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Cardiovascular disease (CVD) is a major cause of morbidity and mortality. Although it has been widely appreciated that obesity is a major risk factor for CVD, treatments that produce effective, durable weight loss and the impact of weight reduction in reducing cardiovascular risk have been elusive. Instead, progress in CVD risk reduction has been achieved through medications indicated for controlling lipids, hyperglycemia, blood pressure, heart failure, inflammation, and/or thrombosis. Obesity has been implicated as promoting all these issues, suggesting that sustained, effective weight loss may have independent cardiovascular benefit. GLP-1 receptor agonists (RAs) reduce weight, improve glycemia, decrease cardiovascular events in those with diabetes, and may have additional cardioprotective effects. The GLP-1 RA semaglutide is in phase 3 studies as a medication for obesity treatment at a dose of 2.4 mg subcutaneously (s.c.) once weekly. Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity (SELECT) is a randomized, double-blind, parallel-group trial testing if semaglutide 2.4 mg subcutaneously once weekly is superior to placebo when added to standard of care for preventing major adverse cardiovascular events in patients with established CVD and overweight or obesity but without diabetes. SELECT is the first cardiovascular outcomes trial to evaluate superiority in major adverse cardiovascular events reduction for an antiobesity medication in such a population. As such, SELECT has the potential for advancing new approaches to CVD risk reduction while targeting obesity.

Physical exercise is an important component in the management of type 1 diabetes across the lifespan. Yet, acute exercise increases the risk of dysglycaemia, and the direction of glycaemic excursions depends, to some extent, on the intensity and duration of the type of exercise. Understandably, fear of hypoglycaemia is one of the strongest barriers to incorporating exercise into daily life. Risk of hypoglycaemia during and after exercise can be lowered when insulin-dose adjustments are made and/or additional carbohydrates are consumed. Glycaemic management during exercise has been made easier with continuous glucose monitoring (CGM) and intermittently scanned continuous glucose monitoring (isCGM) systems; however, because of the complexity of CGM and isCGM systems, both individuals with type 1 diabetes and their healthcare professionals may struggle with the interpretation of given information to maximise the technological potential for effective use around exercise (ie, before, during and after). This position statement highlights the recent advancements in CGM and isCGM technology, with a focus on the evidence base for their efficacy to sense glucose around exercise and adaptations in the use of these emerging tools, and updates the guidance for exercise in adults, children and adolescents with type 1 diabetes. ispartof: PEDIATRIC DIABETES vol:21 issue:8 pages:1375-1393 ispartof: location:Denmark status: published

OBJECTIVE: To quantify age-related variability of insulin needs during day and night closed-loop insulin delivery. RESEARCH DESIGN AND METHODS: We retrospectively analyzed data from hybrid closed-loop studies involving young children (1-6 years old, n = 20), children (7-12 years, n = 21), adolescents (13-17 years, n = 15), and adults (>18 years, n = 58) with type 1 diabetes. The coefficient of variation quantified variability of insulin needs during 3 weeks of unrestricted-living hybrid closed-loop use. RESULTS: Data from 2,365 nights and 2,367 days in 114 participants were analyzed. The coefficient of variation of insulin delivery was higher in young children compared with adults (mean difference at nighttime 10.7 percentage points [95% CI 2.9-18.4], P = 0.003; daytime 6.4 percentage points [95% CI 2.0-10.9], P = 0.002) and compared with adolescents (mean difference at nighttime 10.2 percentage points [95% CI 0.0-20.4], P = 0.049; daytime 7.0 percentage points [95% CI 1.1-12.8], P = 0.014). CONCLUSIONS: Diabetes management in young children is complicated by higher variability in insulin requirements, supporting fast-track clinical practice adoption of closed-loop in this vulnerable population. With increasing application of insulin pump therapy and continuous glucose monitors, hybrid closed-loop has become a feasible treatment modality for people with type 1 diabetes (1,2). Apart from manual meal-time boluses, insulin delivery is autonomously modulated by a control algorithm based on real-time sensor glucose values. Insulin delivery may vary considerably from day to day and night to night due to varying activity levels, insulin set-changes, meal timings and composition, and other factors(3,4).Todate,theassociationbetweenageandinsulinvariabilityhasnotbeen assessed.Inthepresentanalysis,weinvestigatewhetherinsulinrequirementsmaybe more variable in younger age.

BACKGROUND: The role of intensive insulin therapy in patients with severe sepsis is uncertain. Fluid resuscitation improves survival among patients with septic shock, but evidence is lacking to support the choice of either crystalloids or colloids. METHODS: In a multicenter, two-by-two factorial trial, we randomly assigned patients with severe sepsis to receive either intensive insulin therapy to maintain euglycemia or conventional insulin therapy and either 10% pentastarch, a low-molecular-weight hydroxyethyl starch (HES 200/0.5), or modified Ringer's lactate for fluid resuscitation. The rate of death at 28 days and the mean score for organ failure were coprimary end points. RESULTS: The trial was stopped early for safety reasons. Among 537 patients who could be evaluated, the mean morning blood glucose level was lower in the intensive-therapy group (112 mg per deciliter [6.2 mmol per liter]) than in the conventional-therapy group (151 mg per deciliter [8.4 mmol per liter], P

Closed-loop systems that automate insulin delivery may improve glycemic outcomes in patients with type 1 diabetes.In this 6-month randomized, multicenter trial, patients with type 1 diabetes were assigned in a 2:1 ratio to receive treatment with a closed-loop system (closed-loop group) or a sensor-augmented pump (control group). The primary outcome was the percentage of time that the blood glucose level was within the target range of 70 to 180 mg per deciliter (3.9 to 10.0 mmol per liter), as measured by continuous glucose monitoring.A total of 168 patients underwent randomization; 112 were assigned to the closed-loop group, and 56 were assigned to the control group. The age range of the patients was 14 to 71 years, and the glycated hemoglobin level ranged from 5.4 to 10.6%. All 168 patients completed the trial. The mean (±SD) percentage of time that the glucose level was within the target range increased in the closed-loop group from 61±17% at baseline to 71±12% during the 6 months and remained unchanged at 59±14% in the control group (mean adjusted difference, 11 percentage points; 95% confidence interval [CI], 9 to 14; P0.001). The results with regard to the main secondary outcomes (percentage of time that the glucose level was180 mg per deciliter, mean glucose level, glycated hemoglobin level, and percentage of time that the glucose level was70 mg per deciliter or54 mg per deciliter [3.0 mmol per liter]) all met the prespecified hierarchical criterion for significance, favoring the closed-loop system. The mean difference (closed loop minus control) in the percentage of time that the blood glucose level was lower than 70 mg per deciliter was -0.88 percentage points (95% CI, -1.19 to -0.57; P0.001). The mean adjusted difference in glycated hemoglobin level after 6 months was -0.33 percentage points (95% CI, -0.53 to -0.13; P = 0.001). In the closed-loop group, the median percentage of time that the system was in closed-loop mode was 90% over 6 months. No serious hypoglycemic events occurred in either group; one episode of diabetic ketoacidosis occurred in the closed-loop group.In this 6-month trial involving patients with type 1 diabetes, the use of a closed-loop system was associated with a greater percentage of time spent in a target glycemic range than the use of a sensor-augmented insulin pump. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases; iDCL ClinicalTrials.gov number, NCT03563313.).

