Rates Of Overall Hypoglycemia Research Articles

Practical guide in using insulin degludec/insulin aspart: A multidisciplinary approach in Malaysia.

Insulin degludec/insulin aspart (IDegAsp) co-formulation provides both basal and mealtime glycaemic control in a single injection. The glucose level-lowering efficacy of IDegAsp is reported to be superior or non-inferior to that of the currently available insulin therapies with a lower rate of overall hypoglycaemia and nocturnal hypoglycaemia. An expert panel from Malaysia aims to provide insights into the utilisation of IDegAsp across a broad range of patients with type 2 diabetes mellitus (i.e. treatment-naive or insulin-naive patients or patients receiving treatment intensification from basal-only regimens, premixed insulin and basal-bolus insulin therapy). IDegAsp can be initiated as once-daily dosing for the main meal with the largest carbohydrate content with weekly dose adjustments based on patient response. A lower starting dose is recommended for patients with cardiac or renal comorbidities. Dose intensification with IDegAsp may warrant splitting into twice-daily dosing. IDegAsp twice-daily dosing does not need to be split at a 50:50 ratio but should be adjusted to match the carbohydrate content of meals. The treatment of patients choosing to fast during Ramadan should be switched to IDegAsp early before Ramadan, as a longer duration of titration leads to better glycated haemoglobin level reductions. The pre-Ramadan breakfast/lunch insulin dose can be reduced by 30%-50% and taken during sahur, while the preRamadan dinner dose can be taken without any change during iftar. Education on the main meal concept is important, as carbohydrates are present in almost all meals. Patients should not have a misconception of consuming more carbohydrates while taking IDegAsp.

How conclusive is the CONCLUDE trial?

The development of basal insulin analogues has reduced the risk of hypoglycaemia in insulin-treated individuals with type 2 diabetes. Insulin degludec and insulin glargine 300U/ml (glargine U300) represent an evolution of basal insulin analogues, both of them reducing the risk of hypoglycaemia as compared with that associated with glargine U100. However, whether degludec and glargine U300 are equivalent with respect to glycaemic control and risk of hypoglycaemia remains to be fully ascertained. In the CONCLUDE trial, 1609 individuals with type 2 diabetes were randomised to either degludec 200U/ml (degludec U200) or glargine U300. In this issue of Diabetologia (https://doi.org/10.1007/s00125-019-05080-9) the investigators report that during the maintenance period, HbA1c improved to a similar extent in the two groups with no significant difference in the rate of overall hypoglycaemia (the primary endpoint of the study), while rates of nocturnal symptomatic and severe hypoglycaemia (secondary endpoints) were lower with degludec U200 than with glargine U300. These results, although of great interest to the clinician, need to be carefully interpreted as they cannot be considered as conclusive. First, the primary endpoint was not met and, therefore, analyses of secondary endpoints remain exploratory. Even assuming that degludec is superior to glargine in reducing the risk of hypoglycaemia, the mechanism(s) accounting for such an advantage remain elusive and potential differences in pharmacokinetics and pharmacodynamics difficult to appreciate because of methodological issues. The study design had to be amended because of lack of reliability of the glucometers initially used in the trial, particularly in the low blood glucose ranges, so the potential implications of these changes in the subsequent conduct of the trial cannot be excluded. Finally, comparison with the BRIGHT trial, the only other available head-to-head study, is complicated by differences between the two studies in the primary endpoint (HbA1c reduction vs reduction of the risk of hypoglycaemia), study population (insulin-experienced vs insulin-naive) and concomitant glucose-lowering medications. In spite of all this, CONCLUDE teaches us an important lesson regarding the need, particularly in the clinical setting, to monitor the reliability of the glucometers the diabetic individual uses to adjust his/her insulin dose. Insufficient precision or inappropriate use of the glucometer can easily offset any minute advantage a new insulin can offer with respect to glycaemic control and risk of hypoglycaemia.

375-P: Switching to Insulin Degludec from Other Basal Insulins Reduces Rates of Hypoglycemia across Patient Subgroups in Routine Clinical Care: The ReFLeCT Study

