural aspects as expressed by the patients. After a mean of 19 +/- 6 months 669 (98%) patients were interviewed about events of SH since the baseline examination. Using the multiple Cox proportional hazards model, five risk factors of SH were identified: SH during the preceding year [hazard ratio (HR) 2.7, 95% confidence intervals (CI) 1.8-4.2], any history of SH (HR 1.9, CI 1.1-3.4), C-peptide negativity (HR 4.0, CI 1.2-12.7), social status (HR 0.8 for a difference of 5 units for a value range of 0-24, CI 0.6-0.9), and patients' determination to reach normoglycaemia (HR 0.7 for a difference of 1 unit for a value range of 1-6, CI 0.5-0.9), indicating that the lower the social status and the higher the patients' determination to reach normoglycaemia, the higher the risk of SH. After eliminating the history of hypoglycaemia from the model, impaired hypoglycaemia awareness and patients' inappropriate denial of SH as their particular problem became additional significant risk factors of SH. In conclusion, in this population based study of adult Type I diabetic patients, C-peptide negativity, a previous event of SH, patients' determination to reach normoglycaemia and social class were risk factors of SH.

Unlabelled: The objective of this study was to assess the degree of diabetes care and education achieved for Type I (insulin-dependent) diabetes mellitus at the community level in relation to social status and to elucidate potential pathways that mediate any social class gradient. A population-based sample of 684 adults with Type I diabetes (41% women, mean +/- SD age 36 +/- 11, diabetes duration 18 +/- 11 years) in the district of North-Rhine (9.5 million inhabitants), Germany, were examined in their homes using a mobile ambulance., Results: HbA1c (normal 4.3-6.1%) 8.0 +/- 1.5%, incidence of severe hypoglycaemia (injection of glucose or glucagon) 0.21 cases per patient-year; 62% of patients had participated in a structured group treatment and teaching programme for intensification of insulin therapy; 70% used 3 or more insulin injections per day, 9% were on continuous subcutaneous insulin infusion; 91% reported to have had measurements of HbA1c during the preceding year, and 80% to have had an examination of the retina by an ophthalmologist. Care was insufficient with respect to the quality of blood pressure control (70% of patients on antihypertensive drugs had blood pressure values > or = 160/95 mmHg), patient awareness of proteinuria/albuminuria (27% of patients had not heard about it) and prevention of foot complications (only 42% with a diabetes duration over 10 years had remembered to have a foot examination during the preceding 12 months). There was a pronounced social gradient with respect to micro- and macrovascular complications (prevalence of overt nephropathy 7 vs 20% for highest vs lowest quintiles of social class [OR 3.5, 95% CI 1.6-7.5, p = 0.002]) and diabetes-specific quality of life. HbA1c, blood pressure and smoking accounted for part of the association between social class and microvascular complications. The social class gradient was not due to inequality to access to health services, but to lower acceptance among low social class patients of preventive and health maintaining behaviour. In conclusion, achieved standards of care are high with respect to the implementation of intensified treatment regimens, the level of patient education achieved, treatment control and eye care, whereas areas for improvement are blood pressure control and preventive measures for foot care. A substantial social gradient in diabetes care persists despite equal access of patients to health services.

The effect of dietary fibre intake on glycaemic control is still controversial. This study analysed the intake of natural dietary fibre in patients with Type I diabetes mellitus enrolled in the EURODIAB IDDM Complications Study to determine any associations with HbA1c levels and with the prevalence of severe ketoacidosis or severe hypoglycaemia. Dietary intake was assessed by a 3-day dietary record. The relation between intake of fibre (total, soluble and insoluble) and HbA1c was examined in 2065 people with Type I diabetes. Associations with severe ketoacidosis (requiring admission to hospital) and severe hypoglycaemia (requiring the help of another person) were analysed in 2687 people with Type I diabetes. Total fibre intake (g/day) was inversely related to HbA1c (p = 0.02), independently of carbohydrate intake, total energy intake and other factors regarding lifestyle and diabetes management. Severe ketoacidosis risk fell significantly with higher fibre intake (p = 0.002), with an adjusted odds ratio of 0.48 (95 % confidence interval 0.27 to 0.84) in the highest quartile ( > or = 23.0 g fibre/day) compared with the lowest quartile ( < or = 13.7 g fibre/day). The occurrence of severe hypoglycaemia was not related to fibre intake. Beneficial effects of fibre on HbA1c and the risk of severe ketoacidosis were particularly pronounced in patients from southern European centres. This study shows that higher fibre intake is independently related to a reduction in HbA1c levels in European people with Type I diabetes. Furthermore, increased fibre intake may reduce the risk of severe ketoacidosis. These beneficial effects were already observed for fibre intake within the range commonly consumed by people with Type I diabetes.