INTRODUCTION: The increased prevalence of Type 2 diabetes mellitus (T2DM) in severe mental illness (SMI) contributes to increased cardiovascular morbidity and reduced life expectancy for people with SMI. Areas covered: In the present clinical review, we summarize the efficacy, safety and tolerability of selected diabetic pharmacotherapy options in SMI and discuss the quality and strength of evidence. Expert commentary: General principles for treating T2DM in SMI involve identifying treatments which promote weight loss and which have low or no risk of hypoglycemia. Patient engagement in decision making about treatment choices is an important factor to ensure adherence and successful use of the chosen therapy. The first line therapeutic option for T2DM in SMI for which there is most evidence is metformin. Based on general population data, second line treatment options in combination with metformin to achieve glycated haemoglobin treatment goals include GLP-1R agonists, DPP-4 inhibitors, sulphonylureas, SGLT2 inhibitors, pioglitazone and insulin, with most evidence for the use of GLP-1R agonists in SMI. Alongside efficacy and tolerability, treatment for T2DM in SMI should be considered on a patient-tailored basis.

Metformin has been used successfully to treat type 2 diabetes for decades. However, the efficacy of the drug varies considerably from patient to patient and this may in part be due to its pharmacokinetic properties. The aim of this study was to examine if common polymorphisms in SLC22A1, encoding the transporter protein OCT1, affect the hepatic distribution of metformin in humans. We performed non-invasive (11) C-metformin PET/CT to determine hepatic exposure in 12 subjects genotyped for variants in SLC22A1. Hepatic distribution of metformin was significantly reduced after oral intake in carriers of M420del and R61C variants in SLC22A1 without being associated with changes in circulating levels of metformin. Our data show that genetic polymorphisms in transporter proteins cause variation in hepatic exposure to metformin, and it demonstrates the application of novel imaging techniques to investigate pharmacogenetic properties in humans. This article is protected by copyright. All rights reserved.

Aims: Cardiovascular (CV) disease is a major cause of reduced life expectancy in type 1 diabetes (T1D). Intensive insulin therapy prevents CV complications but is constrained by hypoglycaemia and weight gain. Adjunct metformin reduces insulin dose requirement and stabilizes weight but there are no data on its cardiovascular effects. We have therefore initiated an international double-blind, randomized, placebo-controlled trial (REMOVAL: REducing with MetfOrmin Vascular Adverse Lesions in type 1 diabetes) to examine whether metformin reduces progression of atherosclerosis in adults with T1D. Individuals >= 40 years of age with T1D for >= 5 years are eligible if they have >= 3 of 10 specified CV risk factors. The enrolment target is 500 participants in 17 international centres.Materials and methods: After 12 weeks of single-blind placebo-controlled run-in, participants with >= 70% adherence are randomized to metformin or matching placebo for 3 years with insulin titrated towards HbA1c 7.0% (53 mmol/mol). The primary endpoint is progression of averaged mean far wall common carotid intima-media thickness (cIMT) measured by ultrasonography at baseline, 12, 24 and 36 months. This design provides 90% power to detect a mean difference of 0.0167 mm in cIMT progression between treatment arms (alpha = 0.05), assuming that up to 20% withdraw or discontinue treatment. Other endpoints include HbA1c, weight, LDL cholesterol, insulin requirement, progression of retinopathy, endothelial function and frequency of hypoglycaemia.Conclusion: REMOVAL is the largest clinical trial of adjunct metformin therapy in T1D to date and will provide clinically meaningful information on its potential to impact CV disease and other complications.

OBJECTIVE We aimed to assess the feasibility and safety of hybrid closed-loop insulin delivery in children with type 1 diabetes aged 1–7 years as well as evaluate the role of diluted insulin on glucose control. RESEARCH DESIGN AND METHODS In an open-label, multicenter, multinational, randomized crossover study, 24 children with type 1 diabetes on insulin pump therapy (median age 5 years [interquartile range 3–6] and mean ± SD HbA1c 7.4 ± 0.7% [57 ± 8 mmol/mol] and total insulin 13.2 ± 4.8 units/day) underwent two 21-day periods of unrestricted living and we compared hybrid closed-loop with diluted insulin (U20) and hybrid closed-loop with standard strength insulin (U100) in random order. During both interventions, the Cambridge model predictive control algorithm was used. RESULTS The proportion of time that sensor glucose was in the target range between 3.9 and 10 mmol/L (primary end point) was not different between interventions (mean ± SD 72 ± 8% vs. 70 ± 7% for closed-loop with diluted insulin vs. closed-loop with standard insulin, respectively; P = 0.16). There was no difference in mean glucose levels (8.0 ± 0.8 vs. 8.2 ± 0.6 mmol/L; P = 0.14), glucose variability (SD of sensor glucose 3.1 ± 0.5 vs. 3.2 ± 0.4 mmol/L; P = 0.16), or the proportion of time spent with sensor glucose 0.99). Total daily insulin delivery did not differ (17.3 ± 5.6 vs. 18.9 ± 6.9 units/day; P = 0.07). No closed-loop–related severe hypoglycemia or ketoacidosis occurred. CONCLUSIONS Unrestricted home use of day-and-night closed-loop in very young children with type 1 diabetes is feasible and safe. The use of diluted insulin during closed-loop does not provide additional benefits compared with standard strength insulin.

Metformin pharmacokinetics (PK) is highly variable, and researchers have for years tried to shed light on determinants of inter-individual (IIV) and inter-occasion variability (IOV) of metformin PK. We set out to identify the main sources of PK variability using a semi-mechanistic model. We assessed the influence of subject characteristics, including seven genetic variants. Data from three studies of healthy individuals with PK measurements of plasma and urine after single dose or at steady-state were used in this study. In total, 87 subjects were included (16 crossover subjects). Single nucleotide polymorphisms in ATM, OCT1, OCT2, MATE1 and MATE2-K were investigated as dominant, recessive or additive. A three-compartment model with transit absorption and renal elimination with a proportional error was fitted to the data using NONMEM 7.3. Oral parameters were separated from disposition parameters as dose-dependent absolute bioavailability was determined with support from urine data. Clearance was expressed as net renal secretion and filtration, assuming full fraction unbound and fraction excreted. Mean transit time and peripheral volume of distribution were identified as the main sources of variability according to estimates, with 94% IOV and 95% IIV, respectively. Clearance contributed only with 16% IIV. Glomerular filtration rate and body-weight were the only covariates found to affect metformin net secretion, reducing IIV to 14%. None of the genetic variants were found to affect metformin PK. Based on our analysis, finding covariates explaining absorption of metformin is much more valuable in understanding variability and avoiding toxicity than elimination.