ReFLeCT, a multicenter, prospective, observational study evaluated the safety and effectiveness of switching from other basal insulins to insulin degludec (degludec) in patients with type 1 (T1D) or type 2 diabetes (T2D) in routine clinical practice. ReFLeCT comprised a 4-week baseline period (pre-switch basal insulin) and 12-month follow-up period (degludec). The primary endpoint of overall hypoglycemia reported in patient diaries was reduced during the 12-month follow-up period vs. baseline, without compromising glycemic control. In pre-specified subgroup analyses of the primary endpoint, we assessed if the overall result was robust in different subgroups, characterized according to baseline A1C (<7.5, ≥7.5-<8.5, ≥8.5-<9.5, ≥9.5%), diabetes duration (quartiles) and physician’s reason for initiating degludec (hypoglycemia [Yes/No]). The estimated rate ratios of hypoglycemia were similar within subgroups (no significant interactions), and demonstrated overall lower rates (the majority significantly lower) during the 12-month follow-up periods vs. baseline in patients with T1D or T2D (Figure). Irrespective of baseline characteristics or physician’s reason for initiating degludec, switching to degludec from other basal insulins reduced rates of overall hypoglycemia in patients with T1D or T2D, in routine clinical practice. Disclosure H.W. de Valk: Advisory Panel; Self; Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S. M. Feher: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk A/S, Sanofi. Research Support; Self; Amgen Inc., Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk A/S, Sanofi. T.K. Hansen: None. J.H. Jendle: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. Board Member; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. Consultant; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. Research Support; Self; Abbott, Dexcom, Inc., Medtronic, Novo Nordisk A/S. Speaker's Bureau; Self; Eli Lilly and Company, Medtronic, Nordic Infucare, Novo Nordisk A/S, Sanofi. Á. Merchante: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Research & Development, Mundipharma International, Novo Nordisk A/S, Nutricia, Persan Pharma. Consultant; Self; Eli Lilly and Company, Novo Nordisk A/S. M.M. Koefoed: Employee; Self; Novo Nordisk A/S. E. Parvaresh Rizi: Employee; Self; Nestlé, Novo Nordisk A/S. E. Zimmermann: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. G. Fadini: Consultant; Self; AstraZeneca, Novo Nordisk A/S, Sanofi. Research Support; Self; AstraZeneca, Novo Nordisk A/S, Sanofi. Speaker's Bureau; Self; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Sanofi. Funding Novo Nordisk A/S

Attitude and safety of patients with diabetes observing the Ramadan fast

AimsTo describe the attitude of type 2 diabetes patients toward Ramadan fasting. A Secondary purpose was to describe rates of hypoglycemia during Ramadan according to type of treatment. MethodsA prospective, non-randomized study for 2 years. Participants with type 2 diabetes attending Dammam Diabetes Center, Saudi Arabia were stratified for fasting according to ADA recommendations. Results are presented using mean, standard deviation and percentages. ResultsTotal of 360 participants with type 2 diabetes. Mean ± SD glycosylated hemoglobin was 8.9 ± 2.1. More than 80% of individuals were in the ADA higher risk group however, they all fasted Ramadan. The mean non-fasting days was 2.6 days and overall rate of hypoglycaemia was 24.7%. Both parameters were directly proportionate to the risk stratification level (P-value <0.05). Despite hypoglycaemia, 29.3% continued fasting.Hypoglycemia was highest in patients treated with insulin (P-value <0.05) followed by those treated with oral agents including sulphonylurea as compared to oral agents excluding sulfonylurea (P-value = 0.002). Those who experienced hypoglycemia prior to Ramadan had the highest rate of hypoglycemia during Ramadan (53.3%) (P-value = 0.0065). ConclusionsDespite medical advice, the vast majority of type 2 diabetes participants categorized as high risk, fasted Ramadan. Approximately one quarter of people with type 2 diabetes in our cohort experience hypoglycaemia and this was directly related to their fasting risk level. A sizeable proportion continued the fast despite hypoglycemic. Insulin therapy with or without oral agents and previous episodes of hypoglycemia before Ramadan predicted hypoglycemia risk during Ramadan. HbA1c and weight showed some clinical improvements post Ramadan fasting. This is a single center study of mostly high risk fasting patients and hence, these results should not be generalized.

PDB2 - Rate of Hypoglycemic Events in Patients Using Basal Insulin Analogues: A Real World Analysis of four Grade III Class A Hospitals in China

To analyze the rate of hypoglycemic events in patients using basal insulin analogues in China. Retrospective electronic health record data from 4 Grade III Class A hospitals in China from January 2012 to May 2017 was used. Including criteria were patients of type 1 and type 2 diabetes treated with basal insulin analogues, including Hypoglycemia was identified with glycemic value (≤3.9 mmol/L; <2.8 mmol/L and requiring assistance of another person for severe hypoglycemia) supplemented with Chinese descriptions. 4,812 patients were identified with mean age of 60.8 years, 49.1% being male, mean fasting blood glucose of 9.34 mmol/L. 2,393, 991 and 1,428 patients were treated with IGlar, IDet and rIGlar, respectively. Overall, 912(19.0%) patients experienced hypoglycemia including 451(18.8%) patients treated with IGlar, 104(10.5%) patients treated with IDet and 357(25.0%) patients treated with rIGlar. The overall rate of all hypoglycemia was 109.4 events/100 patient-year. The rate of all hypoglycemia among patients treated with IGlar, IDet and rIGlar were 117.06, 82.97, and 114.06 respectively. The overall rate of severe hypoglycemia was 12.84 events/100 patient-year. The rate of severe hypoglycemia among patients treated with IGlar, IDet and rIGlar were 4.39, 0.84 and 46.23 respectively. The overall rate of non-severe hypoglycemia was 96.56 events/100 patient-year. The rate of non-severe hypoglycemia among patients treated with IGlar, IDet and rIGlar were 112.66, 82.13 and 67.84 respectively. The rates of all hypoglycemia and severe hypoglycemia were significantly less with IDet than IGlar and rIGlar (all P<0.05), based on comparison between IDet and IGlar, and comparison between IDet and rIGlar. Hypoglycemic events in patients treated with basal insulin analogues in China was common. There were differences in rate of hypoglycemic events depending on the basal insulin analogue used, with lowest hypoglycemic risk with IDet.