To establish whether impaired hypoglycaemic awareness is associated with increased rate of severe hypoglycaemia and to assess clinical predictors of severe episodes without warning symptoms a prospective study of 130 insulin-dependent diabetic children and adolescents was undertaken for 1 year. Using a structured questionnaire, 48 patients reported impaired awareness and 82 reported normal awareness of hypoglycaemia at baseline of the study. The two groups did not differ regarding clinical and metabolic characteristics. Episodes of severe hypoglycaemia were recorded for 1 year. The rate of severe hypoglycaemia was higher in the group with impaired awareness than in the group with normal awareness (p < 0.0001). Of the severe hypoglycaemic episodes, 34.0% developed without warning symptoms. Patients with impaired awareness experienced more severe episodes without warning symptoms than those with normal awareness (p = 0.0054). Severe hypoglycaemia occurred more frequently in patients with impaired awareness aged 6 years and less (p = 0.0041) than in older counterparts. Impaired awareness reported at baseline [adjusted odds ratio (OR): 5.8; p =0.0021], age 6 years or less (3.4; p = 0.0121), previous severe episode (4.8; p = 0.0043) and more than 5 % of home blood glucose readings 3.3 mmol/l or less in the preceding month (4.2; p = 0.0211) proved to be independently predictive of severe hypoglycaemic events without warning symptoms. In conclusion, impaired hypoglycaemic awareness is associated with an increased rate of severe hypoglycaemia in diabetic children and adolescents. One third of severe episodes developed without warning symptoms. Impaired awareness, young age and recent biochemical or severe hypoglycaemias are independent risk factors for such episodes. Avoidance of hypoglycaemia should be a priority in preschool children with diabetes.

Since 1990 in most Eastern European countries health care systems have been decentralized or are undergoing the processes of decentralization. Increasingly, diabetic patients are no longer treated by diabetologists but by non-specialized physicians. During the same period structured treatment and teaching programmes have been introduced and health care is increasingly influenced by the St. Vincent declaration. To show the effect of these changes on the quality of diabetes care 90% (n = 244) of all insulin-treated diabetic patients aged 16 to 60 years and living in the city of Jena (100247 inhabitants) were studied in 1994/1995. The results were compared with the baseline examination of 1989/1990 (n = 190). HbA1c (HbA1c/mean normal) in IDDM patients under specialized care was similar in 1994/1995 (1.54 +/- 0.27, n = 47) to 1989/1990 (1.52 +/- 0.31, n = 131, p = 0.0018), but higher under non-specialized care (1.71 +/- 0.38, n = 80, p = 0.0087). In the total group of NIDDM patients there was no significant change in HbA1c (1994/1995: 1.75 +/- 0.4, n = 117, vs 1989/1990: 1.78 +/- 0.4, n = 59, p = 0.67), but with a tendency to higher HbA1c under non-specialized (1.81 +/- 0.4, n = 79) compared to specialized care (1.66 +/- 0.39, n = 38, p = 0.06). Incidence of severe hypoglycaemia (IDDM 0.13; NIDDM 0.04), ketoacidosis (0.02; 0.01) and the prevalence of nephropathy (21%; 35%) and neuropathy (24%; 38%) remained unchanged in comparison to 1989/1990, whereas there was an increase in the prevalence of diabetic retinopathy. Specialized care is mandatory for patients with IDDM.