Background In attempting to achieve optimal metabolic control, the day-to-day management is challenging for a child with type 1 diabetes (T1D) and his family and can have a major negative impact on their quality of life. Augmenting an insulin pump with glucose sensor information leads to improved outcomes: decreased haemoglobin A1c levels, increased time in glucose target and less hypoglycaemia. Fear of nocturnal hypoglycaemia remains pervasive amongst parents, leading to chronic sleep interruption and lack of sleep for the parents and their children. The QUEST study, an open-label, single-centre randomized crossover study, aims to evaluate the impact on time in target, in hypoglycaemia and hyperglycaemia and the effect on sleep and quality of life in children with T1D, comparing a sensor-augmented pump (SAP) with predictive low glucose suspend and alerts to the use of the same insulin pump with a flash glucose measurement (FGM) device not interacting with the pump. Methods/design Subjects meeting the inclusion criteria are randomized to treatment with the SAP or treatment with an insulin pump and independent FGM for 5 weeks. Following a 3-week washout period, the subjects cross over to the other study arm for 5 weeks. During the week before and in the last week of treatment, the subjects and one of their caregivers wear a sleep monitor in order to obtain sleep data. The primary endpoint is the between-arm difference in percentage of time in glucose target during the final 6 days of each treatment arm, measured by a blinded continuous glucose measurement (CGM). Additional endpoints include comparison of quantity and quality of sleep as well as quality of life perception of the subjects and one of their caregivers in the two different treatment arms. Recruitment started in February 2017. A total of 36 patients are planned to be randomized. The study recruitment was completed in April 2018. Discussion With this study we will provide more information on whether insulin pump treatment combined with more technology (SmartGuard® feature and alerts) leads to better metabolic control. The inclusion of indicators on quality of sleep with less sleep interruption, less lack of sleep and perception of quality of life in both children and their primary caregivers is essential for this study and might help to guide us to further treatment improvement. Trial registration ClinicalTrials.gov, NCT03103867. Registered on 6 April 2017. Electronic supplementary material The online version of this article (10.1186/s13063-018-3034-4) contains supplementary material, which is available to authorized users.

Continuous glucose monitoring and flash glucose monitoring systems are increasingly used by people with diabetes on multiple daily injections of insulin and continuous subcutaneous insulin infusion. Along with real-time updates on current glucose levels, these technologies also use trend arrows to provide information on the direction and rate of change of glucose. Two systems, the Dexcom G5 and the FreeStyle Libre, have recently been approved for use without the need for adjunct capillary blood glucose, and there is a need for practical guidance for insulin dosing which incorporates rate of change in the insulin dosing algorithm. Here, we review the integration of rate of change trend arrow information into daily glucose management, including rapid-acting insulin dosing decisions. Based on the FreeStyle Libre flash glucose monitoring system, we also review a practical decision-support tool for actions to take when using trend arrows in conjunction with current glucose readings.

Background: Hypoglycemia is an increasingly important endpoint in clinical diabetes trials. The assessment of hypoglycemia should therefore be as complete as possible. Blinded continuous glucose monitoring (CGM) provides an improved opportunity to capture asymptomatic and nocturnal events. Here we report results from the HypoAna trial comparing all-analog-insulin therapy (aspart/detemir) with all-human-insulin therapy (neutral protamine Hagedorn/regular) on non-severe hypoglycemia (symptomatic and asymptomatic hypoglycemia) as assessed by blinded CGM and compared with data obtained by self-monitoring of blood glucose (SMBG) in patients with type 1 diabetes and recurrent severe hypoglycemia. Methods: Fifty-three patients completed a substudy of 4 × 3 days of blinded CGM. CGM traces were reviewed for hypoglycemic events lasting 15 min or longer. Results: At the threshold ≤3.9 mmol/L, the per-protocol analysis demonstrated a 40% rate reduction (95% confidence interval [CI] 20%-60%; P = 0.002) in nocturnal non-severe hypoglycemia during analog treatment, mainly due to a 40% rate reduction (95% CI 0%-70%; P = 0.03) of nocturnal asymptomatic hypoglycemia. Similar nonsignificant trends were seen at the glucose threshold ≤3.0 mmol/L. Overall CGM-detected that nocturnal asymptomatic hypoglycemia ≤3.9 mmol/L was ∼17 times more frequent than SMBG-detected episodes (52 vs. 3 events/patient-year). This translates into a time needed to treat one patient with insulin analogs to prevent one episode that is 34 times shorter using CGM data than SMBG data (1.4 vs. 47 weeks). Conclusions: Capturing hypoglycemic events by the conventional method of SMBG in patients with impaired awareness reveals only a limited number of events. Blinded CGM can provide more complete data, particularly in terms of asymptomatic and nocturnal events.

Context Worldwide, metformin is prescribed to improve pregnancy outcome in polycystic ovary syndrome (PCOS). Metformin may also benefit future health by modulating increased metabolic stress during pregnancy. Objective To investigate whether metformin during pregnancy modified future metabolic health in women with PCOS. Design Follow-up study of a randomized controlled trial that compared metformin with placebo in women with PCOS. Mean follow-up period was 7.7 years (range, 5 to 11 years). Setting Three university hospitals, seven local hospitals, and one gynecological specialist practice. Participants Women with PCOS according to Rotterdam criteria; all former participants in the Metformin in Pregnant PCOS Women Study. Intervention Metformin 2000 mg daily or placebo from first trimester to delivery in the original study. No intervention in the present follow-up study. Main Outcomes and Measures Main outcome measure was weight gain in the follow-up period. Weight, body mass index (BMI), waist and hip circumferences, and blood pressure (BP) were registered. Body composition was assessed by bioelectrical impedance analysis, and fasting lipids, glucose, and insulin were analyzed. Results Of 239 invited women, 131 (55%) participated in the follow-up. Weight gain was similar in women given metformin (2.1 ± 10.5 kg) and women given placebo (1.8 ± 11.2 kg) at 7.7 years’ follow-up after pregnancy (P = 0.834). No difference was found in BMI, waist/hip ratio, BP, body composition, lipids, glucose and insulin levels, or prevalence of metabolic syndrome at follow-up between those treated with metformin and those treated with placebo during pregnancy. Conclusion Metformin treatment during pregnancy did not influence the metabolic profile in women with PCOS at 7.7 years of follow-up. This is a pre-copyedited, author-produced version of an article accepted for publication in Journal of Clinical Endocrinology & Metabolism following peer review. The version of record is available online at: https://academic.oup.com/jcem/article/103/6/2408/4961064 and https://doi.org/10.1210/jc.2018-00485