Efficacy and Safety of Insulin Degludec versus Insulin Glargine: A Systematic Review and Meta-Analysis of Fifteen Clinical Trials.

Aims Insulin degludec (IDeg) and insulin glargine (IGlar) are both proved to be effective in diabetes. This study aimed to assess the effects and safety of IDeg versus IGlar. Methods A systematic literature search was conducted using the PubMed, EMBASE, and Cochrane Library electronic databases to identify all randomized controlled trials (RCTs). Results Fifteen RCTs were identified. The combined data showed that the decrease in the glycosylated hemoglobin (HbA1c) level was slightly different, and the proportion of patients who achieved HbA1c < 7% was similar between the IDeg and IGlar groups. Further, a statistically significant decrease in the fasting plasma glucose level was observed in the IDeg group as compared to the IGlar group. In patients with T2DM, IDeg was associated with lower rates of overall hypoglycemia. Nocturnal hypoglycemia was significantly lower in the case of IDeg than in the case of IGlar in both T1DM and T2DM patients. No statistically significant differences were observed between the groups. Conclusions Compared with IGlar, IDeg is associated with equivalent glycemic control and a statistically significantly lower rate of nocturnal hypoglycemia in patients with T1DM and T2DM. In T2DM patients, IDeg also provides better results in terms of overall hypoglycemia.

Impact of delaying treatment intensification with a glucagon-like peptide-1 receptor agonist in patients with type 2 diabetes uncontrolled on basal insulin: A longitudinal study of a US administrative claims database.

AimTo evaluate the effect of delaying treatment intensification with a glucagon‐like peptide‐1 receptor agonist (GLP‐1 RA) on clinical and economic outcomes in patients with type 2 diabetes (T2D).MethodsWe conducted a retrospective observational claims study using IMPACT (Impact National Managed Care Benchmark Database) in adult patients with T2D who initiated basal insulin between January 1, 2005 and December 31, 2012, with or without OADs, who remained uncontrolled (glycated haemoglobin [HbA1c] ≥7.0%). Patients were categorized into 3 groups: early, delayed, and no intensification with a GLP‐1 RA. We evaluated changes from baseline to follow‐up at 12 months for HbA1c level, rate of hypoglycaemic events, and healthcare costs, and we assessed the association between baseline patient characteristics and subsequent treatment intensification.ResultsA total of 139 patients (9.0% of 1552 eligible patients) met criteria for inclusion in the early intensification group, 588 patients (37.9%) met criteria for inclusion in the delayed intensification group, and 825 patients (53.2%) met criteria for inclusion in the no intensification group. Mean baseline HbA1c values were 9.16%, 9.07%, and 9.34%, respectively. At follow‐up, delayed intensification was associated with significantly smaller decreases in HbA1c from baseline (−0.68%) compared with early intensification (−1.01%). Rates of overall hypoglycaemia were numerically greater in the delayed intensification group than in the early intensification group (0.26 vs 0.06 events/patient‐years of exposure, respectively). Change in semi‐annual total healthcare costs was greater in the no intensification group (+5266 USD) compared with the early intensification group (−560 USD) and the delayed intensification group (+1943 USD).ConclusionsTimely addition of a GLP‐1 RA to therapy for patients with T2D who were not adequately controlled with basal insulin is associated with better clinical and economic outcomes.

U300 Insulin Glargine: A Novel Basal Insulin for Type 1 and Type 2 Diabetes.

Objective: To review clinical efficacy and safety of insulin glargine 300 units/mL (Gla-300), a novel high-concentration basal insulin. Data Sources: A MEDLINE search was performed to identify relevant articles published 1960 through February 2015 using the search term glargine 300. Published abstracts from conference proceedings of the American Diabetes Association 74th Scientific Sessions were identified. Study Selection and Data Extraction: Human studies that evaluated pharmacokinetics, efficacy, or safety of Gla-300 were included. Data Synthesis: Six trials investigated efficacy and safety of Gla-300; 3 of 6 trials were available in abstract form only. The EDITION group of trials compared Gla-300 to insulin glargine 100 units/mL (Gla-100) in several populations. These included subjects with type 1 diabetes continuing mealtime insulin and subjects with type 2 diabetes on basal and mealtime insulin, basal insulin and oral antidiabetic drugs (OADs), and with no prior insulin use. Three studies were multinational including 2 studies exclusive to Japanese participants. Each clinical trial was an open-label, multicenter, randomized study with 6 to 12 months of follow-up. Gla-300 demonstrated similar reductions in HbA1c compared to Gla-100. Basal insulin requirements increased by 11% to 17% with Gla-300 without excessive weight gain. Rates of overall hypoglycemia were similar with Gla-300 compared to Gla-100; however, 16% to 38% less nocturnal hypoglycemia was observed in type 2 clinical trials. Conclusions: Gla-300 in combination with mealtime insulin or OADs has shown comparable glycemic control with higher insulin dose requirements versus Gla-100, and may induce less hypoglycemia in patients with type 2 diabetes.