The objectives of the present analyses were to assess the association between HbA1c levels and severe hypoglycaemia (SH, treatment with glucose i.v. or glucagon injection) and to identify predictors of SH in a prospective multicentre trial. The study population consisted of 636 insulin-dependent diabetic patients who had participated in a structured 5-day in-patient group treatment and teaching programme for intensification of insulin therapy (ITTP) in one of 10 hospitals and who were re-examined after 1, 2, 3, and 6 years including assessment of demographic, disease and treatment related parameters, diabetes-related knowledge, behaviour, and emotional coping. At baseline, age (mean +/- SD) was 27 +/- 7 years, diabetes duration 9 +/- 7 years and HbA1c 8.3 +/- 1.9 %. During the 6-year follow-up, the mean HbA1c value improved to 7.6%, and in patients with a diabetes duration of more than 1 year at entry into the study (n = 538) the incidence of SH decreased from 0.28 cases/patient/year during the year preceding the ITTP to 0.17 cases/patient/year. The patient group was divided into decile groups according to mean follow-up HbA1c values. In each group more than 230 patient years could be analysed. Groups with mean HbA1c values of 5.7, 7.0, 7.4, 7.7 and 8.9% had comparable risks of SH (0.15-0.19 cases/patient/year). In a logistic regression analysis, mean HbA1c during follow-up, a history of SH during the year preceding the ITTP, C-peptide level, emotional coping, carrying emergency carbohydrates (as assessed at the 1-year follow-up), and age at onset of diabetes were significant independent predictors of SH. The incidence of SH between centres varied between 0.05 and 0.27 cases/patient/year. In conclusion, in the present analyses no linear or exponential relationship between HbA1c and severe hypoglycaemia could be identified by using simple group comparisons. Applying complex regression analyses, various patient-related predictors of severe hypoglycaemia were identified.

We report the efficacy of therapy over 5 years follow-up in 758 non-insulin-dependent diabetic patients in a prospective, randomised controlled study of therapy of mild hypertension. Patients were recruited who on antihypertensive therapy had systolic blood pressure over 150 mmHg or diastolic over 85 mmHg, or if not on therapy had systolic blood pressure over 160 mmHg or diastolic over 90 mmHg. Their mean blood pressure at entry to the study was 160/94 mmHg at a mean age of 57 years. They were allocated to tight control (aiming for systolic < 150/diastolic < 85 mmHg) or to less tight control (aiming for systolic < 180/diastolic < 105 mmHg). The tight control group were allocated to primary therapy either with a beta blocker (atenolol) or with an antiotensin converting enzyme inhibitor (captopril), with addition of other agents as required. Over 5 years, the mean blood pressure in the tight control group was significantly lower (143/82 vs 154/88 mmHg, p < 0.001). No difference was seen between those allocated to atenolol or captopril. The proportion of patients requiring three or more antihypertensive therapies to maintain tight control in those allocated to atenolol or captopril increased from 16 and 15%, respectively at 2 years to 25 and 26%, respectively at 5 years, whereas in the less tight control group at 2 and 5 years only 5 and 7%, respectively required three or more therapies. There was no difference in the incidence of side effects or hypoglycaemic episodes between those allocated to atenolol or captopril, but those allocated to atenolol increased their body weight by a mean of 2.3 kg compared with 0.5 kg in those allocated to captopril (p < 0.01). Allocation to atenolol was also associated with small increases in triglyceride, and decreases in LDL and HDL cholesterol, which are of uncertain clinical relevance. The study is continuing to determine whether the improved blood pressure control, which was obtained, will be beneficial in maintaining the health of patients by decreasing the incidence of major clinical complications, principally myocardial infarction and strokes, and microvascular complications, such as severe retinopathy requiring photocoagulation and deterioration of renal function.

