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BEGIN Basal-Bolus Type 1 Trial Investigators. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): A phase 3, randomised, open-label, treat-to-target non-inferiority trial

University of Sheffield, Sheffield, UK. s.heller@sheffi eld.ac.uk
The Lancet (Impact Factor: 45.22). 04/2012; 379(9825):1489-97. DOI: 10.1016/S0140-6736(12)60204-9
Source: PubMed

ABSTRACT

Intensive basal-bolus insulin therapy has been shown to improve glycaemic control and reduce the risk of long-term complications that are associated with type 1 diabetes mellitus. Insulin degludec is a new, ultra-longacting basal insulin. We therefore compared the efficacy and safety of insulin degludec and insulin glargine, both administered once daily with mealtime insulin aspart, in basal-bolus therapy for type 1 diabetes.
In an open-label, treat-to-target, non-inferiority trial, undertaken at 79 sites (hospitals and centres) in six countries, adults (aged ≥18 years) with type 1 diabetes (glycated haemoglobin [HbA(1c)] ≤10% [86 mmol/mol]), who had been treated with basal-bolus insulin for at least 1 year, were randomly assigned in a 3:1 ratio, with a computer-generated blocked allocation sequence, to insulin degludec or insulin glargine without stratification by use of a central interactive response system. The primary outcome was non-inferiority of degludec to glargine, assessed as a reduction in HbA(1c) after 52 weeks, with the intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT00982228.
Of 629 participants, 472 were randomly assigned to insulin degludec and 157 to insulin glargine; all were analysed in their respective treatment groups. At 1 year, HbA(1c) had fallen by 0·40% points (SE 0·03) and 0·39% points (0·07), respectively, with insulin degludec and insulin glargine (estimated treatment difference -0·01% points [95% CI -0·14 to 0·11]; p<0·0001 for non-inferiority testing) and 188 (40%) and 67 (43%) participants achieved a target HbA(1c) of less than 7% (<53 mmol/mol). Rates of overall confirmed hypoglycaemia (plasma glucose <3·1 mmol/L or severe) were similar in the insulin degludec and insulin glargine groups (42·54 vs 40·18 episodes per patient-year of exposure; estimated rate ratio [degludec to glargine] 1·07 [0·89 to 1·28]; p=0·48). The rate of nocturnal confirmed hypoglycaemia was 25% lower with degludec than with glargine (4·41 vs 5·86 episodes per patient-year of exposure; 0·75 [0·59 to 0·96]; p=0·021). Overall serious adverse event rates (14 vs 16 events per 100 patient-years of exposure) were similar for the insulin degludec and insulin glargine groups.
Insulin degludec might be a useful basal insulin for patients with type 1 diabetes because it provides effective glycaemic control while lowering the risk of nocturnal hypoglycaemia, which is a major limitation of insulin therapy.
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    • "On the other hand, patients with type 1 diabetes mellitus are well aware that insulin therapy is essential for life support, and basal insulin is often administered simultaneously with bolus insulin, so these patients may not feel the benefits of flexible injection of degludec. Finally, we found no improvement of Factor 3, " Hypoglycemia " in this study, even though degludec is reported to significantly reduce the frequency of hypoglycemia during the night, compared to glargine or detemir456. The reason for this may be that our target patients had not experienced hypoglycemia while receiving glargine or detemir, and also did not experience it after switching to degludec, so that there was no change of QOL in this respect. "
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    ABSTRACT: Maintainance of a stable basal insulin level is important for glycemic control in treatment of diabetes mellitus. Recently introduced insulin degludec has the longest duration of action among basal insulin formulations. The purpose of this study was to assess changes in quality of life (QOL) associated with switching the basal insulin regimen to degludec in patients with type 1 and type 2 diabetes mellitus. This 24-week open-label intervention study included type 1 (n = 10) and type 2 (n = 20) diabetes mellitus patients, with adequately controlled hemoglobin A1c (HbA1c), who had received insulin glargine or detemir for at least 6 months. The primary outcome was change of QOL from baseline, as assessed by the Diabetes Therapy-Related QOL (DTR-QOL) application, after switching from glargine or detemir to degludec. HbA1c and other parameters were also assessed as secondary outcomes. QOL and HbA1c in patients with type 1 diabetes mellitus were unchanged during this study. In patients with type 2 diabetes mellitus, HbA1c did not change, but total DTR-QOL score was significantly improved from baseline after switching to degludec. The DTR-QOL Factor 2, “Anxiety and dissatisfaction with treatment”, was significantly improved in patients with type 2 diabetes mellitus and especially in the subgroup receiving basal supported oral therapy (BOT). Switching of the basal insulin regimen from glargine or detemir to degludec significantly improved the QOL of patients with type 2 diabetes mellitus who were receiving BOT, by reducing mental stress or anxiety about their treatment.