Similar glucose control with basal–bolus regimen of insulin detemir plus insulin aspart and thrice-daily biphasic insulin aspart 30 in insulin-naive patients with type 2 diabetes: Results of a 50-week randomized clinical trial of stepwise insulin intensification

ObjectiveThis study aimed to demonstrate the non-inferiority of 50-week treatment with stepwise insulin intensification of basal–bolus insulin analogues [insulin detemir (IDet) and aspart (IAsp)] versus biphasic insulin aspart 30 (BIAsp30) in insulin-naive type 2 diabetes mellitus (T2DM) patients not controlled by oral glucose-lowering drugs (OGLDs). Research design and methodsIn this open-label multicentre, multinational, randomized, parallel-arm treat-to-target trial, 403 insulin-naive patients with T2DM in four African countries were randomized to either an IDet+IAsp (n=200) or BIAsp1-2-3 (n=203) treatment group. Stepwise insulin intensification was performed at the end of 14, 26 and 38 weeks, depending on HbA1c values. The primary endpoint was change in HbA1c after 50 weeks of treatment. Safety variables were hypoglycaemia incidence, occurrence of adverse events and weight gain. ResultsNon-inferiority of the IDet+IAsp versus BIAsp1-2-3 treatment regimen was demonstrated by their similar HbA1c levels at the end of trial (IDet+IAsp: baseline 8.6%, 50 weeks 7.4%; BIAsp1-2-3: baseline 8.7%, 50 weeks 7.3%; full analysis set difference: 0.1% [95% CI: −0.1, 0.3]; per protocol: 0.2% [95% CI: −0.1, 0.4]). At week 50, 40.3 and 44.9% of patients achieved HbA1c <7.0% with IDet+IAsp and BIAsp1-2-3, respectively. The rate of overall hypoglycaemia during the trial was also similar in both groups (IDet+IAsp: 9.4 events/patient-year; BIAsp1-2-3: 9.8 events/patient-year). ConclusionInsulin initiation and intensification using IDet+IAsp was not inferior to BIAsp1-2-3 in insulin-naive patients with T2DM not controlled by OGLDs. Both regimens led to similar reductions in HbA1c values after 50 weeks of treatment.

Insulin degludec improves long-term glycaemic control similarly to insulin glargine but with fewer hypoglycaemic episodes in patients with advanced type 2 diabetes on basal-bolus insulin therapy.

The aim of the present study was to compare the long-term safety and efficacy of insulin degludec with those of insulin glargine in patients with advanced type 2 diabetes (T2D) over 78 weeks (the 52-week main trial and a 26-week extension). Patients were randomized to once-daily insulin degludec or insulin glargine, with mealtime insulin aspart ± metformin ± pioglitazone, and titrated to pre-breakfast plasma glucose values of 3.9-4.9 mmol/l (70-88 mg/dl). After 78 weeks, the overall rate of hypoglycaemia was 24% lower (p = 0.011) and the rate of nocturnal hypoglycaemia was 31% lower (p = 0.016) with insulin degludec in the extension trial set, while both groups of patients achieved similar glycaemic control. Rates of adverse events and total insulin doses were similar for both groups in the safety analysis set. During 18 months of treatment, insulin degludec + mealtime insulin aspart ± oral antidiabetic drugs in patients with T2D improves glycaemic control similarly, but confers lower risks of overall and nocturnal hypoglycaemia than with insulin glargine treatment.

Exenatide once weekly versus insulin glargine for type 2 diabetes (DURATION-3): 3-year results of an open-label randomised trial

When patients with type 2 diabetes start their first injectable therapy, clinicians can choose between glucagon-like peptide-1 (GLP-1) receptor agonists and basal insulins. In DURATION-3, exenatide once weekly was compared with insulin glargine (henceforth, glargine) as first injectable therapy. Here, we report the results of the final 3-year follow-up. DURATION-3 was an open-label randomised trial done between May 13, 2008, and Jan 30, 2012. Patients with type 2 diabetes aged 18 years or older were enrolled at 72 sites worldwide. They were eligible when they had suboptimum glycaemic control (HbA1c 7.1-11.0% [54-97 mmol/mol]) despite maximum tolerated doses of metformin alone or with a sulfonylurea for at least 3 months, a stable bodyweight for at least 3 months, and a BMI of 25-45 kg/m(2) (23-45 kg/m(2) in South Korea and Taiwan). Patients were randomly assigned (1:1) by computer-generated random sequence with an interactive voice-response system (block size four, stratified by country and concomitant therapy) to once-weekly exenatide (2 mg subcutaneous injection) or once-daily glargine (titrated to target) to be given in addition to their existing oral glucose-lowering regimens. The primary efficacy measure at 3 years was change in HbA1c from baseline in patients given at least one dose of the assigned drug (ie, analyses by modified intention to treat). Patients, investigators, and data analysts were not masked to treatment assignment. This trial is registered with ClinicalTrials.gov, number NCT00641056. 456 patients underwent randomisation and received at least one dose of the assigned drug (233 given exenatide, 223 glargine). At 3 years, least-squares mean HbA1c change was -1.01% (SE 0.07) in the exenatide group versus -0.81% (0.07) in the glargine group (least-squares mean difference -0.20%, SE 0.10, 95% CI -0.39 to -0.02; p=0.03). Transient gastrointestinal adverse events characteristic of GLP-1 receptor agonists were more frequent with exenatide than glargine (nausea: 36 [15%] of 233 patients vs five [2%] of 223; vomiting: 15 [6%] vs six [3%]; diarrhoea: 32 [14%] vs 15 [7%]), although frequency of these events did decrease after week 26 in the exenatide group. The proportion of patients who reported serious adverse events in the exenatide group (36 patients [15%]) was the same as that in the glargine group (33 [15%]). The exposure-adjusted rate of overall hypoglycaemia was three times higher in patients given glargine (0.9 events per patient per year) than in those given exenatide (0.3 events per patient per year). Efficacy of once-weekly exenatide is sustained for 3 years. GLP-1 receptor agonists could be a viable long-term injectable treatment option in patients with type 2 diabetes who have not yet started taking insulin. Amylin Pharmaceuticals and Eli Lilly.