Background: The use of sensor-augmented insulin pump (SAP) therapy is increasing. Currently, glucose sensors and insulin infusion cannulas are inserted separately. A new device, MiniMed Duo, combines sensing and infusion capabilities on the same platform and is intended to simplify device insertion and site management. We evaluated the device’s performance with respect to insulin delivery and glucose sensing, and its acceptability with patients. Methods: Forty-five patients (mean ± SD age, 45.5 ± 10.9 years, 48% female) with type 1 diabetes and previous use of SAP participated. Each subject was to wear 5 devices connected to insulin pumps over 15 days (3 days/device) and test capillary blood glucose (SMBG) 7 times/day. The primary endpoint was the percentage of sensor-SMBG paired values within 20% of one another. Subject experiences were assessed via questionnaires. Results: Overall, 74.8% of sensor-SMBG paired values were within 20%, meeting the primary accuracy endpoint, and the mean absolute relative difference was 15.5 ± 17.1%. Consensus error grid analysis showed that >95% of points were within the A+B zones, exceeding the threshold for adequate clinical accuracy. Insulin dosage and SMBG values did not change significantly compared to prestudy values. The functional survival of the device entering day 3 was 90.5%. There were no serious adverse events. Mean questionnaire results indicated overall satisfaction with the device. Conclusion: Duo provided insulin infusion and glucose sensing capabilities in a single device, which provided accurate glucose readings during routine use, was safe to wear, and was acceptable to most patients. It may improve satisfaction and convenience for patients using sensor-augmented insulin pumps.

OBJECTIVE To describe the changes in serum levels of calcitonin in liraglutide- and placebo-treated patients in the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results—A Long Term Evaluation (LEADER) trial over a 3.5–5-year period. RESEARCH DESIGN AND METHODS Patients (n = 9,340) with type 2 diabetes and high risk for cardiovascular events were randomized 1:1 to liraglutide or placebo. We analyzed calcitonin levels, thyroid and C-cell adverse events, and neoplasms. RESULTS At 36 months, patients randomized to liraglutide versus placebo showed no evidence of increase in calcitonin concentrations in male (estimated treatment ratio [ETR] 1.03 [95% CI 1.00, 1.06]; P = 0.068) and female (ETR 1.00 [95% CI 0.97, 1.02]; P = 0.671) subgroups. There were no episodes of C-cell hyperplasia or medullary thyroid carcinoma in liraglutide-treated patients. CONCLUSIONS There was no evidence of a difference in calcitonin concentrations between the liraglutide and placebo groups, and no C-cell malignancies occurred in the liraglutide group.

Background: Reduction in cardiovascular death and hospitalization for heart failure (HHF) was recently reported with the sodium-glucose cotransporter-2 inhibitor (SGLT-2i) empagliflozin in patients with type 2 diabetes mellitus who have atherosclerotic cardiovascular disease. We compared HHF and death in patients newly initiated on any SGLT-2i versus other glucose-lowering drugs in 6 countries to determine if these benefits are seen in real-world practice and across SGLT-2i class. Methods: Data were collected via medical claims, primary care/hospital records, and national registries from the United States, Norway, Denmark, Sweden, Germany, and the United Kingdom. Propensity score for SGLT-2i initiation was used to match treatment groups. Hazard ratios for HHF, death, and their combination were estimated by country and pooled to determine weighted effect size. Death data were not available for Germany. Results: After propensity matching, there were 309 056 patients newly initiated on either SGLT-2i or other glucose-lowering drugs (154 528 patients in each treatment group). Canagliflozin, dapagliflozin, and empagliflozin accounted for 53%, 42%, and 5% of the total exposure time in the SGLT-2i class, respectively. Baseline characteristics were balanced between the 2 groups. There were 961 HHF cases during 190 164 person-years follow-up (incidence rate, 0.51/100 person-years). Of 215 622 patients in the United States, Norway, Denmark, Sweden, and the United Kingdom, death occurred in 1334 (incidence rate, 0.87/100 person-years), and HHF or death in 1983 (incidence rate, 1.38/100 person-years). Use of SGLT-2i, versus other glucose-lowering drugs, was associated with lower rates of HHF (hazard ratio, 0.61; 95% confidence interval, 0.51–0.73; P P P Conclusions: In this large multinational study, treatment with SGLT-2i versus other glucose-lowering drugs was associated with a lower risk of HHF and death, suggesting that the benefits seen with empagliflozin in a randomized trial may be a class effect applicable to a broad population of patients with type 2 diabetes mellitus in real-world practice. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT02993614.

BACKGROUND: Reducing glycemic fluctuation is important for optimal diabetes management. This post hoc analysis examined glycemic fluctuations and the proportion of subjects achieving recommended blood glucose targets with the fixed ratio combination of insulin degludec and liraglutide (IDegLira) compared to insulin degludec (IDeg) and liraglutide alone.METHODS: We analyzed nine-point self-monitored blood glucose (SMBG) profiles from two randomized trials involving IDegLira in patients with type 2 diabetes (T2D), and continuous glucose monitoring (CGM) data from a subset of patients in one of these trials to assess glycemic fluctuation and day-to-day variability.RESULTS: Compared with IDeg, IDegLira resulted in a greater proportion of subjects with SMBG values within target ranges (3.9-9.0 mmol/L) than IDeg for all pre- and postprandial values, and for the full nine-point profile (P CONCLUSIONS: Treatment with IDegLira allows more patients with T2D to maintain blood glucose within target ranges throughout the day than either IDeg or liraglutide alone.

OBJECTIVE: The study aimed to confirm the efficacy, through non-inferiority, of patient-driven versus investigator-driven titration of biphasic insulin aspart 30 (BIAsp 30) in terms of glycemic control assessed by HbA1c change.METHODS: SimpleMix was a 20 week, open-label, randomized, two-armed, parallel-group, multicenter study in five countries (Argentina, China, India, Poland, and the UK). Patients with type 2 diabetes were randomized into either patient-driven or investigator-driven BIAsp 30 titration groups.RESULTS: Non-inferiority of patient-driven vs. investigator-driven titration based on change in HbA1c from baseline to week 20 could not be demonstrated. Mean (SE) estimated change from baseline to week 20 was -0.72 (0.08)% in the patient-driven group and -0.97 (0.08)% in the investigator-driven group; estimated difference 0.25% (95% CI: 0.04; 0.46). Estimated mean change (SE) in fasting plasma glucose from baseline to week 20 was similar between groups: -0.94 (0.21) mmol/L for patient-driven and -1.07 (0.22) mmol/L for investigator-driven (difference non-significant). Both treatment arms were well tolerated, and hypoglycemic episode rates were similar between groups, with a rate ratio of 0.77 (95% CI: 0.54; 1.09; p = 0.143) for all hypoglycemic episodes and 0.78 (95% CI: 0.42; 1.43; p = 0.417) for nocturnal hypoglycemic episodes.CONCLUSIONS: Non-inferiority of patient-driven versus investigator-driven titration with regard to change from baseline to end-of-treatment HbA1c could not be confirmed. It is possible that a clinic visit 12 weeks after intensification of treatment with BIAsp 30 in patients with type 2 diabetes inadequately treated with basal insulin may benefit patient-driven titration of BIAsp 30. A limitation of the study was the relatively small number of patients recruited in each country, which does not allow country-specific analyses to be performed. Overall, treatment with BIAsp 30 was well tolerated in both treatment groups.