To evaluate metabolic control and safety parameters (hypoglycaemia frequency and nasal mucosa physiology), 31 insulin-dependent diabetic patients were treated with intranasal insulin at mealtimes for 1 month and with subcutaneous fast-acting insulin at meals for another month in an open, crossover randomized trial. During both treatment periods the patients were treated with intermediate-acting insulin at bedtime. Six of the patients were withdrawn from the study during intranasal insulin therapy due to metabolic dysregulation. Serum insulin concentrations increased more rapidly and decreased more quickly during intranasal as compared with subcutaneous insulin administration. Metabolic control deteriorated, as assessed by haemoglobin A1c concentrations, slightly but significantly after intranasal as compared with subcutaneous insulin therapy. The bioavailability of intranasally applied insulin was low, since intranasal insulin doses were approximately 20 times higher than subcutaneous doses. The frequency of hypoglycaemia was similar during intranasal and subcutaneous insulin therapy, and nasal mucosa physiology was unaffected after intranasal insulin. We conclude that due to low bioavailability and to a high rate of therapeutic failure, intranasal insulin treatment is not a realistic alternative to subcutaneous insulin injections at the present time.

The prevalence of microvascular and acute diabetic complications, and their relation to duration of diabetes and glycaemic control were examined in a cross-sectional study of 3250 IDDM patients in Europe (EURODIAB IDDM Complications Study). Mean (SD) duration of diabetes was 14.7 (9.3) years. HbA1c and AER were measured centrally. Retinopathy was assessed by centrally graded retinal photography. Autonomic neuropathy was measured by heart rate and blood pressure responses to standing up. Sensory neuropathy was measured by biothesiometry. Normal HbA1c was found in 16% of patients. An AER of 20 micrograms/min or higher was found in 30.6% (95% CI 29.0%, 32.2%) of all patients, and 19.3% (15.6%, 23.0%) of those with diabetes for 1 to 5 years. The prevalence of retinopathy (46% in all patients; 82% after 20 or more years) was substantially lower than in comparable studies. Of all patients 5.9% (5.1%, 6.7%) had postural hypotension, 19.3% (17.9%, 20.7%) had abnormal heart rate variability, 32.2% (30.6%, 33.8%) reported one or more severe hypoglycaemic attacks during the last 12 months and 8.6% (7.6%, 9.6%) reported hospital admission for ketosis over the same period. Microvascular and acute complications were clearly related to duration of diabetes and to glycaemic control. However, the relation of glycaemic control to raised albuminuria differed qualitatively from its relation to retinopathy.

We surveyed the clinical presentation, initial management and subsequent course of a prospectively registered, population-based cohort of 230 patients with Type 1 (insulin-dependent) diabetes mellitus diagnosed before age 21 years in the Oxford Regional Health Authority area in 1985 and 1986. Clinical details from the time of diagnosis were available on 219 patients. Thirty-four (16%) were in severe ketoacidosis with pH less than 7.10 or plasma bicarbonate less than 10 mmol/l, and 21 (10%) had mild to moderate ketoacidosis with pH 7.10-7.35 or plasma bicarbonate 10-21 mmol/l. One child died in ketoacidosis. Presentation in severe ketoacidosis was most common in children under age 5 years (p < 0.05), and ketoacidosis of any degree was less frequent in older children (0.05 < p < 0.01) and those with a parent or sibling with diabetes (p < 0.01). Within 4 years of diagnosis, 55 of 211 patients (26%) experienced severe hypoglycaemia, which in 31 (15%) led to one or more admissions. Readmission for unstable glycaemic control excluding acute hypoglycaemia occurred at least once within 1 year of diagnosis in 13% and within 4 years in 28%, and was more common in girls, in children aged less than 10 years at diagnosis, and those with a history of severe hypoglycaemia. A second cohort of 97 similar patients was recruited in 1990. The rates of admission at diagnosis (79%), severe ketoacidosis (13%) and mild to moderate ketoacidosis (13%) did not differ from the 1985/1986 cohort.(ABSTRACT TRUNCATED AT 250 WORDS)