Meta‐analysis of insulin aspart versus regular human insulin used in a basal–bolus regimen for the treatment of diabetes mellitus (在基础—餐时糖尿病治疗方案中使用门冬胰岛素与使用常规人胰岛素对照研究的Meta分析)

Background:The objective of the current study was to compare the efficacy of two different insulin formulations, insulin aspart (IAsp) and regular human insulin (RHI), for prandial insulin coverage with neutral protamine Hagedorn (NPH) insulin as basal insulin using a meta-analysis approach. The primary endpoint was change in A1c over time. Secondary endpoints included incidence of hypoglycemia and postprandial glycemic control.MethodsClinical trials (Type 1 and Type 2 diabetes) complying with Good Clinical Practice, and with individual patient data, were included in the meta-analysis. Trials were randomized, consisting of (at least) two treatment arms and had a minimum duration of 12 weeks. Estimates were calculated using fixed-effects and random-effects models. Heterogeneity was assessed for each analysis. The effect of baseline parameters on A1c was analyzed in extended simultaneous models.ResultsThe mean difference in A1c was 0.1% (95% confidence interval [CI] [−0.15; −0.04], P < 0.001) in favor of IAsp. Higher accumulated dose of IAsp, higher age and increased rates of hypoglycemia were associated with improved A1c outcome. Fasting plasma glucose was not significantly different between regimens. Postprandial glucose was significantly lower after treatment with IAsp compared with RHI, but the analysis did present a significant level of heterogeneity (P < 0.001). The overall rate of hypoglycemia was the same with both regimens, but nocturnal hypoglycemia was significantly lower with IAsp.ConclusionsA basal–bolus regimen with IAsp as bolus insulin provided minimal, but statistically significant, improvement in overall glycemic control with a lower rate of nocturnal hypoglycemic episodes, compared with a corresponding regimen with bolus RHI.

The Effect of Insulin Degludec on Glycemic Control and Nocturnal Hypoglycemia Compared with Insulin Glargine: a 1-year Randomized Trial in Insulin-naïve People with Type 2 Diabetes

s / Can J Diabetes 36 (2012) S24eS76 S58 The study comprised a 1-yr main period followed by 1-yr extension; subjects maintained prior randomization. Subjects were randomized 3:1 to IDeg or IGlar given subcutaneously once daily with mealtime insulin aspart. Basal insulin was titrated to target pre-breakfast plasma glucose (PG) (>3.9e<5.0mmol/L). Data at end of 2yrs of treatment (EOT) are presented. Of 629 subjects (baseline: mean age 43yrs; diabetes duration 18.9yrs; HbA1c 7.7%; fasting PG 9.3mmol/L), 443 (IDeg: 330; IGlar: 113) completed 2yrs’ treatment. EOT HbA1c reduction was similar: e0.27% (IDeg) vs. e0.24% (IGlar); estimated treatment difference (ETD) IDegeIGlar: 0.04% [95%CI 0.17;0.09], p1⁄4NS. Similar proportions of subjects achieved HbA1c<7% (IDeg: 34%; IGlar: 31%; p1⁄4NS). Rates of overall hypoglycemia (PG<3.1mmol/L or severe) were similar for entire period (37.5[IDeg] vs. 37.4[IGlar] episodes/ pt-yr; estimated rate ratio [ERR] IDeg/IGlar: 1.02 [0.85;1.24]; p1⁄4NS) and maintenance period (16wk to EOT, when mean dose and glycemia stabilized; 34.0 vs. 35.0 episodes/pt-yr; ERR: 0.98 [0.80;1.20]; p1⁄4NS). Nocturnal hypoglycemia was significantly lower with IDeg (3.9 vs. 5.3 episodes/pt-yr; ERR: 0.75 [0.59;0.95]; p1⁄40.02). Therefore, treating one patient for w9 months with IDeg will avoid one nocturnal hypoglycemic episode. In conclusion, IDeg safely and effectively improves glycemic control with a lower risk of nocturnal hypoglycemia than IGlar when part of 2-yr BB therapy in T1DM. This furthermore provides evidence for the long-term safety of IDeg in T1DM.