In vitro and animal studies indicate that metformin prevents colorectal cancer (CRC). Epidemiological studies, however, have been equivocal. We undertook this study to assess whether metformin prevents CRC in individuals with type II diabetes. We performed a nested case-control study restricted to Danish citizens with type II diabetes. Data were collected from four Danish nationwide registries. Cases were type II diabetics with a primary CRC between 2000 and 2009, and controls were sampled among subjects with type II diabetes. Long-term exposure to metformin was defined by the redeeming of prescriptions for a cumulative dose of 2000 g within 5 years prior to the index date. To control for potential confounders, we used unconditional logistic regression. We generated adjusted odds ratios (OR) for the association between metformin and CRC and performed subanalyses for selected subgroups and for the dose-response relation. We identified 2088 cases and 9060 controls during the study period. The association between long-term metformin use and CRC gave an adjusted OR at 0.83 (95% CI 0.68-1.00). A protective effect on CRC with long-term use of metformin was only evident for women (OR 0.66 vs. 0.99 for men). There was a significant dose-response association of metformin use >250 defined daily dose (DDD) and for the duration of metformin use >1 year. We found an indication of a protective effect of long-term metformin use against CRC in type II diabetics, although this effect was only seen in women. We performed a nested case-control study restricted to Danish citizens with type II diabetes. The association between long-term metformin use and colorectal cancer (CRC) gave an adjusted odds ratios at 0.83 (95 % CI 0.68-1.00). A protective effect on CRC with long-term use of metformin was only evident for women (OR 0.66 vs. 0.99 for men). There was a significant dose-response association of metformin use >250 defined daily dose (DDD) and for the duration of metformin use >1 year.

OBJECTIVE The extracellular matrix protein fibulin-1 is upregulated in the arterial wall in type 2 diabetes (T2D) and circulates in increased concentrations in diabetes. Metformin is an antidiabetic drug with beneficial cardiovascular disease effects in diabetes. We hypothesized that metformin would influence the increased level of plasma fibulin-1 in diabetes. RESEARCH DESIGN AND METHODS After a 4-week run-in period, 371 eligible patients with T2D were randomized to treatment groups in a factorial design including insulin alone (control), +metformin, +rosiglitazone, or +both metformin and rosiglitazone. Plasma fibulin-1 was analyzed at the beginning of the study and after 18 and 24 months. RESULTS Plasma fibulin-1 increased in all groups throughout the 2-year period; however, the increase was strongly attenuated among patients treated with metformin. A highly significant difference was observed when the mean change in plasma fibulin-1 was compared between metformin- and non–metformin-treated individuals both at 18 and 24 months of treatment, but rosiglitazone had no effect. Metformin and rosiglitazone alone reduced the HbA1c levels to comparable levels and in combination even further. CONCLUSIONS Metformin attenuates the increase in plasma fibulin-1 concentrations in T2D, independently of glycemic effects. Changes in fibulin-1 may reflect an important element in diabetic arteriopathy that can be influenced by metformin.

BACKGROUND: We compared stepwise addition of bolus insulin with a full basal-bolus regimen in patients with type 2 diabetes inadequately controlled on basal insulin plus oral antidiabetic drugs.METHODS: The FullSTEP study was a phase 4, 32-week, randomised, open-label, two-arm, parallel-group, multinational, treat-to-target, non-inferiority trial done at 150 sites across seven countries to assess the effectiveness of a stepwise dosing approach versus a basal-bolus regimen. In this trial, 401 patients (mean age 59·8 years [SD 9·3]; HbA1c 7·9% [63 mmol/mol]; mean diabetes duration 12·6 years [SD 8·0]) were block randomised (ratio 1:1) to receive either stepwise treatment or full basal-bolus treatment. Patients in the basal-bolus group received insulin aspart before every meal throughout the trial. Patients in the stepwise group received one bolus dose with the largest meal, with additional insulin aspart doses before the next largest meal added to their regimen at 11 weeks and 22 weeks if HbA1c remained at 7% or higher. The primary outcome was non-inferiority of stepwise addition of bolus insulin versus complete basal-bolus therapy, as assessed by change in HbA1c from baseline to 32 weeks (non-inferiority margin of 0·4%). This trial is registered with ClinicalTrials.gov, number NCT01165684.FINDINGS: The study was started on Oct 27, 2010, and completed on April 25, 2012. After 32 weeks, HbA1c change from baseline was -0·98% (95% CI -1·09 to -0·87) for the stepwise group and -1·12% (-1·23 to -1·00) for the basal-bolus group; mean treatment difference 0·14 (95% CI -0·02 to 0·30), non-significant (p=0·0876). Fewer hypoglycaemic episodes occurred in the stepwise group than in the basal-bolus group (rate ratio 0·58 [95% CI 0·45 to 0·75]; pINTERPRETATION: Stepwise prandial insulin intensification provides glycaemic control non-inferior to a full basal-bolus regimen after 32 weeks, with significantly lower hypoglycaemia risk and better patient satisfaction.FUNDING: Novo Nordisk.

Patient acceptance is one of the major barriers toward widespread use of mHealth systems. The aim of this study was to assess system operability and whole trial feasibility, including patients' experience with their use of COMMODITY12 mHealth system under. Secondary study aims included assessment of several metabolic parameters as well as patient adherence to the treatment. This was a prospective parallel-arm randomized controlled trial in outpatients diagnosed with DM2, being treated in the primary care settings in Lodz region, Poland, with 6 weeks period of follow-up. Patients opinions were collected with 7-item questionnaire, assessing different aspects of system use, as well as EuroQol-5D-5 L questionnaire, assessing health-related quality of life. Sixty patients (female, 24, male, 36, mean age +/? SD 59.5 +/? 6.8) completed study. All four layers of the COMMODITY12 system proved to work smooth under real-life conditions, without major problems. All dimensions of experience with system use were assessed well, with maximum values for clearness of instructions, and ease of use (4.80, and 4.63, respectively). Health related quality of life, as assessed with cumulative utility measure, improved significantly in COMMODITY12 system users (P?0.05). mHealth system modestly improved glycaemic and blood pressure control, assuring high level of patient adherence with overall adherence reaching 92.9 %. Study proved that the COMODITY12 system is well accepted by type 2 diabetes patients taking part in clinical trial, leading to several clinical benefits, and improved quality of life. Nevertheless, before future commercialisation of the system, several minor problems identified during the study need to be addressed.