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    • "The trial protocol for insulin-experienced patients required that those who were switching from twice-daily to once-daily insulin dosing administer their total pre-trial basal insulin dose in the IDeg arm, but reduce the dose by 20e30% in the IGlar arm (as per the prescribing information). This could have biased the hypoglycaemia rates in favour of IGlar during the first weeks of the trials as the dose was lower [16]. However, the IGlar dose subsequently increased as patients titrated to target and end-of-trial doses for pooled T1D patients were higher with IGlar compared with IDeg [23]. "
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    ABSTRACT: Basal insulin analogues have a reduced risk of hypoglycaemia compared with NPH insulin, but hypoglycaemia still remains a major impediment to achieving recommended fasting plasma glucose (FPG) targets in patients with diabetes. Insulin degludec (IDeg) is a new basal insulin that forms soluble multihexamers after subcutaneous injection resulting in an ultra-long duration of action and stable glucose-lowering effect. The aim of this analysis was to compare the effect of IDeg on FPG and nocturnal confirmed hypoglycaemia as compared to insulin glargine (IGlar). Data were included from seven phase 3a, randomised, open-label, treat-to-target clinical trials in which once-daily IDeg was compared with once-daily IGlar. Two trials included a total of 957 patients with type 1 diabetes (T1D) and five trials included a total of 3360 patients with type 2 diabetes (T2D); all trials were 26 or 52 weeks in duration. Confirmed hypoglycaemia was defined as plasma glucose <3.1 mmol/L or severe episodes requiring assistance, and nocturnal hypoglycaemia occurred between 00:01 and 05:59. In all trials, the mean end-of-trial FPG was lower for IDeg than IGlar, reaching statistical significance in three trials. Similarly, IDeg was associated with a lower rate of nocturnal confirmed hypoglycaemia vs. IGlar, which was statistically significant in three trials, regardless of type of diabetes or background therapy. This analysis shows that the lower rate of nocturnal confirmed hypoglycaemia seen with IDeg relative to IGlar is accompanied by a reduced mean FPG, in particular in patients with T2D. Copyright © 2015 Elsevier B.V. All rights reserved.
    Preview · Article · Jun 2015 · Nutrition, metabolism, and cardiovascular diseases: NMCD
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    • "Another clinical concern with IDeg includes the potential for immunogenicity. However, the concentration of IDeg-specific antibodies and antibodies cross-reacting with IDeg and human insulin was found to be low in studies in patients with T1DM [48, 49] or T2DM [50, 53], indicating that the risk of immunogenicity with IDeg is minimal. Furthermore, the studies showed that there was no apparent association between the development of cross-reacting antibodies and hypoglycaemia, HbA1c or insulin dose [48, 49, 53]. "
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    ABSTRACT: Insulin degludec (IDeg) is a new-generation basal insulin with an ultra-long duration of action. To date, a large number of studies have been conducted to investigate the pharmacokinetic and pharmacodynamic properties of IDeg. Standardised methods for collection and analysis of blood samples (for pharmacokinetic endpoints) and euglycaemic clamp procedures (for pharmacodynamic endpoints) were applied across studies to enable cross-study evaluation of important pharmacokinetic and pharmacodynamic parameters. Data show that IDeg has a half-life of >25 h [compared with ~12 h for insulin glargine (IGlar)] and reaches steady state within 3 days of administration in all patient populations investigated. The pharmacokinetic profile of IDeg demonstrates an even distribution of exposure across one dosing interval. The pharmacodynamic profile of IDeg is flat and stable, demonstrated by an even distribution of glucose-lowering effect across all four 6-h intervals in a 24-h period (one dosing day). These properties were consistently demonstrated across different type 1 and type 2 diabetes mellitus patient populations, including those from different ethnic origins (both males and females with type 2 diabetes), the elderly, and patients with hepatic or renal impairment. IDeg has an ultra-long duration of action exceeding 42 h and demonstrates four times lower day-to-day within-subject variability in glucose-lowering effect than IGlar. This review discusses the pharmacokinetic and pharmacodynamic data accumulated thus far, and the relevance of these results from a clinical perspective.
    Full-text · Article · Sep 2014 · Clinical Pharmacokinetics
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