Insulin initiation in elderly patients with type 2 diabetes in France: a subpopulation of the LIGHT study

Objective:To examine the management of basal insulin analogue initiation in combination with oral antidiabetic drug (OAD) therapy in elderly patients with type 2 diabetes (aged ≥70 years) by physicians via comparison to the same treatment strategy in younger individuals (<70 years).Methods:This subanalysis of a longitudinal observational study took place in a clinical setting across 761 health centres in France. A total of 1802 patients with type 2 diabetes (519 aged ≥70 years and 1283 aged <70 years) participated. The primary endpoint of this study was to assess the management of basal insulin analogue initiation along with OADs in elderly patients (aged ≥70 years) by physicians. Secondary endpoints included HbA1c, percentage of patients achieving HbA1c target (<7.0%), fasting plasma glucose, weight change (kg) and hypoglycaemia.Results:The initial mean (standard deviation [SD]) basal insulin analogue dose was similar in the elderly and younger patient subgroups (0.18 [0.09] IU/kg vs. 0.18 [0.11] IU/kg, respectively; not significant [NS]). The mean (SD) number of injections per day was also comparable between age groups (1 [0.2] per day vs. 1 [0.3] per day, respectively for elderly and younger patients; NS). Three months after initiation of long-acting insulin analogue therapy, 3.5% (n = 18) of elderly patients ceased insulin treatment. At study end, the mean (SD) HbA1c for elderly patients was 7.6% (0.9%), and for younger patients it was 7.5% (0.9%). Also, the rate of overall hypoglycaemia was comparable in the elderly and younger patients (0.38 [1.2] events/patient/month vs. 0.35 [1.0] events/patient/month, respectively; NS). Limitations of this study include the possibility of inaccurate patient recall of hypoglycaemic events and deficiencies in the adverse events reporting system.Conclusion:Basal insulin analogues were successfully initiated in elderly patients in combination with OAD therapies and were shown to provide effective glycaemic control. Levels of hypoglycaemia were also similar to those seen in younger patients.

Prospective operationalization and feasibility of a glycemic control protocol in critically ill children*

To evaluate the feasibility and safe operationalization of a pediatric glycemic control protocol in the setting of a general pediatric intensive care unit in a developing country. Prospective, observational cohort study carried out over 12 months. Fourteen-bed pediatric intensive care unit in Brazil. Children requiring mechanical ventilation with at least one organ system dysfunction were included. Glucose was monitored and insulin used for persistent hyperglycemia (glucose >140 mg/dL [7.8 mmol/L] for at least two observations separated by at least a 1-hr interval), with a target glucose during insulin use of 60-140 mg/dL (3.3-7.8 mmol/L). Out of 410 admissions, 144 children met the criteria for applying the protocol. One hundred fourteen of 144 (79%) children had at least one peak glucose level that was hyperglycemic, but only 44 (31%) children required insulin. Insulin infusion was most frequently started on day 1 (61%), with a glucose level at the time of 229 ± 79 mg/dL (12.7 ± 4.4 mmol/L). The mean glucose level after 6 hrs of insulin was 172 ± 87 mg/dL (9.6 ± 4.8 mmol/L), and the time to achieve the target glucose range was 9.5 (2-20) hrs (median [interquartile range]). The overall duration of insulin was 24.5 (10-48) hrs, and the average dose required was 0.06 ± 0.03 U/kg/hr. In the whole series, the peak glucose level was 202 ± 93 mg/dL (11.2 ± 5.2 mmol/L), with no difference between survivors and nonsurvivors. There was no difference in mortality when different glucose bands were considered and no association between glucose level and mortality. The overall rate of hypoglycemia (glucose <40 mg/dL [2.2 mmol/L]) was 8.3%, and it was more common in those receiving insulin (20% vs. 3%, p < .05). Hyperglycemia is frequent in critically ill children managed in a pediatric intensive care unit in a developing country. Using a glycemic control protocol, one-third of these children required insulin, but attendants should be aware of a significant risk of hypoglycemia in this setting. Based on these data, a trial to detect a 20% relative reduction in mortality (power 90%, p = .05) associated with insulin in a similar population would need to screen >10,000 patients.