Background: As adolescents with obesity and insulin resistance may be refractory to lifestyle intervention therapy alone, additional off-label metformin therapy is often used. In this study, the long-term efficacy and safety of metformin versus placebo in adolescents with obesity and insulin resistance is studied. Methods: In a randomized placebo-controlled double-blinded trial, 62 adolescents with obesity aged 10–16 years old with insulin resistance received 2000 mg of metformin or placebo daily and physical training twice weekly over 18 months. Primary end points were change in body mass index (BMI) and insulin resistance measured by the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR). Secondary end points were safety and tolerability of metformin. Other end points were body fat percentage and HbA1c. Results: Forty-two participants completed the 18-month study (66% girls, median age 13 (12–15) years, BMI 30.0 (28.3 to 35.0) kg m−2 and HOMA-IR 4.08 (2.40 to 5.88)). Median ΔBMI was +0.2 (−2.9 to 1.3) kg m−2 (metformin) versus +1.2 (−0.3 to 2.4) kg m−2 (placebo) (P=0.015). No significant difference was observed for HOMA-IR. No serious adverse events were reported. Median change in fat percentage was −3.1 (−4.8 to 0.3) versus −0.8 (−3.2 to 1.6)% (P=0.150), in fat mass −0.2 (−5.2 to 2.1) versus +2.0 (1.2–6.4) kg (P=0.007), in fat-free mass +2.0 (−0.1 to 4.0) versus +4.5 (1.3 to 11.6) kg (P=0.047) and in ΔHbA1c +1.0 (−1.0 to 2.3) versus +3.0 (0.0 to 5.0) mmol mol−1 (P=0.020) (metformin versus placebo). Conclusions: Long-term treatment with metformin in adolescents with obesity and insulin resistance results in stabilization of BMI and improved body composition compared with placebo. Therefore, metformin may be useful as an additional therapy in combination with lifestyle intervention in adolescents with obesity and insulin resistance.

Background Limited health literacy (HL) may lead to poor health outcomes and inappropriate healthcare use, particularly in patients with chronic diseases. We aimed to assess the association between functional HL (FHL) and quality of care, as measured by process- and outcome-of-care indicators, in patients with diabetes. Methods This cross-sectional study used data from the 2013 CoDiab-VD cohort follow-up, which included non-institutionalised adults with diabetes from canton of Vaud, Switzerland. Using self-administered questionnaires, we collected patients' characteristics, processes [annual HbA1C check, lipid profile, urine test, foot examination, influenza vaccination, eye examination (24 months), physical activity and diet recommendations] and outcomes of care (HbA1C knowledge, HbA1C value, SF-12, ADDQoL, PACIC, self-efficacy). A single validated screening question assessed FHL. Unadjusted and adjusted regression analyses were performed. Results Of 381 patients 52.5% (95%CI: 47.5%–57.5%), 40.7% (95%CI: 35.7%–45.6%) and 6.8% (95%CI: 4.3%–9.4%) reported high, medium and poor FHL, respectively. Significant associations were found for two out of seven outcomes of care; lower self-efficacy scores associated with medium and poor FHL (adjusted: β −0.6, 95%CI −0.9 to −0.2 and β −1.8, 95%CI −2.5 to −1.2, respectively), lower SF-12 mental scores associated with poor FHL (adjusted: β −8.4, 95%CI −12.5 to −4.2). Conclusions This study found few outcomes of care associated with FHL. Further exploration of the impact of limited HL on quality of care indicators will help tailor initiatives – both on patients' and providers' side – to improve diabetes care.

AIM: Insulin analogues reduce the risk of hypoglycaemia compared with human insulin in patients with type 1 diabetes (T1D) and minor hypoglycaemia problems. The HypoAna trial showed that, in patients with recurrent severe hypoglycaemia, treatment based on insulin analogues reduces the risk of severe hypoglycaemia. The present study aims to assess whether this also applies to non-severe hypoglycaemia events during the day and at night.METHODS: This 2-year investigator-initiated multicentre, prospective, randomized, open, blinded endpoint (PROBE) trial involved patients with T1D and at least two episodes of severe hypoglycaemia during the previous year. Using a balanced crossover design, patients were randomized to basal-bolus therapy based on analogue (detemir/aspart) or human (NPH/regular) insulins. A total of 114 participants were included. Endpoints were the number of severe hypoglycaemic events and non-severe events, including documented symptomatic and asymptomatic episodes occurring during the day and at night (ClinicalTrials.gov number: NCT00346996).RESULTS: Analogue-based treatment resulted in a 6% (2-10%; P=0.0025) overall relative risk reduction of non-severe hypoglycaemia. This was due to a 39% (32-46%; PCONCLUSION: In T1D patients prone to severe hypoglycaemia, treatment with analogue insulin reduced the risk of non-severe nocturnal hypoglycaemia compared with human insulin.

PURPOSE: Clinical and observational studies suggest that use of thiazolidinediones (TZDs) is associated with an increased fracture risk. In addition, type 2 diabetes mellitus (T2DM) is a risk factor for osteoporotic fracture. Our aim was to estimate fracture risks in TZD users and users of other antidiabetic drugs, classified according to proxies of disease severity. METHODS: We conducted a population-based cohort study utilizing the Dutch PHARMO database (1998-2008). PHARMO links pharmacy-dispensing data to the National Hospital Registry. Oral antidiabetic users (n = 123,452) were matched 1:4 by year of birth and sex to non-users. Cox proportional hazards models were used to estimate hazard ratios (HRs) of fracture in TZD users. We created a proxy indicator for disease severity. The first stage was defined as current use of either a biguanide or a sulfonylureum, the second stage as current use of a biguanide and a sulfonylureum at the same time, the third stage was assigned to patients using TZDs and the fourth stage to patients using insulin. RESULTS: The risk of osteoporotic fracture was increased 1.5-fold (HR 1.49, 95%CI 1.28-1.73) in patients who currently used TZDs (stage 3), and for patients using insulin (stage 4), the risk was increased 1.2-fold (HR 1.24, 1.14-1.36), as compared with controls. In the first and second stages, risks were lower: HR 1.11 (1.06-1.17) for stage 1 and HR 1.03 (0.96-1.11) for stage 2. CONCLUSIONS: When observational studies assess risk of fracture in patients with TZDs, the severity of T2DM should be taken into account.

BACKGROUND: Intensification of pharmacotherapy in persons with poorly controlled chronic conditions has been proposed as a clinically meaningful process measure of quality. OBJECTIVE: To validate measures of treatment intensification by evaluating their associations with subsequent control in hypertension, hyperlipidemia, and diabetes mellitus across 35 medical facility populations in Kaiser Permanente, Northern California. DESIGN: Hierarchical analyses of associations of improvements in facility-level treatment intensification rates from 2001 to 2003 with patient-level risk factor levels at the end of 2003. PATIENTS: Members (515,072 and 626,130; age >20 years) with hypertension, hyperlipidemia, and/or diabetes mellitus in 2001 and 2003, respectively. MEASUREMENTS: Treatment intensification for each risk factor defined as an increase in number of drug classes prescribed, of dosage for at least 1 drug, or switching to a drug from another class within 3 months of observed poor risk factor control. RESULTS: Facility-level improvements in treatment intensification rates between 2001 and 2003 were strongly associated with greater likelihood of being in control at the end of 2003 (P < or = 0.05 for each risk factor) after adjustment for patient- and facility-level covariates. Compared with facility rankings based solely on control, addition of percentages of poorly controlled patients who received treatment intensification changed 2003 rankings substantially: 14%, 51%, and 29% of the facilities changed ranks by 5 or more positions for hypertension, hyperlipidemia, and diabetes, respectively. CONCLUSIONS: Treatment intensification is tightly linked to improved control. Thus, it deserves consideration as a process measure for motivating quality improvement and possibly for measuring clinical performance.

Essentials It is not known if initiation of glucose-lowering drugs alters the efficacy of vitamin K antagonists (VKA). We examined if glucose-lowering drugs affected international normalized ratio (INR) in VKA-treated patients. Upon initiating glucose-lowering drugs, 51% of patients had INR values below the therapeutic window. Monitoring of INR levels should be intensified upon initiation of glucose-lowering drugs. SummaryBackground It is not known whether initiation of antidiabetic treatment affects the effect of vitamin K antagonists (VKAs). It was previously shown that metformin affects the effect of one VKA, phenprocoumon. Objectives The aim of this study was to determine if initiation of glucose-lowering treatment affects the international normalized ratio (INR) and dose requirements of the anticoagulant VKAs warfarin and phenprocoumon. Patients/methods We performed a self-controlled retrospective register-based study. A total of 118 patients commencing glucose-lowering treatment while being treated with warfarin or phenprocoumon were included in the study. We compared INR, dose/INR and proportion of patients with at least one sub-therapeutic INR measurement before and after initiation of glucose-lowering treatment. Results Initiation of glucose-lowering treatment caused mean INR to decrease from 2.5 to 2.2 (decrease of −0.3 [95% CI: −0.1; −0.5]) and led to more than half of the patients having at least one sub-therapeutic INR measurement. Six to 12 weeks later, the VKA dose/INR was increased by 11%, indicating a weakened effect of the VKA. Conclusion Initiation of glucose-lowering treatment reduces the anticoagulant effect of VKAs to an extent that is likely to be clinically relevant. This finding needs confirmation and mechanistic explanation.

OBJECTIVE The most common form of maturity-onset diabetes of the young (MODY), hepatocyte nuclear factor 1 alpha (HNF1A diabetes: MODY3) is often treated with sulfonylureas that confer a high risk of hypoglycemia. We evaluated treatment with GLP-1 receptor agonists (GLP-1RAs) in patients with HNF1A diabetes. RESEARCH DESIGN AND METHODS Sixteen patients with HNF1A diabetes (8 women; mean age 39 years [range 23-67 years]; BMI 24.9 +/- 0.5 kg/m(2) [mean +/- SEM]; fasting plasma glucose [FPG] 9.9 +/- 0.9 mmol/L; HbA(1c) 6.4 +/- 0.2% [47 +/- 3 mmol/mol]) received 6 weeks of treatment with a GLP-1RA (liraglutide) and placebo (tablets), as well as a sulfonylurea (glimepiride) and placebo (injections), in randomized order, in a double-blind, crossover trial. Glimepiride was up-titrated once weekly in a treat-to-target manner; liraglutide was up-titrated once weekly to 1.8 mg once daily. At baseline and at the end of each treatment period a standardized liquid meal test was performed, including a 30-min light bicycle test. RESULTS FPG decreased during the treatment periods (-1.6 +/- 0.5 mmol/L liraglutide [P = 0.012] and 22.8 +/- 0.7 mmol/L glimepiride [P = 0.003]), with no difference between treatments (P = 0.624). Postprandial plasma glucose (PG) responses (total area under the curve) were lower with both glimepiride (2,136 +/- 292 min x mmol/L) and liraglutide (2,624 +/- 340 min x mmol/L) compared with baseline (3,127 +/- 291 min x mmol/L; P OBJECTIVE: The most common form of maturity-onset diabetes of the young (MODY), hepatocyte nuclear factor 1α (HNF1A diabetes:MODY3) is often treated with sulfonylureas that confer a high risk of hypoglycemia. We evaluated treatment with GLP-1 receptor agonists (GLP-1RAs) in patients with HNF1A diabetes. RESEARCH DESIGN AND METHODS: Sixteen patients with HNF1A diabetes (8 women; mean age 39 years [range 23-67 years]; BMI 24.9 ± 0.5 kg/m 2 [mean ± SEM]; fasting plasma glucose [FPG] 9.9 ± 0.9mmol/L; HbA 1c 6.4 ± 0.2% [ 47 ± 3mmol/mol]) received 6 weeks of treatment with a GLP-1RA (liraglutide) and placebo (tablets), as well as a sulfonylurea (glimepiride) and placebo (injections), in randomized order, in a double-blind, crossover trial. Glimepiride was up-titrated once weekly in a treat-to-target manner; liraglutidewas up-titrated onceweekly to 1.8 mg once daily. At baseline and at the end of each treatment period a standardized liquid meal test was performed, including a 30-min light bicycle test. RESULTS: FPG decreased during the treatment periods (-1.6 ± 0.5 mmol/L liraglutide [P = 0.012] and -2.8 ± 0.7 mmol/L glimepiride [P = 0.003]), with no difference between treatments (P = 0.624). Postprandial plasma glucose (PG) responses (total area under the curve) were lower with both glimepiride (2,136 ± 292 min x mmol/L) and liraglutide (2,624 ± 340 min x mmol/L) compared with baseline (3,127 ± 291 min x mmol/L; P < 0.001, glimepiride; P = 0.017, liraglutide), with no difference between treatments (P = 0.121). Eighteen episodes of hypoglycemia (PG ≤3.9 mmol/L) occurred during glimepiride treatment and one during liraglutide treatment. CONCLUSIONS: Six weeks of treatment with glimepiride or liraglutide lowered FPG and postprandial glucose excursions in patients with HNF1A diabetes. The glucose-lowering effect was greater with glimepiride at the expense of a higher risk of exclusively mild hypoglycemia.

Objectives To develop a multistate model and an algorithm for calculating long-term adherence to medication among patients with a chronic disease. Methods We propose definitions of the different states of waiting, persistence, with sufficient supply to implement the prescribed dosing regimen, gaps, nonpersistence, and nonacceptance and an algorithm for transitions between states to describe long-term adherence to medication treatment. The model and algorithm are operationalized for use in a case with a retrospective cohort of patients with type 2 diabetes mellitus, with access to records of prescribed drugs from a Danish diabetes research hospital and records of filled prescriptions at Danish pharmacies from the Danish Health and Medicines Authority. Results Calculations of long-term adherence to medication are shown for patients with type 2 diabetes mellitus on metformin and/or simvastatin. The study shows how the prevalence of patients waiting to initiate treatment, patients with supply to implement the prescribed dosing regimen, patients not accepting treatment, and patients discontinuing treatment varies over time. Conclusions The proposed multistate model and algorithm can easily be translated and used for the calculation of adherence to medication in any chronic disease. The model and algorithm take time into account, and thus, changes in incidence rates and prevalence of the different states over time can be estimated on several time scales (calendar time, age of the patient, and time since indication for medication).