Insulin Glulisine Compared to Insulin Aspart and to Insulin Lispro Administered by Continuous Subcutaneous Insulin Infusion in Patients with Type 1 Diabetes: A Randomized Controlled Trial

In a previous pilot study comparing insulin glulisine (GLU) with insulin aspart (ASP) administered by continuous subcutaneous insulin infusion (CSII), GLU-treated patients did show a trend toward fewer catheter occlusions compared with ASP-treated patients. Here we performed a randomized open-label, three-way crossover, controlled multicenter study comparing GLU with ASP and insulin lispro (LIS). Subjects with type 1 diabetes were allocated to one of three treatment orders-GLU-ASP-LIS, ASP-LIS-GLU, or LIS-GLU-ASP-with each insulin used for 13 weeks. The study was designed to demonstrate the superiority of GLU over ASP and LIS on unexplained hyperglycemia and/or perceived infusion set occlusion. A prespecified P value of 0.025 was considered significant to correct for multiple testing. Percentages of subjects with at least one unexplained hyperglycemia and/or infusion set occlusion were not significantly different between GLU and ASP (68.4% [62.7-74.1%] vs. 62.1% [56.2-68.1%], P = 0.04) and GLU and LIS (68.4% [62.7-74.1%] vs. 61.3% [55.4-67.3%], P = 0.03). No differences were seen in hemoglobin A1c at end point, most points of the seven-point glucose curves, severe hypoglycemia, and symptomatic ketoacidosis. The overall rate of hypoglycemia with a plasma glucose level below 70 mg/dL per patient-year was significantly different between GLU and ASP (73.84 vs. 65.01, P = 0.008) and GLU and LIS (73.84 vs. 62.69, P < 0.001). Insulin doses remained unchanged during the trial. GLU was not superior to ASP and LIS with no significant difference seen among GLU, ASP, and LIS in CSII use with respect to unexplained hyperglycemia and/or perceived catheter set occlusion. GLU was associated with a higher frequency of symptomatic hypoglycemia, possibly because of slight overdosing, as previous trials suggested lower insulin requirements when GLU is initiated in type 1 diabetes.

The usage of a simplified self‐titration dosing guideline (303 Algorithm) for insulin detemir in patients with type 2 diabetes – results of the randomized, controlled PREDICTIVE™ 303 study

The Predictable Results and Experience in Diabetes through Intensification and Control to Target: An International Variability Evaluation 303 (PREDICTIVE 303) Study (n = 5604) evaluated the effectiveness of insulin detemir, a long-acting basal insulin analogue, using a simplified patient self-adjusted dosing algorithm (303 Algorithm group) compared with standard-of-care physician-driven adjustments (Standard-of-care group) in a predominantly primary care setting, over a period of 6 months. Insulin detemir was to be started once-daily as add-on therapy to any other glucose-lowering regimens or as a replacement of prestudy basal insulin in patients with type 2 diabetes. Investigator sites rather than individual patients were randomized to either the 303 Algorithm group or the Standard-of-care group. Patients from the 303 Algorithm group sites were instructed to adjust their insulin detemir dose every 3 days based on the mean of three 'adjusted' fasting plasma glucose (aFPG) values (capillary blood glucose calibrated to equivalent plasma glucose values) using a simple algorithm: mean aFPG < 80 mg/dl (<4.4 mmol/l), reduce dose by 3 U; aFPG between 80 and 110 mg/dl (4.4-6.1 mmol/l), no change; and aFPG > 110 mg/dl (>1.1 mmol/l), increase dose by 3 U. The insulin detemir dose for patients in the Standard-of-care group was adjusted by the investigator according to the standard of care. Mean A1C decreased from 8.5% at baseline to 7.9% at 26 weeks for the 303 Algorithm group and from 8.5 to 8.0% for the Standard-of-care group (p = 0.0106 for difference in A1C reduction between the two groups). Mean FPG values decreased from 175 mg/dl (9.7 mmol/l) at baseline to 141 mg/dl (7.8 mmol/l) for the 303 Algorithm group and decreased from 174 mg/dl (9.7 mmol/l) to 152 mg/dl (8.4 mmol/l) for the Standard-of-care group (p < 0.0001 for difference in FPG reduction between the two groups). Mean body weight remained the same at 26 weeks in both groups (change from baseline 0.1 and -0.2 kg for the 303 Algorithm group and the Standard-of-care group respectively). At 26 weeks, 91% of the patients in the 303 Algorithm group and 85% of the patients in the Standard-of-care group remained on once-daily insulin detemir administration. The rates of overall hypoglycaemia (events/patient/year) decreased significantly from baseline in both groups [from 9.05 to 6.44 for the 303 Algorithm group (p = 0.0039) and from 9.53 to 4.95 for the Standard-of-care group (p < 0.0001)]. Major hypoglycaemic events were rare in both groups (0.26 events/patient/year for the 303 Algorithm group and 0.20 events/patient/year for the Standard-of-care group; p = 0.2395). In conclusion, patients in the 303 Algorithm group achieved comparable glycaemic control with higher rate of hypoglycaemia as compared with patients in the Standard-of-care group, possibly because of more aggressive insulin dose adjustments. The vast majority of the patients in both groups were effectively treated with once-daily insulin detemir therapy. The use of insulin detemir in this predominantly primary care setting achieved significant improvements in glycaemic control with minimal risk of hypoglycaemia and no weight gain.

Insulin therapy and acute kidney injury in critically ill patients a systematic review

Intensive insulin therapy has been found to reduce mortality in some critically ill patients. We performed a systematic review and meta-analysis to ascertain the effect of intensive insulin therapy on the incidence of acute kidney injury (AKI) in adult critically ill patients. We searched MEDLINE, SCOPUS and the Cochrane Central Register of Controlled Trials for studies that compared 'conventional' vs 'intensive' insulin therapy in critically ill patients. Studies were combined with random effects model meta-analyses. Five studies, three of which were randomized controlled trials, reported AKI as a secondary outcome. Two of the studies were non-concurrent prospective cohort studies. All were single-centre studies conducted in intensive care unit settings. By meta-analysis across all studies, intensive insulin therapy reduced the incidence of AKI by 38% [risk ratio (RR) 0.62; 95% confidence interval (CI) 0.47, 0.83; P = 0.001]. The findings of the randomized and cohort studies were similar and the studies were not statistically heterogeneous. Three studies reported the effect of insulin therapy on dialysis requirement. Overall, intensive insulin therapy reduced the incidence of dialysis requirement by 35%, however, this was not statistically significant (RR 0.65; 95% CI 0.40, 1.05; P = 0.08). The overall rate of hypoglycaemia in the conventional insulin therapy group was 1.3% (range 0.3-3.4%). Intensive insulin therapy was associated with a >4-fold increase in the risk of hypoglycaemia (RR 4.5; 95% CI 2.4, 8.5; P < 0.00001) There is evidence that intensive insulin therapy initiated in critically ill adult patients is associated with a reduction in the incidence of AKI in medical and surgical settings. A large trial primarily designed to examine the effect of insulin on the prevention of AKI is needed to confirm this finding.

Exenatide

Exenatide (Byetta) is a novel, synthetic, incretin mimetic, glucoregulatory peptide approved in the US and Europe for the treatment of patients with type 2 diabetes mellitus who have inadequate glycaemic control despite receiving treatment with maximum tolerated doses of metformin and/or a sulfonylurea. In randomised, controlled, phase III trials and post hoc completer analyses in this patient population, the addition of subcutaneous exenatide twice daily significantly improved glycaemic control and was associated with progressive and significant bodyweight reduction from baseline for up to 2 years. The overall intensity of glycaemic control with exenatide was similar to that achieved with once-daily insulin glargine or twice-daily biphasic insulin aspart. Exenatide was generally well tolerated. Most adverse events were mild to moderate in severity and gastrointestinal in nature. The overall rate of hypoglycaemia was similar to rates observed with placebo (when administered with metformin) and insulin comparators (when administered with metformin and a sulfonylurea). The addition of exenatide to therapy with metformin and a sulfonylurea provided significant improvements in treatment satisfaction and patients' health-related quality of life (HR-QOL). The drug was also cost effective compared with pioglitazone, glibenclamide (glyburide), insulin glargine (all in combination with metformin and/or a sulfonylurea) and metformin alone. Overall, adjunctive therapy with exenatide is a valuable therapeutic option in patients with type 2 diabetes requiring moderate improvements in glycaemic control despite treatment with metformin and/or a sulfonylurea.

Insulin lispro in the treatment of patients with type 2 diabetes mellitus after oral agent failure

This study assessed the safety profile and efficacy of a new combination therapy (insulin lispro plus sulfonylurea) in patients with type 2 diabetes mellitus experiencing secondary oral agent failure. A total of 423 patients were randomly assigned to 3 treatment groups: preprandial insulin lispro plus sulfonylurea (L + S), bedtime neutral protamine Hagedorn (NPH) insulin plus sulfonylurea (N + S), and preprandial insulin lispro plus bedtime NPH insulin (L + N). Mean decreases in glycosylated hemoglobin from baseline were 1.60% ± 1.27% for patients receiving L + S, 1.21% ± 1.21% for those receiving N + S, and 1.40% ±1.46% for those receiving L + N (within treatment, P < 0.001 ; for L + S vs N + S, P = 0.003). Fasting blood glucose level was higher in patients receiving L + S (171 ± 46.5 mg/dL) or L + N (166 ± 52.5 mg/dL) than in those receiving N + S (144 ± 48.2 mg/dL) ( P < 0.001, for both comparisons). Conversely, postprandial blood glucose level was lower in patients receiving L+ S (165 ± 41.6 mg/dL) or L + N (165 ± 46.3 mg/dL) than in those receiving N + S (213 ± 58.3 mg/dL) ( P < 0.001, for both comparisons). The overall rate of hypoglycemia (episodes per 30 days) was not statistically significant when the L + S, N + S, and L + N therapies were compared (0.99 ± 1.74 vs 0.87 ±2.31 vs 1.16 ± 2.38, respectively). The rate of nocturnal hypoglycemia was lowest in the L + S group (0.00 ± 0.00 vs 0.10 ± 0.37 for the N + S group vs 0.15 ± 0.54 for the L + N group; P = 0.004). L + S, which has a safety profile equal to those of N + S and L + N, is an effective treatment for patients with type 2 diabetes who experience oral sulfonylurea agent failure. L + S offers an alternative to these established combination therapies in patients whose type 2 diabetes cannot be controlled with a sulfonylurea alone.