BackgroundIn young children with type 1 diabetes mellitus (T1DM), parents have complete responsibility for the diabetes-management. In toddlers and (pre)schoolers, the tasks needed to achieve optimal blood glucose control may interfere with normal developmental processes and could negatively affect the quality of parent–child interaction. Several observational instruments are available to measure the quality of the parent–child interaction. However, no observational instrument for diabetes-specific situations is available. Therefore, the aim of the present study was to develop a qualitative observation instrument, to be able to assess parent–child interaction during diabetes-specific situations.MethodsFirst, in a pilot study (n = 15), the observation instrument was developed in four steps: (a) defining relevant diabetes-specific situations; (b) videotaping these situations; (c) describing all behaviors in a qualitative observation instrument; (d) evaluating usability and reliability. Next, we examined preliminary validity (total n = 77) by testing hypotheses about correlations between the observation instrument for diabetes-specific situations, a generic observation instrument and a behavioral questionnaire.ResultsThe observation instrument to assess parent–child interaction during diabetes-specific situations, which consists of ten domains: “emotional involvement”, “limit setting”, “respect for autonomy”, “quality of instruction”, “negative behavior”, “avoidance”, “cooperative behavior”, “child’s response to injection”, “emphasis on diabetes”, and “mealtime structure”, was developed for use during a mealtime situation (including glucose monitoring and insulin administration).ConclusionsThe present study showed encouraging indications for the usability and inter-rater reliability (weighted kappa was 0.73) of the qualitative observation instrument. Furthermore, promising indications for the preliminary validity of the observation instrument for diabetes-specific situations were found (r ranged between |.24| and |.45| for significant correlations and between |.10| and |.23| for non-significant trends). This observation instrument could be used in future research to (a) test whether parent–child interactions are associated with outcomes (like HbA1c levels and psychosocial functioning), and (b) evaluate interventions, aimed at optimizing the quality of parent–child interactions in families with a young child with T1DM.Keywords: Type 1 diabetes mellitus, Parent–child interaction, Behavior, Children, Parents, Mealtime, Rating scale

Background: Several clinical studies have shown that low blood glucose (BG) levels affect electroencephalogram (EEG) rhythms through the quantification of traditional indicators based on linear spectral analysis. Nonlinear measures used in the last decades to characterize the EEG in several physiopathological conditions have never been assessed in hypoglycemia. The present study investigates if properties of the EEG signal measured by nonlinear entropy-based algorithms are altered in a significant manner when a state of hypoglycemia is entered. Subjects and Methods: EEG was acquired from 19 patients with type 1 diabetes during a hyperinsulinemic-euglycemic-hypoglycemic clamp experiment. In parallel, BG was frequently monitored by the standard YSI glucose and lactate analyzer and used to identify two 1-h intervals corresponding to euglycemia and hypoglycemia, respectively. In each subject, the P3-C3 EEG derivation in the two glycemic intervals was assessed using the multiscale entropy (MSE) approach, obtaining measures of sample entropy (SampEn) at various temporal scales. The comparison of how signal irregularity measured by SampEn varies as the temporal scale increases in the two glycemic states provides information on how EEG complexity is affected by hypoglycemia. Results: For both glycemic states, the MSE analysis showed that SampEn increases at small time scales and then monotonically decreases as the time scale becomes larger. Comparing the two conditions, SampEn was higher in hypoglycemia only at medium time scales. Conclusions: A decrease in the complexity of EEG occurs when a state of hypoglycemia is entered, because of a degradation of the EEG long-range temporal correlations. Thanks to its ability to assess nonlinear dynamics of the EEG signal, the MSE approach seems to be a useful tool to complement information brought by standard linear indicators and provide new insights on how hypoglycemia affects brain functioning.

Type 2 diabetes mellitus is a progressive and heterogeneous disease. The decrease in insulin secretion by pancreatic beta cells and the increase of glucagon secretion by pancreatic beta cells, are the two major pathophysiologic characteristics. The majority of type 2 diabetics will therefore require insulin in the evolution of their disease, with weight gain and hypoglycaemia as side effects. GLP-1 analogs are effective therapeutic alternatives due to their actions on glucagon and insulin secretion, on satiety and gastric emptying. For patients inadequately controlled with conventional antidiabetics, GLP-1 analogs, introduced as an alternative or in combination with insulin, can prevent or reduce the side effects associated with insulin. Indeed, the risk of hypoglycaemia is reduced and the vicious circle of weight gain secondary to insulin/need to increase insulin doses is limited.

OBJECTIVE: To investigate whether once daily biphasic insulin aspart 30 (BIAsp 30) is noninferior to once daily insulin glargine (IGlar) among Chinese and Japanese insulin-naïve subjects with type 2 diabetes mellitus (T2DM).RESEARCH DESIGN AND METHODS: This was a 24 week treat-to-target trial (NCT01123980) that included patients with T2DM who were poorly controlled on a combination of metformin and insulin secretagogue (or with a maximum of one more OAD) for 6 months. Patients were randomized to once daily BIAsp 30 or once daily IGlar and their secretagogue standardized to glimepiride 4 mg/day, metformin to 1500 or 2500 mg/day before randomization.RESULTS: At Week 24, mean change from baseline in HbA1c was -0.78 ± 0.88% (mean ± SD) and -0.65 ± 0.92% (-8.49 ± 9.65 and -7.08 ± 10.1 mmol/mol) for the BIAsp 30 (n = 261) and IGlar (n = 260) groups, respectively. The estimated between-group difference (BIAsp 30 vs IGlar) in HbA1c change was -0.12% (95% CI: -0.25, 0.02) (-1.28 mmol/mol [95% CI: -2.75, 0.19]), thus treatment with BIAsp 30 was noninferior to IGlar with respect to HbA1c (non-inferiority margin 0.4%). Although reduction in mean 9-point self-measured plasma glucose (SMPG) profile was comparable between the two groups, BIAsp 30 showed significantly lower PG levels at three time points post-dinner and a higher PG level before dinner compared to the IGlar group (all p CONCLUSIONS: BIAsp 30 once daily showed similar HbA1c reduction and a similar safety profile to IGlar when used in insulin-naïve Chinese and Japanese patients on metformin and a sulfonylurea. Moreover, it provided a better coverage of post-dinner glycemic control needs than those who received IGlar. The open-label design and insufficient insulin dose titration were the main limitations of the study.